SMALL-MOLECULAR ADJUVANTS AND IMPLEMENTATIONS THEREOF

Abstract

The present disclosure describes compounds of the general Formula (I) or its stereoisomers, pharmaceutically acceptable salts, poly morphs, sols ales, hydrates, thereof. These compounds or small molecular adjuvants in combination with antibiotics are effective against resistant bacterial infections. The present disclosure also discloses a process of preparation of small-molecular adjuvants, its stereoisomers, pharmaceutically acceptable salts, polymorphs, solvates and hydrates thereof, and to pharmaceutical compositions containing them

##STR00001##

Claims

1. A compound of Formula (I) ##STR00021## or its stereoisomers, pharmaceutically acceptable salts, polymorphs, solvates and hydrates thereof, wherein X is selected from —C(O)(CH.sub.2).sub.oCH—, —(CH.sub.2),C(O)NH—, —C(O)(CH.sub.2).sub.o—, —C(O)NH(CH.sub.2).sub.o—, —C(O)O(CH.sub.2).sub.o—, or —C(O)CH(NHR′)(CH.sub.2).sub.o—; R′ is —C(O)OC(CH.sub.3).sub.3; R.sub.1 and R.sub.2 are independently selected from hydrogen, D or L amino acids, dipeptides of D or L amino acids or tripeptides of D or L amino acids; R.sub.3 is selected from phenyl, naphthyl, indolyl, adarnantyl, biphenyl, norbornane, norbornene, benzothiophene, benzofuran, anthracene, wherein R.sub.3 is optionally substituted with one or more of the groups selected from hydrogen, halogen, hydroxyl, cyano; n and m are independently selected from 1, 2, 3, or 4; o is selected from 1-3; and p is 1 or 2; provided that when n is 1 acid m is 1, then X is not —C(O)CH.sub.2—, and R.sub.3 is not naphthyl.

2. The compound as claimed in claim 1 or its stereoisomers, pharmaceutically acceptable salts, polymorphs, solvates and hydrates thereof, wherein X is selected from —C(O)(CH.sub.2).sub.oCH—, —(CH.sub.2).sub.oC(O)NH—, —C(O)(CH.sub.2).sub.o—, —C(O)NH(CH.sub.2).sub.o—, —C(O)O(CH.sub.2).sub.o—, or —C(O)CH(NHR′)(CH.sub.2).sub.o—; R′ is —C(O)OC(CH.sub.3).sub.3; R.sub.1 and R.sub.2 are independently selected from hydrogen, D or L amino acids, dipeptides of D or L amino acids or tripeptides of D or L amino acids; R.sub.3 is selected from phenyl, naphthyl, indolyl, adamantyl, biphenyl, norbornane, norbornene, benzothiophene, benzofuran, wherein R.sub.3 is optionally substituted with one or more of the groups selected from hydrogen, halogen, hydroxyl, cyano; n and m are independently selected from 1, 2, 3, or 4; o is selected from 1-3; and p is 1 or 2; provided that when n is 1 and m is 1, then X is not —C(O)CH.sub.2—, and R.sub.3 is not naphthyl.

3. The compound as claimed in claim 1 or its stereoisomers, pharmaceutically acceptable salts, polymorphs, solvates and hydrates thereof, wherein X is selected from —C(O)(CH.sub.2).sub.oCH—, —(CH.sub.2).sub.oC(O)NH—, —C(O)(CH.sub.2).sub.o—, —C(O)NH(CH.sub.2).sub.o—, —C(O)O(CH.sub.2).sub.o—, or —C(O)CH(NHR′)(CH.sub.2).sub.o—; R′ is —C(O)OC(CH.sub.3).sub.3; R.sub.1 and R.sub.2 are independently selected from hydrogen, D or L amino acids, dipeptides of D or L amino acids or tripeptides of D or L amino acids; R.sub.3 is selected from phenyl, naphthyl, indolyl, adamantyl, biphenyl, norbornane, norbornene, benzothiophene, benzofuran, anthracene, wherein R.sub.3 is optionally substituted with one or more of the groups selected from hydrogen, halogen, hydroxyl, cyano; n is selected from 2, 3, or 4; m is selected from 1, 2, 3, or 4; o is selected from 1-3; and p is 1 or 2.

4. The compound as claimed in claim 1 or its stereoisomers, pharmaceutically acceptable salts, polymorphs, solvates and hydrates thereof, wherein X is selected from —C(O)(CH.sub.2).sub.oCH—, —(CH.sub.2).sub.oC(O)NH—, —C(O)(CH.sub.2).sub.o—, —C(O)NH(CH.sub.2).sub.o—, —C(O)O(CH.sub.2).sub.o—, or —C(O)CH(NHR′)(CH.sub.2).sub.o—; R′ is —C(O)OC(CH.sub.3).sub.3; R.sub.1 and R.sub.2 are independently selected from hydrogen, D or L amino acids, dipeptides of D or L amino acids or tripeptides of D or L amino acids; R.sub.3 is selected from phenyl, naphthyl, indolyl, adamantyl, biphenyl, norhornane, norhornene, benzothiophene, benzofuran, anthracene, wherein R.sub.3 is optionally substituted with one or more of the groups selected from hydrogen, halogen, hydroxyl, cyano; n is 1; m is 1; o is selected from 1-2; and p is 1 or 2; provided that X is not —C(O)CH.sub.2—, and R.sub.3 is not naphthyl.

5. A compound of Formula (I) or its stereoisomers, pharmaceutically acceptable salts, polymorphs, solvates and hydrates thereof, wherein X is selected from —C(O)(CH.sub.2).sub.oCH—, —(CH.sub.2).sub.oC(O)NH—, —C(O)(CH.sub.2).sub.o—, —C(O)NH(CH.sub.2).sub.o—, —C(O)O(CH.sub.2).sub.o—, or —C(O)CH(NHR′)(CH.sub.2).sub.o—; R′ is —C(O)OC(CH.sub.3).sub.3; R.sub.1 and R.sub.2 are independently selected from hydrogen, D or L amino acids, dipeptides of D or L amino acids or tripeptides of D or L amino acids; R.sub.3 is selected from phenyl, naphthyl, indolyl, adamantyl, biphenyl, norbornane, norbornene, benzothiophene, benzofuran, anthracene, wherein R.sub.3 is optionally substituted with one or more of the groups selected from hydrogen, halogen, hydroxyl, cyano; n is 4; m is 4; o is selected from 1 to 2; and p is 1 or 2.

6. A compound as claimed in claim 1 or its stereoisomers, pharmaceutically acceptable salts, polymorphs, solvates and hydrates thereof, which is selected from a group consisting of: ##STR00022## ##STR00023## ##STR00024##

7. A process of preparation of compounds of Formula (I) as claimed in claim 1 or its stereoisomers, pharmaceutically acceptable salts, polymorphs, solvates and hydrates thereof, the process comprising: (a) reacting a compound of Formula A and Formula B to obtain the compound of Formula C; and (b) deprotecting the compound of Formula C to obtain the compound of Formula I, wherein PG of Formula A or Formula C is selected from at least one protecting group, protected D or L amino acids, protected dipeptides of D or L amino acids or protected tripeptides of D or L amino acids; X of Formula B is selected from —C(O)(CH.sub.2).sub.oCH—, —(CH.sub.2).sub.oC(O)NH—, —C(O)(CH.sub.2).sub.o—, —C(O)NH(CH.sub.2).sub.o—, —C(O)O(CH.sub.2).sub.o—, or —C(O)CH(NHR′)(CH.sub.2).sub.o—; R′ is —C(O)OC(CH.sub.3).sub.3; Q may be selected from halo, or —OH; R.sub.3 is selected from phenyl, naphthyl, indolyl, adamantyl, biphenyl, norbornane, norbornene, benzothiophene, benzofuran, anthracene, wherein R.sub.3 is optionally substituted with one or more of the groups selected from hydrogen, halogen, hydroxyl, cyano; n and m are independently selected from 1, 2, 3, or 4; o is selected from 1-3; and p is 1 or 2; provided that when n is 1 and m is 1, then X is not —C(O)CH.sub.2—, and R.sub.3 is not naphthyl ##STR00025##

8. Use of the compound of Formula (I) as claimed in claim 1, as small molecular adjuvants.

9. A pharmaceutical composition comprising a compound of Formula (I) or its stereoisomers, pharmaceutically acceptable salts, polymorphs, solvates and hydrates thereof as claimed in claim 1 together with a pharmaceutically acceptable carrier, optionally in combination with one or more other antibiotics, or their pharmaceutical composition.

10. A pharmaceutical composition comprising: a) compound of Formula (I) or its stereoisomers, pharmaceutically acceptable salts, polymorphs, solvates and hydrates thereof as claimed in claim 1; b) one or more antibiotics.

11. A pharmaceutical composition comprising: a) compound of Formula (I) or its stereoisomers, pharmaceutically acceptable salts, polymorphs, solvates and hydrates thereof as claimed in claim 1; b) a pharmaceutical composition of one or more antibiotics.

12. The pharmaceutical composition as claimed in claim 10, wherein the antibiotic is selected from the group consisting of rifampicin, tetracycline, fusidic acid, oxazolidinone, glycopeptides, fluoroquinolone, macrolide, beta-lactams, aminoglycosides chloramphenicol polymyxin, lipopeptide, and combinations thereof.

13. The pharmaceutical composition as claimed in claim 10, wherein the antibiotic is selected from the group consisting of rifampicin, tetracycline, minocycline, fusidic acid, linezolid, vancomycin, ciprofloxacin, erythromycin, ampicillin, streptomycin, chloramphenicol, colistin, daptomycin, and combinations thereof.

14. The pharmaceutical composition as claimed in claim 10, for use in treating disease or condition in a patient, wherein said disease or condition is caused by a microorganism selected from the group consisting of bacteria, fungi, and protozoa.

15. The pharmaceutical composition as claimed in claim 10, for use in killing or inhibiting the growth of a microorganism selected from the group consisting of bacteria, fungi, and protozoa.

16. Use of a pharmaceutical composition as claimed in claim 10, in treating a disease or condition in a patient, wherein said disease or condition is caused by microorganism selected from the group consisting of bacteria, fungi, and protozoa.

17. Use of a pharmaceutical composition as claimed in claim 10, in a method of killing or inhibiting the growth of a microorganism selected from the group consisting of bacteria, fungi, and protozoa.

18. A method of treating a disease or condition in a patient, said method comprising administering to a patient a pharmaceutical composition as claimed in claim 10, wherein said disease or condition is caused by microorganism selected from the group consisting of bacteria, fungi, and protozoa.

19. The pharmaceutical composition as claimed in claim 10, wherein the bacteria is Gram-positive bacteria or Gram-negative bacteria.

20. The pharmaceutical composition as claimed in claim 19, wherein the bacteria is a multi-resistant bacterium selected from a group consisting of A. baumannii, P. aeruginosa, E. coli, K. pneumoniae, or any combinations thereof.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0019] The detailed description is described with reference to the accompanying figures. In the figures, the left-most digit(s) of a reference number identifies the figure in which the reference number first appears. The same numbers are used throughout the drawings to reference like features and components.

[0020] FIG. 1 illustrates the bacterial kinetics according to an implementation of the present disclosure. FIG. 1(A) displays the bacterial kinetics of the combination of rifampicin and Compound 13 and rifampicin against A. baumannii R674, whereas FIG. 1(B) displays the bacterial kinetics of the combination of fusidic acid and Compound 14, Compound 14 and fusidic acid against P. aeruginosa R590; Asterisks correspond to <50 CFU/mL.

DETAILED DESCRIPTION

[0021] Those skilled in the art will be aware that the present disclosure is subject to variations and modifications other than those specifically described. It is to be understood that the present disclosure includes all such variations and modifications. The disclosure also includes all such steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively and any and all combinations of any or more of such steps or features.

Definitions

[0022] For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are collected here. These definitions should be read in the light of the remainder of the disclosure and understood as by a person of skill in the art. The terms used herein have the meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.

[0023] The articles “a”, “an” and “the” are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.

[0024] The terms “comprise” and “comprising” are used in the inclusive, open sense, meaning that additional elements may be included. Throughout this specification, unless the context requires otherwise the word “comprise”, and variations, such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated element or step or group of element or steps but not the exclusion of any other element or step or group of element or steps.

[0025] The term “including” is used to mean “including but not limited to”. “Including” and “including but not limited to” are used interchangeably.

[0026] The term “adjuvant” refers to a substance which is used in combination with a biological agent to enhance it's activity.

[0027] In the structural formulae given herein and throughout the present disclosure, the following terms have been indicated meaning, unless specifically stated otherwise.

[0028] Ratios, concentrations, amounts, and other numerical data may be presented herein in a range format. It is to be understood that such range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a temperature range of about 100° C. to about 200° C. should be interpreted to include not only the explicitly recited limits of about 100° C. to about 200° C., but also to include sub-ranges, such as 105° C. to 155° C., 160° C. to 175° C., and so forth, as well as individual amounts, including fractional amounts, within the specified ranges, such as 102.2° C., 150.6° C., and 171.3° C., for example.

[0029] In this specification, the prefix Cx-y as used in terms such as Cx-y alkyl, and the like (where x and y are integers) indicates the numerical range of carbon atoms that are present in the group; for example, C1-6 alkyl includes C1 alkyl (methyl), C2 alkyl (ethyl), C3 alkyl (propyl and isopropyl), and C4 alkyl (butyl, 1-methylpropyl, 2-methylpropyl, and t-butyl). Unless specifically stated, the bonding atom of a group may be any suitable atom of that group; for example, propyl includes prop-1-yl, and prop-2-yl.

[0030] Furthermore, the compound of Formula (I), can be its derivatives, analogs, stereoisomers, diastereomers, geometrical isomers, polymorphs, solvates, co-crystals, intermediates, metabolites, or pharmaceutically acceptable salts and compositions.

[0031] The compounds of Formula (I), and their polymorphs, stereoisomers, solvates, co-crystals, intermediates, pharmaceutically acceptable salts, and metabolites thereof can also be referred as “compounds of the present disclosure”.

[0032] The compounds according to Formula (I), may contain one or more asymmetric centers (also referred to as a chiral centers) and may, therefore, exist as individual enantiomers, diastereoisomers, or other stereoisomeric forms, or as mixtures thereof. Chiral centers, such as chiral carbon atoms, may also be present in a substituent such as an alkyl group. Where the stereochemistry of a chiral center present in Formula (I), or in any chemical structure illustrated herein, is not specified, the structure is intended to encompass any stereoisomer and all mixtures thereof. Thus, compounds according to Formula (I) containing one or more chiral centers may be used as racemic modifications including racemic mixtures and racemates, enantiomerically-enriched mixtures, or as enantiomerically-pure individual stereoisomers.

[0033] Compounds disclosed herein include isotopes of hydrogen, carbon, oxygen, fluorine, chlorine, iodine and sulfur which can be incorporated into the compounds, such as not limited to .sup.2H (D), .sup.3H (T), c .sup.11C, .sup.13C, .sup.14C, .sup.15N, .sup.18F, .sup.35S, .sup.36Cl and .sup.125I. Compounds of this invention wherein atoms were isotopically labeled for example radioisotopes such as .sup.3H, .sup.13C, .sup.14C, and the like can be used in metabolic studies and kinetic studies. Compounds of the invention where hydrogen is replaced with deuterium may improve the metabolic stability and pharmacokinetics properties of the drug such as in vivo half-life.

[0034] Individual stereoisomers of a compound according to Formula (I) which contain one or more asymmetric centers may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out (1) by the formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired form.

[0035] Alternatively, specific stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.

[0036] It is to be understood that the references herein to compounds of Formula (I) and salts thereof covers the compounds of Formula (I) as free bases, or as salts thereof, for example as pharmaceutically acceptable salts thereof. Thus, in one embodiment, the invention is directed to compounds of Formula (I) as the free base. In another embodiment, the invention is directed to compounds of Formula (I) and salts thereof. In a further embodiment, the invention is directed to compounds of Formula (I) and pharmaceutically acceptable salts thereof.

[0037] It will be appreciated that pharmaceutically acceptable salts of the compounds according to Formula (I), may be prepared. Indeed, in certain embodiments of the invention, pharmaceutically acceptable salts of the compounds according to Formula (I) may be preferred over the respective free base because such salts impart greater stability or solubility to the molecule thereby facilitating formulation into a dosage form. Accordingly, the invention is further directed to compounds of Formula (I), and pharmaceutically acceptable salts thereof.

[0038] Included within the scope of the “compounds of the invention” are all solvates (including hydrates), complexes, polymorphs, and stereoisomers of the compounds of Formula (I), and salts thereof.

[0039] The compounds of the invention may exist in solid or liquid form. In the solid-state, the compounds of the invention may exist in crystalline or non-crystalline form, or as a mixture thereof. For compounds of the invention that are in crystalline form, the skilled artisan will appreciate that pharmaceutically acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve non-aqueous solvents such as ethanol, isopropyl alcohol, dimethylsulfoxide (DMSO), acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as “hydrates”. Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates.

[0040] It will be further appreciated that certain compounds of the invention that exist in crystalline form, including the various solvates thereof, may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as “polymorphs”. The invention includes such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. It will be appreciated that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions. The term “polymorphs” refers to crystal forms of the same molecule, and different polymorphs may have different physical properties such as for example, melting temperatures, heats of fusion, solubilities, dissolution rates and/or vibrational spectra as a result of the arrangement or conformation of the molecules in the crystal lattice.

[0041] The term “substituted” in reference to a group indicates that a hydrogen atom attached to a member atom within a group is replaced. It should be understood that the term “substituted” includes the implicit provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound (i.e. one that does not spontaneously undergo transformation such as rearrangement, cyclisation, or elimination). In certain embodiments, a single atom may be substituted with more than one substituent as long as such substitution is in accordance with the permitted valence of the atom. Suitable substituents are defined herein for each substituted or optionally substituted group.

[0042] The term “alkyl” refers to a saturated hydrocarbon chain having the specified number of carbon atoms. For example, which is not limited, C.sub.1-6 alkyl refers to an alkyl group having from 1-6 carbon atoms, or 1-4 carbon atoms. Alkyl groups may be straight or branched chained groups. Representative branched alkyl groups have one, two, or three branches. Preferred alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, and t-butyl.

[0043] The term “alkoxy” refers to an alkyl group attached via an oxygen linkage to the rest of the molecule. For example, C.sub.1-6 alkoxy refers to an alkyl group having from 1-6 carbon atoms, or 1-4 carbon atoms attached via an oxygen linkage to the rest of the molecule. Preferred alkoxy groups include, without limitation, —OCH.sub.3 (methoxy), —OC.sub.2H.sub.5 (ethoxy) and the like.

[0044] The term “haloalkyl” refers to a halogen in an alkyl group as defined above attached via alkyl linkage to the rest of the molecule. For example, C.sub.1-6 haloalkyl refers to an alkyl group having from 1-6 carbon atoms, or 1-4 carbon atoms wherein one or more hydrogen atoms are replaced by the same number of identical or different halogen atoms. Preferred haloalkyl groups include, without limitation, —CH.sub.2Cl, —CHCl.sub.2, trifluoromethyl, 2,2,2-trifluoroethyl, and the like.

[0045] The term “haloalkoxy” refers to a halogen in an alkoxy group as defined above attached via alkoxy linkage to the rest of the molecule. For example, C.sub.1-6 haloalkoxy refers to an alkoxy group having from 1-6 carbon atoms, or 1-4 carbon atoms wherein one or more hydrogen atoms are replaced by the same number of identical or different halogen atoms. Preferred haloalkoxy groups include, without limitation, —OCH.sub.2Cl, —OCHCl.sub.2, and the like

[0046] The term “halo” or “halogen” refers to a halogen radical, for example, fluoro, chloro, bromo, or iodo.

[0047] The term “cycloalkyl” refers to a saturated hydrocarbon ring having a specified number of carbon atoms, which may be monocyclic or polycyclic. For example, which is not limited, C.sub.3-15 cycloalkyl refers to a cycloalkyl group having from 3 to 15 member atoms. The polycyclic ring denotes hydrocarbon systems containing two or more ring systems with one or more ring carbon atoms in common i.e. a spiro, fused or bridged structures. For example, which is not limited, C.sub.3-15 cycloalkyl refers to a cycloalkyl group having from 3 to 15 membered atoms. Preferred cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctanyl, perhydronaphthyl, adamantyl, noradamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups e.g spiro [4.4] non-2-yl, and the like.

[0048] The term “aryl” refers to an aromatic ring having a specified number of carbon atoms. For example, C.sub.6-15 aryl refers to an aryl group having 6 to 15 member atoms, or 6 member atoms. Preferred aryl groups include, without limitation, phenyl, naphthyl, and the like.

[0049] The term “heteroaryl” refers to aromatic rings containing from 1 to 5 heteroatoms in the ring. “Heteroaryl” groups may be substituted with one or one or more substituents if so defined herein. The “C.sub.1-6 heteroaryl” rings having 1 or 6 carbon as member atoms. The term “5-15 membered heteroaryl” has 1 to 15 carbon(s) as member atoms. The “heteroaryl” includes pyridinyl, tetrazolyl, pyrazolyl, or azacyclics, such as carbazole, indole, phenothiazine, and the like. “Heteroatom” refers to a nitrogen, sulfur, or oxygen atom, for example, a nitrogen atom or an oxygen atom.

[0050] The term “heterocyclyl” refers to saturated or unsaturated monocyclic aliphatic rings containing 5, 6, or 7 ring members including 1-3 heteroatoms or saturated or unsaturated bicyclic, tricyclic, tetracyclic aliphatic rings containing 5, 6 or 7 ring members including 1-3 heteroatoms, which may include spiro, fused, or bridged ring systems. In certain embodiments, “heterocyclyl” groups are saturated. In other embodiments, “heterocyclyl” groups are unsaturated. “Heterocyclyl” groups containing more than one heteroatom may contain different heteroatoms. “Heterocyclyl” groups may be substituted with one or more substituents as defined herein. The “C.sub.1-10 heterocyclyl” refers to rings having 1 or 10 carbon as member atoms. “Heterocyclyl” includes piperidinyl, tetrahydropyranyl, azepinyl, oxazepinyl, az abicyclo [3.1.0]hexanyl.

[0051] The phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0052] The phrase “at least one protecting group” refers to protecting groups known in the art. Examples of many of these possible groups may be found in “Protective Groups in Organic Synthesis” by T .W. Green, John Wiley and Sons, 1981. Non-limiting examples for the protecting group may be tert-butoxycarbonyl (Boc or t-Boc), carbobenzoxy (Z or Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), 9-(R).sub.3Si-Fmoc, Xmoc, DHAmoc, their derivatives, and the like.

[0053] As used herein, the term “pharmaceutically acceptable salts” refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free base form with a suitable acid.

[0054] Salts and solvates having non-pharmaceutically acceptable counter-ions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of Formula (I), and their pharmaceutically acceptable salts. Thus, one embodiment of the invention embraces compounds of Formula (I), and salts thereof. Compounds according to Formula (I), contain a basic functional group and are therefore capable of forming pharmaceutically acceptable acid addition salts by treatment with a suitable acid. Suitable acids include pharmaceutically acceptable inorganic acids and pharmaceutically acceptable organic acids. Representative pharmaceutically acceptable acid addition salts include hydrochloride, hydrobromide, nitrate, methylnitrate, sulfate, bisulfate, sulfamate, phosphate, acetate, trifluoroacetate, hydroxyacetate, phenyl acetate, propionate, butyrate, iso-butyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, formate, malate, tartrate, citrate, salicylate, glycollate, lactate, heptanoate, phthalate, oxalate, succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, naphthoate, hydroxynaphthoate, mandelate, tannate, formate, stearate, ascorbate, palmitate, oleate, pyruvate, pamoate, malonate, laurate, glutarate, glutamate, estolate, methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate, benzenesulfonate (besylate), aminobenzenesulfonate, p-toluene sulfonate (tosylate), and naphthalene-2-sulfonate.

[0055] As discussed in the background section, the identification and development of simple, non-active and non-toxic adjuvants which can be used in combination with a number of antibiotics remains an area of immense interest. The present disclosure thus provides small molecular adjuvants which exhibit potentiation of antibiotics.

[0056] A term once described, the same meaning applies for it, throughout the disclosure.

[0057] The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only. Functionally equivalent products, compositions, and methods are clearly within the scope of the disclosure, as described herein.

[0058] In an embodiment of the present disclosure, there is provided a compound of Formula (I)

##STR00004##

or its stereoisomers, pharmaceutically acceptable salts, polymorphs, solvates and hydrates thereof, wherein; X is selected from —C(O)(CH.sub.2).sub.oCH—, —(CH.sub.2).sub.oC(O)NH—, —C(O)(CH.sub.2).sub.o—, —C(O)NH(CH.sub.2).sub.o—, —C(O)O(CH.sub.2).sub.o—, or —C(O)CH(NHR′)(CH.sub.2).sub.o—; R′ is —C(O)OC(CH.sub.3).sub.3; R.sub.1 and R.sub.2 are independently selected from hydrogen, D or L amino acids, dipeptides of D or L amino acids or tripeptides of D or L amino acids; R.sub.3 is selected from C.sub.3-15 cycloalkyl, C.sub.6-15 aryl, or 5-15 membered monocyclic or bicyclic, saturated or unsaturated heteroaryl ring with 1-5 heteroatoms selected from N, S or O, wherein C.sub.3-15 cycloalkyl, C.sub.6-15 aryl, and 5-15 membered monocyclic or bicyclic, saturated or unsaturated heteroaryl ring are optionally substituted with one or more of the groups selected from hydrogen, halogen, hydroxyl, cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.3-6 cycloalkyl, C.sub.1-6 alkylamino, C.sub.1-6 alkoxyamino, C.sub.1-6 acylamino, C.sub.6-15 aryl, or C.sub.1-10 heterocyclyl; n and m are independently selected from 1, 2, 3, or 4; o is selected from 0-3 and p is 1 or 2 ;provided that when n is 1 and m is 1, then X is not —C(O)CH.sub.2—, and R.sub.3 is not naphthyl.

[0059] In an embodiment of the present disclosure, there is provided a compound of Formula (I)

##STR00005##

or its stereoisomers, pharmaceutically acceptable salts, polymorphs, solvates and hydrates thereof, wherein; X is selected from —C(O)(CH.sub.2).sub.oCH—, —(CH.sub.2).sub.oC(O)NH—, —C(O)(CH.sub.2).sub.o—, —C(O)NH(CH.sub.2).sub.o—, —C(O)O(CH.sub.2).sub.o—, or —C(O)CH(NHR′)(CH.sub.2).sub.o—; R′ is —C(O)OC(CH.sub.3).sub.3; R.sub.1 and R.sub.2 are independently selected from hydrogen, D or L amino acids, dipeptides of D or L amino acids or tripeptides of D or L amino acids; R.sub.3 is selected from C.sub.3-15 cycloalkyl, C.sub.6-15 aryl, or 5-15 membered monocyclic or bicyclic, saturated or unsaturated heteroaryl ring with 1-5 heteroatoms selected from N, S or O, wherein C.sub.3-15 cycloalkyl, C.sub.6-15 aryl, and 5-15 membered monocyclic or bicyclic, saturated or unsaturated heteroaryl ring are optionally substituted with one or more of the groups selected from hydrogen, halogen, hydroxyl, cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.3-6 cycloalkyl, C.sub.1-6 alkylamino, C.sub.1-6 alkoxyamino, C.sub.1-6 acylamino, C.sub.6-15 aryl, or C.sub.1-10 heterocyclyl; n and m are independently selected from 1, 2, 3, or 4; o is independently selected from 0 to 3; and p is 1 or 2, provided that when n is 1 and m is 1, then X is not —C(O)CH.sub.2—, and R.sub.3 is not naphthyl.

[0060] In an embodiment of the present disclosure, there is provided a compound of Formula (I), or its stereoisomers, pharmaceutically acceptable salts, polymorphs, solvates and hydrates thereof, wherein X is selected from —C(O)(CH.sub.2).sub.oCH—, —(CH.sub.2).sub.oC(O)NH—, —C(O)(CH.sub.2).sub.o—, —C(O)NH(CH.sub.2).sub.o—, —C(O)O(CH.sub.2).sub.o—, or —C(O)CH(NHR′)(CH.sub.2).sub.o—; R′ is —C(O)OC(CH.sub.3).sub.3; R.sub.1 and R.sub.2 are independently selected from hydrogen, D or L amino acids, dipeptides of D or L amino acids or tripeptides of D or L amino acids; R.sub.3 is selected from C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, or 5-10 membered monocyclic or bicyclic, saturated or unsaturated heteroaryl ring with 1-5 heteroatoms selected from N, S or O, wherein C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, and 5-10 membered monocyclic or bicyclic, saturated or unsaturated heteroaryl ring are optionally substituted with one or more of the groups selected from hydrogen, halogen, hydroxyl, cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.3-6 cycloalkyl, C.sub.1-6 alkylamino, C.sub.1-6 alkoxyamino, C.sub.1-6 acylamino, C.sub.6-10 aryl, or C.sub.1-10 heterocyclyl; n and m are independently selected from 1, 2, 3, or 4; o is selected from 0-3; and p is 1 or 2; provided that when n is 1 and m is 1, then X is not —C(O)CH.sub.2—, and R.sub.3 is not naphthyl.

[0061] In an embodiment of the present disclosure, there is provided a compound of Formula (I), or its stereoisomers, pharmaceutically acceptable salts, polymorphs, solvates and hydrates thereof, wherein X is selected from —C(O)(CH.sub.2).sub.oCH—, —(CH.sub.2).sub.oC(O)NH—, —C(O)(CH.sub.2).sub.o—, —C(O)NH(CH.sub.2).sub.o—, —C(O)O(CH.sub.2).sub.o—, or —C(O)CH(NHR′)(CH.sub.2).sub.o—; R′ is —C(O)OC(CH.sub.3).sub.3; R.sub.1 and R.sub.2 are independently selected from hydrogen, D or L amino acids, dipeptides of D or L amino acids or tripeptides of D or L amino acids; R.sub.3 is selected from C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, or 5-10 membered monocyclic or bicyclic, saturated or unsaturated heteroaryl ring with 1-5 heteroatoms selected from N, S or O, wherein C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, and 5-10 membered monocyclic or bicyclic, saturated or unsaturated heteroaryl ring are optionally substituted with one or more of the groups selected from hydrogen, halogen, hydroxyl, cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.3-6 cycloalkyl, C.sub.1-6 alkylamino, C.sub.1-6 alkoxyamino, C.sub.1-6 acylamino, C.sub.6-10 aryl, or C.sub.1-10 heterocyclyl; n is selected from 2, 3, or 4; m is selected from 1, 2, 3, or 4; o is selected from 0-3; and p is 1 or 2.

[0062] In an embodiment of the present disclosure, there is provided a compound of Formula (I), or its stereoisomers, pharmaceutically acceptable salts, polymorphs, solvates and hydrates thereof, wherein X is selected from —C(O)(CH.sub.2).sub.oCH—, —(CH.sub.2).sub.oC(O)NH—, —C(O)(CH.sub.2).sub.o—, —C(O)NH(CH.sub.2).sub.o—, —C(O)O(CH.sub.2).sub.o—, or —C(O)CH(NHR′)(CH.sub.2).sub.o—; R′ is —C(O)OC(CH.sub.3).sub.3; R.sub.1 and R.sub.2 are independently selected from hydrogen, D or L amino acids, dipeptides of D or L amino acids or tripeptides of D or L amino acids; R.sub.3 is selected from C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, or 5-10 membered monocyclic or bicyclic, saturated or unsaturated heteroaryl ring with 1-5 heteroatoms selected from N, S or O, wherein C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, and 5-10 membered monocyclic or bicyclic, saturated or unsaturated heteroaryl ring are optionally substituted with one or more of the groups selected from hydrogen, halogen, hydroxyl, cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.3-6 cycloalkyl, C.sub.1-6 alkylamino, C.sub.1-6 alkoxyamino, C.sub.1-6 acylamino, C.sub.6-10 aryl, or C.sub.1-10 heterocyclyl; n is 1; m is 1; o is selected from 0-2; and p is 1 or 2; provided that X is not —C(O)CH.sub.2—, and R.sub.3 is not naphthyl.

[0063] In an embodiment of the present disclosure, there is provided a compound of Formula (I), or its stereoisomers, pharmaceutically acceptable salts, polymorphs, solvates and hydrates thereof, wherein X is selected from —C(O)(CH.sub.2).sub.oCH—, —(CH.sub.2).sub.oC(O)NH—, —C(O)(CH.sub.2).sub.o—, —C(O)NH(CH.sub.2).sub.o—, —C(O)O(CH.sub.2).sub.o—, or —C(O)CH(NHR′)(CH.sub.2).sub.o—; R′ is —C(O)OC(CH.sub.3).sub.3; R.sub.1 and R.sub.2 are independently selected from hydrogen, D or L amino acids, dipeptides of D or L amino acids or tripeptides of D or L amino acids; R.sub.3 is selected from C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, or 5-10 membered monocyclic or bicyclic, saturated or unsaturated heteroaryl ring with 1-5 heteroatoms selected from N, S or O, wherein C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, and 5-10 membered monocyclic or bicyclic, saturated or unsaturated heteroaryl ring are optionally substituted with one or more of the groups selected from hydrogen, halogen, hydroxyl, cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.3-6 cycloalkyl, C.sub.1-6 alkylamino, C.sub.1-6 alkoxyamino, C.sub.1-6 acylamino, C.sub.6-10 aryl, or C.sub.1-10 heterocyclyl; n is 4; m is 4; o is selected from 0-2; and p is 1 or 2.

[0064] In an embodiment of the present disclosure, there is provided a compound of Formula I or its stereoisomers, pharmaceutically acceptable salts, polymorphs, solvates and hydrates thereof, wherein X is selected from —C(O)(CH.sub.2).sub.oCH—, —(CH.sub.2).sub.oC(O)NH—, —C(O)(CH.sub.2).sub.o—, —C(O)NH(CH.sub.2).sub.o—, —C(O)O(CH.sub.2).sub.o—, or —C(O)CH(NHR′)(CH.sub.2).sub.o—; R′ is —C(O)OC(CH.sub.3).sub.3; R.sub.1 and R.sub.2 are independently selected from hydrogen, D or L amino acids, dipeptides of D or L amino acids or tripeptides of D or L amino acids; R.sub.3 is selected from C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, or 5-10 membered monocyclic or bicyclic, saturated or unsaturated heteroaryl ring with 1-4 heteroatoms selected from N, S or O, wherein C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, and 5-10 membered monocyclic or bicyclic, saturated or unsaturated heteroaryl ring are optionally substituted with one or more of the groups selected from hydrogen, halogen, hydroxyl, cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.3-6 cycloalkyl, C.sub.1-6 alkylamino, C.sub.1-6 alkoxyamino, C.sub.1-6 acylamino, C.sub.6-10 aryl, or C.sub.1-10 heterocyclyl; n is 1; m is 1; o is selected from 0-2; and p is 1 or 2; provided that X is not —C(O)CH.sub.2—, and R.sub.3 is not naphthyl.

[0065] In an embodiment of the present dislsoure, there is provided a compound of Formula (I) or its stereoisomers, pharmaceutically acceptable salts, polymorphs, solvates and hydrates thereof, wherein X is selected from —C(O)(CH.sub.2).sub.oCH—, —(CH.sub.2).sub.oC(O)NH—, —C(O)(CH.sub.2).sub.o—, —C(O)NH(CH.sub.2).sub.o—, —C(O)O(CH.sub.2).sub.o—, or —C(O)CH(NHR′)(CH.sub.2).sub.o—; R′ is —C(O)OC(CH.sub.3).sub.3; R.sub.1 and R.sub.2 are independently selected from hydrogen, D or L amino acids, dipeptides of D or L amino acids or tripeptides of D or L amino acids; R.sub.3 is selected from C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, or 5-10 membered monocyclic or bicyclic, saturated or unsaturated heteroaryl ring with 1-3 heteroatoms selected from N, or O, wherein C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, and 5-10 membered monocyclic or bicyclic, saturated or unsaturated heteroaryl ring are optionally substituted with one or more of the groups selected from hydrogen, halogen, hydroxyl, cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.3-6 cycloalkyl, C.sub.1-6 alkylamino, C.sub.1-6 alkoxyamino, C.sub.1-6 acylamino, C.sub.6-10 aryl, or C.sub.1-10 heterocyclyl; n is 4; m is 4; o is selected from 0-2; and p is 1 or 2.

[0066] In an embodiment of the present disclosure, there is provided a compound of Formula (I) or its stereoisomers, pharmaceutically acceptable salts, polymorphs, solvates and hydrates thereof, wherein X is selected from —C(O)(CH.sub.2).sub.oCH—, —(CH.sub.2).sub.oC(O)NH—, —C(O)(CH.sub.2).sub.o—, —C(O)NH(CH.sub.2).sub.o—, —C(O)O(CH.sub.2).sub.o—, or —C(O)CH(NHR′)(CH.sub.2).sub.o—; R′ is —C(O)OC(CH.sub.3).sub.3; R.sub.1 and R.sub.2 are independently selected from hydrogen, D or L amino acids, dipeptides of D or L amino acids or tripeptides of D or L amino acids; R.sub.3 is selected from C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, or 5-10 membered monocyclic or bicyclic, saturated or unsaturated heteroaryl ring with 1-3 heteroatoms selected from N, or O, wherein C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, and 5-10 membered monocyclic or bicyclic, saturated or unsaturated heteroaryl ring are optionally substituted with one or more of the groups selected from hydrogen, halogen, hydroxyl, cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.3-6 cycloalkyl, C.sub.1-6 alkylamino, C.sub.1-6 alkoxyamino, C.sub.1-6 acylamino, C.sub.6-10 aryl, or C.sub.1-10 heterocyclyl; n is 4; m is 4; o is independently selected from 0 to 2; and p is from 1 or 2.

[0067] In an embodiment of the present disclosure, there is provided a compound of Formula (I), or its stereoisomers, pharmaceutically acceptable salts, polymorphs, solvates and hydrates thereof, which is selected from a group consisting of

##STR00006## ##STR00007## ##STR00008## ##STR00009##

[0068] In an embodiment of the present disclosure, there is provided a compound of Formula (I), or its stereoisomers, pharmaceutically acceptable salts, polymorphs, solvates and hydrates thereof, which is selected from a group consisting of

##STR00010## ##STR00011##

[0069] In an embodiment of the present disclosure, there is provided a process of preparation of compounds of Formula (I) or its stereoisomers, pharmaceutically acceptable salts, polymorphs, solvates and hydrates thereof as described herein.

[0070] In an embodiment of the present disclosure, there is provided a process of preparation of compounds of Formula (I) or its stereoisomers, pharmaceutically acceptable salts, polymorphs, solvates and hydrates thereof, the process comprising: (a) reacting a compound of Formula A and Formula B to obtain the compound of Formula C; (b) deprotecting the compound of Formula C to obtain the compound of Formula I, wherein PG of Formula A or Formula C is selected from at least one protecting group, protected D or L amino acids, protected dipeptides of D or L amino acids or protected tripeptides of D or L amino acids; X of Formula B is selected from —C(O)(CH.sub.2).sub.oCH—, —(CH.sub.2).sub.oC(O)NH—, —C(O)(CH.sub.2).sub.o—, —C(O)NH(CH.sub.2).sub.o—, —C(O)O(CH.sub.2).sub.o—, or —C(O)CH(NHR′)(CH.sub.2).sub.o—; R′ is —C(O)OC(CH.sub.3).sub.3; Q may be selected from halo, or —OH; R.sub.3 is selected from C.sub.3-15 cycloalkyl, C.sub.6-15 aryl, or 5-15 membered monocyclic or bicyclic, saturated or unsaturated heteroaryl ring with 1-5 heteroatoms selected from N, S or O, wherein C.sub.3-15 cycloalkyl, C.sub.6-15 aryl, and 5-15 membered monocyclic or bicyclic, saturated or unsaturated heteroaryl ring are optionally substituted with one or more of the groups selected from hydrogen, halogen, hydroxyl, cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.3-6 cycloalkyl, C.sub.1-6 alkylamino, C.sub.1-6 alkoxyamino, C.sub.1-6 acylamino, C.sub.6-15 aryl, or C.sub.1-10 heterocyclyl; n and m are independently selected from 1, 2, 3, or 4; o is selected from 0-3; and p is 1 or 2 ; provided that when n is 1 and m is 1, then X is not —C(O)CH.sub.2—, and R.sub.3 is not naphthyl

##STR00012##

[0071] In an embodiment of the present disclosure, there is provided a process of preparation of compounds of Formula (I) or its stereoisomers, pharmaceutically acceptable salts, polymorphs, solvates and hydrates thereof as described herein, wherein triamines like norspermidine, bis(hexamethylene) triamine are taken and their primary amine groups protected by Boc, using di-tert-butyl dicarbonate or reacted with amino acids like N,N-Diboc-.sup.LLysine and the others using HBTU coupling reaction. Then, the secondary amine of the triamine is reacted with different molecules bearing (R.sub.3).sub.p group through HBTU coupling reaction or a nucleophilic substitution reaction. Finally, the Boc groups are deprotected using 1 N HCl or CF.sub.3COOH to yield the final compounds. Examples showing this preparation are given in Scheme 1, Scheme 2, Scheme 3 and Scheme 4.

[0072] In an embodiment of the present disclosure, there is provided a process of preparation of compounds of Formula (I) or its stereoisomers, pharmaceutically acceptable salts, polymorphs, solvates and hydrates thereof as described herein, wherein triamines like bis(hexamethylene) triamine is taken and it's primary amine groups protected by Boc, using di-tert-butyl dicarbonate (Compound 1-6) or reacted with N,N-Diboc-.sup.LLysine (Compound 7-9) using HBTU coupling reaction. Alternatively, bis(hexamethylene) triamine can be used, it's primary amine protected with Boc using using di-tert-butyl dicarbonate (Compound 10-12) or reacted with N,N-Diboc-.sup.LLysine (Compound 13-15) using HBTU coupling reaction.Then, the secondary amine of the triamine is reacted with different molecules bearing (R.sub.3).sub.p group through HBTU coupling reaction or a nucleophilic substitution reaction. Finally, the Boc groups are deprotected using 1 N HCl or CF.sub.3COOH to yield the final compounds. Examples showing this preparation are given in Scheme 3 and Scheme 4.

[0073] In an embodiment of the present disclosure, there is provided a use of the compound of Formula (I) as described herein, as small molecular adjuvants.

[0074] In an embodiment of the present disclosure, there is provided a pharmaceutical composition comprising a compound of Formula (I) or its stereoisomers, pharmaceutically acceptable salts, polymorphs, solvates and hydrates thereof as described herein, together with a pharmaceutically acceptable carrier, optionally in combination with one or more other antibiotics, or their pharmaceutical composition.

[0075] In an embodiment of the present disclosure, there is provided a pharmaceutical composition comprising: a) compound of Formula (I) or its stereoisomers, pharmaceutically acceptable salts, polymorphs, solvates and hydrates thereof, as described herein; b) one or more antibiotics.

[0076] In an embodiment of the present disclosure, there is provided a pharmaceutical composition comprising: a) compound of Formula (I) or its stereoisomers, pharmaceutically acceptable salts, polymorphs, solvates and hydrates thereof, as described herein; b) pharmaceutical composition of one or more antibiotics.

[0077] In an embodiment of the present disclosure, there is provided a pharmaceutical composition as described herein, wherein the antibiotic is selected from the group consisting of rifampicin, tetracycline, fusidic acid, oxazolidinone, glycopeptides, fluoroquinolone, macrolide, beta-lactams, aminoglycosides, chloramphenicol, polymyxin, lipopeptide, and combinations thereof.

[0078] In an embodiment of the present disclosure, there is provided a pharmaceutical composition as described herein, wherein the antibiotic is selected from the group consisting of rifampicin, tetracycline, minocycline, fusidic acid, linezolid, vancomycin, ciprofloxacin, erythromycin, ampicillin, streptomycin, chloramphenicol, colistin, daptomycin, and combinations thereof.

[0079] In an embodiment of the present disclosure, there is provided a pharmaceutical composition as described herein, for use in treating disease or condition in a patient, wherein said disease or condition is caused by a microorganism selected from the group consisting of bacteria, fungi and protozoa.

[0080] In an embodiment of the present disclosure, there is provided a pharmaceutical composition as described herein, for use in killing or inhibiting the growth of a microorganism selected from the group consisting of bacteria, fungi, and protozoa.

[0081] In an embodiment of the present disclosure, there is provided a use of the pharmaceutical composition as described herein, in treating a disease or condition in a patient, wherein said disease or condition is caused by microorganism selected from the group consisting of bacteria, fungi, and protozoa.

[0082] In an embodiment of the present disclosure, there is provided a use of the pharmaceutical composition as described herein, in a method of killing or inhibiting the growth of a microorganism selected from the group consisting of bacteria, fungi, and protozoa.

[0083] In an embodiment of the present disclosure, there is provided a method of treating a disease or condition in a patient, said method comprising administering to a patient a pharmaceutical composition, as described herein, wherein said disease or condition is caused by microorganism selected from the group consisting of bacteria, fungi, and protozoa.

[0084] In an embodiment of the present disclosure, there is provided a pharmaceutical composition as described herein, wherein the bacteria is Gram-positive bacteria or Gram-negative bacteria.

[0085] In an embodiment of the present disclosure, there is provided a pharmaceutical composition as described herein, wherein the bacteria is a multi-resistant bacterium selected from a group consisting of A. baumannii, P. aeruginosa, E. coli, K. pneumoniae, or any combinations thereof.

EXAMPLES

[0086] The disclosure will now be illustrated with working examples, which is intended to illustrate the working of disclosure and not intended to take restrictively to imply any limitations on the scope of the present disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice of the disclosed methods and compositions, the exemplary methods, devices and materials are described herein. It is to be understood that this disclosure is not limited to particular methods, and experimental conditions described, as such methods and conditions may apply.

[0087] The following examples provide the details about the synthesis, characterization and combination efficacies of the small-molecular adjuvants mentioned in the present invention. It should be understood the following examples are representatives only, and that the invention is not limited by the details set forth in these examples.

[0088] All the solvents were of reagent grade, which were distilled and dried before its use. All the reagents were purchased from Sigma-Aldrich, Alfa-Aesar, S.D. Fine, Avra and Spectrochem, and were used without further purification. Analytical thin layer chromatography (TLC) was performed on E. Merck TLC plates pre-coated with silica gel 60 F.sub.254 and visualization was carried out using UV light and Iodine. Column chromatography was performed on silica gel (60-120 mesh) using different ratio of chloroform and methanol solvent system. Nuclear magnetic resonance spectra were recorded on Bruker (AV-400) 400 MHz spectrometer in deuterated solvents. Mass spectra were obtained using 6538-UHD Accurate mass Q-TOF LC-MS instrument. For optical density measurement during bacteriology experiments, Tecan Infinite Pro series M200 Microplate Reader was used. Bacterial strains, A. baumannii (R674), P. aeruginosa (R590), E. coli (R3336) and K. pneumoniae (R3934) were used for the studies.

[0089] The combination efficacy with antibiotics from different classes and individual antibacterial activity of the synthesized adjuvants was evaluated against the above mentioned MDR and NDM-1 strains of Gram-negative bacteria. All the bacteria were grown in peptone. The bacterial samples were freeze dried and stored at −80° C. 3 μl of these stocks were added to 3 mL of peptone and the culture was grown for 6 h at 37° C. prior to the experiments.

Example 1: Synthesis of Compounds 1-5

[0090] Small-molecular adjuvants (SMAs) where R.sub.1=R.sub.2=Hydrogen and R.sub.3=Aromatic radicals were synthesized from N.sup.1-Boc-N.sup.3-(3-(Boc-amino)-propyl) propane-1,3-diamine and different aromatic radical bearing carboxylic acids or amino acids, through simple amide coupling reaction using O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluorophosphate (HBTU) as coupling agent followed by deprotection using trifluoroacetic acid to give the final compounds with CF.sub.3COO.sup.− as counterions. The final compounds can be synthesized with other counterions such as Cl.sup.−, Br.sup.− etc.

Synthesis of N.SUP.1.-Boc-N.SUP.3.-(3-(Boc-amino)propyl)propane-1,3-diamine (5a)

[0091] 10 g (1 equivalent, 76.27 mmol) of norspermidine was dissolved in MeOH (50 mL) and the solution was kept at −80° C. Then 24.94 g (1.5 equivalents, 114.31 mmol) of Boc.sub.2O was dissolved in MeOH (50 mL) and added to the reaction mixture dropwise. The reaction was continued for 1 h at −80° C. Then the reaction mixture was allowed to come at RT. MeOH was removed and purification was done through column chromatography on silica gel (60-120 mesh) using methanol and chloroform (7:93) as eluent to afford the product with 50% yield. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ/ppm: 5.182 (s, NH(—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 2H), 3.190-3.175 (m, NH(—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 4H), 2.649-2.616 (m, NH(—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 4H), 1.860 (s, NH(—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 1H), 1.666-1.602 (m, NH(—CH.sub.2—CH.sub.2—CH.sub.2-NH-Boc).sub.2, 4H), 1.417 (s, NH(—CH.sub.2—CH.sub.2—CH.sub.2—NH—COO—C(CH.sub.3).sub.3).sub.2, 18H). HRMS (m/z): 332.2539 [(M+H).sup.+] (Observed), 332.2549 [(M+H).sup.+] (Calculated).

Synthesis of N-Boc-L-Tryptophan (BocTrp)

[0092] 4.7 g (1 equivalent, 23 mmol) of .sup.LTrp was dissolved in 50 mL water, 3.9 g (2 equivalents, 46 mmol) of NaHCO.sub.3 was added and the reaction mixture was allowed to stir for 15-20 minutes. The reaction mixture was kept at 0° C. and 6 g (1.2 equivalents, 27.6 mmol) of di-t-butylpyrocarbonate (Boc.sub.2O), dissolved in 50 mL of tetrahydrofuran (THF) was added to the reaction mixture dropwise. The ice-bath was removed and the reaction was allowed to happen for 16-24 hours. Then, THF was evaporated and the reaction mixture was acidified using 1N hydrochloric acid (HCl) till a pH of 3-4 was attained. The precipitate obtained after acidifiacton was extracted using dichloromethane (DCM) to afford the pure product with 89% yield. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ/ppm: 12.509 (s, —COOH, 1H), 10.812 (s, —NH.sub.indole, 1H), 7.527-6.925 (m, ArH and —NHBoc, 6H), 4.174-4.119 (m, —CHNHBoc, 1H), 3.152-2.943 (m, —CH.sub.2, 2H), 1.329 (s, —NH—COO—C(CH.sub.3).sub.3, 9H).

General Procedure for Synthesizing 5b-5f

[0093] About 1.2 equivalents of carboxylic acids with aromatic radicals (phenylacetic, naphthylacetic, biphenyl, diphenylpropionic acid) or Boc-protected tryptophan were dissolved in dry DCM (12 mL) at 0° C. In the reaction mixture, 3 equivalents of DIPEA was added followed by 1.2 equivalents of HBTU. Then DMF (3 mL) was added to the reaction mixture. After 10 minutes, 1 equivalent of 5a in dry DCM (1 mL) was added dropwise to the reaction mixture. The reaction mixture was brought to RT and allowed to stir for 24 h. Solvent was evaporated and the residue was diluted in ethyl acetate (50 mL). Then work-up was carried out at first with 1N HCl (50 mL, 3 times) followed by saturated Na.sub.2CO.sub.3 solution (50 mL, 3 times). The crude product was extracted in ethyl acetate layer. Finally, purification was accomplished through column chromatography on silica gel (60-120 mesh) using different ratios of methanol and chloroform as an eluent to afford 5b-5f with 55-80% yield.

N,N-bis(3-(Boc-amino)propyl) phenyl ethanamide (5b)

[0094] Yield-56%; .sup.1H-NMR (400 MHz, CDCl.sub.3) δ/ppm: 7.333-7.297 (m, ArH, 2H), 7.251-7.232 (m, ArH, 3H), 5.363-4.532 (br, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 2H), 3.695 (s, ArCH.sub.2—CO— N(—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 2H), 3.415-3.022 (m, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 8H), 1.662-1.629 (br, R—CO—N((—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 4H), 1.438-1.421 (d, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH—COO—C(CH.sub.3).sub.3).sub.2, 18H). HRMS (m/z): 472.2714 [(M+Na).sup.+] (Observed), 472.2787 [(M+Na).sup.+] (Calculated).

N,N-bis(3-(Boc-amino)propyl) naphthyl ethanamide (5c)

[0095] Yield-55%; .sup.1H-NMR (400 MHz, CDCl.sub.3) δ/ppm: 7.791-7.532 (m, ArH, 3H), 7.515-7.407 (m, ArH, 4H), 5.268-4.484 (br, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 2H), 4.133(s, ArCH.sub.2—CO—N(N(—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 2H), 3.461-3.037 (m, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 8H), 1.709-1.670 (br, R—CO—N((—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 4H), 1.411-1.404 (d, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH—COO—C(CH.sub.3).sub.3).sub.2, 18H). HRMS (m/z): 522.2935 [(M+Na).sup.+] (Observed), 522.2944 [(M+Na).sup.+] (Calculated).

N,N-bis(3-(Boc-amino)propyl) biphenyl methanamide (5d)

[0096] Yield-70%; .sup.1H-NMR (400 MHz, CDCl.sub.3) δ/ppm: 7.642-7.355 (m, ArH, 9H), 5.367 and 4.357 (br, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 2H), 3.603-2.994 (br, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 8H), 1.806-1.670 (br, R—CO—N((—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 4H), 1.496-1.357 (br, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH—COO—C(CH.sub.3).sub.3).sub.2, 18H). HRMS (m/z): 534.2934 [(M+Na).sup.+] (Observed), 534.2944 [(M+Na).sup.+] (Calculated).

N,N-bis(3-(Boc-amino)propyl) 3,3-diphenyl propanamide (5e)

[0097] Yield-74%; .sup.1H-NMR (400 MHz, CDCl.sub.3) δ/ppm: 7.288-7.284 (ArH, 3H), 7.252-7.154 (m, ArH, 7H), 5.227 (br, —NHBoc, 1H), 4.733-4.695 (t, ArCHCH.sub.2—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 1H), 4.560 (br, —NHBoc, 1H), 3.337-3.055 and 2.783-2.739 (m and q, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 8H), 3.036-3.017 (d, ArCHCH.sub.2—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 2H), 1.636-1.439 (br, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 4H), 1.434 (s, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH—COO—C(CH.sub.3).sub.3).sub.2, 18H). HRMS (m/z): 540.3900 [(M+H).sup.+] (Observed), 540.3437 [(M+H).sup.+] (Calculated).

N,N-bis(3-(Boc-amino)propyl) 2′-(Boc-amino), 3′-indolo propanamide (5f)

[0098] Yield-69%; %; .sup.1H-NMR (400 MHz, CDCl.sub.3) δ/ppm: 8.334 (s, —NH.sub.indole, 1H), 7.717-7.698 (d, ArH, 1H), 7.360-7.340 (d, ArH, 1H), 7.210-7.034 (m, ArH, 3H), 5.331-4.586 (br, ArCH.sub.2CH(NHBoc)CO—N((—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 4H), 3.409-2.703 (m, ArCH.sub.2CH(NHBoc)CO—N(—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 10H), 1.728- 1.714 (br, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 4H), 1.452-1.434 (d, ArCH.sub.2CH(NH—COO—C(CH.sub.3).sub.3)CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH—COO—C(CH.sub.3).sub.3).sub.2, 27H). HRMS (m/z): 618.3531 [(M+H).sup.+] (Observed), 618.3867 [(M+H).sup.+] (Calculated).

General Procedure for Synthesizing Final Compounds (Compound 1 to Compound 5)

[0099] At first 1 equivalent of 5b-5f was dissolved in dry DCM. To the intensely stirred solution, 4 equivalents (excess amount) of trifluoroacetic acid (TFA) was added and allowed to stir at RT for 4 h. After that reaction, solvent and unused TFA were removed to get the pure product with 100% yield with CF.sub.3COO.sup.− counterions. The final compounds can be synthesized with other counterions such as Cl.sup.−, Br.sup.− etc.

N,N-bis((3-amino)propyl)phenyl ethanamide bis(trifluoroacetate) (Compound 1)

[0100] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ/ppm: 7.827 (br, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 6H), 7.327-7.290 (ArH, 2H), 7.248-7.231 (d, ArH, 3H), 3.700 (s, ArCH.sub.2—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 2H), 3.411-3.370 (t, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 2H), 3.333-3.297 (R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 2H), 2.856-2.820 (t, R—CO—N-(CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 2H), 2.731-2.695 (t, R—CO—N—(CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 2H), 1.862-1.706 (m, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 4H). HRMS (m/z): 250.9104 [(M+H).sup.+] (Observed), 250.1919 [(M+H).sup.+] (Calculated).

N,N-bis((3-amino)propyl)naphthyl ethanamide bis(trifluoroacetate) (Compound 2)

[0101] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ/ppm: 7.913-7.824 (m, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2 and ArH, 8H), 7.542-7.329 (m, ArH, 5H), 4.176 (s, ArCH.sub.2—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 2H), 3.556-3.517 (t, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 2H), 3.373-3.339 (t, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 2H), 2.901-2.886 (br, R—CO—N—(CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 2H), 2.743-2.729 (br, R—CO—N—(CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 2H), 1.987-1.889 (quint, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 2H), 1.803-1.767 (quint, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 2H). HRMS (m/z): 300.2338 [(M+H).sup.+] (Observed), 300.2076 [(M+H).sup.+] (Calculated).

N,N-bis((3-amino)propyl)biphenyl methanamide bis(trifluoroacetate) (Compound 3)

[0102] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ/ ppm: 7.961-7.394 (m, ArH and Ar—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 15H), 3.369-3.318 (br, Ar—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 4H), 2.968-2.664 (br, Ar—CO—N—(CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 4H), 1.903-1.735 (br, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 4H). HRMS (m/z): 312.2069 [(M+H).sup.+] (Observed), 312.2076 [(M+H).sup.+] (Calculated).

N,N-bis((3-amino)propyl)3,3-diphenyl propanamide bis(trifluoroacetate) (Compound 4)

[0103] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ/ppm: 7.845-7.648 (br, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 6H), 7.326-7.140 (m, ArH, 10H), 4.555-4.517 (t, ArCHCH.sub.2—CO—N((—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 1H), 3.384-3.346 (t, R—CO—N(CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 2H), 3.235-3.202 (t, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 2H), 3.119-3.100 (d, ArCHCH.sub.2—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 2H), 2.972-2.816 (m, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 4H), 1.808-1.754 (quint, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 2H), 1.629-1.578 (quint, R—CO—N(CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 2H). HRMS (m/z): 340.2379 [(M+H).sup.+] (Observed), 340.2389 [(M+H).sup.+] (Calculated).

N,N-bis((3-amino)propyl) 2′-(Boc-amino), 3′-indolo propanamide tris(trifluoroacetate) (Compound 5)

[0104] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ/ppm: 11.071 (s, —NH.sub.indole, 1H), 8.232-7.802 (br, ArCH.sub.2CH(NH.sub.3.sup.+)CO—N(CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 9H), 7.524-7.504 (d, ArH, 1H), 7.396-6.993 (m, ArH, 4H), 4.446-4.434 (br, ArCH.sub.2CH(NH.sub.3.sup.+)CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 1H), 3.395-3.325 (m, ArCH.sub.2CH(NH.sub.3.sup.+)CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 2H), 3.168-2.688 (m, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 8H), 1.663 (br, R—CO—N(CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 4H). HRMS (m/z): 318.2097 [(M+H).sup.+] (Observed), 318.2294 [(M+H).sup.+] (Calculated).

Example 2: Synthesis of N-(Adamantan-2-yl)-2-[N′,N′-{bis-(3-amino) propyl} amino] ethanamide tris(trifluoroacetate) (Compound 6)

[0105] SMAs where R.sub.1=R.sub.2=Hydrogen and R.sub.3=Cyclic aliphatic radical (adamantyl group) were synthesized from N.sup.1-Boc-N.sup.3-[3-(Boc amino) propyl] propane-1,3-diamine (5a) and N-(Adamantan-2-yl)-2-bromoethanamide (2a), through simple nucleophilic substitution reaction followed by deprotection using trifluoroacetic acid to give the final compounds with CF.sub.3COO.sup.− as counterions. The final compounds can be synthesized with other counterions such as Cl.sup.−, Br.sup.− etc.

Example 2.1: Synthesis of N-(adamantan-2-yl)-2-bromoethanamide (2a)

[0106] About 500 mg of 2-Adamantyl amine hydrochloride (1 equivalent, 2.66 mmol) was dissolved in 12 mL DCM and 552 mg of K.sub.2CO.sub.3 (1.5 equivalents, 3.99 mmol) dissolved in 10 mL of water was added to it at 5° C. 806.5 mg of Bromoacetyl bromide (1.5 equivalents, 3.99 mmol) was dissolved in 8 mL DCM and slowly added to the reaction mixture using a dropper funnel. The reaction was kept at 5° C. for 30 minutes, until the addition of bromoacetyl bromide and then at room temperature for 12 h. After 12 h, the reaction was stopped, DCM layer collected, worked up with water 3 times and finally evaporated to get the desired pure product with 85% yield. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ/ppm: 6.914 (br, Ad—NH—CO—CH.sub.2Br, 1H), 4.046-4.025 (t, AdH, 1H), 3.912 (s, Ad—NH—CO—CH.sub.2Br, 2H), 1.944-1.612 (m, AdH, 14H).

N-(Adamantan-2-yl)-2-[N′,N′-{bis-(3-Boc-amino) propyl} amino] ethanamide (6a)

[0107] 300 mg of N.sup.1-Boc-N.sup.3-(3-(Boc-amino)-propyl) propane-1,3-diamine, 5a (1 equivalent, 0.905 mmol) was dissolved in DMF. 187.6 mg of K.sub.2CO.sub.3 (1.5 equivalents, 1.36 mmol) was added to the reaction mixture. Then, 246.33 mg of N-(adamantan-2-yl)-2-bromoethanamide, 2a (1 equivalent, 0.905 mmol), dissolved in DMF was added to the reaction mixture. The reaction was stirred at room temperature for 24 hours. The reaction mixture was then dissolved in ethyl acetate and work-up was performed with ice-cold water (3 times) to remove the DMF. The ethyl acetate layer was collected and the solvent evaporated to get the pure product with 80% yield. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ/ppm: 4.747 (br, Ad—NH—CO—CH.sub.2—N(—CH.sub.2—CH.sub.2—CH.sub.2—NHBoc).sub.2, 2H), 4.126-4.040 (m, AdH, 1H), 3.178-3.087 (br, Ad—NH—CO—CH.sub.2—N(—CH.sub.2—CH.sub.2—CH.sub.2—NHBoc).sub.2, 6H), 2.560 (br, Ad—NH—CO—CH.sub.2—N(—CH.sub.2—CH.sub.2—CH.sub.2—NHBoc).sub.2, 4H), 1.903-1.664(br, AdH and Ad—NH—CO—CH.sub.2—N(—CH.sub.2—CH.sub.2—CH.sub.2—NHBoc).sub.2, 17H), 1.432 (s, Ad—NH—CO—CH.sub.2—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH—COO—C(CH.sub.3).sub.3).sub.2, 18H). HRMS (m/z): 523.3971 [(M+H).sup.+] (Observed), 523.3859 [(M+H).sup.+] (Calculated).

N-(Adamantan-2-yl)-2-[N′,N′-{bis-(3-amino) propyl} amino] ethanamide tris(trifluoroacetate) (Compound 6)

[0108] At first 380 mg (1 equivalent, 0.73 mmol) of 6a was dissolved in dry DCM. To the intensely stirred solution 4 equivalents (excess amount) of trifluoroacetic acid (TFA) was added and allowed to stir at RT for 4-6 h. After that reaction, solvent and unused TFA was removed to get the pure product with 100% yield with CF.sub.3COO— counterions. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ/ppm: 8.391 (br, AdNHCOCH.sub.2—NH.sup.+(—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 1H), 7.937 (br, AdNHCOCH.sub.2—NH.sup.+(—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 6H), 3.922-3.905 (br, AdH, 1H), 2.990-2.860 (br, AdNHCOCH.sub.2—NH.sup.+(—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 6H), 1.959-1.704 (m, AdH and AdNHCOCH.sub.2—NH.sup.+(—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 18H), 1.545-1.235 (m, AdNHCOCH.sub.2—NH.sup.+(—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 4H). HRMS (m/z): 323.2791 [(M+H).sup.+] (Observed), 323.2811 [(M+H).sup.+] (Calculated).

Example 3: Synthesis of N,N-bis-[(6-(.SUP.L.Lys)amido) propyl] naphthyl ethanamide tetrakis(trifluoroacetate) (Compound 7)

[0109] SMAs where R.sub.1=R.sub.2=.sup.LLysine and R.sub.3=Aromatic radicals were synthesized from N.sup.1(Boc-.sup.LLys)-N.sup.3-[{3-(Boc-.sup.LLys)amino} propyl] propane-1,3-diamine, 7a and different aromatic radical bearing carboxylic acids or amino acids, through simple amide coupling reaction using O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluorophosphate (HBTU) as coupling agent followed by deprotection using trifluoroacetic acid to give the final compounds with CF.sub.3COO.sup.− as counterions. The final compounds can be synthesized with other counterions such as Cl.sup.−, Br.sup.− etc.

Synthesis of N.SUP.1.-(Boc-.SUP.L.Lys)-N.SUP.3.-[{3-(Boc-.SUP.L.Lys)amido} propyl] propane-1,3-diamine (7a)

[0110] About 3.17 g (2.4 equivalents, 9.14 mmol) of N,N′-DiBoc-L-Lysine was dissolved in about 25 mL of dry DCM at 0° C. In the reaction mixture, about 3.32 mL (5 equivalents, 19.05 mmol) of DIPEA was added followed by about 3.47 g (2.4 equivalents, 9.14 mmol) of HBTU. Now about 8 mL of DMF was added to the reaction mixture. After 10 minutes, about 500 mg (1 equivalent, 3.81 mmol) of norspermidine, dissolved in 10 mL of DCM was added dropwise to the reaction mixture. The reaction mixture was allowed to stir for 48 h at 0° C. Then the reaction solvent was evaporated and the residue was diluted in ethyl acetate. Thereafter work-up was done with 1N HCl (50 mL, 3 times) followed by saturated Na.sub.2CO.sub.3 solution (50 mL, 3 times). The crude product was collected in the ethyl acetate layer. Finally, column chromatography was done using different ratios of chloroform and methanol solution, to isolate the product with 42% yield. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ/ppm: 7.337 (br, NH(—(CH.sub.2).sub.3—NH—CO—CH(NHBoc)-(CH.sub.2).sub.4-NHBoc).sub.2, 2H), 5.566 (br, NH(—(CH.sub.2).sub.3—NH—CO—CH(NHBoc)-(CH.sub.2).sub.4-NHBoc).sub.2, 2H), 4.808 (br, NH(—(CH.sub.2).sub.3—NH—CO—CH(NHBoc)-(CH.sub.2).sub.4-NHBoc).sub.2, 2H), 4.053 (br, NH(—(CH.sub.2).sub.3—NH—CO—CH(NHBoc)-(CH.sub.2).sub.4-NHBoc).sub.2, 2H), 3.475-3.323 and 3.102-3.088 (br, NH(—(CH.sub.2).sub.2—CH.sub.2—NH—CO—CH(NHBoc)-(CH.sub.2).sub.3—CH.sub.2-NHBoc).sub.2, 8H), 2.745 (br, NH(—CH.sub.2—(CH.sub.2).sub.2—NH—CO—CH(NHBoc)-(CH.sub.2).sub.4-NHBoc).sub.2, 4H), 2.349 and 1.802-1.788 (br, NH(—CH.sub.2—CH.sub.2—CH.sub.2—NH—CO—CH(NHBoc)—CH.sub.2—(CH.sub.2).sub.3-NHBoc).sub.2, 8H), 1.666-1.580 (m, NH(—CH.sub.2—CH.sub.2—CH.sub.2—NH—CO—CH(NHBoc)-(CH.sub.2).sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 4H), 1.422 (br, NH(—(CH.sub.2).sub.3—NH—CO—CH(NH—COO—C(CH.sub.3).sub.3)—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2—NH—COO—C(CH.sub.3).sub.3).sub.2, 40H). HRMS (m/z): 788.5462 [(M+H).sup.+] (Observed), 788.5497 [(M+H).sup.+] (Calculated).

N,N-bis-[{3-(Boc-.SUP.L.Lys)amido} propyl] naphthyl ethanamide (7b)

[0111] 113.4 mg (1.2 equivalents, 0.609 mmol) of Naphthyl acetic acid was dissolved in dry DCM (4 mL) at 0° C. In the reaction mixture, 265 μL (3 equivalents, 1.52 mmol) of N,N-diisopropylethylamine (DIPEA) was added followed by 231 mg (1.2 equivalents, 0.609 mmol) of N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU). Then DMF (2 mL) was added to the reaction mixture to dissolve the HBTU. After 15 min, 400 mg (1 equivalent, 0.51 mmol) of N.sup.1-(Boc-.sup.LLys)-N.sup.3-[{3-(Boc-.sup.LLys) amido} propyl] propane-1,3-diamine, 7a dissolved in dry DCM (4 mL) was added dropwise to the reaction mixture. The reaction mixture was brought to room temperature and allowed to stir for 24 h. Solvent was evaporated, and residue was diluted in ethyl acetate (50 mL). Then workup was carried out first with 1 N HCl (50 mL, 3 times) followed by saturated Na.sub.2CO.sub.3 solution (50 mL, 3 times). The crude product was extracted in ethyl acetate layer. Finally, purification was accomplished through column chromatography on silica gel (60-120 mesh) using different ratios of methanol and chloroform as an eluent to afford compound 7b with 51% yield. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ/ppm: 7.930-7.909 (d, ArH, 1H), 7.866-7.847 (d, ArH, 1H), 7.844-7.775 (d, ArH, 1H), 7.536-7.482 (quint, ArH, 2H), 7.465-7.407 (t, ArH, 1H), 7.387-7.321 (d, ArH, 1H), 7.172 (br, R—CO—N(—(CH.sub.2).sub.3—NH—CO—CH(NHBoc)-(CH.sub.2).sub.4-NHBoc).sub.2, 2H), 5.352 (br, R—CO—N(—(CH.sub.2).sub.3—NH—CO—CH(NHBoc)-(CH.sub.2).sub.4-NHBoc).sub.2, 2H), 5.257-5.240 (br, R—CO—N(—(CH.sub.2).sub.3—NH—CO—CH(NHBoc)-(CH.sub.2).sub.4-NHBoc).sub.2, 2H), 4.667 (br, R—CO—N((—(CH.sub.2).sub.3—NH—CO—CH(NHBoc)-(CH.sub.2).sub.4-NHBoc).sub.2, 2H), 4.120 (s, ArCH.sub.2—CO—N(—(CH.sub.2).sub.3—NH—CO—CH(NHBoc)-(CH.sub.2).sub.3—CH.sub.2-NHBoc).sub.2, 4H), 3.473-3.362 (br, R—CO—N(—(CH.sub.2).sub.2—CH.sub.2—NH—CO—CH(NHBoc)-(CH.sub.2).sub.4-NHBoc).sub.2, 4H), 3.243 (br, ArCH.sub.2—CO—N(—(CH.sub.2).sub.3—NH—CO—CH(NHBoc)-(CH.sub.2).sub.3—CH.sub.2-NHBoc).sub.2, 2H), 3.079-3.047 (t, R—CO—N(—CH.sub.2—(CH.sub.2).sub.2—NH—CO—CH(NHBoc)-(CH.sub.2).sub.3—CH.sub.2-NHBoc).sub.2, 4H), 1.772 (br, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH—CO—CH(NHBoc)-(CH.sub.2).sub.3—CH.sub.2-NHBoc).sub.2, 4H), 1.689 (br, R—CO—N(—(CH.sub.2).sub.3—NH—CO—CH(NHBoc)—CH.sub.2—(CH.sub.2).sub.3-NHBoc).sub.2, 4H), 1.595 (br, R—CO—N(—(CH.sub.2).sub.3—NH—CO—CH(NHBoc)-(CH.sub.2).sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 4H), 1.430-1.396 (d, R—CO—N(—(CH.sub.2).sub.3—NH—CO—CH(NH—COO—C(CH.sub.3).sub.3)—(CH.sub.2).sub.4—NH—COO—C(CH.sub.3).sub.3).sub.2, 36H), 1.254 (br, R—CO—N(—(CH.sub.2).sub.3—NH—CO—CH(NHBoc)—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 4H). HRMS (m/z): 956.5919 [(M+H).sup.+] (Observed), 956.6072 [(M+H).sup.+] (Calculated).

N,N-bis-[(6-(.SUP.L.Lys)amido) propyl] naphthyl ethanamide tetrakis(trifluoroacetate) (Compound 7)

[0112] At first 250 mg (1 equivalent, 0.26 mmol) of 7b was dissolved in dry DCM. To the intensely stirred solution, 4 equivalents (excess amount) of trifluoroacetic acid (TFA) was added and allowed to stir at RT for 4-6 h. After that reaction, solvent and unused TFA were removed to get the pure product with 100% yield with CF.sub.3CO.sup.− counterions. The final compounds can be synthesized with other counterions such as Cl.sup.−, Br.sup.− etc. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ/ppm: 8.581-8.426 (dt, ArH, 2H), 8.164-8.130 (d, ArH, —NH.sub.amide and —NH.sub.3.sup.+, 6H), 7.947.7.753 (m, ArH, —NH.sub.amide and —NH.sub.3.sup.+, 9H), 7.531-7.316 (m, ArH and —NH.sub.3.sup.+, 4H), 4.128 (s, ArCH.sub.2CO—N(—(CH.sub.2).sub.3—NH—CO—CH(NH.sub.3.sup.+)—(CH.sub.2).sub.3—CH.sub.2—NH.sub.3.sup.+).sub.2, 2H), 3.699-3.686 (br, R—CO—Ne(CH.sub.2).sub.3—NH—CO—CH(NH.sub.3.sup.+)—(CH.sub.2).sub.3—CH.sub.2—NH.sub.3.sup.+).sub.2, 2H), 3.461-3.309 (br, R—CO—N(—(CH.sub.2).sub.3—NH—CO—CH(NH.sub.3.sup.+)—(CH.sub.2).sub.3—CH.sub.2—NH.sub.3.sup.+).sub.2, 4H), 3.203-3.109 and 2.744-2.694 (br, R—CO—NeCH.sub.2—CH.sub.2—CH.sub.2—NH—CO—CH(NH.sub.3.sup.+)—(CH.sub.2).sub.3—CH.sub.2—NH.sub.3.sup.+).sub.2, 8H), 1.821-1.656 (m, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH—CO—CH(NH.sub.3.sup.+)—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 8H), 1.533-1.457 (m, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH—CO—CH(NH.sub.3.sup.+)—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 8H), 1.332-1.235 (m, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH—CO—CH(NH.sub.3.sup.+)—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 4H). HRMS (m/z): 556.3870 [(M+H).sup.+] (Observed), 556.3975 [(M+H).sup.+] (Calculated).

Example 4: Synthesis of N,N-bis-[(6-(.SUP.L.Lys)amido) propyl] 3,3-diphenyl propanamide tetrakis(trifluoroacetate) (Compound 8)

N,N-bis-[{3-(Boc-.SUP.L.Lys)amido} propyl] 3,3-diphenyl propanamide (7c)

[0113] 275.6 mg (1.2 equivalents, 1.22 mmol) of 3,3-diphenyl propionic acid was dissolved in dry DCM (4 mL) at 0° C. In the reaction mixture, 530.5 μL (3 equivalents, 3.04 mmol) of N,N-diisopropylethylamine (DIPEA) was added followed by 462 mg (1.2 equivalents, 1.22 mmol) of N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU). Then DMF (2 mL) was added to the reaction mixture to dissolve the HBTU. After 15 min, 800 mg (1 equivalent, 1.01 mmol) of N.sup.1-(Boc-.sup.LLys)-N.sup.3-[{3-(Boc-.sup.LLys) amido} propyl] propane-1,3-diamine, 7a dissolved in dry DCM (4 mL) was added dropwise to the reaction mixture. The reaction mixture was brought to room temperature and allowed to stir for 24 h. The solvent was evaporated, and the residue was diluted in ethyl acetate (50 mL). Then workup was carried out first with 1 N HCl (50 mL, 3 times) followed by saturated Na.sub.2CO.sub.3 solution (50 mL, 3 times). The crude product was extracted in ethyl acetate layer. Finally, purification was accomplished through column chromatography on silica gel (60-120 mesh) using different ratios of methanol and chloroform as an eluent to afford compound 7c with 57% yield. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ/ppm: 7.241-7.147 (m, ArH, 10H), 5.345-5.235 (br, —NH.sub.amide, 3H), 4.719-4.682 (t, ArCHCH.sub.2CO—N(—(CH.sub.2).sub.3—NH—CO—CH(NHBoc)-(CH.sub.2).sub.3—CH.sub.2-NHBoc).sub.2, 3H), 4.146-4.092 (q, —NH.sub.amide, 3H), 3.388-2.788 (m, ArCHCH.sub.2CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH—CO—CH(NHBoc)-(CH.sub.2).sub.3—CH.sub.2-NHBoc).sub.2, 18H), 1.691-1.590 (br, R—CO—N(—(CH.sub.2).sub.3—NH—CO—CH(NHBoc)—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 8H), 1.432-1.422 (d, R—CO—N(—(CH.sub.2).sub.3—NH—CO—CH(NH—COO—C(CH.sub.3).sub.3—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2—NH—COO—C(CH.sub.3).sub.3).sub.2, 36H), 1.419-1.338 (br, R—CO—N(—(CH.sub.2).sub.3—NH—CO—CH(NHBoc)—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 4H). HRMS (m/z): 996.6348 [(M+H).sup.+] (Observed), 996.6385 [(M+H).sup.+] (Calculated).

[0114] At first 490 mg (1 equivalent, 0.49 mmol) of 7c was dissolved in dry DCM. To the intensely stirred solution, 4 equivalents (excess amount) of trifluoroacetic acid (TFA) was added and allowed to stir at RT for 4-6 h. After that reaction, solvent and unused TFA were removed to get the pure product with 100% yield with CF.sub.3COO.sup.− counterions. The final compounds can be synthesized with other counterions such as Cl.sup.−, Br.sup.− etc. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ/ppm: 8.558 (t, —NH.sub.amide, 1H), 8.318 (t, —NH.sub.amide, 1H), 8.172-7.801 (br, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH—CO—CH(NH.sub.3.sup.+)—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 12H), 7.308-7.130 (m, ArH, 10H), 4.539-4.502 (t, ArCHCH.sub.2—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH—CO—CH(NH.sub.3.sup.+)—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 1H), 3.683-3.670 (br, ArCHCH.sub.2—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH—CO—CH(NH.sub.3.sup.+)—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 3H), 3.330-2.730 (m, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH—CO—CH(NH.sub.3.sup.+)—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 12H), 1.700-1.235 (m, R—CO—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH—CO—CH(NH.sub.3.sup.+)—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 16H). HRMS (m/z): 596.4248 [(M+H).sup.+] (Observed), 596.4288 [(M+H).sup.+] (Calculated).

Example 5: Synthesis of N-(adamantan-2-yl)-2-[N′,N′-{bis-(3-.SUP.L.Lys) amido)propyl} amino] ethanamide pentakis(trifluoroacetate) (Compound 9)

[0115] SMAs where R.sub.1=R.sub.2=Lysine and R.sub.3=Cyclic aliphatic radical (adamantyl group) were synthesized from N.sup.1-(Boc-.sup.LLys)-N.sup.3-[{3-(Boc-.sup.LLys)amido} propyl] propane-1,3-diamine (7a, in Example 7.1) and N-adamantyl-2-bromoethanamide (2a, in Example 2.1), through simple nucleophilic substitution reaction followed by deprotection using trifluoroacetic acid with CF.sub.3COO.sup.− counterions. The final compounds can be synthesized with other counterions such as Cl.sup.−, Br.sup.− etc.

N-(adamantan-2-yl)-2-[N′,N′-{bis-(3-(Boc-.SUP.L.Lys)amido)propyl} amino] ethanamide (8a)

[0116] 390 mg of N.sup.1-(Boc-.sup.LLys)-N.sup.3-[{3-(boc-.sup.LLys)amido}propyl] propane-1,6-diamine, 7a (1 equivalent, 0.77 mmol) in DMF. 154.6 mg of K.sub.2CO.sub.3 (1.5 equivalents, 1.12 mmol) was added to the reaction mixture. Then, 203 mg of N-(adamantan-2-yl)-2-bromoethanamide (1 equivalent, 0.77 mmol), dissolved in DMF was added to the reaction mixture. The reaction was stopped after 24 hours. The reaction mixture was then dissolved in ethyl acetate and work-up was performed with ice-cold water (3 times) to remove the DMF. The ethyl acetate layer was collected and the solvent evaporated to get the pure product with 40% yield. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ/ppm: 6.902 (br, AdNH—CO—CH.sub.2—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH—CO—CH(NHBoc)—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 1H), 5.590 (br, AdNH—CO—CH.sub.2—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH—CO—CH(NHBoc)—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 2H), 4.786 (br, AdNH—CO—CH.sub.2—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH—CO—CH(NHBoc)—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 2H), 4.123-4.027 (m, AdH and AdNH—CO—CH.sub.2—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH—CO—CH(NHBoc)—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 3H), 3.461 (br, AdNH—CO—CH.sub.2—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH—CO—CH(NHBoc)—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 2H), 3.208-2.519 (br, AdNH—CO—CH.sub.2—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH—CO—CH(NHBoc)—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 10H), 2.039-1.479 (br, AdH and AdNH—CO—CH.sub.2—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH—CO—CH(NHBoc)—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 34H), 1.429-1.422 (d, AdNH—CO—CH.sub.2—N(—CH.sub.2—CH.sub.2—CH.sub.2—NH—CO—CH(NH—COO—C(CH.sub.3).sub.3)—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2—NH—COO—C(CH.sub.3).sub.3).sub.2, 36H). HRMS (m/z): 979.6745 [(M+H).sup.+] (Observed), 979.6807 [(M+H).sup.+] (Calculated).

N-(adamantan-2-yl)-2-[N′,N′-{bis-(3-.SUP.L.Lys) amido)propyl} amino] ethanamide pentakis(trifluoroacetate) (Compound 9)

[0117] 280 mg (1 equivalent, 0.28 mmol) of 8a was dissolved in dry DCM. To the intensely stirred solution, 4 equivalents (excess amount) of trifluoroacetic acid (TFA) was added and allowed to stir at RT for 4-6 h. After that reaction, solvent and unused TFA were removed to get the pure product with 100% yield with CF.sub.3COO.sup.− counterions. The final compounds can be synthesized with other counterions such as Cl.sup.−, Br.sup.− etc. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ/ppm: 9.688 (br, AdNH—CO—CH.sub.2—NH.sup.+(—CH.sub.2—CH.sub.2—CH.sub.2—NH—CO—CH(NH.sub.3.sup.+)—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 1H), 8.673 (br, AdNH—CO—CH.sub.2—NH.sup.+(—CH.sub.2—CH.sub.2—CH.sub.2—NH—CO—CH(NH.sub.3.sup.+)—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 2H), 8.482 (br, AdNH—CO—CH.sub.2—NH.sup.+(—CH.sub.2—CH.sub.2—CH.sub.2—NH—CO—CH(NH.sub.3.sup.+)—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 1H), 8.207 (bs, AdNH—CO—CH.sub.2—NH.sup.+(—CH.sub.2—CH.sub.2—CH.sub.2—NH—CO—CH(NH.sub.3.sup.+)—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 6H), 7.836 (bs, AdNH—CO—CH.sub.2—NH.sup.+(—CH.sub.2—CH.sub.2—CH.sub.2—NH—CO—CH(NH.sub.3.sup.+)—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 6H), 3.915-3.864 (t, AdH and AdNH—CO—CH.sub.2—NH.sup.+(—CH.sub.2—CH.sub.2—CH.sub.2—NH—CO—CH(NH.sub.3.sup.+)—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 3H), 3.820 (s, AdNH—CO—CH.sub.2—NH.sup.+(—CH.sub.2—CH.sub.2—CH.sub.2—NH—CO—CH(NH.sub.3.sup.+)—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 2H), 3.167-3.142 (br, AdNH—CO—CH.sub.2—NH.sup.+(—CH.sub.2—CH.sub.2—CH.sub.2—NH—CO—CH(NH.sub.3.sup.+)—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 8H), 2.758 (br, AdNH—CO—CH.sub.2—NH.sup.+(—CH.sub.2—CH.sub.2—CH.sub.2—NH—CO—CH(NH.sub.3.sup.+)—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 4H), 1.823-1.518 (br, AdH and AdNH—CO—CH.sub.2—NH.sup.+(—CH.sub.2—CH.sub.2—CH.sub.2—NH—CO—CH(NH.sub.3.sup.+)—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 30H). HRMS (m/z): 579.4681 [(M+H).sup.+] (Observed), 579.4710 [(M+H).sup.+] (Calculated).

##STR00013## ##STR00014##

##STR00015## ##STR00016##

Example 6: Synthesis of N,N-bis-[(6-amino) hexyl] naphthyl ethanamide bistrifluoroacetate (Compound 10)

Synthesis of N.SUP.1.-Boc-N.SUP.6.-(6-(Boc-amino)-hexyl) hexane-1,6-diamine (1a)

[0118] About 2 g (1 equivalent, 9.29 mmol) of Bis(hexamethylene) triamine was dissolved in about 20 mL of methanol and the solution was kept at −80° C. Then, 3.04 g (1.5 equivalents, 3.93 mmol) of di-tert-butyl dicarbonate (Boc.sub.2O) was dissolved in MeOH (30 mL) and added to the reaction mixture dropwise. The reaction was continued for 1 h at −80° C. Then the reaction mixture was allowed to come to room temperature. MeOH was removed under reduced pressure and purification was done through column chromatography on silica gel (60-120 mesh) using methanol and chloroform as an eluent to afford the product with 68% yield. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ/ppm: 4.541 (s, NH(—(CH.sub.2).sub.6-NHBoc).sub.2, 2H), 3.112-3.065 (q, NH(—(CH.sub.2).sub.5—CH.sub.2-NHBoc).sub.2, 4H), 2.602-2.565 (t, NH(—CH.sub.2—(CH.sub.2).sub.5-NHBoc).sub.2, 4H), 1.930 (s, NH(—(CH.sub.2).sub.6-NHBoc).sub.2, 1H), 1.507-1.296 (m, NH(—CH.sub.2—(CH.sub.2).sub.4—CH.sub.2—NH—COO—C(CH.sub.3).sub.3).sub.2, 34H). HRMS (m/z): 416.3419 [(M+H).sup.+] (Observed), 416.3488 [(M+H).sup.+] (Calculated).

N,N-bis-[(6-Boc-amino) hexyl] naphthyl ethanamide (1b)

[0119] 268.8 mg (1.2 equivalent, 1.44 mmol) of Naphthyl acetic acid was dissolved in dry DCM (4 mL) at 0° C. In the reaction mixture, 628.6 μL (3 equivalents, 3.609 mmol) of N,N-diisopropylethylamine (DIPEA) was added followed by 547.5 mg (1.2 equivalents, 1.44 mmol) of N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU). Then DMF (2 mL) was added to the reaction mixture to dissolve the HBTU. After 15 min, 500 mg (1 equivalent, 1.2 mmol) of N.sup.1Boc-N.sup.6-(6-(boc-amino)-hexyl) hexane-1,6-diamine (1a), dissolved in dry DCM (4 mL) was added dropwise to the reaction mixture. The reaction mixture was brought to room temperature and allowed to stir for 24 h. The solvent was evaporated, and residue was diluted in ethyl acetate (50 mL). Then workup was carried out first with 1 N HCl (50 mL, 3 times) followed by saturated Na.sub.2CO.sub.3 solution (50 mL, 3 times). The crude product was extracted in ethyl acetate layer. Finally, purification was accomplished through column chromatography on silica gel (60-120 mesh) using different ratios of methanol and chloroform as eluent to afford compound 1b with 68% yield. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ/ppm: 7.541-7.527 (d, ArH, 1H), 7.524-7.520 (d, ArH, 1H), 7.507-7.503 (d, ArH, 1H), 7.500-7.329 (m, ArH, 4H), 4.417 (s, R—CO—N(—(CH.sub.2).sub.6-NHBoc).sub.2, 2H), 4.115 (s, ArCH.sub.2CO—N(—(CH.sub.2).sub.6-NHBoc).sub.2, 2H), 3.363-3.037 (m, R—CO—N(—CH.sub.2—(CH.sub.2).sub.4—CH.sub.2-NHBoc).sub.2, 8H), 1.743 (br, R—CO—N(—CH.sub.2—CH.sub.2—(CH.sub.2).sub.4-NHBoc).sub.2, 4H), 1.593-1.253 (m, R—CO—N(—CH.sub.2—(CH.sub.2)3—CH.sub.2—CH.sub.2—NH—COO—C(CH.sub.3).sub.3).sub.2, 22H), 1.187-1.171 (m, R—CO—N(—CH.sub.2—CH.sub.2—(CH.sub.2).sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 8H). HRMS (m/z): 584.4106 [(M+H).sup.+] (Observed), 584.40635 [(M+H).sup.+] (Calculated).

N,N-bis-[(6-amino) hexyl] naphthyl ethanamide bistrifluoroacetate (Compound 10)

[0120] 480 mg (1 equivalent, 0.822 mmol) of 1b was dissolved in dry DCM. To the intensely stirred solution 4 equivalents (excess amount) of trifluoroacetic acid (TFA) was added and allowed to stir at RT for 4-6 h. After that reaction, solvent and unused TFA was removed to get the pure product with 100% yield with CF.sub.3COO.sup.− counterions. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ/ppm: 7.921-7.707 (m, ArH and R—CO—N—((CH.sub.2).sub.6—NH.sub.3.sup.+).sub.2), 9H), 7.538-7.426 (m, ArH, 3H), 7.343-7.326 (d, ArH, 1H), 4.117 (s, ArCH.sub.2CO—N(—(CH.sub.2).sub.6—NH.sub.3.sup.+).sub.2, 2H), 3.276-3.240 (t, R—CO—N((CH.sub.2).sub.5—CH.sub.2—NH.sub.3.sup.+).sub.2, 4H), 2.772-2.722 (q, R—CO—N—(CH.sub.2—(CH.sub.2).sub.5—NH.sub.3.sup.+).sub.2, 4H), 1.536-1.440 (m, R—CO—N—(CH.sub.2—CH.sub.2—(CH.sub.2).sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 8H), 1.335-1.220 (m, R—CO—N—(CH.sub.2—CH.sub.2—(CH.sub.2).sub.2—CH.sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 8H). HRMS (m/z): 384.3040 [(M+H).sup.+] (Observed), 384.3015 [(M+H).sup.+] (Calculated).

Example 7: Synthesis of N,N-bis-[(6-amino) hexyl] 3,3-diphenyl propanamide bistrifluoroacetate (Compound 11)

N,N-bis-[(6-Boc-amino) hexyl] 3,3-diphenyl propanamide (1c)

[0121] 326.6 mg (1.2 equivalents, 1.44 mmol) of 3,3-Diphenyl propionic acid was dissolved in dry DCM (4 mL) at 0° C. In the reaction mixture, 628.65 μL (3 equivalents, 3.609 mmol) of N,N-diisopropylethylamine (DIPEA) was added followed by 547.48 mg (1.2 equivalents, 1.44 mmol) of N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU). Then DMF (2 mL) was added to the reaction mixture to dissolve the HBTU. After 15 min, 500 mg (1 equivalent, 1.203 mmol) of N.sup.1-Boc-N.sup.6-(6-(boc-amino)-hexyl) hexane-1,6-diamine (1a), dissolved in dry DCM (4 mL) was added dropwise to the reaction mixture. The reaction mixture was brought to room temperature and allowed to stir for 24 h. Solvent was evaporated, and residue was diluted in ethyl acetate (50 mL). Then workup was carried out first with 1 N HCl (50 mL, 3 times) followed by saturated Na.sub.2CO.sub.3 solution (50 mL, 3 times). The crude product was extracted in ethyl acetate layer. Finally, purification was accomplished through column chromatography on silica gel (60-120 mesh) using different ratios of methanol and chloroform as eluent to afford compounds 1c with 68% yield. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ/ppm: 7.282 (s, ArH, 1H), 7.245-7.147 (m, ArH, 9H), 4.741-4.704 (t, ArCHCH.sub.2CO—N(—(CH.sub.2).sub.6-NHBoc).sub.2, 1H), 4.522 (br, R—CO—N(—(CH.sub.2).sub.6-NHBoc).sub.2, 2H), 3.227-3.059 (m, R—CO—N(CH.sub.2—(CH.sub.2).sub.4—CH.sub.2-NHBoc).sub.2, 8H), 3.003-3.984 (d, ArCHCH.sub.2CO—N(—(CH.sub.2).sub.6-NHBoc).sub.2, 2H), 1.442 (s, R—CO—N(—(CH.sub.2).sub.6—NH—COO—C(CH.sub.3).sub.3).sub.2, 18H), 1.406-1.101 (m, R—CO—N(CH.sub.2—(CH.sub.2).sub.4—CH.sub.2-NHBoc).sub.2, 16H). HRMS (m/z): 624.4347 [(M+H).sup.+] (Observed), 624.4376 [(M+H).sup.+] (Calculated).

[0122] 510 mg (1 equivalent, 0.817 mmol) of 1c was dissolved in dry DCM. To the intensely stirred solution 4 equivalents (excess amount) of trifluoroacetic acid (TFA) was added and allowed to stir at RT for 4-6 h. After that reaction, solvent and unused TFA was removed to get the pure product with 100% yield with CF.sub.3COO.sup.− counterions. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ/ppm: 7.735 (bs, R—CO—N—((CH.sub.2).sub.6—NH.sub.3.sup.+).sub.2, 6H), 7.296-7.097 (m, ArH, 10H), 4.541-4.504 (t, ArCHCH.sub.2CO—N(—(CH.sub.2).sub.6—NH.sub.3.sup.+).sub.2, 1H), 3.241-3.109 (dt, R—CO—N(CH.sub.2—(CH.sub.2).sub.4—CH.sub.2—NH.sub.3.sup.+).sub.2, 4H), 3.036-3.018 (d, ArCHCH.sub.2CO—N(—(CH.sub.2).sub.6—NH.sub.3.sup.+).sub.2, 2H), 2.788-2.701 (m, R—CO—N(CH.sub.2—(CH.sub.2).sub.4—CH.sub.2—NH.sub.3.sup.+).sub.2, 4H), 1.532-1.077 (m, R—CO—N(CH.sub.2—(CH.sub.2).sub.4—CH.sub.2—NH.sub.3.sup.+).sub.2, 16H). HRMS (m/z): 424.3299 [(M+H).sup.+] (Observed), 424.3328 [(M+H).sup.+] (Calculated).

Example 8: Synthesis of N-(adamantan-2-yl)-2-[N′,N′-{bis-(6-amino) hexyl} amino] ethanamide tristrifluoroacetate (Compound 12)

Synthesis of N-(adamantan-2-yl)-2-bromoethanamide (2a)

[0123] About 500 mg of 2-Adamantyl amine hydrochloride (1 equivalent, 2.66 mmol) was dissolved in 12 mL DCM and 552 mg of K.sub.2CO.sub.3 (1.5 equivalents, 3.99 mmol) dissolved in 10 mL of water was added to it at 5° C. 806.5 mg of Bromoacetyl bromide (1.5 equivalents, 3.99 mmol) was dissolved in 8 mL DCM and slowly added to the reaction mixture using a dropper funnel. The reaction was kept at 5° C. for 30 minutes, till the addition of Bromoacetyl bromide and then at room temperature for 12 h. After 12 h, the reaction was stopped, DCM layer collected, worked up with water 3 times and finally evaporated to get the desired pure product with 85% yield. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ/ppm: 6.914 (br, Ad-NH—CO—CH.sub.2Br, 1H), 4.046-4.025 (t, AdH, 1H), 3.912 (s, Ad-NH—CO—CH.sub.2Br, 2H), 1.944-1.612 (m, AdH, 14H).

N-(adamantan-2-yl)-2-[N′,N′-{bis-(6-Boc-amino) hexyl} amino] ethanamide (2b)

[0124] 300 mg of N.sup.1-Boc-N.sup.6-(6-(Boc-amino)-hexyl) hexane-1,6-diamine, 1a (1 equivalent, 0.72 mmol) was dissolved in DMF. 149.6 mg of K.sub.2CO.sub.3 (1.5 equivalents, 1.1 mmol) was added to the reaction mixture. Then, 196.5 mg of N-(adamantan-2-yl)-2-bromoethanamide, 2a (1 equivalent, 0.72 mmol), dissolved in DMF was added to the reaction mixture. The reaction was stirred at room temperature for 24 hours. The reaction mixture was then dissolved in ethyl acetate and work-up was performed with ice-cold water (3 times) to remove the DMF. The ethyl acetate layer was collected and the solvent evaporated to get the pure product with 61% yield. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ/ppm: 8.575 (br,Ad-NH—CO—CH.sub.2—N(—(CH.sub.2).sub.6-NHBoc).sub.2, 1H), 4.660-4.489 (br, Ad-NH—CO—CH.sub.2—N(—(CH.sub.2).sub.6-NHBoc).sub.2, 2H), 4.145-4.027 (m, AdH, 1H), 3.103 (br, Ad-NH—CO—CH.sub.2—N(—CH.sub.2—(CH.sub.2).sub.4—CH.sub.2-NHBoc).sub.2, 6H), 2.041-1.594 (m, AdH and —CH.sub.2-.sub.(Boc-aminohexyl), 26H), 1.440 (s, Ad-NH—CO—CH.sub.2—N(—(CH.sub.2).sub.6—NH—COO—C(CH.sub.3).sub.3).sub.2, 18H), 1.375-1.238 (m, AdH and —CH.sub.2-.sub.(Boc-ammohexyl), 8H). HRMS (m/z): 607.4764 [(M+H).sup.+] (Observed), 607.4798 [(M+H).sup.+] (Calculated).

N-(adamantan-2-yl)-2-[N′,N′-{bis-(6-amino) hexyl} amino] ethanamide tristrifluoroacetate (Compound 12)

[0125] 270 mg (1 equivalent, 0.445 mmol) of 2b was dissolved in dry DCM. To the intensely stirred solution 4 equivalents (excess amount) of trifluoroacetic acid (TFA) was added and allowed to stir at RT for 4-6 h. After that reaction, solvent and unused TFA was removed to get the pure product with 100% yield with CF.sub.3COO.sup.− counterions. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ/ppm: 8.540-8.457 (br, Ad-NH—CO—CH.sub.2—NH.sup.+(—(CH.sub.2).sub.6—NH.sub.3.sup.+).sub.2, 1H), 7.800 (br, Ad-NH—CO—CH.sub.2—NH.sup.+(—(CH.sub.2).sub.6—NH.sub.3.sup.+).sub.2, 6H), 3.902-3.820 (m, AdH and Ad-NH—CO—CH.sub.2—NH.sup.+(—(CH.sub.2).sub.6—NH.sub.3.sup.+).sub.2, 3H), 3.082-2.669 (br, Ad-NH—CO—CH.sub.2—NH.sup.+(—CH.sub.2—(CH.sub.2).sub.4—CH.sub.2—NH.sub.3.sup.+).sub.2, 8H), 1.967-1.235 (m, AdH and —CH.sub.2-.sub.(ammohexyl), 30H). HRMS (m/z): 407.3724 [(M+H).sup.+] (Observed), 407.3749 [(M+H).sup.+] (Calculated).

##STR00017## ##STR00018##

Example 9: Synthesis of N,N-bis-[(6-(.SUP.L.Lys)amido) hexyl] naphthyl ethanamide tetrakistrifluoroacetate (Compound 13)

Synthesis of N.SUP.1.-(Boc-.SUP.L.Lys)-N.SUP.6.-[{6-(Boc-.SUP.L.Lys)amido} hexyl] hexane-1,6-diamine (3a)

[0126] About 6.4 g (2 equivalents, 18.56 mmol) of N,N′-DiBoc-L-Lysine was dissolved in about 25 mL of dry DCM at 0° C. In the reaction mixture, about 6.5 mL (4 equivalents, 37.1 mmol) of DIPEA was added followed by about 7.0 g (2 equivalents, 18.6 mmol) of HBTU. Now about 8 mL of DMF was added to the reaction mixture. After 10 minutes, about 2 g (1 equivalent, 9.3 mmol) of Bis(hexamethylene) triamine, dissolved in 10 mL of DCM was added dropwise to the reaction mixture. The reaction mixture was allowed to stir for 48 h at 0° C. Then reaction solvent was evaporated and the residue was diluted in ethyl acetate. Thereafter work-up was done with 1N HCl (50 mL, 3 times) followed by saturated Na.sub.2CO.sub.3 solution (50 mL, 3 times). The crude product was collected in ethyl acetate layer. Finally, column was done using different ratios of chloroform and methanol solution, to isolate the product with 34% yield. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ/ppm: 6.489-6.323 (m, NH(—(CH.sub.2).sub.6—NH—CO—CH(NHBoc)-(CH.sub.2).sub.4-NHBoc).sub.2, 2H), 5.296 (br, NH(—(CH.sub.2).sub.6—NH—CO—CH(NHBoc)(CH.sub.2).sub.4-NHBoc).sub.2, 2H), 4.705 (br, NH(—(CH.sub.2).sub.6—NH—CO—CH(NHBoc)((CH.sub.2).sub.4-NHBoc).sub.2, 2H), 4.020 (br, NH(—(CH.sub.2).sub.6—NH—CO—CH(NHBoc)(CH.sub.2).sub.4-NHBoc).sub.2, 2H), 3.246-3.075 (m, NH(—(CH.sub.2).sub.5—CH.sub.2—NH—CO—CH(NHBoc)(CH.sub.2).sub.3—CH.sub.2-NHBoc).sub.2, 8H), 2.729 (br, NH(—CH.sub.2—(CH.sub.2).sub.5—NH—CO—CH(NHBoc)(CH.sub.2).sub.4-NHBoc).sub.2, 4H), 1.836-1.480 (m, NH(—CH.sub.2—CH.sub.2—(CH.sub.2).sub.2—CH.sub.2—CH.sub.2—NH—CO—CH(NHBoc) (—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 16H), 1.431 (s, NH(—(CH.sub.2).sub.6—NH—CO—CH(NH—COO—C(CH.sub.3).sub.3) (CH.sub.2).sub.4—NH—COO—C(CH.sub.3).sub.3).sub.2, 36H), 1.382-1.347 (m, NH(—CH.sub.2—CH.sub.2—(CH.sub.2).sub.2—CH.sub.2—CH.sub.2—NH—CO—CH(NHBoc)(—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2-NHBoc).sub.2, 12H). HRMS (m/z): 872.6286 [(M+H).sup.+] (Observed), 872.6436 [(M+H).sup.+] (Calculated).

N,N-bis-[{6-(Boc-.SUP.L.Lys)amido} hexyl] naphthyl ethanamide (3b)

[0127] 41 mg (1.2 equivalents, 0.22 mmol) of Naphthyl acetic acid was dissolved in dry DCM (4 mL) at 0° C. In the reaction mixture, 96 μL (3 equivalents, 0.55 mmol) of N,N-diisopropylethylamine (DIPEA) was added followed by 83.5 mg (1.2 equivalents, 0.22 mmol) of N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU). Then DMF (2 mL) was added to the reaction mixture to dissolve the HBTU. After 15 min, 160 mg (1 equivalent, 0.18 mmol) of N.sup.1-(Boc-.sup.LLys)-N.sup.6-[{6-(boc-.sup.LLys) amino} hexyl] hexane-1,6-diamine, 3a dissolved in dry DCM (4 mL) was added dropwise to the reaction mixture. The reaction mixture was brought to room temperature and allowed to stir for 24 h. The solvent was evaporated, and the residue was diluted in ethyl acetate (50 mL). Then workup was carried out first with 1 N HCl (50 mL, 3 times) followed by saturated Na.sub.2CO.sub.3 solution (50 mL, 3 times). The crude product was extracted in ethyl acetate layer. Finally, purification was accomplished through column chromatography on silica gel (60-120 mesh) using different ratios of methanol and chloroform as an eluent to afford compound 3b with 47% yield. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ/ppm: 7.949-7.929 (d, ArH, 1H), 7.873-7.854 (d, ArH, 1H), 7.850-7.777 (d, ArH, 1H), 7.757-7.469 (m, ArH, 2H), 7.432-7.393 (t, ArH, 1H), 7.339-7.322 (d, ArH, 1H), 6.472-6.495 (d, R—CO—N(—(CH.sub.2).sub.6—NH—CO-.sup.LLys(Boc).sub.2).sub.2, 2H), 5.289-5.180 (d, R—CO—N(—(CH.sub.2).sub.6—NH—CO—CH(NHBoc)(CH.sub.2).sub.4-NHBoc).sub.2, 2H), 4.637 (br, R—CO—N(—(CH.sub.2).sub.6—NH—CO—CH(NHBoc)(CH.sub.2).sub.4-NHBoc).sub.2, 2H), 4.123 (s, Ar—CH.sub.2—CO—N(—(CH.sub.2).sub.6—NH—CO—CH(NHBoc)(CH.sub.2).sub.4-NHBoc).sub.2, 2H), 4.005 (br, R—CO—Ne(CH.sub.2).sub.6—NH—CO—CH(NHBoc)(CH.sub.2).sub.4-NHBoc).sub.2, 2H), 3.375-3.079 (m, R—CO—N(—CH.sub.2—(CH.sub.2).sub.4—CH.sub.2—NH—CO—CH(NHBoc)(CH.sub.2).sub.3—CH.sub.2-NHBoc).sub.2, 12H), 1.717-1.538 (m, —CH.sub.2—, 20H), 1.433 (s, R—CO—N((CH.sub.2).sub.6—NH—CO—CH(NH—COO—C(CH.sub.3).sub.3)(CH.sub.2).sub.4—NH—COO—C(CH.sub.3).sub.3).sub.2, 36H), 1.346-1.219 (m, —CH.sub.2—, 8H). HRMS (m/z): 1040.6816 [(M+H).sup.+] (Observed), 1040.7011 [(M+H).sup.+] (Calculated).

N,N-bis-[(6-(.SUP.L.Lys)amido) hexyl] naphthyl ethanamide tetrakistrifluoroacetate (Compound 13)

[0128] 90 mg (1 equivalent, 0.087 mmol) of 3b was dissolved in dry DCM. To the intensely stirred solution, 4 equivalents (excess amount) of trifluoroacetic acid (TFA) was added and allowed to stir at RT for 4-6 h. After that reaction, solvent and unused TFA were removed to get the pure product with 100% yield with CF.sub.3COO.sup.− counterions. The final compounds can be synthesized with other counterions such as Cl.sup.−, Br.sup.− etc. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ/ppm: 8.408-7.722 (m, ArH and R—CO—Ne(CH.sub.2).sub.6—NH—CO—CH(NH.sub.3.sup.+)(CH.sub.2).sub.4—NH.sub.3.sup.+).sub.2, 18H), 7.527-7.324 (m, ArH, 3H), 4.117 (s, ArCH.sub.2CO—N—(—(CH.sub.2).sub.6—NH—CO—CH(NH.sub.3.sup.+)(CH.sub.2).sub.4—NH.sub.3.sup.+).sub.2, 2H), 3.665 (br, R—CO—Ne(CH.sub.2).sub.6—NH—CO—CH(NH.sub.3.sup.+)(CH.sub.2).sub.4—NH.sub.3.sup.+).sub.2, 2H), 3.273-3.077 (m, R—CO—N((CH.sub.2).sub.5—CH.sub.2—NH—CO—CH(NH.sub.3.sup.+)(CH.sub.2).sub.3—CH.sub.2—NH.sub.3.sup.+).sub.2, 8H), 2.737 (br, R—CO—N(CH.sub.2—(CH.sub.2).sub.5—NH—CO—CH(NH.sub.3.sup.+)(CH.sub.2).sub.3—CH.sub.2—NH.sub.3.sup.+).sub.2, 4H), 1.689-1.652 (m, R—CO—N(—(CH.sub.2).sub.6—NH—CO—CH(NH.sub.3.sup.+)(CH.sub.2—(CH.sub.2).sub.3—NH.sub.3.sup.+).sub.2, 4H), 1.519-1.235 (m, R—CO—NeCH.sub.2—(CH.sub.2).sub.4—CH.sub.2—NH—CO—CH(NH.sub.3.sup.+)(CH.sub.2—(CH.sub.2).sub.2—CH.sub.2—NH.sub.3.sup.+).sub.2, 24H). HRMS (m/z): 640.4956 [(M+H).sup.+] (Observed), 640.4914 [(M+H).sup.+] (Calculated).

Example 10: Synthesis of N,N-bis-[(6-(.SUP.L.Lys)amido) hexyl] 3,3-diphenyl propanamide tetrakis trifluoroacetate (Compound 14)

N,N-bis-[{6-(Boc-.SUP.L.Lys)amido} hexyl] 3,3 diphenyl propanamide (3c)

[0129] 233 mg (1.2 equivalents, 1.0 mmol) of 3,3-Diphenyl propionic acid was dissolved in dry DCM (4 mL) at 0° C. In the reaction mixture, 448.9 μL (3 equivalents, 2.6 mmol) of N,N-diisopropylethylamine (DIPEA) was added followed by 390.63 mg (1.2 equivalents, 1.0 mmol) of N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU). Then DMF (2 mL) was added to the reaction mixture to dissolve the HBTU. After 15 min, 750 mg (1 equivalent, 0.859) of N.sup.1-(Boc-.sup.LLys)-N.sup.6-[{6-(boc-.sup.LLys) amino} hexyl] hexane-1,6-diamine, 3a dissolved in dry DCM (4 mL) was added dropwise to the reaction mixture. The reaction mixture was brought to room temperature and allowed to stir for 24 h. The solvent was evaporated, and the residue was diluted in ethyl acetate (50 mL). Then workup was carried out first with 1 N HCl (50 mL, 3 times) followed by saturated Na.sub.2CO.sub.3 solution (50 mL, 3 times). The crude product was extracted in ethyl acetate layer. Finally, purification was accomplished through column chromatography on silica gel (60-120 mesh) using different ratios of methanol and chloroform as an eluent to afford compound 3c with 59% yield. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ/ppm: 7.275 (s, ArH, 2H), 7.240-7.147 (m, ArH, 8H), 6.463-6.311 (d, R—CO—N(—(CH.sub.2).sub.6—NH—CO—CH(NHBoc)(CH.sub.2).sub.4-NHBoc).sub.2, 2H), 5.310-5.159 (d, R—CO—N(—(CH.sub.2).sub.6—NH—CO—CH(NHBoc)(CH.sub.2).sub.4-NHBoc).sub.2, 2H), 4.736-4.699 (t, Ar—CH—CH.sub.2—N(—(CH.sub.2).sub.6—NH—CO—CH(NHBoc)(CH.sub.2).sub.4-NHBoc).sub.2, 1H), 4.640 (br, R—CO—N(—(CH.sub.2).sub.6—NH—CO—CH(NHBoc)(CH.sub.2).sub.4-NHBoc).sub.2, 2H), 4.108-3.995 (br, R—CO—N(—(CH.sub.2).sub.6—NH—CO—CH(NHBoc)(CH.sub.2).sub.4-NHBoc).sub.2, 2H), 3.232-3.088 (m, R—CO—N(—CH.sub.2—(CH.sub.2).sub.4—CH.sub.2—NH—CO—CH(NHBoc)(CH.sub.2).sub.3—CH.sub.2-NHBoc).sub.2, 12H), 3.013-2.994 (d, Ar—CH—CH.sub.2—N(—(CH.sub.2).sub.6—NH—CO—CH(NHBoc)(CH.sub.2).sub.4-NHBoc).sub.2, 2H), 1.823-1.561 (m, —CH.sub.2—, 12H), 1.433 (s, R—CO—N((CH.sub.2).sub.6—NH—CO—CH(NH—COO—C(CH.sub.3).sub.3)(CH.sub.2).sub.4—NH—COO—C(CH.sub.3).sub.3).sub.2, 36H), 1.392-1.097 (m, —CH.sub.2—, 16H). HRMS (m/z): 1080.7631 [(M+H).sup.+] (Observed), 1080.7324 [(M+H).sup.+] (Calculated).

[0130] 550 mg (1 equivalent, 0.51 mmol) of 3c was dissolved in dry DCM. To the intensely stirred solution, 4 equivalents (excess amount) of trifluoroacetic acid (TFA) was added and allowed to stir at RT for 4-6 h. After that reaction, solvent and unused TFA were removed to get the pure product with 100% yield with CF.sub.3COO.sup.− counterions. The final compounds can be synthesized with other counterions such as Cl.sup.−, Br.sup.− etc. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ/ppm: 8.459- 7.839 (m, R—CO—N(—(CH.sub.2).sub.6—NH—CO—CH(NH.sub.3+)(CH.sub.2).sub.4—NH.sub.3+).sub.2, 12H), 7.292-7.128 (m, ArH, 10H), 5.155-5.133 (br, R—CO—Ne(CH.sub.2).sub.6—NH—CO—CH(NH.sub.3+)(CH.sub.2).sub.4—NH.sub.3+).sub.2, 2H), 4.534-4.498 (t, ArCHCH.sub.2—CO—Ne(CH.sub.2).sub.6—NH—CO—CH(NH.sub.3+)(CH.sub.2).sub.4—NH.sub.3+).sub.2, 1H), 3.698-3.685 (d, R—CO—Ne(CH.sub.2).sub.6—NH—CO—CH(NH.sub.3+)(CH.sub.2).sub.4—NH.sub.3+).sub.2, 2H), 3.220-2.687 (m, ArCHCH.sub.2—CO—N(—CH.sub.2—(CH.sub.2).sub.4—CH.sub.2—NH—CO—CH(NH.sub.3+)(CH.sub.2).sub.3—CH.sub.2—NH.sub.3+).sub.2, 14H), 1.696-1.042 (m, R—CO—N(—CH.sub.2—(CH.sub.2).sub.4—CH.sub.2—NH—CO—CH(NH.sub.3.sup.+)((CH.sub.2).sub.3—CH.sub.2—NH.sub.3.sup.+).sub.2, 28H). HRMS (m/z): 680.5191 [(M+H).sup.+] (Observed), 680.5227 [(M+H).sup.+] (Calculated).

Example 11: Synthesis of N-(adamantan-2-yl)-2-[N′,N′-{bis-(6-.SUP.L.Lys) amido)hexyl} amino] ethanamide pentakistrifluoroacetate (Compound 15)

N-(adamantan-2-yl)-2-[N′,N′-{bis-(6-(Boc-.SUP.L.Lys)amido)hexyl} amino] ethanamide (4a)

[0131] 300 mg of N.sup.1-(Boc-.sup.LLys)-N.sup.6-[{6-(boc-.sup.LLys)amido} hexyl] hexane-1,6-diamine, 3a (1 equivalent, 0.344 mmol) in DMF. 71.29 mg of K.sub.2CO.sub.3 (1.5 equivalents, 0.52 mmol) was added to the reaction mixture. Then, 93.60 mg of N-(adamantan-2-yl)-2-bromoethanamide (1 equivalent, 0.34 mmol), dissolved in DMF was added to the reaction mixture. The reaction was stopped after 24 hours. The reaction mixture was then dissolved in ethyl acetate and work-up was performed with ice-cold water (3 times) to remove the DMF. The ethyl acetate layer was collected and the solvent evaporated to get the pure product with 52% yield. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ/ppm: 6.517 (br, Ad-NH—CO—CH.sub.2—N(—(CH.sub.2).sub.6—NH—CO—CH(NHBoc)(CH.sub.2).sub.4-NHBoc).sub.2, 2H), 5.2913 (br, Ad-NH—CO—CH.sub.2—N(—(CH.sub.2).sub.6—NH—CO—CH(NHBoc)(CH.sub.2).sub.4-NHBoc).sub.2, 2H), 4.699 (br, Ad-NH—CO—CH.sub.2—N(—(CH.sub.2).sub.6—NH—CO—CH(NHBoc)(CH.sub.2).sub.4-NHBoc).sub.2, 2H), 4.144-4.033 (m, AdH and Ad-NH—CO—CH.sub.2—N(—(CH.sub.2).sub.6—NH—CO—CH(NHBoc)(CH.sub.2).sub.4-NHBoc).sub.2, 3H), 3.227-3.090 (br, Ad-NH—CO—CH.sub.2—N(—(CH.sub.2).sub.5—CH.sub.2—NH—CO—CH(NHBoc)(CH.sub.2).sub.3—CH.sub.2-NHBoc).sub.2, 10H), 2.039-1513 (m, AdH, —CH.sub.2-.sub.(Boc-Lys)amidohexyl and —CH.sub.2-.sub.(Lys), 34H), 1.430 (s, Ad-NH—CO—CH.sub.2—N(—(CH.sub.2).sub.5—CH.sub.2—NH—CO—CH(NH—COO—C(CH.sub.3).sub.3)(CH.sub.2).sub.3—CH.sub.2—NH—COO—C(CH.sub.3).sub.3).sub.2, 36H), 1.357-1.236 (m, AdH, —CH.sub.2-.sub.(Boc-Lys)amidohexyl and —CH.sub.2-.sub.(Lys), 12H). HRMS (m/z): 1063.7691 [(M+H).sup.+] (Observed), 1063.7746 [(M+H).sup.+] (Calculated).

[0132] 190 mg (1 equivalent, 0.18 mmol) of 4a was dissolved in dry DCM. To the intensely stirred solution, 4 equivalents (excess amount) of trifluoroacetic acid (TFA) was added and allowed to stir at RT for 4-6 h. After that reaction, solvent and unused TFA were removed to get the pure product with 100% yield with CF.sub.3COO.sup.− counterions. The final compounds can be synthesized with other counterions such as Cl.sup.−, Br.sup.− etc. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ/ppm: 9.509 (br, Ad-NH—CO—CH.sub.2—N(—(CH.sub.2).sub.6—NH—CO—CH(NH.sub.3.sup.+)(CH.sub.2).sub.4—NH.sub.3.sup.+).sub.2, 1H), 8.480-8.457 (t, Ad-NH—CO—CH.sub.2—N(—(CH.sub.2).sub.6—NH—CO—CH(NH.sub.3.sup.+)(CH.sub.2).sub.4—NH.sub.3.sup.+).sub.2, 2H), 8.149 (br, —NH.sub.3.sup.+, 6H), 7.816 (br, —NH.sub.3.sup.+, 6H), 3.975-3.899 (br, Ad-NH—CO—CH.sub.2—N(—(CH.sub.2).sub.6—NH—CO—CH(NH.sub.3+)(CH.sub.2).sub.4—NH.sub.3+).sub.2, 2H), 3.820 (s, Ad-NH—CO—CH.sub.2—N(—(CH.sub.2).sub.6—NH—CO—CH(NH.sub.3+)(CH.sub.2).sub.4—NH.sub.3+).sub.2, 2H), 3.696-3.685 (br, AdH, 1H), 3.096-3.086 (br, Ad-NH—CO—CH.sub.2—N(—(CH.sub.2).sub.5—CH.sub.2—NH—CO—CH(NH.sub.3+)(CH.sub.2).sub.3—CH.sub.2—NH.sub.3+).sub.2, 8H), 2.751 (br, Ad-NH—CO—CH.sub.2—N(—CH.sub.2—(CH.sub.2).sub.5—NH—CO—CH(NH.sub.3+)(CH.sub.2).sub.3—CH.sub.2—NH.sub.3+).sub.2, 4H), 1.968-1.235 (m, AdH, —CH.sub.2-.sub.(Lys amidohexyl) and —CH.sub.2-.sub.(Lys), 42H). HRMS (m/z): 663.5619 [(M+H).sup.+] (Observed), 663.5649 [(M+H).sup.+] (Calculated).

##STR00019## ##STR00020##

Example 12: In-vitro Combination Efficacy

[0133] All synthesized compounds were assayed for their antibacterial activity in combination with antibiotics in a modified chequerboard micro-dilution broth format. Stock solutions were made by serially diluting the compounds using autoclaved millipore water. The bacterial freeze dried stock samples were stored at −80° C. About 3 μL of these stocks were added to about 3 mL of the respective broth and the culture was grown for about 6 h at about 37° C. with prior to the experiments. This 6 h grown culture gives about 10.sup.8 cfu/mL in case of A. baumannii R674, P. aeruginosa R590, E. coli R3336 and K. pneumoniae R3934 which were determined by spread plating method. This 6 h grown culture was diluted to give effective cell concentration of 10.sup.5 cfu/mL, and then used for the chequerboard assay. Adjuvants and antibiotics were serially diluted in two-fold, in sterile millipore water. 25 μL of these serial dilutions of the antibiotics and 25 μL of compounds were added to the wells of 96 well plate followed by the addition of about 150 μL of bacterial solution (˜10.sup.5 cfu/mL). The plates were then incubated at about 37° C., 150 rpm in the incubator and O.D at 600 nm was recorded at 24 h using TECAN (Infinite series, M200 pro) Plate Reader. The wells with similar OD as the media control contained the required concentration of the antibiotic and adjuvant for antibacterial efficacy. The potentiation ability of the adjuvants was determined by calculating the potentiation factor and the Fractional Inhibitory concentration (FIC) index. Fractional Inhibitory Concentration (FIC) is expressed as, FIC=[X]/MIC.sub.X, where [X] is the lowest inhibitory concentration of antibiotic in the presence of the adjuvant. Whereas FIC index is expressed as, FICI=FIC.sub.antibiotic+FIC.sub.adjuvant. The values of FIC index give an insight about the nature of the combination. Potentiation factor which means fold-reduction in the MIC of the antibiotic, when used in combination with the adjuvant was also determined. Potentiation factor=[Minimum inhibitory concentration (MIC) of antibiotic in absence of adjuvant]/[MIC of antibiotic in presence of adjuvant]. The adjuvants exhibited decent to good potentiation of the antibiotics with potentiation factor as high as >1024. The combination efficacies of adjuvants with various antibiotics are furnished in Table 1. It should be noted that various other resistant strains of bacteria (Gram-positive and Gram-negative) can be tested with a number of other antibiotics to check the potentiation capacity of the adjuvants.

TABLE-US-00001 TABLE 1 Combination efficacies of adjuvants with antibiotics against MDR strains of Gram-negative bacteria MIC of antibiotic Bacterial in presence of Potentiation Adjuvant strain Antibiotic adjuvant (μg mL.sup.−1) factor FICI Compound 1 A. baumannii Rifampicin 32 2 <0.75 R674 Tetracycline 64 2 <0.5 Compound 2 A. baumannii Rifampicin 8 8 <0.375 R674 Tetracycline 64 2 <0.625 P. aeruginosa Rifampicin 16 8 <0.375 R590 Tetracycline 64 4 <0.5 Compound 3 A. baumannii Rifampicin 16 4 <0.5 R674 Tetracycline >64 <2 ND P. aeruginosa Rifampicin 32 4 <0.5 R590 Tetracycline >64 <4 ND Compound 4 A. baumannii Rifampicin 1 64 <0.26 R674 Tetracycline 32 4 <0.5 P. aeruginosa Rifampicin 4 32 <0.28 R590 Tetracycline 64 4 <0.5 Compound 5 A. baumannii Rifampicin 8 8 <0.375 R674 Tetracycline >64 <2 ND P. aeruginosa Rifampicin 8 16 <0.3125 R590 Tetracycline >64 <4 ND Compound 6 A. baumannii Rifampicin <0.25 >256 <0.06 R674 Tetracycline >64 <2 ND P. aeruginosa Rifampicin <0.25 >512 <0.06 R590 Tetracycline >64 <4 ND Compound 7 A. baumannii Rifampicin 8 8 <0.25 R674 Tetracycline 32 4 <0.5 P. aeruginosa Rifampicin 4 32 <0.28 R590 Tetracycline 64 4 <0.5 Compound 8 A. baumannii Rifampicin 4 16 <0.19 R674 Tetracycline >64 <2 ND P. aeruginosa Rifampicn 2 64 <0.14 R590 Tetracycline 64 4 <0.375 Compound 9 A. baumannii Rifampicin 1 64 <0.14 R674 Tetracycline 16 8 <0.25 P. aeruginosa Rifampicin 0.5 256 <0.13 R590 Tetracycline 16 16 <0.19 Compound 10 A. baumannii Rifampicin 1 64 <0.14 R674 Tetracycline 16 8 <0.375 P. aeruginosa Rifampicin 1 128 <0.133 R590 Tetracycline 32 8 <0.375 Compound 11 A. baumannii Rifampicin 0.5 128 0.1328 R674 Tetracycline 64 2 1 P. aeruginosa Rifampicin 1 128 0.07 R590 Tetracycline 32 8 0.375 Compound 12 A. baumannii Rifampicin <0.125 >512 <0.252 R674 Tetracycline 16 8 0.625 P. aeruginosa Rifampicin 0.125 1024 0.251 R590 Tetracycline 64 4 0.75 Compound 13 A. baumannii Rifampicin 1 64 0.023 R674 Tetracycline 16 8 0.375 Minocycline 0.5 16 0.1875 Fusidic acid <0.5 >128 <0.023 Linezolid 32 8 0.1875 Vancomycin 32 2 0.5625 Ciprofloxacin 64 4 0.3125 Erythromycin 16 32 0.156 Ampicillin No potentiation - - Streptomycin No potentiation - - P. aeruginosa Rifampicin <0.5 >256 <0.019 R590 Tetracycline 4 64 0.266 Minocycline 0.5 16 0.1875 Fusidic acid 2 32 0.094 Linezolid 32 8 0.1875 Chloramphenicol 32 4 0.375 Colistin No potentiation - - Daptomycin No potentiation - - E. coli Rifampicin 8 64 <0.031 R3336 Minocycline 0.5 64 <0.031 Fusidic acid 32 >16 <0.125 Linezolid No potentiation - - K. pneumoniae Rifampicin 1 512 <0.064 R3934 Minocycline 0.5 128 <0.07 Fusidic acid 4 128 <0.133 Linezolid 64 >8 <0.25 Compound 14 A. baumannii Rifampicin <0.125 >512 <0.017 R674 Tetracycline 16 8 <0.25 Minocycline 1 8 <0.129 Fusidic acid <0.5 >128 <0.012 Linezolid 32 8 <0.156 Vancomycin 16 4 <0.3125 Ciprofloxacin 64 4 <0.281 Erythromycin 16 32 <0.0625 Ampicillin No potentiation — — Streptomycin No potentiation — — Rifampicin <0.125 >1024 <0.016 P. aeruginosa Tetracycline 16 16 <0.1875 R590 Minocycline 1 8 <0.156 Fusidic acid <0.25 >256 <0.012 Linezolid 32 8 <0.156 Chloramphenicol 32 4 <0.3125 Colistin 0.25 4 <0.266 Daptomycin No potentiation — — E. coli Rifampicin 4 128 <0.047 R3336 Minocycline <0.25 >128 <0.0156 Fusidic acid 16 >32 <0.0625 Linezolid No potentiation — — K. pneumoniae Rifampicin 0.5 1024 <0.126 R3934 Minocycline 0.5 128 <0.1328 Fusidic acid 2 256 <0.1289 Linezolid 64 >8 <0.1328 Compound 15 A. baumannii Rifampicin 0.25 256 0.1289 R674 Tetracycline 2 64 0.5156 Minocycline 0.5 16 0.5625 Fusidic acid <0.5 >128 <0.07 Linezolid 32 8 1.125 Vancomycin 32 2 0.5625 Ciprofloxacin 64 4 1.25 Erythromycin 32 16 0.1875 Ampicillin No potentiation — — Streptomycin No potentiation — — P. aeruginosa Rifampicin <0.125 >1024 <0.126 R590 Tetracycline 2 128 0.5078 Minocycline 2 4 0.5 Fusidic acid <0.25 >256 <0.1289 Linezolid 64 4 0.2812 Chloramphenicol 32 4 1.25 Colistin 0.25 4 0.3125 Daptomycin No potentiation — — E. coli Rifampicin 16 32 <0.0469 R3336 Minocycline 0.5 64 <0.0469 Fusidic acid 32 >16 <0.1875 Linezolid No potentiation — — K. pneumoniae Rifampicin 2 256 <0.1289 R3934 Minocycline 0.5 128 <0.07 Fusidic acid 8 64 <0.0781 Linezolid No potentiation — —

TABLE-US-00002 TABLE 2 Antibacterial efficacies and toxicity of Compounds 1 to 15 MIC against clinical isolates of bacteria (μg/mL) or HC.sub.50 (μg/mL) A. baumannii P. aeruginosa E. coli K. pneumoniae Adjuvants R674 R590 R3336 R3934 HC.sub.50 Compound 1 >512 ND ND ND >1024 Compound 2 >512 >512 ND ND >1024 Compound 3 >512 >512 ND ND >1024 Compound 4 >512 >512 ND ND >1024 Compound 5 >512 >512 ND ND >1024 Compound 6 512 512 ND ND >1024 Compound 7 >512 >512 ND ND >1024 Compound 8 >512 >512 ND ND >1024 Compound 9 >512 >512 ND ND >1024 Compound 10 >512 >512 ND ND >1024 Compound 11 128 256 ND ND >1024 Compound 12 64 64 ND ND >1024 Compound 13 512 512 >512 >512 >1024 Compound 14 >512 >512 >512 >512 >1024 Compound 15 128 64 >512 >512 >1024

Example 13: Determination of Haemolytic Activity

[0134] Erythrocytes were isolated from freshly drawn, heparanized human blood and re-suspended to 5 vol % in PBS (pH 7.4). In a 96-well microtiter plate, 150 μl of erythrocyte suspension was added to 50 μl of serially diluted compound. Two controls were made, one without compound and other with 50 μl of 1 vol % solution of Triton X-100. The plate was incubated for 1 h at 37° C. The plate was then centrifuged at 3,500 rpm for 5 min, 100 μl of the supernatant from each well was transferred to a fresh 96-well microtiter plate, and A.sub.540 was measured. Percentage of hemolysis was determined as (A−A.sub.0)/(A.sub.total−A.sub.0)×100, where A is the absorbance of the test well, A.sub.0 the absorbance of the negative controls (without compound), and A.sub.total the absorbance of 100% hemolysis wells (with Triton X-100), all at 540 nm.

[0135] Toxicity studies of the compounds were done on freshly drawn human RBCs. Toxicity of the compounds were defined by their HC.sub.50 values (Table 2), i.e. the concentration of compound at which 50% of the blood cells are lysed. All the compounds exhibited high HC.sub.50 values and were highly non-toxic against human red blood cells.

Example 14: Determination of Bactericidal Time-Kill Kinetics

[0136] Briefly, A. baumannii R674 and P. aeruginosa R590 were grown in nutrient broth at 37° C. for 6 h. Combinations of Compound 13 and rifampicin (4 μg/mL+2 μg/mL and 8 μg/mL+2 μg/mL) and rifampicin alone (32 μg/mL) were inoculated with aliquots of A. baumannii R674 suspended in fresh media at ˜1.8×10.sup.5 CFU/mL. Similarly, combination of Compound 15 and fusidic acid (8 μg/mL+1 μg/mL), Compound 15 (128 μg/mL) and fusidic acid (16 μg/mL) were inoculated with aliquots of P. aeruginosa R590 suspended in fresh media at ˜1.8×10.sup.5 CFU/mL. After specified time intervals (0, 1, 2, 4, 6 and 12 h), 20 μL aliquots were serially diluted 10-fold in 0.9% saline, plated on sterile MacConkey agar plates and incubated at 37° C. overnight. The viable colonies were counted the next day and represented as logio (CFU/mL) (FIG. 1). Combination of rifampicin and Compound 13 could completely kill the bacteria in 2 h and combination of fusidic acid and Compound 14 could kill bacteria in 12 h.