Preparation of sulfonamide-containing antimicrobials and substrate treating compositions of sulfonamide-containing antimicrobials
10939684 · 2021-03-09
Assignee
Inventors
- DANIEL FOUCHER (TORONTO, CA)
- Gideon Wolfaardt (Mississauga, CA)
- ALEXANDER GABRIEL CASCHERA (AMARANTH, CA)
- Aman Ullah Khan (Toronto, CA)
- Kamlesh Mistry (Etobicoke, CA)
- Evan Lindsay Gilmore Ronan (Toronto, CA)
- Lukasz Porosa (Scarborough, CA)
Cpc classification
C07C307/06
CHEMISTRY; METALLURGY
C07C311/05
CHEMISTRY; METALLURGY
C07F9/4006
CHEMISTRY; METALLURGY
A01N55/00
HUMAN NECESSITIES
C07C311/18
CHEMISTRY; METALLURGY
International classification
A01N55/00
HUMAN NECESSITIES
C07F7/18
CHEMISTRY; METALLURGY
C07C311/05
CHEMISTRY; METALLURGY
C07C311/18
CHEMISTRY; METALLURGY
C07C307/06
CHEMISTRY; METALLURGY
Abstract
A quaternary ammonium sulfonamide compound of formula (I): wherein R=(II), C.sub.1-C.sub.3 linear or branched alkyl, R.sub.1 and R.sub.2 are the same or different and selected from C.sub.1 to C.sub.18 linear or branched alkyl, R.sub.3 and R.sub.4 are the same or different and selected from C.sub.1 to C.sub.4 linear or branched alkyl, CF.sub.3, OR.sub.5 where R.sub.5 is C.sub.1 to C.sub.8 linear or branched alkyl or polyethylene oxide, l is 1, 2, 3, 4, 5, 6, 7 or 8, m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18, wherein the aryl groups of R may be substituted or unsubstituted, X=halogen, and Y=(III) wherein R.sub.6, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are the same or different and selected from C.sub.1 to C.sub.6 linear or branched alkyl and the benzophenone is selected from the group consisting of substituted benzophenone and unsubstituted benzophenone, process for preparing the compound and antimicrobial surface coating compositions of the compound. ##STR00001##
Claims
1. A quaternary ammonium sulfonamide compound of formula (I): ##STR00078## wherein ##STR00079## C.sub.1-C.sub.3 linear or branched alkyl, R.sub.1 and R.sub.2 are the same or different and selected from C.sub.1 to C.sub.18 linear or branched alkyl, R.sub.3 and R.sub.4 are the same or different and selected from C.sub.1 to C.sub.4 linear or branched alkyl, CF.sub.3, OR.sub.5 where R.sub.5 is C.sub.1 to C.sub.8 linear or branched alkyl or polyethylene oxide, 1 is 1, 2, 3, 4, 5, 6, 7 or 8, m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18, X=halogen, and ##STR00080## wherein R.sub.6, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are the same or different and selected from C.sub.1 to C.sub.6 linear or branched alkyl, and wherein when ##STR00081## Y may be substituted or unsubstituted, and the aryl group of R is unsubstituted.
2. The compound of claim 1 wherein the X is Br.
3. The compound of claim 1 wherein the X is Cl.
4. The compound of claim 1 wherein l is 1, m is 2 and n is 0.
5. The compound of claim 1 wherein R.sub.1 and R.sub.2 are the same and methyl.
6. The compound of claim 1 wherein ##STR00082##
7. The compound of claim 1 wherein ##STR00083##
8. The compound of any one of claims 1 to 5 wherein ##STR00084##
9. The use of the compound of claim 1 for reducing bacterial growth on a solid/air interface comprising introducing said compound to said solid/air interface.
10. A process for preparing a quaternary ammonium sulfonamide of formula (I): ##STR00085## comprising reacting a compound of formula (II) ##STR00086## with an alkyl halide of formula (III) ##STR00087## wherein ##STR00088## C.sub.1-C.sub.3 linear or branched alkyl, R.sub.1 and R.sub.2 are the same or different and selected from C.sub.1 to C.sub.18 linear or branched alkyl, R.sub.3 and R.sub.4 are the same or different and selected from C.sub.1 to C.sub.4 linear or branched alkyl, CF.sub.3, OR.sub.5 where R.sub.5 is C.sub.1 to C.sub.8 linear or branched alkyl or polyethylene oxide, 1 is 1, 2, 3, 4, 5, 6, 7 or 8, m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18, X=halogen, and ##STR00089## wherein R.sub.6, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are the same or different and selected from C.sub.1 to C.sub.6 linear or branched alkyl.
11. An antimicrobial substrate treating composition comprising a compound of formula (I) ##STR00090## wherein ##STR00091## C.sub.1-C.sub.3 linear or branched alkyl, R.sub.1 and R.sub.2 are the same or different and selected from C.sub.1 to C.sub.18 linear or branched alkyl, R.sub.3 and R.sub.4 are the same or different and selected from C.sub.1 to C.sub.4 linear or branched alkyl, CF.sub.3, OR.sub.5 where R.sub.5 is C.sub.1 to C.sub.8 linear or branched alkyl or polyethylene oxide, 1 is 1, 2, 3, 4, 5, 6, 7 or 8, m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18, X=halogen, and ##STR00092## wherein R.sub.6, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are the same or different and selected from C.sub.1 to C.sub.6 linear or branched alkyl, and an environmentally friendly carrier selected from the group consisting of water and at least one alkanol.
12. The composition of claim 11 wherein said environmentally friendly carrier is a mixture of water and at least one alkanol.
13. The composition of claim 12 wherein said water is distilled water and said at least one alkanol is selected from the group consisting of methanol, ethanol, isopropanol and combinations thereof.
14. A method of reducing growth of at least one microbe on a substrate comprising treating said substrate with an antimicrobial composition of claim 11.
15. A method of reducing growth of at least one microbe on a substrate comprising treating said substrate with an antimicrobial composition comprising 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(2,4,6-trimethylphenylsulfonamido)propyl)propan-1- aminium bromide.
16. A method of reducing growth of at least one microbe on a substrate comprising treating said substrate with an antimicrobial composition comprising 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(4-methylphenylsulfonamido)propyl)propan- 1-aminium bromide.
17. A method of reducing growth of at least one microbe on a substrate comprising treating said substrate with an antimicrobial composition comprising 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(phenylsulfonamido)propyl)propan-1-aminium bromide.
18. A method of reducing growth of at least one microbe on a substrate comprising treating said substrate with an antimicrobial composition comprising 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(naphthalene-1- sulfonamido)propyl)propan-1-aminium bromide.
19. A method of reducing growth of at least one microbe on a substrate comprising treating said substrate with an antimicrobial composition comprising N,N-dimethyl-3-(trimethoxysilyl)-N-(3-(2,4,6-trimethylphenylsulfonamido)propyl)propan-1-aminium chloride.
20. A method of reducing growth of at least one microbe on a substrate comprising treating said substrate with an antimicrobial composition comprising N,N-dimethyl-3-(4-methylphenylsulfonamido)-N-(3-(trimethoxysilyl)propyl)propan-1-aminium chloride.
21. A method of reducing growth of at least one microbe on a substrate comprising treating said substrate with an antimicrobial composition comprising N,N-dimethyl-3-(phenylsulfonamido)-N-(3-(trimethoxy silyl)propyl)propan-1-aminium chloride.
22. A method of reducing growth of at least one microbe on a substrate comprising treating said substrate with an antimicrobial composition comprising N,N-dimethyl-3-(naphthalene-1-sulfonamido)-N-(3-(trimethoxysilyl)propyl)propan-1-aminium chloride.
23. The method of any one of claims 14 to 22 wherein the at least one microbe is selected from the group consisting of Listeria monocytogenes, Arthrobacter, Staphylococcus aureus, Pseudomonas aeruginosa Escherichia coli and combinations thereof.
24. A process for treating a substrate with an antimicrobial, said process comprising the steps of: i) contacting the substrate with an antimicrobial composition comprising at least one compound of formula (I) ##STR00093## wherein ##STR00094## C.sub.1-C.sub.3 linear or branched alkyl, R.sub.1 and R.sub.2 are the same or different and selected from C.sub.1 to C.sub.18 linear or branched alkyl, R.sub.3 and R.sub.4 are the same or different and selected from C.sub.1 to C.sub.4 linear or branched alkyl, CF.sub.3, OR.sub.5 where R.sub.5 is C.sub.1 to C.sub.8 linear or branched alkyl or polyethylene oxide, 1 is 1, 2, 3, 4, 5, 6, 7 or 8, m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18, X=halogen, and ##STR00095## wherein R.sub.6, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are the same or different and selected from C.sub.1 to C.sub.6 linear or branched alkyl, and an environmentally friendly carrier, (ii) drying the treated substrate passively or actively, and (iii) optionally irradiating the treated substrate wherein said environmentally friendly carrier is selected from the group consisting of water and at least one alkanol.
25. A process for treating a substrate with an antimicrobial, said process comprising the steps of: (i) contacting the substrate with an antimicrobial composition comprising a compound of formula (I) ##STR00096## wherein ##STR00097## C.sub.1-C.sub.3 linear or branched alkyl, R.sub.1 and R.sub.2 are the same or different and selected from C.sub.1 to C.sub.18 linear or branched alkyl, R.sub.3 and R.sub.4 are the same or different and selected from C.sub.1 to C.sub.4 linear or branched alkyl, CF.sub.3, OR.sub.5 where R.sub.5 is C.sub.1 to C.sub.8 linear or branched alkyl or polyethylene oxide, l is 1, 2, 3, 4, 5, 6, 7 or 8, m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18, X=halogen, and ##STR00098## and an environmentally friendly carrier, (ii) drying the coated substrate passively or actively, and (iii) irradiating the coated substrate, wherein said environmentally friendly carrier is selected from the group consisting of water and at least one alkanol.
26. The process of claim 24 or 25, wherein said environmentally friendly carrier is a mixture of water and at least one alkanol.
27. The process of claim 26, wherein said water is distilled water and said at least one alkanol is selected from the group consisting of methanol, ethanol, isopropanol and combinations thereof.
28. A process for treating a substrate with an antimicrobial, said process comprising the steps of: i) contacting the substrate with an antimicrobial composition comprising a compound of formula (I) ##STR00099## wherein ##STR00100## C.sub.1-C.sub.3 linear or branched alkyl, R.sub.1 and R.sub.2 are the same or different and selected from C.sub.1 to C.sub.18 linear or branched alkyl, R.sub.3 and R.sub.4 are the same or different and selected from C.sub.1 to C.sub.4 linear or branched alkyl, CF.sub.3, OR.sub.5 where R.sub.5 is C.sub.1 to C.sub.8 linear or branched alkyl or polyethylene oxide, 1 is 1, 2, 3, 4, 5, 6, 7 or 8, m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18, X=halogen, and ##STR00101## ii) drying the substrate; and iii) washing the treated substrate.
29. The process of claim 28, further comprising stirring and heating the substrate.
30. A process for treating a substrate with an antimicrobial coating, said process comprising the steps of: i) contacting a heated substrate with a composition comprising a compound of formula (I) ##STR00102## wherein ##STR00103## C.sub.1-C.sub.3 linear or branched alkyl, R.sub.1 and R.sub.2 are the same or different and selected from C.sub.1 to C.sub.18 linear or branched alkyl, R.sub.3 and R.sub.4 are the same or different and selected from C.sub.1 to C.sub.4 linear or branched alkyl, CF.sub.3, OR.sub.5 where R.sub.5 is C.sub.1 to C.sub.8 linear or branched alkyl or polyethylene oxide, 1 is 1, 2, 3, 4, 5, 6, 7 or 8, m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18, X=halogen, and ##STR00104## and ii) drying the substrate.
31. Use of an antimicrobial composition comprising a compound of formula (I): ##STR00105## wherein ##STR00106## C.sub.1-C.sub.3 linear or branched alkyl, R.sub.1 and R.sub.2 are the same or different and selected from C.sub.1 to C.sub.18 linear or branched alkyl, R.sub.3 and R.sub.4 are the same or different and selected from C.sub.1 to C.sub.4 linear or branched alkyl, CF.sub.3, OR.sub.5 where R.sub.5 is C.sub.1 to C.sub.8 linear or branched alkyl or polyethylene oxide, 1 is 1, 2, 3, 4, 5, 6, 7 or 8, m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18, wherein the aryl groups of R may be substituted or unsubstituted, X=halogen, and ##STR00107## to protect a substrate from a bio-fouling comprising treating said substrate with said antimicrobial composition.
Description
BRIEF DESCRIPTION OF THE FIGURES
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)
(10)
DETAILED DESCRIPTION
(11) A series of alkyl and aryl, UV and heat curable quaternary ammonium sulfonamide antimicrobials may be prepared by both conventional and microwave synthesis. Common to all the UV curable compounds is the sulfonamide linkage, the quaternary ammonium site and the benzophenone linker moiety. Additionally, compounds containing a silane linker, preferably for attaching to porous substrates and the like, or a phosphonate linker, preferably for attaching to metal substrates and the like, may be prepared using similar techniques.
(12) These materials may be designed with dual functionality: 1) a functional anchoring group that grafts selectively to porous or non-porous substrates and 2) a quaternary ammonium charge and sulfonamide linkage for attracting bacteria, preferably harmful bacteria and kill them, for example, by mechanical means operating at the solid/air interface.
(13) The term quaternary ammonium sulfonamide refers to quaternary ammonium compounds that have been substituted with a sulfonamide group RS(O).sub.2 wherein
(14) ##STR00041##
C.sub.1-C.sub.3 linear or branched alkyl, wherein the aryl rings of R may be substituted or unsubstituted, wherein R.sub.3 and R.sub.4 are the same or different and selected from C.sub.1 to C.sub.4 linear or branched alkyl, CF.sub.3, OR.sub.5 where R.sub.5 is C.sub.1 to C.sub.8 linear or branched alkyl or polyethylene oxide, and the sulfonamide moiety is linked to the quaternary ammonium nitrogen centre by a carbon atom chain, preferably a saturated chain, more preferably a three carbon chain, most preferably a saturated three carbon chain.
(15) The term polar, aprotic solvent means a solvent that has a dipole moment but does not have an acidic hydrogen. Non-limiting examples include acetonitrile, dimethylformamide, dimethylsulfoxide and dichloromethane.
(16) The quaternary ammonium sulfonamide compounds presently disclosed utilize a covalently bound linkage to metal (phosphonate linkage), plastics (UV curable benzophenone linkage) or textiles and glass (silane linkage) and sulfonamide functionality along with a quaternary ammonium salt that renders these materials antimicrobial. Antimicrobial coating compositions of these compounds may be formulated as an alcohol-based, water/alcohol or water based formulations. The use of such solvent systems make these compositions non-toxic, low cost, with minimum impact to the environment and may be applied by electrospray or traditional painting techniques.
(17) These formulations require no photoinitiator in order to graft the quaternary ammonium sulfonamide compounds to substrates. These antimicrobial coating compositions may be sprayed, aerosolized or painted on to non-porous and porous surfaces, allowed to dry and are then actively grafted or cured (covalently attached) to these substrates via low heat, air or UV irradiation to form self-assembled monolayers. These cured antimicrobial coatings form durable bonds to these hard-to-stick-to-surfaces and as a result may inhibit biofilm formation at solid/air interface. The solid/air interface is where many biofilms, and the harmful bacteria that can reside in them, exist. These formulations are non-leaching and water-based and may provide effective preventative protection against harmful bacteria. These compounds work at a solid/air interface where desiccant tolerant pathogenic bacteria can persist where individual or colonizing bacteria flourish.
(18) The antimicrobial quaternary ammonium sulfonamide compounds of the present disclosure may be applied to protect a variety of porous and non-porous substrates, preferably surfaces. In one embodiment, benzophenone-attachment compounds may be attached, for example, to polymers including polyethylene and polypropylene; silane-attachment compounds may be attached, for example, to cellulosic fibres and textiles including cotton and cotton blends; and phosphonate-attachment compounds may be attached, for example, to metal and metal oxide substrates, composites and glasses. The substrate attached terminated sulfonamide containing quaternary ammonium salts form a protective self-assembled monolayer that is 1-2 molecules thick at the substrate. These protective coatings may find applications where antimicrobial substrates are required, in particular, biomedical applications.
(19) In one preferred embodiment, coating of a polymer substrate was achieved by first dissolving the quaternary salt in 10:90 solution of ethanol:water, followed by electrostatic spraying (2), and a short 30 sec UV cure cycle.
(20) Microbiological assessment of antimicrobial quaternary ammonium sulfonamide coated substrates of the present disclosure reveal them to be highly potent.
(21) With reference to
(22) With reference to
(23) With reference to
(24) With reference to
(25) With reference to
(26) With reference to
(27) With reference to
(28) With reference to
(29) With reference to
(30) With reference to
(31) The following non-limiting examples are provided.
(32) Acronyms:
(33) ACNacetonitrile
(34) DCMdichloromethane
(35) Et.sub.2Odiethyl ether
(36) Et.sub.3Ntriethylamine
(37) QAC, QUATquaternary ammonium compound
(38) TSBtryptic soy broth
(39) General Method 1 Aromatic Sulfonamides Precursor
(40) To a flame dried, round bottom flask on ice bath equipped with a stir bar containing 40-50 mL of anhydrous DCM, 1.0 equivalent of respective sulfonyl chloride was added followed by 1.5 equivalents of Et.sub.3N, and dropwise addition of 1.5 equivalents of 3-(dimethylamino)propylamine. The reaction mixture was taken off ice bath and allowed to stir for the indicated time at room temperature. The reaction was then transferred to a separatory funnel and extracted with a 30-70 mL of distilled water. Volatiles and/or solvent were removed from the organic phase using a rotary evaporator followed by drying under 10.sup.3 mm Hg vacuum.
(41) ##STR00042##
(42) General Method 2 Aliphatic Sulfonamides
(43) To a flame dried, round bottom flask on ice bath equipped with a stir bar containing 40-50 mL of anhydrous DCM, 1.0 equivalent of 3-(dimethylamino)propylamine was added followed by drop wise addition of the respective sulfonyl chlorides (1.0 equivalents). The reaction mixture was taken off ice bath and allowed to stir for 3-5 hours at room temperature. Upon completion the reaction solvent was evaporated using rotary evaporator, the resultant residue was then dissolved in an appropriate amount of potassium carbonate solution (0.05 M) and extracted using 40-60 mL of DCM. Volatiles and/or solvent were removed from the organic phase using a rotary evaporator followed by drying under 10.sup.3 mm Hg vacuum.
(44) ##STR00043##
(45) General Method 3 Sealed Tube Menschutkin Quaternization Reactions
(46) In a 20 mL scintillation/microwave vial 1.0 equivalent of the sulfonamide was added followed by addition of 1.0-1.5 equivalents of respective linker group (Silane, phosphonate, or benzophenone) along with a magnetic stir bar and sealed with a screw cap. The reaction mixture was heated using an oil bath at 110 C. for 3-48 hours. The crude material was purified by addition of Et.sub.2O (10-30 mL) directly into the reaction mixture followed by decanting (Et.sub.2O wash3) and dried under 10.sup.1 mm Hg vacuum.
(47) ##STR00044##
(48) Synthesis of Aromatic Sulfonamides
(49) ##STR00045##
Example 1N-(3-(dimethylamino)propyl)benzenesulfonamide (1)
(50) This compound was synthesized according to General Method 1 using benzenesulfonyl chloride (1.4 mL, 11.32 mmol), triethylamine (2.4 mL, 16.99 mmol, 1.5 eqv.), and 3-(dimethylamino)propylamine (2.1 mL, 16.99 mmol, 1.5 eqv.) in DCM (30 mL) for 4 hours yielding a clear solution. The solution was then extracted using distilled water (40 mL), the extracted organic layer was dried using rotary evaporator yielding a greenish yellow oil; which was further dried under 10.sup.3 mm Hg vacuum yielding in light yellow waxy solid product. Yield 98% (2.69 g). .sup.1H NMR (CDCl.sub.3, 400 MHz, ): 7.68 (dd, 2H, J.sub.3-2=8.3 Hz, H3), 7.40-7.30 (m, 3H, H1 and H2), 2.86 (t, 2H, J.sub.6-7=5.8 Hz, H6)), 2.11 (t, 2H, J.sub.8-7=5.9 Hz, H8), 1.98 (s, 6H, H9), 1.45-1.36 (m, 2H, H7) ppm; .sup.13C {.sup.1H} NMR (CDCl.sub.3, 100 MHz, ): 140.20 (C4), 132.33 (C1), 128.99 (C2), 126.96 (C3), 59.13 (C8), 45.28 (C9), 44.05 (C6), 25.12 (C7) ppm. HRMS-ESI-TOF (m/z): [M.sup.++H.sup.+] calculated for C.sub.11H.sub.19N.sub.2O.sub.2S.sub.1, 243.3458, found, 243.1162.
(51) ##STR00046##
Example 2N-(3-(dimethylamino)propyl)-4-methylbenzenesulfonamide (2)
(52) This compound was synthesized according to General Method 1 using p-toluenesulfonyl chloride (10.505 g, 55.10 mmol), triethylamine (11.5 mL, 82.65 mmol, 1.5 eqv.), and 3-(dimethylamino)propylamine (10.4 mL, 82.65 mmol, 1.5 eqv.) in DCM (100 mL) for 4 hours yielding a milky white solution. The solution was then extracted using distilled water (100 mL), the extracted organic layer was dried using rotary evaporator yielding a pale yellow oil; which was further dried under 10.sup.3 mm Hg vacuum yielding in pale white waxy solid product. Yield 98% (13.85 g). .sup.1H NMR (CDCl.sub.3, 400 MHz, ): 7.73 (d, 2H, J.sub.4-2=8.3 Hz, H4), 7.29 (d, 2H, J.sub.2-4=7.9 Hz, H2), 3.03 (t, 2H, J.sub.7-8=5.8 Hz, H7), 2.42 (s, 3H, H1), 2.29 (t, 2H, J.sub.9-8=5.8 Hz, H9), 2.16 (s, 6H, H10), 1.62-1.53 (m, 2H, H8) ppm; .sup.13C {.sup.1H} NMR (CDCl.sub.3, 100 MHz, ): 142.83 (C5), 137.11 (C3), 129.44 (C2), 126.88 (C4), 58.76 (C9), 45.15 (C10), 43.65 (C7), 25.23 (C8), 21.32 (C1) ppm. HRMS-ESI-TOF (m/z): [M.sup.++H.sup.+] calculated for C.sub.12H.sub.21N.sub.2O.sub.2S.sub.1, 257.3723, found, 257.1322.
(53) ##STR00047##
Example 3N-(3-(dimethylamino)propyl)-2,4,6-trimethylbenzenesulfonamide (3)
(54) This compound was synthesized according to General Method 1 using 2,4,6-trimethylbenzene-1-sulfonyl chloride (2 g, 9.14 mmol), triethylamine (1.9 mL, 13.72 mmol, 1.5 eqv.), and 3-(dimethylamino)propylamine (1.7 mL, 13.72 mmol, 1.5 eqv.) in DCM (50 mL) for 3 hours yielding a clear solution. The solution was then extracted using distilled water (75 mL), the extracted organic layer was dried using rotary evaporator yielding a clear oil; which was further dried under 10.sup.3 mm Hg vacuum yielding in pale white waxy solid product. Yield 98.5% (2.56 g). .sup.1H NMR (CDCl.sub.3, 400 MHz, ): 7.04 (br. s, 1H, H7), 6.93 (s, 2H, H3), 2.94 (t, 2H, J.sub.8-9=5.7 Hz, H8), 2.61 (s, 6H, H4), 2.32 (t, 2H, J.sub.10-9=5.6 Hz, H10), 2.27 (s, 3H, H1), 2.18 (s, 6H, H11), 1.69-1.56 (m, 2H, H9) ppm; .sup.13C {.sup.1H} NMR (CDCl.sub.3, 100 MHz, ): 141.74 (C6), 139.07 (C2), 133.80 (C5), 131.87 (C3), 59.66 (C10), 45.48 (C11), 43.72 (C8), 24.99 (C9), 22.88 (C4), 20.95 (C1) ppm. HRMS-ESI-TOF (m/z): [M.sup.++H.sup.+] calculated for C.sub.14H.sub.25N.sub.2O.sub.2S.sub.1, 285.4255, found, 285.1643.
(55) ##STR00048##
Example 4N-(3-(dimethylamino)propyl)-2,4,6-triisopropylbenzenesulfonamide (4)
(56) This compound was synthesized according to General Method 1 using 2,4,6-triisopropylbenzene-1-sulfonyl chloride (2 g, 6.60 mmol), triethylamine (1.4 mL, 9.91 mmol, 1.5 eqv.), and 3-(dimethylamino)propylamine (1.2 mL, 9.91 mmol, 1.5 eqv.) in DCM (50 mL) for 3 hours yielding a clear solution. The solution was then extracted using distilled water (75 mL), the extracted organic layer was dried using rotary evaporater yielding a faint green oil; which was further dried under 10.sup.3 mm Hg vacuum yielding in pale white waxy solid product. Yield 97% (2.36 g). .sup.1H NMR (CDCl.sub.3, 400 MHz, ): 7.15 (s, 2H, H4), 4.23-4.11 (m, 2H, H6), 3.08 (t, 2H, J.sub.9-10=5.9 Hz, H9), 2.89 (m, 1H, H2), 2.60-2.40 (br. m, 2H, H11), 2.30 (br. s, 6H, H12), 1.83-1.66 (br. m, 2H, H10), 1.29-1.22 (br. m, 18H, H1 and H1a) ppm; .sup.13C {.sup.1H} NMR (CDCl.sub.3, 100 MHz, ): 152.48 (C7), 150.45 (C5), 132.57 (C3), 123.79 (C4), 59.03 (C11), 45.28 (C12), 42.93 (C9), 34.25 (C2), 29.74 (C6), 25.61 (C10), 25.10 (C1a), 23.73 (C1) ppm. HRMS-ESI-TOF (m/z): [M.sup.++H.sup.+] calculated for C.sub.20H.sub.37N.sub.2O.sub.2S.sub.1, 369.5850, found, 369.2570.
(57) ##STR00049##
Example 5N-(3-(dimethylamino)propyl)naphthalene-1-sulfonamide (5)
(58) This compound was synthesized according to General Method 1 using naphthalene-1-sulfonyl chloride (4 g, 18.04 mmol), triethylamine (3.8 mL, 27.06 mmol, 1.5 eqv.), and 3-(dimethylamino)propylamine (3.4 mL, 27.06 mmol, 1.5 eqv.) in DCM (50 mL) for 3 hours yielding a clear solution. The solution was then extracted using distilled water (50 mL), the extracted organic layer was dried using rotary evaporator yielding a greenish yellow oil; which was further dried under 10.sup.3 mm Hg vacuum yielding in pale white waxy solid product. Yield 99.7% (5.27 g). .sup.1H NMR (CDCl.sub.3, 400 MHz, ): 8.67 (d, 1H, J.sub.1-2=8.5 Hz, H1), 8.25 (d, 1H, J.sub.8-7=6.2 Hz, H8), 8.05 (d, 1H, J.sub.7=8.2 Hz, H6), 7.95 (d, 1H, J.sub.4-3=7.8 Hz, H4), 7.65 (m, 1H, H2), 7.59 (m, 1H, H3), 7.52 (t, 1H, H7), 2.95 (t, 2H, J.sub.12-13=5.6 Hz H12), 2.21 (t, 2H, J.sub.14-13=5.6 Hz, H14), 2.12 (s, 6H, H15), 1.55 (m, 2H, H13) ppm; .sup.13C {.sup.1H} NMR (CDCl.sub.3, 100 MHz, ): 134.85 (C9), 134.45 (C5), 133.96 (C4), 129.79 (C6), 129.16 (C2), 128.42 (C10), 128.21 (C3), 126.82 (C8), 124.76 (C7), 124.28 (C1), 59.80 (C14), 45.56 (C15), 44.77 (C12), 24.68 (C13) ppm. HRMS-ESI-TOF (m/z): [M.sup.++H.sup.+] calculated for C.sub.15H.sub.21N.sub.2O.sub.2S.sub.1, 293.4044, found, 293.1319.
(59) Synthesis of Aliphatic Sulfonamides
(60) ##STR00050##
Example 6N-(3-(dimethylamino)propyl)methanesulfonamide (6)
(61) This compound was synthesized according to General Method 2 using methanesulfonyl chloride (1.4 mL, 17.46 mmol) and 3-(dimethylamino)propylamine (2.2 mL, 17.46 mmol, 1.5 eq.) in DCM (50 mL) for 4 hours and extracted using K.sub.2CO.sub.3 (0.05 M, 40 mL) yielding in clear oil after drying under 10.sup.3 mm Hg vacuum. Yield: 65% (2.05 g). .sup.1H NMR (CDCl.sub.3, 400 MHz, ): 3.23 (t, 2H, H3), 2.91 (s, 3H, H1), 2.43 (t, 2H, H5), 2.22 (s, 6H, H6), 1.77-1.65 (m, 2H, H4) ppm; .sup.13C {.sup.1H} NMR (CDCl.sub.3, 100 MHz, ): 59.26 (C5), 45.37 (C6), 44.08 (C3), 39.70 (C1), 25.72 (C4) ppm.
(62) ##STR00051##
Example 7N-(3-(dimethylamino)propyl)ethanesulfonamide (7)
(63) This compound was synthesized according to General Method 2 using ethanesulfonyl chloride (0.7 mL, 7.78 mmol) and 3-(dimethylamino)propylamine (1.5 mL, 11.67 mmol, 1.5 eq.) in DCM (50 mL) for 4 hours and extracted using K.sub.2CO.sub.3 (0.05 M, 50 mL) yielding in clear oil after drying under 10.sup.3 mm Hg vacuum. Yield: 61% (0.92 g). .sup.1H NMR (CDCl.sub.3, 400 MHz, ): 3.19 (t, 2H, J.sub.4-5=5.8 Hz, H4), 3.0 (q, 2H, J.sub.2-1=7.4 Hz, H2), 2.42 (t, 2H, J.sub.6-5=5.8 Hz, H6), 2.22 (s, 6H, H7), 1.75-1.64 (m, 2H, H5), 1.34 (t, 3H, J.sub.1-2=7.4 Hz, H1) ppm; .sup.13C {.sup.1H} NMR (CDCl.sub.3, 100 MHz, ): 59.33 (C6), 46.05 (C2), 45.41 (C7), 44.11 (C4), 25.91 (C5), 8.35 (C1) ppm. HRMS-ESI-TOF (m/z): [M.sup.++H.sup.+] calculated for C.sub.7H.sub.19N.sub.2O.sub.2S.sub.1, 195.1162, found, 195.1167.
(64) ##STR00052##
Example 8N-(3-(dimethylamino)propyl)butane-1-sulfonamide (8)
(65) This compound was synthesized according to General Method 2 using butanesulfonyl chloride (1.7 mL, 12.77 mmol) and 3-(dimethylamino)propylamine (2.4 mL, 19.15 mmol, 1.5 eq.) in DCM (50 mL) for 4 hours and extracted using K.sub.2CO.sub.3 (0.05 M, 50 mL) yielding in clear oil after drying under 10.sup.3 mm Hg vacuum. Yield: 81% (2.31 g). .sup.1H NMR (CDCl.sub.3, 400 MHz, ): 3.15 (t, 2H, J.sub.6-7=5.9 Hz, H6), 2.94 (t, 2H, J.sub.4-3=7.9 Hz, H4), 2.38 (t, 2H, J.sub.8-7=5.9 Hz, H8), 2.18 (s, 6H, H9), 7.78-1.61 (m, 4H, H), 1.48-1.34 (m, 2H, H2), 0.91 (t, 3H, J.sub.1-2=7.3 Hz, H1) ppm; .sup.13C {.sup.1H} NMR (CDCl.sub.3, 100 MHz, ): 59.08 (C8), 51.56 (C4), 45.38 (C9), 43.83 (C6), 26.05 (C3), 25.70 (C7), 21.54 (C2), 13.63 (C1) ppm. HRMS-ESI-TOF (m/z): [M.sup.++H.sup.+] calculated for C.sub.9H.sub.23N.sub.2O.sub.2S.sub.1, 223.1475, found, 223.1480.
(66) ##STR00053##
Example 9N-(2-(dimethylamino)propyl)-N,N-Dimethyl-sulfamide (9)
(67) This compound was synthesized according to General Method 2 using N,N-dimethylsulfamoyl chloride (1.5 mL, 13.93 mmol) and 3-(dimethylamino)propylamine (2.6 mL, 20.89 mmol, 1.5 eq.) in DCM (50 mL) for 4 hours and extracted using K.sub.2CO.sub.3 (0.05 M, 50 mL) yielding in clear oil after drying under 10.sup.3 mm Hg vacuum. Yield: 79.8% (2.33 g). .sup.1H NMR (CDCl.sub.3, 400 MHz, ): 3.11 (t, 2H, J.sub.3-4=6.0 Hz, H3), 2.75 (s, 6H, H1), 2.38 (t, 2H, J.sub.5-4=6.0 Hz, H5), 2.19 (s, 6H, H6), 1.69-1.61 (m, 2H, H4) ppm. .sup.13C {.sup.1H} NMR (CDCl.sub.3, 100 MHz, ): 59.24 (C5), 45.39 (C6), 44.31 (C3), 38.00 (C1), 25.62 (C4) ppm. HRMS-ESI-TOF (m/z): [M.sup.++H.sup.+] calculated for C.sub.7H.sub.20N.sub.3O.sub.2S.sub.1, 210.1271, found, 210.1276.
Example 9A 3-(((1S,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methylsulfonamido)-N,N-dimethylpropan-1-aminium chloride
(68) ##STR00054##
(69) This compound was synthesized according to Method 1 using (1 S)-(+)-camphorsulfonyl chloride (20.938 g, 83.75 mmol), and 3-(dimethylamino)propylamine (10.5 mL, 83.75 mmol, 1.0 eqv.) in DCM (50 mL) for 3 hours at room temperature yielding a light yellow cloudy precipitate. The mixture was dried on a rotary evaporated yielding a yellow oil which solidified under a pressurized vacuum system to a pale off white hard solid of the HCl camphor amine salt. Yield 100% (26.151 g, 83.5 mmol). .sup.1H NMR (CDCl.sub.3, 400 MHz, ): 5.44 (s, 1H), 4.33 (s, 4H), 3.69 (s, 4H), 3.44 (s, 4H), 2.77 (s, 4H), 2.71 (s, 4H), 2.52-2.48 (m, 8H), 2.43-2.06 (m, 37H), 2.10 (d, J=2.3 Hz, 9H), 2.10 (d, J=2.3 Hz, 7H), 2.04 (s, 5H), 1.86 (s, 3H), 1.74-1.64 (m, 8H), 1.59 (s, 3H), 1.34 (s, 3H), 1.04 (s, 3H, H1), 0.87 (s, 3H, H1) ppm; Agrees well with literature values. (Eur. J. Pharm. Sci. 65 (2014) 29-37).
(70) General Procedure 4 for the Menschutkin Quaternization
(71) 1.0 equivalent of sulfonamide containing tertiary amine and 1.0-1.5 equivalents of respective end functionality (silane, phosphorus or benzophenone) halide were mixed in ACN using Method 3 and heated for 3-48 hours. The reaction vial was allowed to cool to RT and the crude product was purified as indicated in Method 3.
(72) Synthesis of Organosilane based QAC
(73) ##STR00055##
Example 10N,N-dimethyl-3-(phenylsulfonamido)-N-(3-(trimethoxysilyl)propyl)propan-1-aminium chloride (1a)
(74) This compound was synthesized using N-(3-(dimethylamino)propyl)benzenesulfonamide (1.0 g, 4.13 mmol) and (3-Chloropropyl)trimethoxysilane (1.1 mL, 6.19 mmol, 1.5 eq.) in ACN (3 mL) for 4 hours resulting in viscous golden yellow brown solution. The product was purified using Et.sub.2O (10 mL3) and obtained as clear golden brown gummy oil after drying under 10.sup.3 mm Hg vacuum at room temperature. Yield: 97.5% (1.77 g). .sup.1H NMR (CDCl.sub.3, 400 MHz, ): 8.39 (br. S, 1H, H5), 7.96 (d, 2H, H3), 7.54-7.341 (m, 3H, H1 & H2), 3.69-3.62 (m, 2H, H8), 3.51 (s, 9H, H13), 3.37-3.30 (t, 2H, H10), 3.21 (s, 6H, H9), 3.03-2.96 (m, 2H, H6), 2.12-2.015 (m, 2H, H7), 1.80-1.68 (m, 2H, H11), 0.59 (t, 2H, J.sub.12-11=7.8 Hz, H12) ppm. .sup.13C {.sup.1H} NMR (CDCl.sub.3, 100 MHz, ): 139.86 (C4), 132.41 (C1), 129.14 (C2), 127.20 (C3), 65.94 (C10), 62.45 (C8), 51.10 (C9), 50.72 (C13), 39.93 (C6), 22.61 (C7), 16.45 (C11), 5.57 (C12) ppm. .sup.29Si {.sup.1H} NMR (79.4 MHz, CDCl.sub.3, ): 44.41 ppm.
(75) ##STR00056##
Example 11N,N-dimethyl-3-(4-methylphenylsulfonamido)-N-(3-(trimethoxysilyl)propyl) propan-1-aminium chloride (2a)
(76) This compound was synthesized using N-(3-(dimethylamino)propyl)-4-methylbenzenesulfonamide (1.0 g, 3.90 mmol) and (3-Chloropropyl)trimethoxysilane (1.1 mL, 5.85 mmol, 1.5 eq.) in ACN (3 mL) for 3.5 hours resulting in viscous golden yellow brown solution. The product was purified using Et.sub.2O (10 mL3) and obtained as clear golden brown gummy oil after drying under 10.sup.3 mm Hg vacuum at room temperature. Yield: 97% (1.67 g). .sup.1H NMR (CDCl.sub.3, 400 MHz, ): 8.18 (br. s, 1H, H6), 7.85 (d, 2H, J.sub.4-2=7.9 Hz, H4), 7.29 (d, 2H, J.sub.2-4=7.7 Hz, H2), 3.75-3.62 (m, 2H, H9), 3.55 (s, 9H, H14), 3.41-3.32 (m, 2H, H11), 3.25 (s, 6H, H10), 3.08-2.94 (m, 2H, H7), 2.40 (s, 3H, H1), 2.15-2.05 (m, 2H, H8), 1.84-1.58 (m, 2H, H12), 0.63 (t, 2H, J.sub.4-2=7.7 Hz, H13) ppm. .sup.13C {.sup.1H} NMR (CDCl.sub.3, 100 MHz, ): 143.08 (C5), 136.85 (C3), 129.70 (C2), 127.85 (C4), 65.82 (C11), 62.45 (C9), 51.10 (C14), 50.70 (C10), 39.91 (C7), 22.66 (C1), 21.46 (C8), 16.44 (C12), 5.57 (C13) ppm. .sup.29Si {(H} NMR (79.4 MHz, CDCl.sub.3, ): 44.37 ppm. HRMS-ESI-TOF (m/z): [M.sup.+Cl.sup.] calculated for C.sub.18H.sub.35N.sub.2O.sub.5S.sub.1Si.sub.1, 419.6309, found, 419.2026.
(77) ##STR00057##
Example 12N,N-dimethyl-3-(trimethoxysilyl)-N-(3-(2,4,6-trimethylphenylsulfonamido) propyl)propan-1-aminium chloride (3a)
(78) This compound was synthesized using N-(3-(dimethylamino)propyl)-2,4,6-trimethylbenzenesulfonamide (2.0 g, 7.03 mmol) and (3-Chloropropyl)trimethoxysilane (1.9 mL, 10.55 mmol, 1.5 eq.) in ACN (3 mL) for 4.5 hours resulting in viscous golden yellow brown solution. The product was purified using Et.sub.2O (10 mL3) and obtained as clear golden brown gummy oil after drying under 10.sup.3 mm Hg vacuum at room temperature. Yield: 92.6% (3.27 g). .sup.1H NMR (CDCl.sub.3, 400 MHz, ): 7.74 (t, 1H, J.sub.7=6.0 Hz, H7), 6.90 (s. 2H, H3), 3.70 (t, 2H, J.sub.8-9=7.9 Hz, H8), 3.53 (s, 9H, H15), 3.40-3.33 (m, 2H, H12), 3.25 (s, 6H, H11), 3.02-2.94 (m, 2H, H10), 2.62 (br. s, 6H, H4), 2.25 (s, 3H, H1), 2.14-2.04 (m, 2H, H9), 1.83-1.72 (m, 2H, H13), 0.62 (t, 2H, J.sub.14-13=7.9 Hz, H14) ppm. .sup.13C {.sup.1H} NMR (CDCl.sub.3, 100 MHz, ): 142.01 (C6), 139.22 (C5), 133.83 (C2), 132.01 (C3), 66.06 (C12), 62.51 (C10), 51.22 (C11), 50.81 (C15), 39.33 (C8), 23.28 (C4), 22.88 (C1), 20.95 (C9), 16.57 (C13), 5.70 (C14) ppm. .sup.29Si {.sup.1H} NMR (79.4 MHz, CDCl.sub.3, ): 44.43 ppm. HRMS-ESI-TOF (m/z): [M.sup.+Cl.sup.] calculated for C.sub.20H.sub.39N.sub.2O.sub.5S.sub.1Si.sub.1, 447.6840, found, 447.2357.
(79) ##STR00058##
Example 13N,N-dimethyl-3-(naphthalene-1-sulfonamido)-N-(3-(trimethoxysilyl)propyl)propan-1-aminium chloride (5a)
(80) This compound was synthesized using N-(3-(dimethylamino)propyl)naphthalene-1-sulfonamide (0.5 g, 2.21 mmol) and (3-Chloropropyl)trimethoxysilane (0.6 mL, 3.31 mmol, 1.5 eq.) in ACN (3 mL) for 5 hours resulting in viscous golden yellow brown solution. The product was purified using Et.sub.2O (10 mL3) and obtained as clear golden brown gummy oil after drying under 10.sup.3 mm Hg vacuum at room temperature. Yield: 78.8% (0.85 g). .sup.1H NMR (CDCl.sub.3, 400 MHz, ): 8.83 (d, 1H, J.sub.8-7=8.6 Hz, H8), 8.47 (t, 1H, J.sub.11-12=5.7 Hz, H11), 8.20 (d, 1H, J.sub.6-7=7.3 Hz, Hs6), 7.99 (d, 1H, J.sub.1-2=8.1 Hz, H1), 7.87 (d, 1H, J.sub.4-3=8.1 Hz, H4), 7.74-7.65 (m, 1H, H7), 7.55-7.46 (m, 2H, H3 & H2), 3.51-3.46 (m, 11H, H14 & H19), 3.22-3.16 (m, 2H, H16), 3.09-3.01 (m, 8H, H12 & H15), 1.98-1.86 (m, 2H, H13), 1.68-1.54 (m, 2H, H17), 0.51 (t, 2H, J.sub.18-17=7.8 Hz, H18) ppm. .sup.13C {.sup.1H} NMR (CDCl.sub.3, 100 MHz, 5): 135.12 (C9), 134.16 (C5), 133.91 (C1), 129.07 (C6), 128.8 (C4), 128.56 (C7), 128.12 (C10), 127.02 (C3), 125.30 (C8), 124.31 (C2), 65.84 (C16), 62.32 (C14), 50.92 (C15), 50.69 (C19), 39.79 (C12), 22.81 (C13), 16.33 (C17), 5.48 (C18) ppm. .sup.29Si {.sup.1H} NMR (79.4 MHz, CDCl.sub.3, ): 44.49 ppm. HRMS-ESI-TOF (m/z): [M.sup.+Cl.sup.] calculated for C.sub.21H.sub.35N.sub.2O.sub.5S.sub.1Si.sub.1, 455.2030, found, 455.2018.
(81) ##STR00059##
Example 143-(ethylsulfonamido)-N,N-dimethyl-N-(3-(trimethoxysilyl)propyl)propan-1-aminium chloride (7a)
(82) This compound was synthesized using N-(3-(dimethylamino)propyl)ethanesulfonamide (1.0 g, 5.15 mmol) and (3-Chloropropyl)trimethoxysilane (1.4 mL, 7.72 mmol, 1.5 eq.) in ACN (3 mL) for 5 hours resulting in viscous golden yellow brown solution. The product was purified using Et.sub.2O (10 mL3) and obtained as clear golden brown gummy oil after drying under 10.sup.0.3 mm Hg vacuum at room temperature. Yield: 86.0% (1.73 g). .sup.1H NMR (CDCl.sub.3, 400 MHz, ): 7.63 (s, 1H, H3), 3.75-3.47 (m, 11H, H6 & H1), 3.39-3.31 (m, 2H, H8), 3.25-3.15 (m, 8H, H7 & H4), 3.07-2.98 (m, 2H, H2), 2.19-2.02 (m, 2H, H5), 1.88-1.69 (m, 2H, H9), 1.31 (td, 3H, J.sub.1-2=7.3 Hz, J.sub.1-1a=3.4 Hz, H1 &H1a), 0.62 (t, 2H, J.sub.10-9=7.8 Hz, H10) ppm. .sup.13C {.sup.1H} NMR (CDCl.sub.3, 100 MHz, ): 65.89 (C8), 62.40 (C6), 51.18 (C7), 50.81 (C11), 46.37 (C2), 40.09 (C4), 23.58 (C5), 16.54 (C9), 8.28 (C1), 5.73 (C10) ppm. .sup.29Si {.sup.1H} NMR (79.4 MHz, CDCl.sub.3, ): 44.51 ppm.
(83) ##STR00060##
Example 153-(butylsulfonamido)-N,N-dimethyl-N-(3-(trimethoxysilyl)propyl)propan-1-aminium chloride (8a)
(84) This compound was synthesized using N-(3-(dimethylamino)propyl)butanesulfonamide (1.0 g, 4.50 mmol) and (3-Chloropropyl)trimethoxysilane (1.2 mL, 6.75 mmol, 1.5 eq.) in ACN (3 mL) for 5 hours resulting in viscous golden yellow brown solution. The product was purified using Et.sub.2O (10 mL5) and obtained as clear golden brown gummy oil after drying under 10.sup.1 mm Hg vacuum at room temperature. Yield: 60.0% (1.13 g). .sup.1H NMR (CDCl.sub.3, 400 MHz, ): 7.62 (br. s, 1H, H5), 3.67-3.60 (m, 2H, H8), 3.51 (s, 9H, H13), 3.36-3.29 (m, 2H, H4), 2.15-2.04 (m, 2H, H7), 1.83-1.66 (m, 4H, H11 & H3), 1.41-1.33 (m, 2H, H2), 0.87 (td, J.sub.1-2=7.3 Hz, J.sub.1-1a=3.1 Hz, H1 & H1a), 0.60 (t, 2H, J.sub.12-11=7.3 Hz, H12) ppm. .sup.13C {.sup.1H} NMR (CDCl.sub.3, 100 MHz, ): 65.82 (C10), 51.81 (C4), 51.12 (C9), 50.74 (C13), 40.04 (C6), 25.38 (C3), 23.50 (C7), 21.58 (C2), 16.50 (C11), 13.62 (C1), 5.68 (C12) ppm. .sup.29Si {.sup.1H} NMR (79.4 MHz, CDCl.sub.3, ): 44.50 ppm. HRMS-ESI-TOF (m/z): [M.sup.+Cl.sup.] calculated for C.sub.15H.sub.37N.sub.2O.sub.5S.sub.1Si.sub.1, 385.2187, found, 385.2185.
(85) ##STR00061##
Example 163-((N,N-dimethylsulfamoyl)amino)-N,N-dimethyl-N-(3-(trimethoxysilyl) propyl)propan-1-aminium chloride (9a)
(86) Synthesis of Organophosphosophorus based QAC
(87) ##STR00062##
Example 173-(diisopropoxyphosphoryl)-N,N-dimethyl-N-(3-(phenylsulfonamido)propyl) propan-1-aminium bromide (1b)
(88) This compound was synthesized using N-(3-(dimethylamino)propyl)benzenesulfonamide (1.0 g, 4.13 mmol) and diisopropyl (3-bromopropyl)phosphonate (1.10 mL, 4.13 mmol, 1 eq.) in ACN (3 mL) for 4 hours resulting in viscous golden yellow brown solution. The product was purified using Et.sub.2O (10 mL3) and obtained as pale yellow fluffy/gummy powder after drying under 10.sup.3 mm Hg vacuum at room temperature. Yield: 86.0% (1.87 g). .sup.1H NMR (CDCl.sub.3, 400 MHz, ): 7.94 (d, 2H, J.sub.3-2=6.5 Hz, H3), 7.65 (t, 1H, J.sub.5-6=5.9 Hz, H5), 7.54-7.46 (m, 3H, H1 & H2), 4.70-4.57 (m, 2H, H13), 3.73-3.65 (m, 2H, H8), 3.64-3.56 (m, 2H, H10), 3.27 (s, 6H, H9), 3.02 (dd, 2H, J.sub.6-5=11.3 Hz, J.sub.6-7=5.6 Hz, H6), 2.16-1.94 (m, 4H, (H7, H11, & ACN)), 1.79 (dt, 2H, J.sub.12-P=17.7 Hz, H8, J.sub.12-11=7.2 Hz, H12), 1.28 (dd, 12H, J.sub.14-P=6.2 Hz, H8, J.sub.14-13=1.7 Hz, H14) ppm. .sup.13C {.sup.1H} NMR (CDCl.sub.3, 100 MHz, ): 139.57 (C4), 132.59 (C2), 129.23 (C1), 127.19 (C3), 70.82 (d, .sup.2J.sub.13-P=6.7 Hz, C13), 6.74 (d, .sup.3J.sub.10-P=15.1 Hz, C10), 62.41 (C8), 51.28 (C9), 39.89 (C6), 24.12 (d, J.sub.14-P=4.5 Hz, C14), 23.99 (d, J.sub.14-P=4.0 Hz, C14), 23.82 & 22.38 (d, J.sub.12-P=144.3 Hz, C12), 22.68 (C7), 16.67 (C11) ppm. .sup.31P{(H} NMR (CDCl.sub.3, 121.45 MHz, ): 27.36 ppm. HRMS-ESI-TOF (m/z): [M.sup.+Br.sup.] calculated for C.sub.20H.sub.38N.sub.2O.sub.5P.sub.1S.sub.1, 449.2234, found, 449.2232.
(89) ##STR00063##
Example 183-(diisopropoxyphosphoryl)-N,N-dimethyl-N-(3-(4-methylphenylsulfon amido)propyl)propan-1-aminium bromide (2b)
(90) This compound was synthesized using N-(3-(dimethylamino)propyl)-4-methylbenzenesulfonamide (0.50 g, 1.95 mmol) and diisopropyl (3-bromopropyl)phosphonate (0.50 mL, 1.95 mmol, 1 eq.) in ACN (3 mL) for 3 hours resulting in pale yellow solution with some precipitate formation. The product was purified using Et.sub.2O (10 mL3) and obtained as white puffy powder after drying under 10.sup.0.3 mm Hg vacuum at room temperature. Yield: 89.5% (0.95 g). .sup.1H NMR (CDCl.sub.3, 400 MHz, ): 7.78 (d, 2H, J.sub.4-2=8.2 Hz, H4), 7.55 (t, 1H, J.sub.6-7=5.8 Hz, H6), 7.28-7.23 (m, 2H, H2 and CDCl.sub.3), 4.72-4.49 (m, 2H, H14), 3.72-3.63 (m, 2H, H9), 3.62-3.54 (m, 2H, H11), 3.25 (s, 6H, H10), 3.00-2.90 (m, 2H, H7), 2.36 (s, 3H, H1), 2.16-1.90 (m, 4H, H8 & H12), 1.75 (dt, 2H, J.sub.13-P=17.8 Hz, J.sub.13-12=7.1 Hz, H13), 1.25 (dd, 12H, J.sub.15-P=56.15 Hz, J.sub.15-14=2.1 Hz, H15) ppm. .sup.13C {.sup.1H} NMR (CDCl.sub.3, 100 MHz, ): 143.25 (C5), 136.46 (C3), 129.74 (C2), 127.22 (C4), 70.71 (d, .sup.2J.sub.14-P=6.7 Hz, C14), 63.67 (d, .sup.3J.sub.11-P=15.8 Hz, C11), 62.42 (C9), 51.17 (C10), 39.86 (C7), 24.10 (d, J.sub.15-P=4.5 Hz, C15), 23.97 (d, J.sub.15-P=4.0 Hz, C15), 23.79 & 22.36 (d, J.sub.13-P=144.1 Hz, C13), 22.52 (C8), 21.47 (C1), 16.69 (d, .sup.2J.sub.12-P=4.1 Hz, C12) ppm. .sup.31P {.sup.1H} NMR (CDCl.sub.3, 121.45 MHz, ): 27.15 ppm. HRMS-ESI-TOF (m/z): [M.sup.+Br.sup.] calculated for C.sub.21H.sub.40N.sub.2O.sub.5P.sub.1S.sub.1, 463.5909, found, 463.2394.
(91) ##STR00064##
Example 193-(diisopropoxyphosphoryl)-N,N-dimethyl-N-(3-(2,4,6-trimethylphenylsulfon amido)propyl)propan-1-aminium bromide (3b)
(92) This compound was synthesized using N-(3-(dimethylamino)propyl)-2,4,6-trimethylbenzenesulfonamide (0.50 g, 1.76 mmol) and diisopropyl (3-bromopropyl)phosphonate (0.40 mL, 1.76 mmol, 1 eq.) in ACN (3 mL) for 4 hours resulting in viscous golden yellow brown solution. The product was purified using Et.sub.2O (10 mL3) and obtained as pale yellow fluffy/gummy powder after drying under 10.sup.3 mm Hg vacuum at room temperature. Yield: 71.0% (0.71 g). .sup.1H NMR (CDCl.sub.3, 400 MHz, ): 7.14 (t, 1H, J.sub.7=6.0 Hz, H7), 6.92 (s, 2H, H3), 4.71-4.57 (m, 2H, H15), 3.84-3.75 (m, 2H, H10), 3.74-3.60 (m, 2H, H12), 3.32 (s, 6H, H11), 3.01 (dd, 2H, J.sub.8-7=11.2 Hz, J.sub.8-9=5.6 Hz, H8), 2.63 (s, 6H, H4), 2.27 (s, 3H, H1), 2.22-2.00 (m, 4H, H9 & H13), 1.81 (dt, 2H, J.sub.14-P=17.8 Hz, J.sub.14-13=7.0 Hz, H14), 1.30 (d, 12H, J.sub.16-15=6.2 Hz, H16) ppm. .sup.13C {.sup.1H} NMR (CDCl.sub.3, 100 MHz, ): 142.11 (C6), 139.07 (C2), 133.33 (C5), 132.00 (C3), 70.80 (d, .sup.2J.sub.15-P=6.7 Hz, C15), 63.68 (d, .sup.2J.sub.12-P=15.0 Hz, C112), 62.35 (C10), 51.32 (C11), 39.20 (11C8), 24.13 (d, J.sub.16-P=4.5 Hz, C16), 24.00 (d, J.sub.16-P=4.0 Hz, C16), 23.81 & 22.38 (d, J.sub.14-P=144.3 Hz, C14), 23.22 (C4), 22.68 (C9), 20.89 (C1), 16.76 (C13) ppm. .sup.31P {.sup.1H} NMR (CDCl.sub.3, 121.45 MHz, ): 27.16 ppm. HRMS-ESI-TOF (m/z): [M.sup.+Br.sup.] calculated for C.sub.23H.sub.44N.sub.2O.sub.5P.sub.1S.sub.1, 491.2703, found, 491.2693.
(93) ##STR00065##
Example 203-(diisopropoxyphosphoryl)-N,N-dimethyl-N-(3-(naphthalene-1-sulfonamido) propyl)propan-1-aminium bromide (5b)
(94) This compound was synthesized using N-(3-(dimethylamino)propyl)naphthalene-1-sulfonamide (0.50 g, 4.13 mmol) and diisopropyl (3-bromopropyl)phosphonate (0.50 mL, 3.42 mmol, 1 eq.) in ACN (3 mL) for 5.5 hours resulting in viscous golden yellow brown solution. The product was purified using Et.sub.2O (10 mL3) and obtained as pale yellow fluffy/gummy powder after drying under 10.sup.3 mm Hg vacuum at room temperature. Yield: 77.4% (0.77 g). .sup.1H NMR (CDCl.sub.3, 400 MHz, ): 8.82 (d, 1H, J.sub.6-7=8.7 Hz, H8), 8.20 (d, 1H, J.sub.6-7=7.3 Hz, H6), 8.02 (d, 1H, J.sub.1-2=8.3 Hz, H1), 7.92-7.84 (m, 2H, H4 & H11), 7.73-7.62 (m, 1H, H7), 7.57-7.48 (m, 2H, H3 & H2), 4.69-4.50 (m, 2H, H19), 3.62-3.47 (m, 4H, H14 & H16), 3.12 (s, 6H, H15), 3.03 (dd, 2H, J.sub.12-11=11.2 Hz, J.sub.12-13=5.6 Hz, H12), 2.08-1.82 (m, 7H, (ACN, H13 & H17)), 1.71 (dt, 2H, J.sub.18-P=17.5 Hz, J.sub.18-17=7.2 Hz, H18), 1.12 (t, 12H, J.sub.20-19=6.0 Hz, H20) ppm. .sup.13C {.sup.1H} NMR (CDCl.sub.3, 100 MHz, ): 134.63 (C9), 134.18 (C5), 13.14 (C1), 129.37 (C6), 128.92 (C4), 128.63 (C7), 128.03 (C10), 127.08 (C3), 125.17 (C8), 124.36 (C2), 70.80 (d, .sup.2J.sub.19-P=6.7 Hz, C19), 63.60 (d, .sup.3J.sub.16-P=15.1 Hz, C16), 62.36 (C14), 51.14 (C15), 39.74 (C12), 24.12 (d, J.sub.20-P=4.5 Hz, C20), 23.99 (d, J.sub.20-P=4.0 Hz, C20), 23.74 & 22.31 (d, J.sub.18-P=144.5 Hz, C18), 22.68 (C13), 16.65 (d, .sup.2J.sub.17-P=144.3 Hz, C17) ppm. .sup.31P{.sup.1H} NMR (CDCl.sub.3, 121.45 MHz, ): 27.19 ppm. HRMS-ESI-TOF (m/z): [M.sup.+Br.sup.] calculated for C.sub.24H.sub.40N.sub.2O.sub.5P.sub.1S.sub.1, 499.2390, found, 499.2385.
(95) ##STR00066##
Example 213-(diisopropoxyphosphoryl)-N-(3-(ethylsulfonamido)propyl)-N,N-dimethyl propan-1-aminium bromide (7b)
(96) This compound was synthesized using N-(3-(dimethylamino)propyl)ethanesulfonamide (0.25 g, 1.29 mmol) and diisopropyl (3-bromopropyl)phosphonate (0.30 mL, 1.29 mmol, 1 eq.) in ACN (3 mL) for 5 hours resulting in viscous golden yellow brown solution. The product was purified using Et.sub.2O (10 mL3) and obtained as white gummy powder after drying under 10.sup.3 mm Hg vacuum at room temperature. Yield: 86.0% (0.53 g). .sup.1H NMR (CDCl.sub.3, 400 MHz, ): 7.08 (t, 1H, J.sub.3-4=5.8 Hz, H3), 4.76-4.54 (m, 2H, H11), 3.74 (t, 2H, J.sub.6-5=7.6 Hz, H6), 3.63 (t, 2H, J.sub.8-9=7.9 Hz, H8), 3.35-3.16 (m, 8H, H7 & H4), 3.07 (q, 2H, J.sub.2-1=7.4 Hz, H2), 2.27-2.13 (m, 2H, H5), 2.12-1.96 (m, 2H, H9), 1.82 (dt, 2H, J.sub.10-P=17.4 Hz, J.sub.10-9=7.2 Hz, H10), 1.44-1.24 (m, 15H, H1 & H12) ppm. .sup.13C {.sup.1H} NMR (CDCl.sub.3, 100 MHz, ): 70.74 (d, .sup.2J.sub.11-P=6.7 Hz, C11), 63.75 (d, .sup.3J.sub.8-P=15.7 Hz, C8), 62.36 (C6), 51.20 (C7), 46.22 (C2), 39.97 (C4), 24.12 (d, J.sub.12-P=4.5 Hz, C12), 23.98 (d, J.sub.12-P=4.0 Hz, C12), 23.86 & 22.43 (d, .sup.2J.sub.10-P=144.3 Hz, C10), 23.36 (C8), 16.74 (C9), 8.24 (C1) ppm. .sup.31P{(H} NMR (CDCl.sub.3, 121.45 MHz, ): 27.05 ppm. HRMS-ESI-TOF (m/z): [M.sup.+Br.sup. ] calculated for C.sub.16H.sub.38N.sub.2O.sub.5P.sub.1S.sub.1, 401.2234, found, 401.2235.
(97) ##STR00067##
Example 223-(butylsulfonamido)-N-(3-(diisopropoxyphosphoryl)propyl)-N,N-dimethyl propan-1-aminium bromide (8b)
(98) This compound was synthesized using N-(3-(dimethylamino)propyl)butane-1-sulfonamide (0.50 g, 2.25 mmol) and diisopropyl (3-bromopropyl)phosphonate (0.60 mL, 2.25 mmol, 1 eq.) in ACN (3 mL) for 3 hours resulting in viscous golden yellow brown solution. The product was purified using Et.sub.2O (10 mL3) and obtained as pale yellow gummy powder after drying under 10.sup.3 mm Hg vacuum at room temperature. Yield: 82.0% (0.94 g). .sup.1H NMR (CDCl.sub.3, 400 MHz, ): 7.07 (t, 1H, J.sub.3-4=6.1 Hz, H5), 4.69 (qd, 2H, J.sub.13-P=12.4 Hz, J.sub.13-14=6.2 Hz, H13), 3.78 (t, 2H, J.sub.8-7=7.8 Hz, H8), 3.66 (t, 2H, J.sub.10-11=8.4 Hz, H10), 3.33 (s, 6H, H9), 3.28 (dd, 2H, J.sub.6-5=12.0 Hz, J.sub.6-7=6.0 Hz, H6), 3.29 (t, 2H, J.sub.4-3=8.4 Hz, H4), 2.24-2.15 (m, 2H, H7), 2.15-2.03 (m, 2H, H11), 1.89-1.75 (m, 4H, H3 & H12), 1.45 (dq, 2H, J.sub.2-3=14.7, J.sub.2-1=7.3, H2), 1.38-1.29 (m, 12H, H14), 0.96 (t, 3H, J.sub.1-2=7.4 Hz, H1) ppm. .sup.13C {.sup.1H} NMR (CDCl.sub.3, 100 MHz, ): 70.77 (d, .sup.2J.sub.13-P=6.7 Hz, C13), 63.73 (d, .sup.3J.sub.10-P=15.5 Hz, C10), 62.36 (C8), 51.72 (C4), 51.25 (C9), 39.98 (C6), 25.35 (C3), 24.14 (d, J.sub.14-P=4.5 Hz, C14), 24.00 (d, J.sub.14-P=4.0 Hz, C14), 23.87 & 22.43 (d, J.sub.12-P=144.4 Hz, C12), 23.37 (C7), 21.51 (C2), 16.73 (d, .sup.2J.sub.11-P=4.2 Hz, C11), 13.62 (C1) ppm. .sup.31P{.sup.1H}NMR (CDCl.sub.3, 121.45 MHz, ): 27.22 ppm. HRMS-ESI-TOF (m/z): [M.sup.+Br.sup.] calculated for C.sub.18H.sub.42N.sub.2O.sub.5P.sub.1S.sub.1, 429.2547, found, 429.2543.
(99) ##STR00068##
Example 233-(diisopropoxyphosphoryl)-N-(3-((N,N-dimethylsulfamoyl)amino)propyl)-N,N-dimethylpropan-1-aminium bromide (9b)
(100) This compound was synthesized using N-(2-(dimethylamino)propyl)-N,N-Dimethyl-sulfamide (0.50 g, 2.39 mmol) and diisopropyl (3-bromopropyl)phosphonate (0.6 mL, 2.39 mmol, 1 eq.) in ACN (3 mL) for 3 hours resulting in viscous pale yellow solution. The product was purified using Et.sub.2O (10 mL3) and obtained as pale yellow fluffy/gummy powder after drying under 10.sup.3 mm Hg vacuum at room temperature. Yield: 91.7% (1.09 g). .sup.1H NMR (CDCl.sub.3, 400 MHz, ): 7.02 (t, 1H, J.sub.2-3=5.9 Hz, H2), 4.62 (qd, 2H, J.sub.10-P=12.4 Hz, J.sub.10-11=6.2 Hz, H10), 3.66 (t, 2H, J.sub.5-4=7.9 Hz, H5), 3.59 (t, 2H, J.sub.7-8=8.2 Hz, H7), 3.26 (s, 6H, H6), 3.14 (dd, 2H, J.sub.3-2=12.0 Hz, J.sub.3-4=6.0 Hz, H3), 2.75 (s, 6H, H1), 2.20-2.06 (m, 2H, H4), 2.05-1.97 (m, 2H, H8), 1.78 (dt, 2H, J.sub.9-P=17.4 Hz, J.sub.9-8=7.2 Hz, H9), 1.31-1.20 (m, 12H, H11) ppm. .sup.13C {.sup.1H} NMR (CDCl.sub.3, 100 MHz, ): 70.78 (d, .sup.2J.sub.10-P=6.6 Hz, C10), 63.74 (d, .sup.3J.sub.7-P=15.4 Hz, C7), 62.44 (C5), 51.24 (C6), 40.19 (C6), 38.15 (C1), 24.13 (d, J.sub.11-P=4.5 Hz, C11), 24.06 (d, J.sub.11-P=4.0 Hz, C11), 23.87 & 22.44 (d, J.sub.9-P=144.0 Hz, C9). 22.84 (C4), 16.74 (C8) ppm. .sup.31P{H} NMR (CDCl.sub.3, 121.45 MHz, ): 27.27 ppm. HRMS-ESI-TOF (m/z): [M.sup.+Br.sup.] calculated for C.sub.16H.sub.39N.sub.3O.sub.5P.sub.1S.sub.1, 416.2343, found, 416.2341.
(101) Synthesis of Benzophenone based QAC
(102) ##STR00069##
Example 243-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(phenylsulfonamido)propyl) propan-1-aminium bromide (1c)
(103) This compound was synthesized using N-(3-(dimethylamino)propyl)phenylsulfonamide (0.921 g, 3.8 mmol) and 4-(3-bromopropoxy)benzophenone (1.29 g, 4.0 mmol) in ACN (10 mL) for 48 hours; yielding in viscous pale yellow solution. The product was obtained as fluffy pale yellow powder after washing with Et.sub.2O (10 mL3) and drying under 10.sup.3 mm Hg vacuum at room temperature. Yield: 82% (1.74 g). .sup.1H NMR (CDCl.sub.3, 400 MHz, ): 7.96-7.89 (m, 2H, H3), 7.86-7.77 (m, 1H, H5), 7.74-7.62 (m, 4H, H15 & H19), 7.57-7.49 (m, 1H, H21), 7.49-7.37 (m, 5H, (H1, H2, & H20)), 6.89 (d, 2H, J.sub.14-15=8.9 Hz, H14), 4.11 (t, J.sub.12-11=5.3 Hz, H12), 3.79-3.56 (m, 4H, H8 & H10), 3.27 (s, 6H, H9), 3.06-2.92 (m, 2H, H6), 2.36-2.19 (m, 2H, H11), 2.19-1.97 (m, 2H, H7) ppm. .sup.13C {.sup.1H} NMR (CDCl.sub.3, 100 MHz, ): 195.58 (C17), 161.80 (C13), 139.64 (C1), 137.99 (C4), 132.71 (C18), 132.51 (C15), 132.19 (C21), 130.60 (C16), 139.75 (C2), 129.32 (C19), 128.35 (C20), 127.22 (C3), 114.31 (C14), 64.68 (C12), 62.44 (C8), 62.06 (C10), 39.98 (C6), 23.08 (C11), 22.75 (C7) ppm. HRMS-ESI-TOF (m/z): [M.sup.+Br.sup.] calculated for C.sub.27H.sub.33N.sub.2O.sub.4S, 481.2156; found 481.2155.
(104) ##STR00070##
Example 253-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(4-methylphenylsulfonamido) propyl)propan-1-aminium bromide (2c)
(105) This compound was synthesized using N-(3-(dimethylamino)propyl)-4-methylphenyl)sulfonamide (1.05 g, 4.1 mmol) and 4-(3-bromopropoxy)benzophenone (1.417 g, 4.44 mmol) in ACN (10 mL) for 48 hours; yielding in viscous pale yellow solution. The product was obtained as fluffy pale yellow powder after washing with Et.sub.2O (10 mL3) and drying under 10.sup.3 mm Hg vacuum at room temperature. Yield: 80% (1.88 g). .sup.1H NMR (CDCl.sub.3, 400 MHz, ): 7.80 (d, 2H, J.sub.4-2=8.2 Hz, H4), 7.73-7.65 (m, 4H, H16 & H20), 7.56-7.59 (m, 1H, H22), 7.42 (t, J.sub.4-2=7.2 Hz 2H, H22), 7.21 (d, 2H, J.sub.2-4=8.2 Hz, H2), 6.89 (d, 2H, J.sub.15-16=8.8 Hz, H15), 4.12 (t, 2H, J.sub.13-12=5.4 Hz, H13), 3.79-3.59 (m, 4H, H9 & H11), 3.29 (s, 6H, H10), 3.07-2.90 (m, 2H, H7), 2.35-2.23 (m, 5H, H1 & H12), 2.19-2.03 (m, 2H, H8) ppm. .sup.13C {.sup.1H} NMR (CDCl.sub.3, 100 MHz, ): 195.57 (C18), 161.82 (C14), 143.50 (C3), 138.05 (C5), 136.53 (C19), 132.54 (C16), 132.19 (C22), 130.69 (C17), 129.90 (C20), 129.80 (C2), 128.36 (C21), 127.34 (C4), 114.32 (C15), 64.71 (C13), 62.53 (C9), 62.11 (C11), 51.62 (C10), 40.01 (C7), 23.15 (C12), 22.75 (C8), 21.57 (C1) ppm. HRMS-ESI-TOF (m/z): [M.sup.+Br.sup.] calculated for C.sub.28H.sub.35N.sub.2O.sub.4S, 495.2312; found 495.2319.
(106) ##STR00071##
Example 263-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(2,4,6-trimethylphenylsulfonamido) propyl)propan-1-aminium bromide (3c)
(107) This compound was synthesized using N-(3-(dimethylamino)propyl)-2,4,6-trimethylphenyl)sulfonamide (0.853 g, 3.0 mmol) and 4-(3-bromopropoxy)benzophenone (1.0 g, 3.13 mmol) in ACN (10 mL) for 48 hours; yielding in viscous pale yellow solution. The product was obtained as fluffy white powder after washing with Et.sub.2O (10 mL3) and drying under 10-mm Hg vacuum at room temperature. Yield: 67% (1.20 g). .sup.1H NMR (CDCl.sub.3, 400 MHz, ): 7.76 (d, 2H, J.sub.17-16=8.7 Hz, H17), 7.72 (d, 2H, J.sub.21-22=7.2 Hz, H21), 7.56 (t, 2H, J.sub.23-22=7.4 Hz, H23), 7.49-7.41 (m, 2H, H22), 7.22 (t, 1H, J.sub.4-2=6.2 Hz, H7), 6.94 (t, 2H, J.sub.16-17=6.0 Hz, H16), 6.90 (s, 2H, H3), 4.21 (t, 2H, J.sub.14-13=5.4 Hz, H14), 3.90-3.80 (m, 2H, H10), 3.80-3.68 (m, 2H, H12), 3.37 (s, 6H, H11), 3.04 (dd, 2H, J.sub.8-7=11.4 Hz, J.sub.8-9=5.7 Hz, H8), 2.63 (s, 6H, H4), 2.43-2.32 (m, 2H, H13), 2.25 (s, 3H, H1), 2.23-2.13 (m, 2H, H9) ppm. .sup.13C {.sup.1H} NMR (CDCl.sub.3, 100 MHz, ): 195.63 (C19), 161.81 (C15), 142.40 (C5), 139.24 (C2), 138.15 (20), 133.41 (C6), 132.66 (C17), 132.22 (C23), 132.18 (C3), 130.91 (C18), 129.90 (C21), 128.39 (C22), 64.72 (C14), 62.68 (C10), 62.29 (C12), 51.77 (C11), 39.36 (C8), 23.42 (C4), 23.27 (C13), 23.05 (C9), 21.03 (C1) ppm. HRMS-ESI-TOF (m/z): [M.sup.+Br.sup.] calculated for C.sub.30H.sub.39N.sub.2O.sub.4S, 523.2625; found 523.2636.
(108) ##STR00072##
Example 273-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(2,4,6-triisopropylphenylsulfon amido)propyl)propan-1-aminium bromide (4c)
(109) This compound was synthesized using N-(3-(dimethylamino)propyl)-2,4,6-triisopropylbenzenesulfonamide (0.379 g, 1.03 mmol) and 4-(3-bromopropoxy)benzophenone (0.329 g, 1.03 mmol) in ACN (10 mL) for 48 hours; yielding in viscous pale yellow solution. The product was obtained as fluffy pale white powder after washing with Et.sub.2O (10 mL3) and drying under 10.sup.3 mm Hg vacuum at room temperature. Yield: 92% (0.65 g). .sup.1H NMR (CDCl.sub.3, 400 MHz, ): 7.78-765 (m, 4H, H18 & H22), 7.57-7.49 (m, 1H, H24), 7.43 (t, 2H, J.sub.23-22=7.5 Hz, H23), 7.12 (s, 2H, H4), 7.06 (t, 1H, J.sub.8-9=6.1 Hz, H8), 6.93 (d, 2H, J.sub.17-18=8.9 Hz, H17), 4.20 (t, 2H, J.sub.15-14=5.5 Hz, H15), 4.16-4.05 (m, 2H, H6), 3.90-3.81 (m, 2H, H11), 3.80-3.69 (m, 2H, H13), 3.39 (s, 6H, H12), 3.10 (dd, 1H, J.sub.9-8=11.3 Hz, J.sub.9-10=5.7 Hz, H9), 2.91-2.79 (m, 2H, H2), 2.45-2.31 (m, 2H, H14), 2.28-2.14 (m, 2H, H10), 1.21 (dd, 18H, J.sub.1-2=6.8 Hz, J.sub.1a-6=2.3 Hz, H1 & H1a) ppm. .sup.13C {.sup.1H} NMR (CDCl.sub.3, 100 MHz, ): 195.55 (C20), 161.75 (C16), 152.76 (C3), 150.33 (C7), 138.01 (C21), 132.50 (C18), 132.06 (C24), 131.96 (C5), 130.66 (C19), 129.74 (C22), 128.24 (C23), 123.88 (C4), 114.22 (C17), 64.67 (C15), 62.49 (C11), 62.03 (C13), 51.66 (C12), 39.47 (C9), 34.10 (C2), 29.54 (C6), 25.12 (C1), 23.14 (C14), 23.07 (C10) ppm. HRMS-ESI-TOF (m/z): [M.sup.+Br.sup.] calculated for C.sub.36H.sub.51N.sub.2O.sub.4S, 607.3564; found 607.3555.
(110) ##STR00073##
Example 283-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(naphthalene-1-sulfonamido) propyl)propan-1-aminium bromide (5c)
(111) This compound was synthesized using N-(3-(dimethylamino)propyl)naphthalene-1-sulfonamide (0.584 g, 2.0 mmol) and 4-(3-bromopropoxy)benzophenone (0.702 g, 2.2 mmol) in ACN (10 mL) for 48 hours; yielding in viscous pale yellow solution. The product was obtained as fluffy white powder after washing with Et.sub.2O (10 mL3) and drying under 10.sup.3 mm Hg vacuum at room temperature. Yield: 82% (1.0 g). .sup.1H NMR (CDCl.sub.3, 400 MHz, ): 8.80 (d, 1H, J.sub.1-2=8.7 Hz, H1), 8.15 (d, 1H, J.sub.8-7=7.3 Hz, H8), 7.96 (s, 1H, H11), 7.91 (d, 1H, J.sub.8-7=8.3 Hz, H6), 7.78 (d, 1H, J.sub.4-3=8.2 Hz, H4), 7.70-7.55 (m, 4H, (H2, H25, & H21)), 7.51 (t, 2H, J.sub.27-26=7.4 Hz, H27), 7.46-7.34 (m, 4H, (H3, H26, & H7), 6.77 (d, 2H, J.sub.20-21=8.7 Hz, H20), 4.00-3.85 (m, 2H, H18), 3.59-3.37 (m, 4H, H14 & H16), 3.19-2.91 (m, 8H, H15 & H12), 2.17-1.99 (m, 2H, H17), 1.97-1.76 (m, 2H, H13) ppm. .sup.13C {.sup.1H} NMR (CDCl.sub.3, 100 MHz, ): 195.59 (C23), 161.77 (C19), 138.04 (C24), 134.85 (C9), 134.21 (C6), 132.50 (C25), 132.20 (C27), 130.56 (C10), 129.80 (C2), 129.36 (C8), 129.05 (C4), 128.76 (C21), 128.37 (C7), 128.00 (C22), 127.18 (C3), 125.20 (C1), 124.52 (C26), 114.25 (C20), 64.59 (C18), 62.42 (C14), 62.10 (C16), 51.42 (15), 39.83 (C12), 22.92 (C17 & C13) ppm. HRMS-ESI-TOF (m/z): [M.sup.+Br.sup.] calculated for C.sub.31H.sub.35N.sub.2O.sub.4S, 531.2312; found 531.2328.
(112) ##STR00074##
Example 293-(4-benzoylphenoxy)-N-(3-(ethylsulfonamido)propyl)-N,N-dimethylpropan-1-aminium bromide (7c)
(113) This compound was synthesized using N-(3-(dimethylamino)propyl)ethanesulfonamide (0.250 g, 1.29 mmol) and 4-(3-bromopropoxy)benzophenone (0.411 g, 1.29 mmol) in ACN (10 mL) for 48 hours; yielding in viscous pale yellow solution. The product was obtained as fluffy pale yellow powder after washing with Et.sub.2O (10 mL3) and drying under 10.sup.3 mm Hg vacuum at room temperature. Yield: 77% (0.52 g). .sup.1H NMR (CDCl.sub.3, 400 MHz, ): 7.78 (d, 2H, J.sub.13-12=8.7 Hz, H13), 7.72 (d, 2H, J.sub.17-18=7.4 Hz, H17), 7.56 (t, 2H, J.sub.19-18=7.4 Hz, H19), 7.50-7.40 (m, 2H, H18), 7.12 (t, 1H, J.sub.34=6.0 Hz, H3), 6.98 (d, 2H, J.sub.12-13=8.8 Hz, H12), 4.21 (t, 2H, J.sub.10-9=5.3 Hz, H10), 3.86-3.75 (m, 2H, H6), 3.75-3.65 (m, 2H, H8), 3.35 (s, 6H, H7), 3.31-3.22 (m, 2H, H4), 3.07 (q, 2H, J.sub.2-3=7.3 Hz, H2), 2.43-2.29 (m, 2H, H9), 2.27-2.13 (m, 2H, H5), 1.34 (t, 3H, J.sub.2-3=7.4 Hz, H1) ppm. .sup.13C {.sup.1H} NMR(CDCl.sub.3, 100 MHz, ): 195.55 (C15), 161.66 (C11), 137.94 (C16), 132.55 (C13), 132.16 (C19), 130.83 (C14), 129.78 (C17), 128.29 (C18), 114.22 (C12), 64.57 (C10), 62.46 (C6), 62.17 (C5), 51.61 (C7), 46.44 (C2), 39.95 (C4), 23.64 (C5), 23.11 (C9), 8.27 (C1) ppm. HRMS-ESI-TOF (m/z): [M.sup.+Br.sup.] calculated for C.sub.23H.sub.33N.sub.2O.sub.4S, 433.2156; found 433.2153.
(114) ##STR00075##
Example 303-(4-benzoylphenoxy)-N-(3-(butylsulfonamido)propyl)-N,N-dimethylpropan-1-aminium bromide (8c)
(115) This compound was synthesized using N-(3-(dimethylamino)propyl)butane-1-sulfonamide (0.324 g, 1.46 mmol) and 4-(3-bromopropoxy)benzophenone (0.466 g, 1.46 mmol) in ACN (10 mL) for 48 hours; yielding in viscous pale yellow solution. The product was obtained as fluffy pale yellow powder after washing with Et.sub.2O (10 mL3) and drying under 10.sup.3 mm Hg vacuum at room temperature. Yield: 73% (0.58 g). .sup.1H NMR (CDCl.sub.3, 400 MHz, ): 7.74 (d, 2H, J.sub.15-14=8.7 Hz, H15), 7.69 (d, 2H, J.sub.19-20=7.1 Hz, H19), 7.54 (t, 1H, J.sub.21-20=7.4 Hz, H21), 7.47-7.38 (m, 2H, H20), 7.10 (t, 1H, J.sub.5-6=5.6 Hz, H5), 6.96 (d, 2H, J.sub.14-15=8.8 Hz, H14), 4.18 (t, 1H, J.sub.12-11=5.2 Hz, H12), 3.79-3.61 (m, 2H, H8 & H10), 3.33 (s, 6H, H9), 3.27-3.20 (m, 2H, H6), 3.10-2.96 (m, 2H, H4), 2.42-2.25 (m, 2H, H11), 2.25-2.07 (m, 2H, H7), 1.80-1.65 (m, 2H, H3), 1.38 (dq, 2H, J.sub.2-3=14.6 Hz, J.sub.2-1=7.4 Hz, H2), 0.87 (t, 3H, J.sub.1-2=7.3 Hz, H1) ppm. .sup.13C {.sup.1H} NMR (CDCl.sub.3, 100 MHz, ): 195.56 (C17), 161.17 (C13), 137.89 (C18), 132.50 (C15), 132.16 (C21), 130.62 (C16), 129.71 (C19), 128.29 (C20), 114.27 (C14), 64.67 (C12), 62.30 (C8), 61.96 (C10), 51.79 (C4), 51.56 (C9), 25.37 (C3), 23.55 (C7), 23.05 (C11), 21.51 (C2), 13.64 (C1) ppm. HRMS-ESI-TOF (m/z): [M.sup.+Br.sup.] calculated for C.sub.25H.sub.37N.sub.2O.sub.4S, 461.2469; found 461.2458.
(116) ##STR00076##
Example 313-(4-benzoylphenoxy)-N-(3-((N,N-dimethylsulfamoyl)amino)propyl)-N,N-dimethylpropan-1-aminium bromide (9c)
(117) This compound was synthesized using N-(2-(dimethylamino)propyl)-N,N-Dimethyl-sulfamide (0.232 g, 1.11 mmol) and 4-(3-bromopropoxy)benzophenone (0.354 g, 1.11 mmol) in ACN (10 mL) for 48 hours; yielding in viscous pale yellow solution. The product was obtained as fluffy pale yellow powder after washing with Et.sub.2O (10 mL3) and drying under 10.sup.3 mm Hg vacuum at room temperature. Yield: 60% (0.36 g). .sup.1H NMR (CDCl.sub.3, 400 MHz, ): 7.70 (d, 2H, J.sub.12-11=8.7 Hz, H12), 7.65 (d, 2H, J.sub.16-17=7.2 Hz, H16), 7.51 (t, 1H, J.sub.18-17=7.4 Hz, H18), 7.44-7.36 (m, 2H, H17), 7.03-6.87 (m, 3H, H11 & H2), 4.15 (t, 2H, J.sub.9-8=4.7 Hz, H9), 3.71-3.53 (m, 4H, H5 & H7), 3.28 (s, 6H, H6), 3.20-3.12 (m, 2H, H3), 2.72 (s, 6H, H1), 2.37-2.22 (m, 2H, H8), 2.19-2.02 (m, 2H, H4) ppm. .sup.13C {.sup.1H} NMR (CDCl.sub.3, 100 MHz, ): 195.62 (C14), 161.88 (C9), 137.87 (C15), 132.50 (C12), 132.17 (C18), 130.49 (C13), 129.73 (C16), 128.30 (C17), 114.35 (C11), 64.82 (C9), 62.24 (C5), 61.76 (C7), 51.62 (C6), 40.18 (C3), 38.15 (C1), 23.06 (C4), 22.97 (C8) ppm. HRMS-ESI-TOF (m/z): [M.sup.+Br.sup.] calculated for C.sub.23H.sub.34N.sub.3O.sub.4S, 448.2265; found 448.2262.
Example 31AN-(3-(4-benzoylphenoxy)propyl)-3-((7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methylsulfonamido)-N,N-dimethylpropan-1-ide-1-aminium, bromide salt
(118) ##STR00077##
(119) This compound was synthesized using 1-(7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)-N-(3-(dimethylamino)propyl)methanesulfonamide (1.32 g, 4.187 mmol) and 4-(3-bromopropoxy)benzophenone (1.403 g, 4.39 mmol, 1.05 eq.) in refluxing EtOAc (10 mL) for 3 hours; yielding a viscous pale yellow oil. The product was obtained as fluffy white powder after purification. Yield: 58% (1.535 g), Mp=33-34 C. .sup.1H NMR (CDCl.sub.3, 400 MHz, ): 7.80-7.73 (m, 2H, H3), 7.73-7.58 (m, 2H, H7), 7.48 (s, 1H, H1), 7.43-7.37 (m, 2H, H2), 7.09-6.95 (m, 2H, H8), 4.04-4.00 (m, 2H, H10), 3.69 (s, 1H, H18), 3.54-3.39 (m, 5H, H18, H12, H14), 3.36-3.32 (m, 6H, H13), 2.76 (d, J=7.4 Hz, 2H, H16), 2.36 (s, 1H), 2.22-2.18 (m, 2H, H11), 2.11 (s, 1H), 2.03 (dd, J=19.1, 0.6 Hz, 4H), 1.83 (s, 1H, H25), 1.59 (s, 1H, H24), 1.34 (s, 1H, H24), 1.11 (s, 3H, H22), 1.08 (m, 3H, H22) ppm.
Example 32Application and Curing of Benzophenone-Anchored Antimicrobials to Test Surfaces
(120) 1% (w/v) solutions of the benzophenone-anchored sulfonamide quaternary ammonium cation (QUAT) antimicrobials were prepared by dissolving the desired antimicrobial compound within a range of ethanol:water mixture between 10:90 to 40:60, depending on the solubility of the antimicrobial compound. An emphasis was made to reduce ethanol content where applicable. Coating of the test samples, which consisted of 25 mm (5 mm)25 mm (5 mm)1 mm coupons of each plastic material, was performed via an ESS AD-LG electrospray apparatus set to 150 kPa that applied the compound uniformly over the test surfaces. After application, the coated surfaces were allowed to air-dry before proceeding to a UV curing step which involved exposing the surfaces to 5000 mW intensity UV light for 1 minute. This coating and curing sequence was repeated a second time to ensure adequate coverage of the compound, as confirmed with bromophenol blue staining which allowed for visualization of the surface-bound sulfonamide QUAT compound. Stock polystyrene and polyethylene material was supplied by VWR International, polyvinyl chloride was sourced from Home Depot and polyether ether ketone was sourced from Drake Plastics.
Example 33Application and Curing of Silicone-Anchored Antimicrobials to Test Surfaces
(121) 1% (w/v) solutions of the silane-anchored sulfonamide QUAT antimicrobials were prepared in a range of methanol:water mixtures between 30:70 to 70:30, depending on the solubility of the antimicrobial compound. An emphasis was made to reduce methanol content where applicable. Coating of the test samples was performed via gently heating and agitating cotton samples at 40 C. within the coating solution for 5 minutes. After application, the coated surfaces were allowed to air-dry before rinsing with water. Coating quality of the treated cotton samples was confirmed with bromophenol blue staining, which allowed for visualization of the surface-bound sulfonamide QUAT compound. Stock cotton fabric was supplied by META Labware.
Example 34Testing Antimicrobial Efficacy at Solid-Air Interfaces
(122) Large-droplet inoculation method (Ronan E. et al, Biofouling 2013, 29, 1087-1096) Many pathogens are able to remain viable during extended periods of desiccation on inanimate surfaces. Long-term survival of pathogens in the inanimate environment pose a significant risk for infection transmission and contamination in high-risk environments such as hospital rooms or food-processing plants. The large-droplet inoculation method was developed to simulate the deposition of bacterial species onto exposed surfaces and to determine the ability of these cells to survive desiccation.
(123) For these tests, small surface coupons were first coated with the antimicrobial using the method described above. Bacterial test species were grown overnight in a shaking incubator and cultures
(124) were washed twice to replace the growth media with sterile water. 100 L aliquots of the prepared culture were then inoculated onto multiple coated surfaces and allowed to air-dry within a biological safety cabinet. Drying typically occurred 2-3 hours after inoculation, and surviving cells were enumerated immediately and 24 hours after drying. For enumeration, inoculated coupons were sacrificed in triplicate and placed inside separate tubes containing 5 mL of a 0.9% saline collection liquid. Each coupon was agitated vigorously for 1 minute with a bench-top vortex to transfer cells from the test surface to the collection liquid. Plate counts were then performed on serial dilutions of the collection liquid, and colony counts from triplicate treated surfaces were averaged and compared to colony counts from tests of untreated control surfaces carried out in parallel.
(125) A range of bacterial species were used in these tests. Arthrobacter spp., a gram-positive lab strain originally isolated from indoor air was used in the bulk of the testing, as it is known to be highly resistant to desiccation and therefore was used as a model for desiccation-tolerant pathogens. Efficacy tests were also carried out against, for example, gram-negative Escherichia coli (E. coli) and gram-positive Staphylococcus aureus (S. aureus), since they all contain pathogenic strains and have been implicated in major nosocomial outbreaks.
(126) TABLE-US-00001 A (cfu) B (cfu) C (cfu) Average Deviation Polystyrene Control 0 hours (Load) 1.28E+08 1.28E+08 1.28E+08 1.28E+08 0.00E+00 3 hours 9.75E+06 7.65E+06 8.60E+06 8.67E+06 1.05E+06 24 hours 7.75E+03 9.10E+03 2.50E+02 5.70E+03 4.77E+03 Polystyrene Mesityl 0 hours (Load) 1.28E+08 1.28E+08 1.28E+08 1.28E+08 0.00E+00 3 hours 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 24 hours 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 Cotton Control 0 hours (Load) 1.28E+08 1.28E+08 1.28E+08 1.28E+08 0.00E+00 3 hours 2.20E+06 1.65E+06 2.75E+06 2.20E+06 5.50E+05 24 hours 5.60E+05 2.65E+05 3.10E+05 3.78E+05 1.59E+05 Cotton Tosyl 0 hours (Load) 1.28E+08 1.28E+08 1.28E+08 1.28E+08 0.00E+00 3 hours 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 24 hours 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00
(127)
(128) TABLE-US-00002 A (cfu) B (cfu) C (cfu) Average Deviation Cotton Control 0 hours 4.04E+07 4.04E+07 4.04E+07 4.04E+07 0.00E+00 (Load) 3 hours 1.76E+03 1.92E+04 7.60E+03 9.50E+03 8.85E+03 24 hours 1.20E+02 0.00E+00 0.00E+00 4.00E+01 6.92E+01 Cotton Mesityl 0 hours 4.04E+07 4.04E+07 4.04E+07 4.04E+07 0.00E-1-00 (Load) 3 hours 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 24 hours 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 Cotton Tosyl 0 hours 4.04E+07 4.04E+07 4.04E+07 4.04E+07 0.00E+00 (Load) 3 hours 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 24 hours 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 Cotton Control 0 hours 6.10E+07 6.10E+07 6.10E+07 6.10E+07 0.00E+00 (Load) 3 hours 8.75E+04 2.70E+05 3.15E+05 2.24E+05 1.20E+05 24 hours 6.95E+04 5.85E+04 7.15E+04 6.65E+04 7.00E+03 Cotton Benzyl 0 hours 6.10E+07 6.10E+07 6.10E+07 6.10E+07 0.00E+00 (Load) 3 hours 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 24 hours 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 Cotton Naphthyl 0 hours 6.10E+07 6.10E+07 6.10E+07 6.10E+07 0.00E+00 (Load) 3 hours 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 24 hours 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00
(129)
(130) TABLE-US-00003 A (cfu) B (cfu) C (cfu) Average Deviation Polyethylene Control 0 hours (Load) 2.70E+07 2.70E+07 2.70E+07 2.70E+07 0.00E+00 3 hours 1.80E+04 7.00E+06 9.00E+05 2.64E+06 3.80E+06 24 hours 4.00E+02 7.00E+02 5.00E+02 5.33E+02 1.53E+02 Polyethylene Naphthyl 0 hours (Load) 2.70E+07 2.70E+07 2.70E+07 2.70E+07 0.00E+00 3 hours 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 24 hours 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 Polyethylene Control 0 hours (Load) 2.70E+07 2.70E+07 2.70E+07 2.70E+07 0.00E+00 3 hours 1.80E+04 7.00E+06 9.00E+05 2.64E+06 3.80E+06 24 hours 4.00E+02 7.00E+02 5.00E+02 5.33E+02 1.53E+02 Polyethylene Phenyl 0 hours (Load) 2.70E+07 2.70E+07 2.70E+07 2.70E+07 0.00E+00 3 hours 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 24 hours 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00
(131)
(132) TABLE-US-00004 A (cfu) B (cfu) C (cfu) Average Deviation E. coli Control 0 hours (Load) 5.05E+07 5.05E+07 5.05E+07 5.05E+07 0.00E+00 3 hours 5.00E+02 2.50E+02 4.50E+02 4.00E+02 1.32E+02 24 hours 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 E. coil Mesityl 0 hours 5.05E+07 5.05E+07 5.05E+07 5.05E+07 0.00E+00 3 hours 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 24 hours 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 S. aureus Control 0 hours (Load) 8.30E+05 8.30E+05 8.30E+05 8.30E+05 0.00E+00 3 hours 1.10E+04 7.50E+03 8.00E+03 8.83E+03 1.89E+03 24 hours 1.14E+04 3.20E+03 1.95E+03 5.52E+03 5.13E+03 S. aureus Mesityl 0 hours (Load) 8.30E+05 8.30E+05 8.30E+05 8.30E+05 0.00E+00 3 hours 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 24 hours 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00
(133)
(134) TABLE-US-00005 A (cfu) B (cfu) C (cfu) Average Deviation Polyethylene Control 0 hours 4.63E+08 4.63E+08 4.63E+08 4.63E+08 0 (Load) 3 hours 4.20E+06 8.55E+06 9.10E+06 7.28E+06 2.68E+06 Polyethylene Treated 0 hours 4.63E+08 4.63E+08 4.63E+08 4.63E+08 0 (Load) 3 hours 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0
Example 34Testing Antimicrobial Efficacy at Static Solid-Liquid Interfaces
Static Biofilm Tests
(135) The interior of polyethylene test tubes was coated with the sulfonamide QUAT antimicrobial similarly as in Example 32. Tubes were filled with 2.7 mL of growth media (3 g/L TSB) into which 300 L of Arthrobacter spp. bacterial culture was inoculated. Planktonic cells were sampled after 48 hours of incubation and agitation by removing 100 L aliquots from each tube. After 48 hours, the liquid in each tube was removed completely so that biofilm attachment to the interior of the tubes could be assessed. To test for biofilm attachment the tubes were first gently rinsed in a saline solution to remove any loosely attached or residual planktonic cells. Next, 1 mL of saline solution was added to each tube before the tubes were vortexed vigorously for 1 minute to transfer biofilm cells to the collection liquid. Plate counts were then performed on serial dilutions of this collection liquid. Planktonic and biofilm colony counts from triplicate coated tubes were averaged and compared to colony counts from tests of uncoated control tubes carried out in parallel.
(136) After 14 days of exposure to ambient air, the tubes used in the above test were subjected to a second static biofilm test as described above, without reapplying the antimicrobial. This test was performed to determine whether the antimicrobial effects of the coating persisted following repeated exposures.
(137)
(138) TABLE-US-00006 A (cfu) B (cfu) C (cfu) Average Deviation Initial Planktonic Control 0 hours 7.75E+08 7.75E+08 7.75E+08 7.75E+08 0.00E+00 (Load) 48 hours 1.48E+08 1.58E+08 1.59E+08 1.55E+08 6.08E+06 Initial Planktonic Treated 0 hours 7.75E+08 7.75E+08 7.75E+08 7.75E+08 0.00E+00 (Load) 48 hours 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 Rechallenge Planktonic Control 0 hours 8.00E+08 8.00E+08 8.00E+08 8.00E+08 0.00E+00 (Load) 48 hours 2.88E+08 1.61E+09 2.93E+09 1.61E+09 1.32E+09 Rechallenge Planktonic Treated 0 hours 8.00E+08 8.00E+08 8.00E+08 8.00E+08 0.00E+00 (Load) 48 hours 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00
(139)
(140) TABLE-US-00007 A (cfu) B (cfu) C (cfu) Average Deviation Initial Biofilm Control 0 hours 7.75E+08 7.75E+08 7.75E+08 7.75E+08 0.00E+00 (Load) 48 hours 9.00E+04 1.10E+05 6.20E+05 2.73E+05 3.00E+05 Iniitial Biofilm Treated 0 hours 7.75E+08 7.75E+08 7.75E+08 7.75E+08 0.00E+00 (Load) 48 hours 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 Rechallenge Biofilm Control 0 hours 8.00E+08 8.00E+08 8.00E+08 8.00E+08 0.00E+00 (Load) 48 hours 8.90E+06 7.20E+06 6.70E+06 7.60E+06 1.15E+06 Rechallenge Biofilm Treated 0 hours 8.00E+08 8.00E+08 8.00E+08 8.00E+08 0.00E+00 (Load) 48 hours 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00
(141) As many changes can be made to the preferred embodiment of the above without departing from the scope thereof, it is intended that all matter contained herein be considered illustrative and not in a limiting sense.