COMPOUNDS AND METHODS FOR REPELLING BLOOD-FEEDING ARTHROPODS AND DETERRING THEIR LANDING AND FEEDING
20210322291 · 2021-10-21
Inventors
Cpc classification
A01N37/18
HUMAN NECESSITIES
International classification
A01N37/18
HUMAN NECESSITIES
Abstract
This invention relates to a group of compounds for repelling blood-feeding ectoparasitic arthropods, and a method of deterring their landing and feeding on animals including humans, by applying in one or more formulations compounds that incorporate one or more sulfide and one or more hydroxyl groups to the skin, clothing or environment of animals, including humans. A method of repelling and deterring landing and feeding by blood-feeding arthropods on an animal by applying in effective amount one or more compounds that incorporate alkyl sulfide and alcohol moieties, or alkyl sulfide and amide moieties, or alkyl sulfide and amide moieties to the skin, clothing or environment of an animal.
Claims
1. A method of repelling and deterring landing and feeding by blood-feeding arthropods on an animal by applying in effective amount one or more compounds that incorporate alkyl sulfide and alcohol moieties, or alkyl sulfide and amide moieties, or allyl sulfide and amide moieties to the skin, clothing or environment of an animal.
2. The method of claim 1 wherein compounds that incorporate alkyl sulfide and alcohol moieties are aliphatic primary, secondary or tertiary alcohols with alkylsulfide moiety.
3. The methods of claim 1-2, wherein said blood-feeding arthropod repellent and deterrent compounds are selected from the group including, but not limited to, the following: 8-methylsulfanyloctan-1-ol, 8-ethylsulfanyloctan-1-ol, 8-propylsulfanyloctan-1-ol, 8-butylsulfanyloctan-1-ol, 8-pentylsulfanyloctan-1-ol, (N,N)-diethyl-8-allylsulfanyl-octanamide.
4. The methods of claims 1-2, wherein effective amounts of said compounds that incorporate alkyl sulfide and alcohol moieties, or alkyl sulfide and amide moieties, or allyl sulfide and amide moieties are combined with one or more additional compounds applied in effective amount to improve the repellent and deterrent effect against landing and feeding by blood-feeding arthropods.
5. The methods of claims 1-4, wherein the blood-feeding arthropods include, but are not limited to, ticks and mites in the Order Acari (also known as Acarina) and insects in the Orders Mallophaga, Anoplura, Siphonaptera, Hemiptera (Families Cimicidae and Reduviidae), and Diptera (Families Culicidae, Tabanidae, Psychodidae, Simuliidae, Muscidae and Ceratopogonidae).
6. The methods of claim 1-4, wherein the blood-feeding insects in the family Culicidae include, but are not limited to, species in the genera Aedes, Culex, Anopheles, Chagasia, Bironella, Culiseta, Ochlerotatus, Psorophora, Toxorhynchites, Mansonia, and Coquillettidia.
7. The method of claim 6, wherein the insects can be Aedes aegypti, Anopheles gambiae and Culex quinquefasciatus.
8. The methods of claims 1-4, wherein the animal can be a mammal, bird, reptile or amphibian.
9. The method of claim 8, wherein the mammal can be a human.
10. The methods of claims 1-4, wherein the environment of an animal may include, but not be limited to, bedding, furniture, dwellings and vehicles.
11. The methods of claims 1-4, wherein effective amount of said blood-feeding arthropod repellent and deterrent compounds can range from 1 nanogram to 100 milligrams per square centimeter of skin, clothing or environmental substrate.
12. The methods of claims 1-4, wherein said blood-feeding arthropod repellent and deterrent compounds are formulated in effective amount with a carrier material for application to the skin, clothing or environment of an animal.
13. A composition for repelling and deterring landing and feeding by blood-feeding arthropods on an animal comprising an effective amount one or more compounds that incorporate alkyl sulfide and alcohol moieties, or alkyl sulfide and amide moieties, or allyl sulfide and amide moieties.
14. The composition of claim 13 wherein the compounds that incorporate alkyl sulfide and alcohol moieties are aliphatic primary, secondary or tertiary alcohols with alkylsulfide moiety.
15. The compositions of claim 13-14, wherein the compounds are selected from the group including, but not limited to, the following: 8-methylsulfanyloctan-1-ol, 8-ethylsulfanyloctan-1-ol, 8-propylsulfanyloctan-1-ol, 8-butylsulfanyloctan-1-ol, 8-pentylsulfanyloctan-1-ol, (N,N)-diethyl-8-allylsulfanyl-octanamide.
16. The compositions of claims 13-14, wherein effective amounts of said compounds that incorporate alkyl sulfide and alcohol moieties, or alkyl sulfide and amide moieties, or allyl sulfide and amide moieties are combined with one or more additional compounds applied in effective amount to improve the repellent and deterrent effect of the compounds.
17. The compositions of claims 13-16, wherein the blood-feeding arthropods include, but are not limited to, ticks and mites in the Order Acari (also known as Acarina) and insects in the Orders Mallophaga, Anoplura, Siphonaptera, Hemiptera (Families Cimicidae and Reduviidae), and Diptera (Families Culicidae, Tabanidae, Psychodidae, Simuliidae, Muscidae and Ceratopogonidae).
18. The compositions of claim 13-16, wherein the blood-feeding arthropods are of the family Culicidae and include, but are not limited to, species in the genera Aedes, Culex, Anopheles, Chagasia, Bironella, Culiseta, Ochlerotatus, Psorophora, Toxorhynchites, Mansonia, and Coquillettidia.
19. The composition of claim 18, wherein the arthropods can be Aedes aegypti, Anopheles gambiae and Culex quinquefasciatus.
20. The compositions of claims 13-16, wherein the animal can be a mammal, bird, reptile or amphibian.
21. The composition of claim 20, wherein the mammal can be a human.
22. The compositions of claims 13-16, wherein the environment of an animal may include, but not be limited to, bedding, furniture, dwellings and vehicles.
23. The compositions of claims 13-16, wherein an effective amount of said blood-feeding arthropod repellent and deterrent compounds can range from 1 nanogram to 100 milligrams per square centimeter of skin, clothing or environmental substrate.
24. The compositions of claims 13-16, wherein said blood-feeding arthropod repellent and deterrent compounds are formulated in effective amount with a carrier material for application to the skin, clothing or environment of an animal.
Description
DESCRIPTION OF THE DRAWINGS
[0018]
[0019]
[0020]
DETAILED DESCIRIPTION OF THE INVENTION
[0021] The inventors' own research (Gries et al. 2008) has shown that 9-allylsulfanylnonan-1-ol, 8-allylsulfanyloctan-2-ol, and 8-allylsulfanyloctan-1-ol are repellent to mosquitoes.
[0022] In this application, the inventors disclose the discovery of a new set of compounds, including 8-methylsulfanyloctan-1-ol, 8-ethylsulfanyloctan-1-ol, 8-propylsulfanyloctan-1-ol, 8-butylsulfanyloctan-1-ol, 8-pentylsulfanyloctan-1-ol and (N,N)-diethyl-8-allylsulfanyl-octanamide that among other insects are deterrent to mosquitoes.
[0023]
EXAMPLE 1
Experimental Insects
[0024] A black-eyed Liverpool strain of Aedes aegypti was obtained from Dr. Carl Lowenberger, Simon Fraser University (SFU). Insects were reared under standardized conditions (60-70% relative humidity, 26-28° C., 14 h light:10 h dark photoperiod) in SFU's insectary. Neonate larvae that hatched in glass dishes of sterilized hypoxic water were transferred to trays of distilled water provisioned with Nutrafin® Basix Staple Food fish diet. Pupae were collected daily and separated by sex, and 15 females and 10 males were placed in a paper cup (7.5 cm diameter, 8.5 cm high) with a mesh lid. Emergent adults were fed a 10% (w/v) sucrose solution via braided cotton dental rolls. Arm-fed gravid females were offered water-containing paper cups, lined with paper-towel as an oviposition substrate.
EXAMPLE 2
General Bioassay Procedure
[0025] Candidate repellents and deterrents were bioassayed according to a modified protocol from the World Health Organization (1996). At least 1 hour prior to each bioassay, 75 host-seeking non blood-fed, nulliparous, 5- to 8-day-old female Aedes aegypti were placed into a wood-framed cage (26.5 cm on each side and 42.5 cm high) with a wooden floor, screened mesh sides and top, and a clear acrylic front fitted with a cotton stockinette sleeve (10 cm diameter). The test subject's arm was covered with an elbow-length polyethylene glove with an excised patch (16.6 cm long, 6 cm wide) to expose the ventral forearm of the test subject. Candidate deterrents were formulated in mineral (paraffin) oil and applied to the exposed forearm 5 min prior to inserting the arm into the cage. The inserted arm remained in the cage for 3 min every 30 min. Prior to each 3-min bioassay period, the hand of the untreated arm was inserted into the cage to ascertain that it received 10 bites within 30 sec as an indication of “biting pressure”.
[0026] The bioassay was terminated when the treated arm received ≥2 bites in one 3-min bioassay period or one bite in each of two consecutive bioassay periods. The time elapsed from experiment initiation to first bite was recorded as deterrent failure or complete protection time.
EXAMPLE 3
Synthesis of (N,N)-Diethyl-8-allylsulfanyl-octanamide (FIG. 2, Scheme 1)
[0027] A mixture of allylbromide (1, 1.30 ml, 15 mmol) and thiourea (1.45 g, 15 mmol) was refluxed in 50 ml of anhydrous ethanol for 3 hours and cooled to 25° C. Pellets of KOH (1.62 g, 30 mmol) were added together with water (0.30 ml). The reaction mixture was then refluxed for 2 hours. 8-Bromooctanoic acid was alkylated with potassium allylmercaptade (Jie et al. 1989) by adding to the reaction mixture 8-bromooctanoic acid (2.23 g, 10 mmol) and KOH (1.30 g), and refluxing for 5 hours under argon. Thereafter, water (50 ml) was added and the reaction mixture was extracted with hexane (2×40 ml). The aqueous solution was acidified with conc. HCl and extracted again with ether (2×40 ml). Ethereal extracts were washed with a saturated aq. NaCl solution and were dried over anh. MgSO.sub.4. Evaporation of solvents gave 8-allylsulfanyl-octanoic acid (2) (50% pure by GC); MS [m/z (rel. intensity)]: 216 (M+,100), 199 (26), 169 (20), 157 (37), 139 (18), 123 (19), 113 (49), 95(26), 87 (34), 74 (69), 55 (52), 45(62), 41 (69).
[0028] Without further purification, the crude acid was dissolved in dry benzene (50 ml), and freshly distilled thionyl chloride (1.50 ml) was added. The reaction mixture was warmed to 50° C. and stirred for 5 hours under argon. Excess thionyl chloride and benzene were removed in vacuo. The residue in 20 ml of ether was stirred at 0° C., and diethylamide (4 ml) was added slowly. After 20 min, water (10 ml) was added and the product was extracted (2×40 ml) with a 1:1 ether/hexane mixture. Extracts were washed with a saturated aq. NaCl solution, dried over anh. MgSO.sub.4, concentrated and purified by flash chromatography, using ether/hexane mixtures with increasing proportions of ether (40, 50 and 70%) as consecutive eluents. The yield of (N,N)-diethyl-8-allylsulfanyl-octanamide (3)(75% pure by GC) was 0.87 g (24% yield); MS [m/z (rel. intensity)]: 272 (M+1, 74), 230 (100), 198 (44), 157 (20), 126 (24), 115 (36), 100 (66), 74 (48), 58 (31), 44 (29).
EXAMPLE 4
Synthesis of 8-methylsulfanyl-1-octanol (FIG. 2, Scheme 2)
[0029] A 2.5 M BuLi solution (4 ml, 10 mmol) in hexane was added at −78° C. under stirring to 8-mercapto-1-octanol (4) (0.84 g, 4.76 mmol) (Narchem Corp., Chicago Ill.) dissolved in a 4:1 mixture of THF/HMPA. After 30 min, iodomethane (0.6 ml, 10 mmol) was added in one portion. The reaction mixture was allowed to warm to room temperature, quenched with water, and extracted with ether (2×30 ml). Ethereal extracts were washed with a saturated aq. NaCl solution, dried over anh. MgSO.sub.4, and concentrated. Purification by flash chromatography afforded 0.65 g of known 8-methylsulfanyl-1-octanol (5) (Bennett & Gudgeon 1938; Kawabato et al. 1989) (>99% pure by GC, 78% yield).
[0030] Other 8-alkylsulfanyl-1-octanols, including 8-methylsulfanyloctan-1-ol, 8-ethylsulfanyloctan-1-ol (compound previously known; Hu & Neckers, 1997), 8-propylsulfanyloctan-1-ol, 8-butylsulfanyloctan-1-ol and 8-pentylsulfanyloctan-1-ol were furnished in similar ways.
EXAMPLE 5
Synthesis of 8-propylsulfanyl-1-octanol (FIG. 2, Scheme 3)
[0031] 8-Propylsulfanyl-1-octanol (7) was produced via hydrogenation of 8-allylsulfanyl-1-octanol (6) (Gries et al. 2008) in hexanes with 5% Pd/C as a catalyst (quantitative yield).
EXAMPLE 6
Deterrence of Five 8-alkylsulfanyloctan-1-ols Against Aedes Aegypti
[0032] To determine the deterrence of 8-allylsulfanyloctan-1-ols against Aedes aegypti, a 10% formulation of either 8-methylsulfanyloctan-1-ol, 8-ethylsulfanyloctan-1-ol, 8-propylsulfanyloctan-1-ol, 8-butylsulfanyloctan-1-ol, or 8-pentylsulfanyloctan-1-ol in mineral oil was applied in Experiments 1-5 at a dose of 1.5 mg (total composition) per cm.sup.2 to the skin of the test person, and was bioassayed according to the protocol described under EXAMPLE 2. In Experiment 6, a 10% formulation of 8-allylsulfanyl-1-octanol (Gries et al. 2008) in mineral oil was bioassayed for comparison. Each of Experiments 1-6 was replicated 3-4 times.
[0033] In Experiments 1-5, 10% formulations of the 8-alkylsulfanyl-octan-1-ols in mineral oil provided protection from bites by Aedes egypti for an average duration ranging between 11-154 minutes (
[0034]
EXAMPLE 7
Deterrence of (N,N)-diethyl-8-allylsulfanyl-octanamide Against Aedes Aegypti
[0035] To determine the deterrence of (N,N)-diethyl-8-allylsulfanyl-octanamide against Aedes aegypti, a 10% formulation of (N,N)-diethyl-8-allylsulfanyl-octanamide in mineral oil was applied in Experiment 7 at a dose of 1.5 mg (total composition) per cm.sup.2 to the skin of the test person, and was bioassayed according to the protocol described under EXAMPLE 2. Experiment 7 was replicated 4 times.
[0036] In Experiment 7, a 10% formulation of (N,N)-diethyl-8-allylsulfanyl-octanamide in mineral oil provided protection from bites by Aedes egypti for an average duration of 156 min, which was slightly longer than the average duration of protection provided by 8-allylsulfanyl-1-octanol in Experiment 6.
[0037]
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