WO2008157552A2 - Inhibiteur d'acétylcholinestérase d'invertébrés - Google Patents

Inhibiteur d'acétylcholinestérase d'invertébrés Download PDF

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WO2008157552A2
WO2008157552A2 PCT/US2008/067236 US2008067236W WO2008157552A2 WO 2008157552 A2 WO2008157552 A2 WO 2008157552A2 US 2008067236 W US2008067236 W US 2008067236W WO 2008157552 A2 WO2008157552 A2 WO 2008157552A2
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coch
chch
alkyl
nhcoch
phch
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PCT/US2008/067236
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WO2008157552A3 (fr
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Yuan-Ping Pang
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Mayo Foundation For Medical Education And Research
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Priority claimed from US11/764,580 external-priority patent/US20080312091A1/en
Application filed by Mayo Foundation For Medical Education And Research filed Critical Mayo Foundation For Medical Education And Research
Priority to PCT/US2008/067236 priority Critical patent/WO2008157552A2/fr
Publication of WO2008157552A2 publication Critical patent/WO2008157552A2/fr
Publication of WO2008157552A3 publication Critical patent/WO2008157552A3/fr
Priority to US12/641,900 priority patent/US20100168114A1/en
Priority to US13/530,687 priority patent/US20120284004A1/en

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    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
    • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
    • A01N43/06—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
    • A01N43/707—1,2,3- or 1,2,4-triazines; Hydrogenated 1,2,3- or 1,2,4-triazines
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
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    • A01N47/28—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N<
    • A01N47/34—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N< containing the groups, e.g. biuret; Thio analogues thereof; Urea-aldehyde condensation products
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
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    • C07—ORGANIC CHEMISTRY
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    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
    • C07D253/06—1,2,4-Triazines
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
    • C—CHEMISTRY; METALLURGY
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
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    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/28—Oxygen atom
    • C07D473/30—Oxygen atom attached in position 6, e.g. hypoxanthine
    • C—CHEMISTRY; METALLURGY
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
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    • C40B30/00—Methods of screening libraries
    • C40B30/06—Methods of screening libraries by measuring effects on living organisms, tissues or cells
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
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    • G16B35/00—ICT specially adapted for in silico combinatorial libraries of nucleic acids, proteins or peptides
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
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    • G16C20/00—Chemoinformatics, i.e. ICT specially adapted for the handling of physicochemical or structural data of chemical particles, elements, compounds or mixtures
    • G16C20/60—In silico combinatorial chemistry
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16C—COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE
    • G16C20/00—Chemoinformatics, i.e. ICT specially adapted for the handling of physicochemical or structural data of chemical particles, elements, compounds or mixtures
    • G16C20/60—In silico combinatorial chemistry
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Definitions

  • TECHNICAL FIELD This invention relates to invertebrate acetylcholinesterase inhibitors, including insect, such as mosquito, acetylcholinesterase inhibitors, and methods for identifying the same, and more particularly to the use of a refined 3D model of the Anopheles gambiae acetylcholinesterase enzyme in the design and selection of invertebrate- and insect- specific acetylcholinesterase inhibitors.
  • Acetylcholinesterase (AChE), a serine hydrolase vital for regulating the neurotransmitter acetylcholine in mammals and in insects, has long been used as a target for pesticides.
  • the enzyme has a deep and narrow active site, the bottom and opening regions of which are known as catalytic and peripheral sites, respectively.
  • Current anticholinesterase pesticides for controlling pests including the African malaria-carrying mosquito (Anopheles gambiae), were developed during the World War II era. These pesticides are toxic to mammals because they target a catalytic serine residue of acetylcholinesterases (AChEs) that is present in both insects and in mammals, and thus the use of these pesticides has been severely limited.
  • the present disclosure is directed to, among other things, materials and methods for controlling, e.g., selectively killing, insect populations, e.g., to control insect-borne diseases and to limit or stop crop damage mediated by insects.
  • the present disclosure identifies conserved AChE target sites that are present in invertebrate, including insect such as mosquito, AChEs. Such regions can be used as better target sites for the design of new pesticides that would be devoid of the mammalian toxicity and resistance problems of current pesticides.
  • the 17 invertebrates having the cysteine include house mosquito, Japanese encephalitis mosquito, African malaria mosquito, German cockroach, Florida lancelet, rice leaf beetle, African bollworm, beet armyworm, codling moth, diamondback moth, domestic silkworm, honey bee, oat or wheat aphid, the greenbug, melon or cotton aphid, green peach aphid, and English grain aphid.
  • the 4 insect species having the arginine are house mosquito, Japanese encephalitis mosquito, African malaria mosquito, and German cockroach. These 4 insect species have both the cysteine and arginine that correspond to the R339 and C286 of A. gambiae.
  • invertebrate-specific residues enables the design of effective and safer pesticides that target one or more of the invertebrate (insect, e.g. , mosquito) AChE-specific residues, rather than the serine residue present in both insect and mammalian AChE enzymes, thus potentially offering an effective control of invertebrate-borne (e.g., insect-borne) diseases (e.g., mosquito-borne diseases such as malaria, encephalitis, and West Nile virus).
  • invertebrate-borne e.g., insect-borne
  • mosquito-borne diseases e.g., mosquito-borne diseases such as malaria, encephalitis, and West Nile virus.
  • compositions for use in eliminating or controlling insect populations that contribute to significant crop damage e.g., wheat, soybean, grain, sorghum, barley, oat, peach, or melon damage caused by insects such as aphids, are also described.
  • a computer-assisted method of generating a test inhibitor of the acetylcholinesterase site activity of an invertebrate acetylcholinesterase (AChE) polypeptide uses a programmed computer comprising a processor and an input device and includes:
  • test inhibitor molecule determining, based on the docking, whether the test inhibitor molecule would be capable of interacting with a residue of the invertebrate AChE polypeptide corresponding to Arg339 of ⁇ gAChE.
  • the acetylcholinesterase active site can have acetylcholine bound.
  • the method can further include derivatizing the test inhibitor molecule so that the test inhibitor molecule is capable of interacting with a residue of the invertebrate AChE polypeptide corresponding to Cys286 of ⁇ gAChE.
  • the method can also further include derivatizing the test inhibitor molecule so that the test inhibitor molecule is capable of interacting with a residue of the invertebrate AChE polypeptide corresponding to Trp84 of ⁇ gAChE.
  • the inhibitory activity of the test inhibitor can be evaluated on an invertebrate or mammalian AChE polypeptide in vitro.
  • the invertebrate AChE polypeptide can be selected from Anopheles gambiae AChE, Culexpipiens AChE, or Culex tritaeniorhynchus AChE.
  • a method of generating a compound that inhibits the acetylcholinesterase site activity of the Anopheles gambiae AChE polypeptide is provided which includes:
  • test compound is further capable of interacting with Cys286. In some embodiments, the test compound is further capable of interacting with W84. In yet other embodiments, the test compound is further capable of interacting with both Cys286 and W84.
  • compositions of matter are also provided herein.
  • a composition of matter can include a compound according to any of Formula I, II, III, IV, V, VI, VII, or VIII described herein, or an acceptable salt or derivative thereof.
  • Insecticidal and pesticidal compositions comprising a compound according to any of Formula I-VIII and a carrier are also provided.
  • A: B: wherein E's R 1 H or Me; and n for A-E ranges from 0 to 5;
  • R 4 is selected from :
  • a compound according to Formula I is a compound according to Formula IA:
  • a compound according to Formula I is according to Formula IB:
  • Formula IB :
  • X 5 alkyl (Ci-C 5 ) or -(O) 2 alkyl (Ci-C 5 ); and wherein R 3 is selected from H and one of the moieties A, B, C, D, and E:
  • E's R 1 H or Me; and n for A-E ranges from 0 to 5.
  • a compound according to Formula I is according to Formula IC:
  • R 1 is selected from H and one of the moieties A, B, C, D, and E:
  • X 5 alkyl (C 1 -C 5 ) or -(O) 2 alkyl (C 1 -C 5 );
  • R 5 is as above in Formula I.
  • a compound according to Formula I is according to Formula ID:
  • R 1 is selected from selected from H and one of the moieties A, B, C, D, and E:
  • E's R 1 H or Me; and n for A-E ranges from 0 to 5;
  • X 5 alkyl (C 1 -C 5 ) or -(O) 2 alkyl (C 1 -C 5 ).
  • a compound according to Formula I is according to Formula IE:
  • R 3 is H or CH 3 ; wherein R 1 is selected from H and one of the moieties A, B, C, D, and E:
  • a compound for use in the present methods is according to Formula II:
  • R 1 is H, OMe, OEt, NH 2 , alkyl (Ci-C 5 ), or is selected from: A, B, C, D, and E:
  • E's R 1 H or Me; and n for A-E ranges from O to 5;
  • R 2 and R 3 are independently selected from: -(CH 2 )J, -(CH 2 ) n Br, -(CH 2 ) n X 4 , -
  • X 5 alkyl (Ci-C 5 ) or -(O) 2 alkyl (Ci-C 5 ); wherein R 4 is selected from: H and one of the moieties A, B, C, D, and E:
  • E's R 1 H or Me; and n for A-E ranges from 0 to 5.
  • a compound according to Formula II is according to Formula HA or Formula HB, below:
  • a compound for use in the methods described herein is according to Formula IIIA or Formula HIB:
  • R 2 is selected from: H and one of the moieties A, B, C, D, and E:
  • E's R 1 H or Me; and n for A-E ranges from 0 to 5.
  • X 5 alkyl (C 1 -C 5 ) or -(O) 2 alkyl (C 1 -C 5 ); and R 2 is selected from H and alkyl(Ci-Cs); and R 3 is selected from: H and one of the moieties A, B, C, D, and E:
  • E's R 1 H or Me; and n for A-E ranges from 0 to 5.
  • a compound for use in the invention is according to Formula IV:
  • X 5 alkyl (Ci-C 5 ) or -(O) 2 alkyl (Ci-C 5 ); and R 2 is selected from H and alkyl(Ci-Cs); and R 3 is selected from: H and one of the moieties A, B, C, D, and E:
  • E's R 1 H or Me; and n for A-E ranges from 0 to 5.
  • a compound for use in the methods described herein is according to Formula V:
  • R 1 and R 2 are independently selected from H and substituted or unsubstituted, saturated or unsaturated, cyclic or linear alkyl or heteroalkyl moieties and substituted or unsubstituted aryl or heteroaryl moieties, or together R 1 and R 2 form a saturated or unsaturated cyclic alkyl or heteroalkyl moiety, or an aryl or heteroaryl moiety, any of which may be substituted or unsubstituted (e.g., with a fused aryl ring (which may be substituted with R 4 and/or R 5 moieties), or with alkyl moieties (which may be substituted with R 4 and R 5 moieties)); wherein R 3 is selected from H, a substituted or unsubstituted alkyl, aryl, or amine moiety (e.g., substituted with R and/or R or is R ) or is selected from one of the moieties A, B
  • X 5 alkyl (Ci-C 5 ) or -(O) 2 alkyl (Ci-C 5 ); wherein R 6 and R 7 are independently selected from H or alkyl(Ci-Cs); and wherein R 8 is selected from CH 3 and CH 2 CH 3 .
  • a compound according to Formula V can be according to one of Formulae VA-VF, wherein Y can be O, S, or CH 2 .
  • R is selected from:
  • X 5 alkyl (Ci-C 5 ) or -(O) 2 alkyl (Ci-C 5 ); and wherein R 3 is selected from H and is selected from one of the moieties A, B, C, D, and
  • a compound according to Formula VI is according to Formula VIA or VIB:
  • a compound for use in the methods is according to Formula VII:
  • X 5 alkyl (Ci-C 5 ) or -(O) 2 alkyl (Ci-C 5 ); and wherein R 4 is selected from H and from one of the moieties A, B, C, D, and E:
  • E's R 1 H or Me; and n for A-E ranges from 0 to 5.
  • a compound for use in the methods is according to Formula VIII: wherein R 1 is selected from H, halogen, and one of the moieties A, B, C, D, and E:
  • E's R 1 H or Me; and n for A-E ranges from 0 to 5;
  • X 5 alkyl (C 1 -C 5 ) or -(O) 2 alkyl (C 1 -C 5 ); wherein R 3 , R 4 together form a saturated or unsaturated cyclic alkyl or cyclic heteroalkyl moiety, which may be substituted (e.g., with one or more R 2 , R 5 , or R 6 groups), or together form an aryl or heteroaryl moiety which may be substituted (e.g., with one or m m iiioo ⁇ rrieec R R iv 22 .,, R R iv 55 ., wherein R 5 is selected from H or alkyl (C 1 -Cs) ; wherein R 6 is selected from H and one of the moieties A, B, C, D, and E:
  • E's R 1 H or Me; and n for A-E ranges from 0 to 5; and wherein X is selected from O, S, and NH.
  • a compound according to Formula VIII is selected from Formula VIIIA or Formula VIIIB.
  • X 6 if present, can be selected from:
  • the disclosure provides a method for killing pests comprising: providing a pesticidal composition as described herein; and applying the pesticidal composition to an area infested with pests, such that the pests can ingest or be contacted with the pesticidal composition.
  • the pests can be selected from mosquitoes, cockroaches, lancelets, rice leaf beetles, African bollworms, beet armyworms, codling moths, diamondback moths, domestic silkworms, honey bees, oat or wheat aphids, greenbugs, melon or cotton aphids, green peach aphids, and English grain aphids.
  • the disclosure provides a method for controlling the growth or spread of a pest population, comprising treating or contacting plants, propagation stocks, seeds, grains, foodstuffs, soils, water, industrial materials, or combinations thereof with an effective amount of a pesticidal composition described herein. Treating can include applying the composition in a manner selected from the group consisting of watering, spraying, atomizing, scattering, spreading, dry dressing, wet dressing, liquid dressing, slurry treatment of seeds, incrustation, and combinations thereof.
  • a method of controlling the mosquito-borne spread of malaria comprising treating or contacting plants, propagation stocks, seeds, grains, foodstuffs, soils, water, industrial materials, or combinations thereof with an effective amount of a pesticidal composition described herein. Treating can include applying the composition in a manner selected from the group consisting of watering, spraying, atomizing, scattering, spreading, dry dressing, wet dressing, liquid dressing, slurry treatment of seeds, incrustation, and combinations thereof.
  • West Nile Virus or encephalitis is provided which includes applying an insecticidal composition described herein to an area infested with mosquitoes, such that the mosquitoes can ingest or be contacted with the insecticidal composition.
  • a method of controlling crop, seed, bean, foodstuff, grain, or fruit damage mediated by pests can include treating or contacting the crop, seed, bean, foodstuff, grain or fruit with a pesticidal composition described herein.
  • all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting. Other features and advantages of the invention will be apparent from the following description, from the drawings and from the claims.
  • FIG 1 is the SwissModel-generated multiple sequence alignments of Anopheles gambiae with mouse and electric eel acetylcholinesterases.
  • the A. gambiae-specific residues (C286 and R339) are bolded.
  • FIG 2 sets forth the amber atom types and charges of acetylcholine used in the homology modeling.
  • FIG 3 shows multiple sequence alignments of acetylcholinesterases of insects and mammals.
  • the alignments were generated by CLUSTAL W (Version 1.83).
  • C286 and R339 of Anopheles gambiae acetylcholinesterase (AChE) and the corresponding C or R residues in other species are bolded (SEQ ID NOS 5-43 are disclosed respectively in order of appearance).
  • FIG 4 Multiple sequence alignments of acetylcholinesterases of the 73 species which are publicly available. The alignments were generated by CLUSTAL W (Version 1.83). C286 and R339 of Anopheles gambiae acetylcholinesterase and the corresponding C and R residues in other species are bolded (SEQ ID NOS 44-152 are disclosed respectively in order of appearance).
  • FIGs. 5 - 10 illustrate synthetic mechanisms for preparing the compositions described herein.
  • derivatives of a compound include salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, solvates, or hydrates thereof.
  • Such derivatives may be readily prepared by those of skill in this art using known methods for such derivatization.
  • the compounds produced may be employed as insecticides and may be without substantial toxic effects to animals or humans.
  • Salts include, but are not limited to, amine salts, such as but not limited to N 5 N'- dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N- benzylphenethylamine, 1 -para-chlorobenzyl-2-pyrrolidin- 1 '-ylmethyl-benzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not limited to zinc; and other metal salts, such as but not limited to sodium hydrogen phosphate and disodium phosphate; and also including, but not limited to, nitrates, borates, methanes
  • Esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl and heterocyclyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids, sulf ⁇ nic acids and boronic acids.
  • Solvates and hydrates are complexes of a compound with one or more solvent or water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules.
  • alkyl As used herein, “alkyl,” “alkenyl” and “alkynyl” refer to carbon chains that may be straight or branched. Exemplary alkyl, alkenyl and alkynyl groups herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, isohexyl, allyl (propenyl) and propargyl (propynyl).
  • cycloalkyl refers to a saturated mono- or multi- cyclic ring system, in certain embodiments of 3 to 10 carbon atoms, in other embodiments of 3 to 6 carbon atoms.
  • the ring systems of the cycloalkyl groups may be composed of one ring or two or more rings which may be joined together in a fused, bridged or spiro-connected fashion. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • aryl refers to aromatic monocyclic or multicyclic groups containing from 6 to 19 carbon atoms.
  • Aryl groups include, but are not limited to groups such as unsubstituted or substituted fluorenyl, unsubstituted or substituted phenyl, and unsubstituted or substituted naphthyl.
  • heteroaryl refers to a monocyclic or multicyclic aromatic ring system, in certain embodiments, of about 5 to about 15 members, where one or more, in one embodiment 1 to 4, of the atoms in the ring system is a heteroatom, that is, an element other than carbon, including but not limited to, nitrogen, oxygen or sulfur.
  • heteroaryl group may be optionally fused to a benzene ring.
  • Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, quinolinyl and isoquinolinyl.
  • heterocyclyl refers to a monocyclic or multicyclic non-aromatic ring system, in one embodiment of 3 to 10 members, in another embodiment of 4 to 7 members, in a further embodiment of 5 to 6 members, where one or more, in certain embodiments, 1 to 3, of the atoms in the ring system is a heteroatom, that is, an element other than carbon, including but not limited to, nitrogen, oxygen or sulfur.
  • halo refers to F, Cl, Br or I.
  • pseudohalides or pseudohalo groups are groups that behave substantially similar to halides. Such compounds can be used in the same manner and treated in the same manner as halides. Pseudohalides include, but are not limited to, cyanide, cyanate, thiocyanate, selenocyanate, trifluoromethoxy, and azide.
  • haloalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by halogen.
  • Carboxy refers to a divalent radical, -C(O)O-.
  • aminocarbonyl refers to -C(O)NH 2 .
  • aminoalkyl refers to -RNH 2 , in which R is alkyl.
  • alkoxy and RS- refer to RO- and RS-, in which R is alkyl.
  • aryloxy and arylthio refer to RO- and RS-, in which R is aryl.
  • amido refers to the divalent group -C(O)NH.
  • hydroazide refers to the divalent group -C(O)NHNH-.
  • haloalkyl may include one or more of the same or different halogens.
  • AChE polypeptide is a mosquito AChE, such as the house mosquito, Japanese encephalitis mosquito, or African malaria-carrying mosquito ⁇ Anopheles gambiae), including insecticide-resistant forms of the same.
  • active site of an AChE polypeptide includes residues that comprise the catalytic acylation site (A-site) at the base of the catalytic gorge of the polypeptide as well as residues that are understood by those having ordinary skill in the art to comprise the peripheral site (P-site) located at the entrance of the gorge; see Pang et al, Journal of Biol. Chem. 271(39):23646-23649.
  • the inventors have determined a refined 3D homology model of ⁇ gAChE using multiple molecular dynamics simulations.
  • the inventors have determined that the residues corresponding to Ag' s R339 and C286 represent invertebrate- (and in some cases insect-)- specific amino acids that are located at the peripheral site of AChE and that may be involved in stabilizing active site residues. These residues are not present in the mammalian species that were compared. Thus, given the homology model described herein as well as the identification of conserved R and C residues corresponding to R339 and C286 of A.
  • gambiae as useful invertebrate- or insect-specific residues to target
  • one having ordinary skill in the art would know how to use standard molecular modeling or other techniques to identify peptides, peptidomimetics, and small-molecules that would bind to or interact with one or more of the particular invertebrate's AChE 's R or C residues that correspond to ⁇ gAChE's R339 and C286.
  • one having ordinary skill in the art would be able to combine targeting such C and/or R residues with the targeting of other amino acids (such as a Trp corresponding to A. gambiae 's Trp84) that are known to be within the ⁇ gAChE active site.
  • the invertebrate or insect activity would be inhibited selectively, e.g., mammalian activity would not be inhibited, with the use of one of the designed inhibitors.
  • molecular modeling is meant quantitative and/or qualitative analysis of the structure and function of physical interactions based on three-dimensional structural information and interaction models. This includes conventional numeric-based molecular dynamic and energy minimization models, interactive computer graphic models, modified molecular mechanics models, distance geometry and other structure-based constraint models. Molecular modeling typically is performed using a computer and may be further optimized using known methods. See the Examples below.
  • Methods of designing compounds that bind specifically (e.g., with high affinity) to one or more of the residues described previously typically are also computer-based, and involve the use of a computer having a program capable of generating an atomic model.
  • Computer programs that use X-ray crystallography data or molecular model coordinate data, such as the data that are available from the PDB, are particularly useful for designing such compounds.
  • Programs such as RasMol for example, can be used to generate a three dimensional model.
  • Computer programs such as INSIGHT (Accelrys, Burlington, MA), Auto-Dock (Accelrys), and Discovery Studio 1.5 (Accelrys) allow for further manipulation and the ability to introduce new structures.
  • Compounds can be designed using, for example, computer hardware or software, or a combination of both. However, designing is preferably implemented in one or more computer programs executing on one or more programmable computers, each containing a processor and at least one input device.
  • the computer(s) preferably also contain(s) a data storage system (including volatile and non-volatile memory and/or storage elements) and at least one output device.
  • Program code is applied to input data to perform the functions described above and generate output information.
  • the output information is applied to one or more output devices in a known fashion.
  • the computer can be, for example, a personal computer, microcomputer, or work station of conventional design.
  • Each program is preferably implemented in a high level procedural or object oriented programming language to communicate with a computer system.
  • the programs can be implemented in assembly or machine language, if desired. In any case, the language can be a compiled or interpreted language.
  • Each computer program is preferably stored on a storage media or device (e.g.,
  • ROM or magnetic diskette readable by a general or special purpose programmable computer.
  • the computer program serves to configure and operate the computer to perform the procedures described herein when the program is read by the computer.
  • the method of the invention can also be implemented by means of a computer-readable storage medium, configured with a computer program, where the storage medium so configured causes a computer to operate in a specific and predefined manner to perform the functions described herein.
  • a method of designing a test compound can involve:
  • the method can include designing a test compound based on the determined site on the first molecule or complex that is involved in binding the test compound.
  • a computer-assisted method of generating a test inhibitor of the acetylcholinesterase site activity of an invertebrate acetylcholinesterase (AChE) polypeptide uses a programmed computer comprising a processor and an input device, and can include:
  • the AChE is an insect AChE. In other embodiments, the
  • AChE is a mosquito AChE, e.g., house mosquito, Japanese encephalitis mosquito, and African malaria mosquito.
  • the AChE is an invertebrate AChE selected from German cockroach, Florida lancelet, rice leaf beetle, African bollworm, beet armyworm, codling moth, diamondback moth, domestic silkworm, honey bee, oat or wheat aphid, the greenbug, melon or cotton aphid, green peach aphid, and English grain aphid.
  • the test inhibitor molecule can interact with the residue corresponding to R339 of ⁇ gAChE with a minimum interaction energy of -5 to about -50 kcal/mol, e.g., -20 to -40 kcal/mol.
  • the residue corresponding to R339 is an arginine.
  • the test inhibitor would be capable of forming a hydrogen bond with the residue corresponding to R339.
  • the test inhibitor is also capable of interacting with a residue of the AChE polypeptide corresponding to C286 of ⁇ gAChE.
  • the test inhibitor capable of interacting with the residue corresponding to R339 is modified and/or derivatized to be capable of interacting with a residue of the AChE polypeptide corresponding to C286 of ⁇ gAChE.
  • the residue of the AChE polypeptide corresponding to C286 is a cysteine.
  • the test inhibitor would be capable of forming a covalent bond with the residue corresponding to C286.
  • a test inhibitor that is capable of forming a covalent bond with the residue corresponding to C286 is an irreversible inhibitor.
  • the test inhibitor is also capable of interacting with a residue of the AChE polypeptide corresponding to W84 of ⁇ gAChE.
  • the test inhibitor capable of interacting with the residue corresponding to R339 and/or C286 is modified and/or derivatived to be capable of interacting with a residue corresponding to W84 of ⁇ gAChE.
  • the test inhibitor is capable of interacting with residues of the AChE polypeptide corresponding to R339, C286, and W84 of AgAChE.
  • the active site of an AChE has acetylcholine bound.
  • the test inhibitor can be synthesized and/or derivatized so that the test inhibitor molecule is capable of interacting with a residue corresponding to Cys286 and/or W84 of AgAChE.
  • the inhibitory activity of the test inhibitor on an invertebrate or mammalian AChE polypeptide in vitro can be evaluated.
  • the inhibitory activity of the test inhibitor on the growth of a eukaryotic (e.g., mammalian) cell can also be evaluated.
  • a method of generating a compound that inhibits the acetylcholinesterase site activity of the Anopheles gambiae AChE polypeptide includes: (a) providing a three-dimensional structure of the Anopheles gambiae AChE polypeptide acetylcholinesterase active site; and
  • the test compound is further capable of interacting with Cys286. In some embodiments, the test compound is derivatized to be capable of interacting with Cys286. In some embodiments, the test compound is derivatized to be capable of forming a covalent bond with Cys286.
  • the test compound can also be capable of interacting with W84, or be derivatized to be capable of interacting with W84.
  • inhibitory compounds e.g., peptides, non-peptide small molecules, peptidomimetics, and aptamers ⁇ e.g., nucleic acid aptamers)
  • inhibitory compounds e.g., peptides, non-peptide small molecules, peptidomimetics, and aptamers ⁇ e.g., nucleic acid aptamers)
  • the appropriate 3-D structure e.g., at certain residues and that interact in certain manners ⁇ e.g., hydrogen-bonding, ion bonding, covalent bonding, pi-pi interactions, sulfur- aromatic interactions, steric interactions, and/or van der Waals interactions.
  • one of skill in the art could design inhibitory compounds that could interact with one or more of the residues corresponding to R339, C286, or Trp84 of ⁇ gAChE.
  • AChE polypeptide 3-D structure may be taken from one species (e.g., ⁇ gAChE), one of skill in art could, by standard methods, e.g., homology alignments (i.e., ClustalW (1.83)) or molecular modeling, establish the corresponding residues of interest in other species.
  • homology alignments i.e., ClustalW (1.83)
  • molecular modeling e.g., molecular modeling
  • the method can involve an additional step of outputting to an output device a model of the 3-D structure of the compound.
  • the 3-D data of candidate compounds can be compared to a computer database of, for example, 3-D structures stored in a data storage system.
  • Candidate compounds identified as described above can then be tested in standard cellular or cell-free enzymatic or enzymatic inhibition assays familiar to those skilled in the art. Inhibitory activity can be compared with inhibition to one or more mammalian (e.g., human, cat, dog, mouse, rat, monkey, horse, cow) AChEs.
  • mammalian e.g., human, cat, dog, mouse, rat, monkey, horse, cow
  • AChEs e.g., human, cat, dog, mouse, rat, monkey, horse, cow
  • the 3-D structure of molecules can be determined from data obtained by a variety of methodologies. These methodologies include: (a) x-ray crystallography; (b) nuclear magnetic resonance (NMR) spectroscopy; (c) molecular modeling methods, e.g. , homology modeling techniques, threading algorithms, and in particular the refined homology modeling methods described below in the Examples.
  • Any available method can be used to construct a 3-D model of an AChE region of interest, such as the active site, peripheral site, or catalytic site, from the x-ray crystallographic, molecular modeling, and/or NMR data using a computer as described above.
  • a model can be constructed from analytical data points inputted into the computer by an input device and by means of a processor using known software packages, e.g., CATALYST (Accelrys), INSIGHT (Accelrys) and CeriusII, HKL,
  • the model constructed from these data can be visualized via an output device of a computer, using available systems, e.g., Silicon Graphics, Evans and Sutherland, SUN, Hewlett Packard, Apple Macintosh, DEC, IBM, or Compaq.
  • a compound that has substantially the same 3-D structure or contains a domain that has substantially the same structure as the identified compound can be made.
  • “has substantially the same 3-D structure” means that the compound possesses a hydrogen bonding and hydrophobic character that is similar to the identified compound.
  • a compound having substantially the same 3-D structure as the identified compound can include a heterocyclic ring system and regions displaying hydrophobic character in close proximity to a hydrogen bonding region, although the hydrophobic regions can contain some hydrogen bonding character.
  • Compounds of this class would include, without limitation, substituents able to impart steric bulk in a region of space that would otherwise encapsulate the manganese and carbonate-coordinated phosphate backbone characteristic of an identified compound.
  • substituents able to impart steric bulk in a region of space that would otherwise encapsulate the manganese and carbonate-coordinated phosphate backbone characteristic of an identified compound.
  • chemical structure e.g., amino acid sequence in the case of a protein
  • derivatize such compounds include chemical synthetic methods and, in the case of proteins, recombinant methods.
  • Such blocking agents can include, without limitation, additional related or unrelated peptide sequences that can be attached to the amino and/or carboxyl terminal residues of the peptide to be administered. This can be done either chemically during the synthesis of the peptide or by recombinant DNA technology by methods familiar to artisans of average skill.
  • blocking agents such as pyroglutamic acid or other molecules known in the art can be attached to the amino and/or carboxyl terminal residues, or the amino group at the amino terminus or carboxyl group at the carboxyl terminus can be replaced with a different moiety.
  • the peptide compounds can be covalently or noncovalently coupled to pharmaceutically acceptable "carrier" proteins prior to administration.
  • peptidomimetic compounds are synthetic compounds having a three-dimensional conformation (i.e., a "peptide motif) that is substantially the same as the three-dimensional conformation of a selected peptide.
  • Peptidomimetic compounds can have additional characteristics that enhance their in vivo utility, such as increased cell permeability and prolonged biological half-life.
  • the peptidomimetics typically have a backbone that is partially or completely non-peptide, but with side groups that are identical to the side groups of the amino acid residues that occur in the peptide on which the peptidomimetic is based.
  • Several types of chemical bonds e.g., ester, thioester, thioamide, retroamide, reduced carbonyl, dimethylene and ketomethylene bonds, are known in the art to be generally useful substitutes for peptide bonds in the construction of protease-resistant peptidomimetics.
  • Small-molecule compounds that can bind to and/or interact with a residue corresponding to R339 of ⁇ gAChE, and/or the residue corresponding to C286 of ⁇ gAChE, and/or the residue corresponding to W84 of ⁇ gAChE, including in particular those that are trifunctional, e.g., are designed to bind to the residues corresponding to R339, C286, and W84 of ⁇ gAChE, are of particular interest. Additional information on particular classes of small molecules is provided below, as well as synthetic methodologies for preparation of such molecules.
  • the compounds provided herein may specifically inhibit invertebrate ⁇ e.g. , insect) acetylcholinesterase activity as compared to mammalian acetylcholinesterase activity, and thus may be useful as safe, non-toxic pesticides and insecticides.
  • the compounds provided herein may inhibit the AChE of the house mosquito, Japanese encaphilitis mosquito, and/or African malaria mosquito, and thus may be useful to specifically target populations of mosquitoes, e.g., to prevent the spread of malaria or other mosquito-borne diseases such as malaria, West Nile virus, encephalitis, etc.
  • the compounds may inhibit the AChE of other invertebrate pest species, including cockroaches, beetles, bollworms, moths, and aphids, and thus can be used as pesticides that are useful in controlling pest populations e.g. , on farms and in food storage and transportation facilities.
  • pesticides or insecticides e.g., to kill insect populations, to prevent or minimize crop damage, or to prevent or minimize the spread of insect-borne diseases, is also contemplated.
  • X 5 alkyl (Ci-C 5 ) or -(O) 2 alkyl (Ci-C 5 ); and b) H and one of the moieties A, B, C, D, and E:
  • E's R 1 H or Me; and n for A-E ranges from 0 to 5;
  • E's R 1 H or Me; and n for A-E ranges from 0 to 5;
  • R 4 is selected from :
  • a compound according to Formula I is a compound according to Formula IA:
  • a compound according to Formula I is according to Formula IB:
  • Formula IB :
  • X 5 alkyl (Ci-C 5 ) or -(O) 2 alkyl (Ci-C 5 ); and wherein R 3 is selected from H and one of the moieties A, B, C, D, and E:
  • E's R 1 H or Me; and n for A-E ranges from 0 to 5.
  • a compound according to Formula I is according to Formula IC:
  • R 1 is selected from H and one of the moieties A, B, C, D, and E:
  • X 5 alkyl (C 1 -C 5 ) or -(O) 2 alkyl (C 1 -C 5 );
  • R 5 is as above in Formula I.
  • a compound according to Formula I is according to Formula ID:
  • R 1 is selected from selected from H and one of the moieties A, B, C, D, and E:
  • E's R 1 H or Me; and n for A-E ranges from 0 to 5;
  • X 5 alkyl (C 1 -C 5 ) or -(O) 2 alkyl (C 1 -C 5 ).
  • a compound according to Formula I is according to Formula IE:
  • R 3 is H or CH 3 ; wherein R 1 is selected from H and one of the moieties A, B, C, D, and E:
  • a compound for use in the present methods is according to Formula II:
  • R 1 is H, OMe, OEt, NH 2 , alkyl (Ci-C 5 ), or is selected from: A, B, C, D, and E:
  • E's R 1 H or Me; and n for A-E ranges from O to 5;
  • R 2 and R 3 are independently selected from: -(CH 2 )J, -(CH 2 ) n Br, -(CH 2 ) n X 4 , -
  • X 5 alkyl (Ci-C 5 ) or -(O) 2 alkyl (Ci-C 5 ); wherein R 4 is selected from: H and one of the moieties A, B, C, D, and E:
  • E's R 1 H or Me; and n for A-E ranges from 0 to 5.
  • a compound according to Formula II is according to Formula HA or Formula HB, below:
  • a compound for use in the methods described herein is according to Formula IIIA or Formula HIB:
  • R 2 is selected from: H and one of the moieties A, B, C, D, and E:
  • E's R 1 H or Me; and n for A-E ranges from 0 to 5.
  • X 5 alkyl (C 1 -C 5 ) or -(O) 2 alkyl (C 1 -C 5 ); and R 2 is selected from H and alkyl(Ci-Cs); and R 3 is selected from: H and one of the moieties A, B, C, D, and E:
  • E's R 1 H or Me; and n for A-E ranges from 0 to 5.
  • a compound for use in the invention is according to Formula IV:
  • X 5 alkyl (Ci-C 5 ) or -(O) 2 alkyl (Ci-C 5 ); and R 2 is selected from H and alkyl(Ci-Cs); and R 3 is selected from: H and one of the moieties A, B, C, D, and E:
  • E's R 1 H or Me; and n for A-E ranges from 0 to 5.
  • a compound for use in the methods described herein is according to Formula V:
  • R 1 and R 2 are independently selected from H and substituted or unsubstituted, saturated or unsaturated, cyclic or linear alkyl or heteroalkyl moieties and substituted or unsubstituted aryl or heteroaryl moieties, or together R 1 and R 2 form a saturated or unsaturated cyclic alkyl or heteroalkyl moiety, or an aryl or heteroaryl moiety, any of which may be substituted or unsubstituted (e.g., with a fused aryl ring (which may be substituted with R 4 and/or R 5 moieties), or with alkyl moieties (which may be substituted with R 4 and R 5 moieties)); wherein R 3 is selected from H, a substituted or unsubstituted alkyl, aryl, or amine moiety (e.g., substituted with R and/or R or is R ) or is selected from one of the moieties A, B
  • X 5 alkyl (Ci-C 5 ) or -(O) 2 alkyl (Ci-C 5 ); wherein R 6 and R 7 are independently selected from H or alkyl(Ci-Cs); and wherein R 8 is selected from CH 3 and CH 2 CH 3 .
  • a compound according to Formula V can be according to one of Formulae VA-VF, wherein Y can be O, S, or CH 2 .
  • R is selected from:
  • X 5 alkyl (Ci-C 5 ) or -(O) 2 alkyl (Ci-C 5 ); and wherein R 3 is selected from H and is selected from one of the moieties A, B, C, D, and
  • a compound according to Formula VI is according to Formula VIA or VIB:
  • a compound for use in the methods is according to Formula VII:
  • X 5 alkyl (Ci-C 5 ) or -(O) 2 alkyl (Ci-C 5 ); and wherein R 4 is selected from H and from one of the moieties A, B, C, D, and E:
  • E's R 1 H or Me; and n for A-E ranges from 0 to 5.
  • a compound for use in the methods is according to Formula VIII: wherein R 1 is selected from H, halogen, and one of the moieties A, B, C, D, and E:
  • E's R 1 H or Me; and n for A-E ranges from 0 to 5;
  • X 5 alkyl (C 1 -C 5 ) or -(O) 2 alkyl (C 1 -C 5 ); wherein R 3 , R 4 together form a saturated or unsaturated cyclic alkyl or cyclic heteroalkyl moiety, which may be substituted (e.g., with one or more R 2 , R 5 , or R 6 groups), or together form an aryl or heteroaryl moiety which may be substituted (e.g., with one or m m iiioo ⁇ rrieec R R iv 22 .,, R R iv 55 ., wherein R 5 is selected from H or alkyl (C 1 -Cs) ; wherein R 6 is selected from H and one of the moieties A, B, C, D, and E:
  • E's R 1 H or Me; and n for A-E ranges from 0 to 5; and wherein X is selected from O, S, and NH.
  • a compound according to Formula VIII is selected from Formula VIIIA or Formula VIIIB.
  • X 6 if present, can be selected from:
  • compositions and methods provided herein may be prepared by methods well known to those of skill in the art or by the methods shown herein (e.g., see FIGs. 5-10).
  • One of skill in the art would be able to prepare all of the compounds for use herein by routine modification of these methods using the appropriate starting materials .
  • the activity of the compounds provided herein as inhibitors of AChE may be measured by a variety of methods for measuring AChE known to those having ordinary skill in the art; see, e.g., Pang et al, J. Biol. Chem. 271(30):23646-23649 (1996).
  • the inhibitory activity can be evaluated in a number of species, e.g., a number of insect and mammalian species, to determine compounds that would be safe and non-toxic to mammalian species.
  • a pesticidal (e.g. , insecticidal) composition provided herein contains one or more of the compounds provided herein and can be used to kill, or to prevent or inhibit the increase or spread of, select pest, e.g., insect, populations.
  • a composition can optionally include an agriculturally acceptable insecticidal carrier.
  • a composition may also contain other additive such as surfactants, emulsif ⁇ ers, defoamers, buffers, thickeners, dyes, extenders, emetic agent(s) and the like.
  • a pesticidal or insecticidal composition can be in any form, e.g., in the form of an aqueous, oil-based, or liquid spray composition, in the form of gel pellets or granules, in the form of a powder, in the form of a solid sheet, and the like.
  • a carrier is any material with which the active ingredient is formulated to facilitate application to the locus to be treated, which may be, without limitation, a plant, seed, grain, food, water source, or soil, or to facilitate storage, transport or handling.
  • a carrier may be a solid or a liquid, including material which is normally a gas but which has been compressed to form a liquid or a combination thereof.
  • Carriers include any such carriers known to those skilled in the art to be suitable for the particular mode of administration. These carriers are selected by those skilled in the art with the view to enhance handling, application to the infected sites, persistence, and storage.
  • An agriculturally acceptable carrier may be solid, liquid or both.
  • Solid carries are selected from, typically, mineral earth such as silicas, silica gels, silicates, talc, kaolin, montmorillonite, attapulgite, pumice, sepiolite, bentonite, limestone, lime, chalk, bole, loes, clay, dolomite, diatomaceous earth, calcite, calcium sulfate, magnesium sulfate, magnesium sulfate, magnesium oxide, sand, ground plastics, fertilizers such as ammonium sulfate, ammonium phosphate, ammonium nitrate, ureas, and crushed products of vegetable origin such as cereal meal, tree bark meal, wood meal and nutshell meal, cellulose powders, or other solid carriers.
  • a carrier is selected from alginates, clays, activated carbons, and powdery carriers (e.g., talcum, zinc and titanium dioxide, calcined magnesia or
  • compositions are often formulated and transported in a concentrated form which is subsequently diluted by the user before application.
  • the presence of small amounts of a surfactant facilitates this process of dilution.
  • a composition according to the present invention comprises, if desired, at least one surfactant.
  • the composition may contain one or more carriers and at least one surfactant.
  • Surfactant(s) can be non-ionic, cationic and/or anionic in nature and surfactant mixtures which have good emulsifying, dispersing and wetting properties, depending on the nature of the active ingredient to be formulated.
  • Suitable anionic surfactants can be both water-soluble soaps and water-soluble synthetic surface-active compounds.
  • Soaps which may be included as a surfactant can be the alkali metal, alkaline earth metal or substituted or unsubstituted ammonium salts of higher fatty acids, for example the sodium or potassium salt of oleic or stearic acid, or of natural fatty acid mixtures.
  • the pesticidal or insecticidal composition may be dispersed in a solid or liquid diluent for application to the pest or insect, its food supply, breeding ground or habitat as a dilute spray or as a solid dust or dust concentrate.
  • An pesticidal or insecticidal composition is generally in a ready to use form which may be diluted at the place of application for suitable concentration of the active ingredients.
  • a method for killing pests that includes providing a pesticidal composition described herein; and applying the pesticidal composition to an area infested with pests, such that the pests can ingest or be contacted with the pesticidal composition.
  • the pests can be selected from mosquitoes, cockroaches, lancelets, rice leaf beetles, African bollworms, beet armyworms, codling moths, diamondback moths, domestic silkworms, honey bees, oat or wheat aphids, greenbugs, melon or cotton aphids, green peach aphids, and English grain aphids.
  • a method for controlling the growth or spread of a pest population is also provided, which includes treating or contacting plants, propagation stocks, seeds, grains, foodstuffs, soils, water, industrial materials, or combinations thereof with an effective amount of a pesticidal composition described herein.
  • Treating can include applying the composition in a manner selected from the group consisting of watering, spraying, atomizing, scattering, spreading, dry dressing, wet dressing, liquid dressing, slurry treatment of seeds, incrustation, and combinations thereof.
  • the insecticidal compositions can also be used to reduce or eliminate mosquito populations, e.g., mosquito populations that carry diseases.
  • the present disclosure also provides a method of controlling the mosquito-borne spread of malaria, West Nile Virus, or encephalitis comprising applying an insecticidal composition described herein to an area infested with mosquitoes, such that the mosquitoes can ingest or be contacted with the insecticidal composition.
  • the pesticidal compositions can be used to control damage to crops, plants, fruits, etc.
  • a method of controlling crop, seed, bean, foodstuff, grain, or fruit damage mediated by pests can include treating or contacting the crop, seed, bean, foodstuff, grain or fruit with a pesticidal composition described herein.
  • a 3D model of a substrate-bound ⁇ gAChE that is susceptible to current pesticides was determined.
  • the protein sequence of this AChE was obtained from GenBank (accession number: BN000066).
  • a homology model of ⁇ gAChE was first generated by the SWISS-MODEL program (available at swissmodel.expasy.org//SWISS- MODEL.html [7] ⁇ according to multiple sequence alignments using X-ray structures of two mouse and one electric eel AChEs as templates ( Figure 1).
  • the Protein Data Bank (PDB) IDs of the mouse AChEs are 1J07 and 1N5R [8]; the PDB ID of the electric eel
  • AChE is 1C2O [9]. These crystal structures were automatically identified by the SWISS- MODEL program and have the highest sequence identity (46%) to ⁇ gAChE.
  • the homology model of the apo ⁇ gAChE was automatically generated by the SWISS-MODEL program. No manual adjustments were made to improve the multiple sequence alignment shown in Figure 1.
  • the substrate -bound ⁇ gAChE model was then built by manually docking acetylcholine into the active site of the homology model, guided by the substrate-bound Torpedo AChE (PDB ID: 2ACE [I]).
  • PDB ID: 2ACE [I] substrate-bound Torpedo AChE
  • the fully extended conformation of acetylcholine was used in the manual docking.
  • the atomic charges of acetylcholine were obtained according to the RESP procedure [24] with an ab initio calculation at the HF/6-31G* level using the Gaussian98 program [25], and such charges are provided in Figure 2.
  • the resulting ⁇ gAChE complex model has nearly the same backbone conformation as those of the mouse and electric eel AChE structures except for residues 280-288 (loop 2) of ⁇ gAChE, although many side-chain conformations of ⁇ gAChE are different from the corresponding ones in the mouse and electric eel enzymes.
  • loop 2 of ⁇ gAChE is much shorter because it contains a region of deletion ( Figure 1). Therefore, as part of the peripheral site, loop 2 of ⁇ gAChE required extensive refinement.
  • the homology complex model was then refined by multiple molecular dynamics simulations (MMDSs).
  • MMDSs multiple molecular dynamics simulations
  • the stochastic sampling of protein conformations achieved by MMDSs is more efficient than the sampling by a single long molecular dynamics simulation [10-15], and it is effective in refining loop conformations [15].
  • MMDS refinement has been previously validated through the successful identification of small- molecule inhibitors of an MMDS-refined 3D model of a protease [15,16].
  • the MMDS refinement method has also proven successful in refining a homology model, provided by the Protein Structure Prediction Centre (TMROl, available at http://predictioncenter.org/caspR/), to a refined model that was nearly identical to the corresponding crystal structure (Protein Data Bank ID: IXEl).
  • the alpha carbon root mean square deviation of the refined model was 1.7 A
  • the alpha carbon root mean square deviation of the homology model was 4.6 A
  • the delta alpha carbon root mean square deviation for the MMDS-refined model is -2.9 A.
  • This result confirmed the effectiveness of MMDSs in loop refinement, and thus MMDSs were used to refine ⁇ gAChE, especially its loop 2 region.
  • 100 different molecular dynamics simulations (2.0 ns for each simulation with a 1.0-fs time step and with a different seed for starting velocity) were performed according to a published protocol [15].
  • MMDSs were performed according to a published protocol [15] using the SANDER module of the AMBER 8.0 program [26] with the Cornell et al. force field (parm96.dat) [27] .
  • the topology and coordinate files used in the MMDSs were generated by the PREP, LINK, EDIT, and PARM modules of the AMBER 5.0 program [26].
  • the solvated ⁇ gAChE complex system had a total of 56,926 atoms; it was first energy-minimized for 200 steps to remove close van der Waals contacts in the system, slowly heated to 300 K (10 K/ps), and then equilibrated for 1.5 ns.
  • the energy minimization used the default method of AMBER 5.0 (10 cycles of the steepest descent method followed by the conjugate gradient method).
  • the CARNAL module was used for geometric analysis and for obtaining the time-average structure. All MMDSs were performed on 200 Apple G5 processors dedicated to the Computer- Aided Molecular Design Laboratory
  • the refined model Compared to the unrefined model and human AChE (hAChE), the refined model has different main-chain conformations in three adjacent loops of residues: 70-77 (loop 1), 280-288 (loop 2), and 333-349 (loop 3), that comprise most of the peripheral site of AChE.
  • the refined model has the thiol group of C286 interacting with W280 and Y333 via sulfur-aromatic interaction [17] and the guanidino group of R339 partially accessible to solvent. The latter was caused by the side-chain conformational changes of F75 and Y332 and by the conformational change of loop 1.
  • R339 Located at the peripheral site of the refined ⁇ gAChE model, R339 has cation-pi interactions with F75, F78, Y332, and W431; this cationic residue stabilizes the aromatic residues that comprise part of the active site.
  • the stabilizing role suggests that R339 is a conserved residue in mosquito AChEs.
  • the residue corresponding to R339 of ⁇ gAChE is absent in human AChE (hAChE); instead the phenol group of Y77 of hAChE occupies the region that corresponds to the region occupied by the guanidinium group of the R339.
  • the four insect species that have the conserved Arg (R) are house mosquito (Culex pipiens), Japanese encephalitis-carrying mosquito ⁇ Culex tritaeniorhynchus), African malaria-carrying mosquito ⁇ Anopheles gambiae), including the one that is resistant to current pesticides (the G119S mutant, GenBank ID: AJ515149 [4]), and German cockroach ⁇ Blattella germanic ⁇ ).
  • C286 Located on the opposite side of R339, C286 has favorable sulfur-aromatic interactions [17] with W280 and Y333, both located at the opening of the active site.
  • the residue corresponding to C286 of ⁇ gAChE is F295 that is located in the middle of the active site.
  • the change of C286 to F295 in loop 2 has a large displacement; the distance between two alpha carbon atoms of C286 and F295 in the overlay of the two structures is 4.8 A.
  • a sequence analysis of AChEs from the 73 species shows that C286 is present in AChEs of 17 invertebrate species and absent in AChEs of all other species.
  • the 17 invertebrates include house mosquito ⁇ Culex pipiens), Japanese encephalitis-carrying mosquito ⁇ Culex tritaeniorhynchus), African malaria- carrying mosquito ⁇ Anopheles gambiae) including the one that is resistant to current pesticides ⁇ GenBank ID: AJ515149 [4] ⁇ , German cockroach (Blattella germanica), Florida lancelet (Branchiostoma floridae), rice leaf beetle (Oulema oryzae), African bollworm (Helicoverpa armigera), beet armyworm (Spodoptera exigua), codling moth (Cydia pomonella), diamondback moth (Plutella xylostell ⁇ ), domestic silkworm (Bombyx mor ⁇ ), honey bee (Apis mellifera), oat or wheat aphid (Rhopalosiphum padi), the greenbug (Schizaphis graminum), melon
  • Example 4 Use of 3D model to design inhibitors It has been reported that a native or engineered cysteine residue near the active site of an enzyme can bind a small molecule that interacts, even loosely, at the active site, as long as the cysteine residue is able to react with an electrophilic group of the molecule [19] . It has also been reported that reactive chemicals which are covalently bonded to an engineered cysteine (H287C) at the peripheral site of mammalian AChEs are able to interfere with substrate binding and subsequently inhibit the enzymes [20, 21] .
  • H287C engineered cysteine
  • C286 and R339 can be used as species markers for developing effective and safer pesticides that can covalently bond to C286 and noncovalently to R336 of ⁇ gAChE.
  • the absence of a cysteine residue in the peripheral site of mammalian AChEs means that pesticides targeting C286 and R339 would have less toxicity to mammals than current pesticides targeting the catalytic serine residue present in both mammals and insects.
  • R339 can be used as an anchor to facilitate the reaction of an inhibitor with C286 of ⁇ gAChE.
  • the unique presence of R339 and C286 in ⁇ gAChE and the corresponding R and C groups in certain of the other insect species permits the design of molecules capable of acting as suicide inhibitors that first interacts with R339, leaving an electrophile in the proximity of C286 that can react with C286; see also [22].
  • Example 5 Reaction Schemes
  • the compositions described above can be prepared using the synthetic schemes set forth in Figures 5-10.
  • Pang Y-P Three-dimensional model of a substrate-bound SARS chymotrypsin-like cysteine proteinase predicted by multiple molecular dynamics simulations: catalytic efficiency regulated by substrate binding. Proteins 57: 747-757. 16. Dooley AJ, Shindo N, Taggart B, Park JG, Pang Y-P (2006) From genome to drug lead: identification of a small-molecule inhibitor of the SARS virus. Bioorg Med Chem Lett 16: 830-833.

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Abstract

L'invention concerne des procédés pour déterminer des résidus d'acétylcholinestérase spécifiques des invertébrés et des insectes, tels que spécifiques des moustiques. Les procédés peuvent être utilisés pour concevoir des pesticides et insecticides qui sont spécifiques des enzymes d'invertébrés ou d'insectes (par exemple, de moustique), conduisant à une réduction de la toxicité pour les mammifères. Des compositions pour inhiber les acétylcholinestérases d'invertébrés et d'insectes (par exemple de moustique) et des procédés de préparation de ceux-ci sont également proposés.
PCT/US2008/067236 2007-06-18 2008-06-17 Inhibiteur d'acétylcholinestérase d'invertébrés WO2008157552A2 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10906888B2 (en) 2016-07-14 2021-02-02 Pfizer Inc. Pyrimidine carboxamides as inhibitors of Vanin-1 enzyme

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3879386A (en) * 1973-06-22 1975-04-22 Scott & Sons Co O M Amino substituted 1,2,4-triazinones
US20050065145A1 (en) * 2003-09-08 2005-03-24 Syrrx, Inc. Dipeptidyl peptidase inhibitors

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3879386A (en) * 1973-06-22 1975-04-22 Scott & Sons Co O M Amino substituted 1,2,4-triazinones
US20050065145A1 (en) * 2003-09-08 2005-03-24 Syrrx, Inc. Dipeptidyl peptidase inhibitors

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BILLICH ANDREAS ET AL: 'Stimulation of MCF-7 breast cancer cell proliferation by estrone sulfate and dehydroepiandrosterone sulfate: inhibition by novel non-steroidal steroid sulfatase inhibitors' JOURNAL OF STEROID BIOCHEMISTRY & MOLECULAR BIOLOGY vol. 73, 2000, pages 225 - 235 *
FIELD AK ET AL: '9{[2-Hydroxy-1-(hydroxymethyl)ethoxy]methy l}guanine: A selective inhibitor of herpes group virus replication' PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES vol. 80, 1983, pages 4139 - 4143 *
PEREZ, JOSE MARIA ET AL: 'Hetero Diels-Alder of 1-Acetylamino- and 1-Dimethylamino-1- azadienes with Benzoquinones' TETRAHEDRON vol. 56, 2000, pages 1561 - 1567 *
STERN E ET AL: 'Pharmacomodulations around the 4-oxo-1,4-dihydroquinoline-3-carboxamides, a class ofpotent CB2-selective Cannabinoid receptor ligands' JOURNAL OF MEDICINAL CHEMISTRY vol. 50, 2007, pages 5471 - 5484 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10906888B2 (en) 2016-07-14 2021-02-02 Pfizer Inc. Pyrimidine carboxamides as inhibitors of Vanin-1 enzyme

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