title: Difluoromethyl ketones: Potent inhibitors of wild type and carbamate-insensitive G119S mutant Anopheles gambiae acetylcholinesterase.
abstract: Malaria is a devastating disease in sub-Saharan Africa, and current vector control measures are threatened by emerging resistance mechanisms. With the goal of developing new, selective, resistance-breaking insecticides we explored α-fluorinated methyl ketones as reversible covalent inhibitors of Anopheles gambiae acetylcholinesterase (AgAChE). Trifluoromethyl ketones 5 demonstrated remarkable volatility in microtiter plate assays, but 5c,e-h exhibited potent (1-100 nM) inhibition of wild type (WT) AgAChE and weak inhibition of resistant mutant G119S mutant AgAChE. Fluoromethyl ketones 10c-i exhibited submicromolar to micromolar inhibition of WT AgAChE, but again only weakly inhibited G119S AgAChE. Interestingly, difluoromethyl ketone inhibitors 9c and 9g had single digit nanomolar inhibition of WT AgAChE, and 9g had excellent potency against G119S AgAChE. Approach to steady-state inhibition was quite slow, but after 23 h incubation an IC50 value of 25.1 ± 1.2 nM was measured. We attribute the slow, tight-binding G119S AgAChE inhibition of 9g to a balance of steric size and electrophilicity. However, toxicities of 5g, 9g, and 10g to adult A. gambiae in tarsal contact, fumigation, and injection assays were lower than expected based on WT AgAChE inhibition potency and volatility. Potential toxicity-limiting factors are discussed.
authors.affiliation: Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Camerino
authors.affiliation: Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA.
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Wong
authors.affiliation: Department of Entomology and Nematology, Emerging Pathogens Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Tong
authors.affiliation: Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA.
authors.forename: Florian
authors.initials: F
authors.lastname: Körber
authors.affiliation: Department of Entomology and Nematology, Emerging Pathogens Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Gross
authors.affiliation: Department of Entomology and Nematology, Emerging Pathogens Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Rafique
authors.initials: R
authors.lastname: Islam
authors.affiliation: Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Viayna
authors.affiliation: Department of Entomology and Nematology, Emerging Pathogens Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Mutunga
authors.affiliation: Department of Biochemistry, Virginia Tech, Blacksburg, VA 24061, USA.
authors.forename: Jianyong
authors.initials: J
authors.lastname: Li
authors.affiliation: Molsoft LLC, 11199 Sorrento Valley Road, San Diego, CA 92121, USA.
authors.forename: Maxim M
authors.initials: MM
authors.lastname: Totrov
authors.affiliation: Department of Entomology and Nematology, Emerging Pathogens Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Bloomquist
authors.affiliation: Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Carlier
mesh_terms: D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000852:Anopheles / Q000201:enzymology*; D002219:Carbamates / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009154:Mutation; D013329:Structure-Activity Relationship
chemical_list: D002219:Carbamates; D004791:Enzyme Inhibitors; D007659:Ketones; D000110:Acetylcholinesterase
keywords: Acetylcholinesterase; Anopheles gambiae; Fluorinated ketones; Malaria; Trifluoroketones