ArticleBioorganic & medicinal chemistry letters2015
Difluoromethyl ketones: Potent inhibitors of wild type and carbamate-insensitive G119S mutant Anopheles gambiae acetylcholinesterase.
Article in Bioorganic & medicinal chemistry letters, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 51 citations in OpenAlex.
- Net Oxidative Photocatalytic Strategy toward theOrganic letters · 2026Article
- Potent and selective indole-based inhibitors targeting disease-transmitting mosquitoes.RSC medicinal chemistry · 2026Article
- Catalytic Asymmetric Difluoroalkylation Using In Situ Generated Difluoroenol Species as the Privileged Synthon.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Structure-Activity Relationships Reveal Beneficial Selectivity Profiles of Inhibitors Targeting Acetylcholinesterase of Disease-Transmitting Mosquitoes.Journal of medicinal chemistry · 2023Article
- Direct electrochemical hydrodefluorination of trifluoromethylketones enabled by non-protic conditions.Chemical science · 2021Article
- Pseudo-Dipeptide Bearing α,α-Difluoromethyl Ketone Moiety as Electrophilic Warhead with Activity against Coronaviruses.International journal of molecular sciences · 2021Article
- Synthesis and Structure ofMolecules (Basel, Switzerland) · 2021Article
- Select β- and γ-branched 1-alkylpyrazol-4-yl methylcarbamates exhibit high selectivity for inhibition ofPesticide biochemistry and physiology · 2018Article
- Structure of the G119S Mutant Acetylcholinesterase of the Malaria Vector Anopheles gambiae Reveals Basis of Insecticide Resistance.Structure (London, England : 1993) · 2018Article
- CFJournal of the American Chemical Society · 2017Article
- Discovery of Species-selective and Resistance-breaking Anticholinesterase Insecticides for the Malaria Mosquito.Current medicinal chemistry · 2017Review
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12 authors at 3 institutions in 1 country.
Funding
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.
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