title: 3-Oxoisoxazole-2(3H)-carboxamides and isoxazol-3-yl carbamates: Resistance-breaking acetylcholinesterase inhibitors targeting the malaria mosquito, Anopheles gambiae.
abstract: To identify potential selective and resistance-breaking mosquitocides against the African malaria vector Anopheles gambiae, we investigated the acetylcholinesterase (AChE) inhibitory and mosquitocidal properties of isoxazol-3-yl dimethylcarbamates (15), and the corresponding 3-oxoisoxazole-2(3H)-dimethylcarboxamide isomers (14). In both series, compounds were found with excellent contact toxicity to wild-type susceptible (G3) strain and multiply resistant (Akron) strain mosquitoes that carry the G119S resistance mutation of AChE. Compounds possessing good to excellent toxicity to Akron strain mosquitoes inhibit the G119S mutant of An. gambiae AChE (AgAChE) with ki values at least 10- to 600-fold higher than that of propoxur, a compound that does not kill Akron mosquitoes at the highest concentration tested. On average, inactivation of WT AgAChE by dimethylcarboxamides 14 was 10-20 fold faster than that of the corresponding isoxazol-3-yl dimethylcarbamates 15. X-ray crystallography of dimethylcarboxamide 14d provided insight into that reactivity, a finding that may explain the inhibitory power of structurally-related inhibitors of hormone-sensitive lipase. Finally, human/An. gambiae AChE inhibition selectivities of these compounds were low, suggesting the need for additional structural modification.
authors: Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA.
authors: Astha
authors: A
authors: Verma
authors: Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA.
authors: Dawn M
authors: DM
authors: Wong
authors: Department of Entomology and Nematology, Emerging Pathogens Institute, University of Florida, Gainesville, FL 32610, USA.
authors: Rafique
authors: R
authors: Islam
authors: Department of Entomology and Nematology, Emerging Pathogens Institute, University of Florida, Gainesville, FL 32610, USA.
authors: Fan
authors: F
authors: Tong
authors: Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA.
authors: Maryam
authors: M
authors: Ghavami
authors: Department of Entomology and Nematology, Emerging Pathogens Institute, University of Florida, Gainesville, FL 32610, USA.
authors: James M
authors: JM
authors: Mutunga
authors: Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA.
authors: Carla
authors: C
authors: Slebodnick
authors: Department of Biochemistry, Virginia Tech, Blacksburg, VA 24061, USA.
authors: Jianyong
authors: J
authors: Li
authors: Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA.
authors: Elisabet
authors: E
authors: Viayna
authors: Molsoft LLC, 11199 Sorrento Valley Road, San Diego, CA 92121, USA.
authors: Polo C-H
authors: PC
authors: Lam
authors: Molsoft LLC, 11199 Sorrento Valley Road, San Diego, CA 92121, USA.
authors: Maxim M
authors: MM
authors: Totrov
authors: Department of Entomology and Nematology, Emerging Pathogens Institute, University of Florida, Gainesville, FL 32610, USA.
authors: Jeffrey R
authors: JR
authors: Bloomquist
authors: Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA. Electronic address: pcarlier@vt.edu.
authors: Paul R
authors: PR
authors: Carlier
mesh_terms: D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000852:Anopheles / Q000187:drug effects* / Q000201:enzymology*; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008288:Malaria / Q000635:transmission; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D002219:Carbamates; D002800:Cholinesterase Inhibitors; D007555:Isoxazoles; D000110:Acetylcholinesterase
keywords: Acetylcholinesterase; Anopheles gambiae; Carbamate; Carboxamide; Malaria