Mosquito Acetylcholinesterase as a Target for Novel Phenyl-Substituted Carbamates

James M. Mutunga, Ming Ma, Qiao-Hong Chen, Joshua A. Hartsel, Dawn M. Wong, Sha Ding, Max Totrov, Paul R. Carlier and Jeffrey R. Bloomquist
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James M. Mutunga: Emerging Pathogens Institute, Entomology and Nematology Department, University of Florida, Gainesville, FL 32610, USA
Ming Ma: Department of Chemistry, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
Qiao-Hong Chen: Department of Chemistry, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
Joshua A. Hartsel: Department of Chemistry, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
Dawn M. Wong: Department of Chemistry, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
Sha Ding: Department of Chemistry, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
Max Totrov: Molsoft LLC, 11199 Sorrento Valley Road, S209 San Diego, CA 92121, USA
Paul R. Carlier: Department of Chemistry, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
Jeffrey R. Bloomquist: Emerging Pathogens Institute, Entomology and Nematology Department, University of Florida, Gainesville, FL 32610, USA

IJERPH, 2019, vol. 16, issue 9, 1-13

Abstract: New insecticides are needed for control of disease-vectoring mosquitoes and this research evaluates the activity of new carbamate acetylcholinesterase (AChE) inhibitors. Biochemical and toxicological characterization of carbamates based on the parent structure of terbam, 3- tert -butylphenyl methylcarbamate, was performed. In vitro enzyme inhibition selectivity ( Anopheles gambiae versus human) was assessed by the Ellman assay, as well as the lethality to whole insects by the World Health Organization (WHO) paper contact assay. Bromination at the phenyl C6 position increased inhibitory potency to both AChEs, whereas a 6-iodo substituent led to loss of potency, and both halogenations caused a significant reduction of mosquitocidal activity. Similarly, installation of a hexyl substituent at C6 drastically reduced inhibition of Ag AChE, but showed a smaller reduction in the inhibition of hAChE. A series of 4-carboxamido analogs of the parent compound gave reduced activity against Ag AChE and generally showed more activity against hAChE than Ag AChE. Replacement of the 3- t -buyl group with CF 3 resulted in poor anticholinesterase activity, but this compound did have measurable mosquitocidal activity. A series of methyl- and fluoro- analogs of 3-trialkylsilyl compounds were also synthesized, but unfortunately resulted in disappointing activity. Finally, a series of sulfenylated proinsecticides showed poor paper contact toxicity, but one of them had topical activity against adult female Anopheles gambiae . Overall, the analogs prepared here contributed to a better understanding of carbamate structure–activity relationships (SAR), but no new significant leads were generated.

Keywords: Anopheles gambiae; anticholinesterase; insecticide; toxicity (search for similar items in EconPapers)
JEL-codes: I I1 I3 Q Q5 (search for similar items in EconPapers)
Date: 2019
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