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ARS Home » Southeast Area » Gainesville, Florida » Center for Medical, Agricultural and Veterinary Entomology » Mosquito and Fly Research » Research » Publications at this Location » Publication #350216

Research Project: Biting Arthropod Surveillance and Control

Location: Mosquito and Fly Research

Title: Aryl Trifluoromethyl Iximes: potential new mosquito insecticides

item Richoux, Gary - University Of Florida
item Demares, Fabien - University Of Florida
item Coquerel, Quentin - University Of Florida
item Bernier, Ulrich - Uli
item Linthicum, Kenneth - Ken
item Bloomquist, Jeffrey - University Of Florida

Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: 2/2/2018
Publication Date: 2/15/2018
Citation: Richoux, G., Demares, F., Coquerel, Q., Bernier, U.R., Linthicum, K., Bloomquist, J.R. 2018. Aryl Trifluoromethyl Iximes: potential new mosquito insecticides. Meeting Abstract. pg. 1.

Interpretive Summary:

Technical Abstract: Fluorinated methylketones have been identified as potential mosquitocides, suspected of acting as reaction coordinate analogues that inhibit acetylcholinesterase (AChE) thereby leading to paralysis and eventual death. Previous work has explored trifluoro-, difluoro-, and fluoromethylketone analogues with pyrazole substituted trifluoromethylketone (TFK) derivatives exhibiting some of the highest inhibition and mosquito selectivity. Although TFKs were found to be potent inhibitors of Anopheles gambiae AChE, poor topical toxicity was observed, and this is believed to be due in part to high volatility and metabolism issues. Use of an oxime moiety to mask the ketone and offer a more metabolically robust derivative improves topical toxicity to some degree but does not afford the toxicity expected from the previously observed high AChE inhibition from TFKs. Hypothetically, the oxime should readily undergo hydrolysis to the TKF at acidic pH, but it is possible that the TFK oxime does not fully hydrolyze within the mosquito. We also suspect that the polar hydroxyl group limits compound uptake at the mosquito cuticle and potentially limits CNS penetration. To this end, we synthesized a series of derivatives in which the oxime hydroxyl group was converted to the less polar oxime ether or oxime ester. We also investigated the effects of electron donating and withdrawing groups to determine if the electron density about the oxime ester/ether oxygen had an effect on lability through hydrolysis susceptibility. Although none of the synthesized compounds exhibited 100% mortality through topical application of 1 µg/mg of mosquito, a few trends were observed. The introduction of electron donating groups (cmpds 14-19) gave less favorable results than those with electron withdrawing groups (cmpds 8-13) suggesting that electron withdrawing groups might increase the nucleophilicity of the compound. It was also seen that an increase in the functional group size led to an increase in mortality, and it is possible that this portion of the molecule is interacting with the hydrophobic residues of the acyl pocket within AChE. Because none of the oxime ethers or oxime esters exhibited topical toxicities better or equal to the previously made oximes, this suggest that the oxime does not act as a pro-drug by hydrolyzing to the TFK. Further derivatization of TFK analogs will investigate substitution on the pyrazole ring to potentially decrease volatility and metabolism.