Trifluoromethyl ketones: Potential insecticides towards Anopheles gambiae

Malaria continues to cause significant mortality in sub-Saharan Africa and elsewhere, and existing vector control measures are being threatened by growing resistance to pyrethroid insecticides. With the goal of developing new human-safe, resistance-breaking insecticides we have explored several classes of acetylcholinesterase inhibitors. In vitro assay studies have shown that trifluoromethyl ketones (TFK's) are potent inhibitors of An. gambiae AChE (AgAChE), that inhibit the enzyme by making a covalent adduct with the catalytic serine of the enzyme. However research in the Carlier group has shown that trifluoromethyl ketones bearing benzene and pyrazole cores have shown very little toxicity to An. gambiae, perhaps due to hydration and rapid clearance. Focus was directed towards synthesis of oximes, oxime ethers, and hydrazones as potential prodrugs to prevent immediate hydration and reach the central nervous system. The synthesis of various oximes, oxime ethers, and hydrazones has been shown to give cimpounds toxic to Anopheles gambiae within 3- to 4-fold of the toxicity of propoxur. However, thus far we have not been able to link the toxicity of these compounds to a cholinergic mechanism. Pre-incubation studies suggest that significant hydrolysis of these compounds to TFKs does not occur or 22 h at pH 7.7 or 5.5. Future work will be directed towards TFKs that have better pharmacokinetic properties. Work will also be directed at synthesis of oxime and hydrazone TFK isosteres to determine the mechanism of action of these compounds.

Name thesis:degree_name

Master of Science

Level thesis:degree_level

masters

Discipline thesis:degree_discipline

Chemistry

Department dc:contributor.department

Chemistry

Grantor dc:publisher

Virginia Tech

Year dc:date.issued

2013

Author dc:creator

• Camerino, Eugene

Chair dc:contributor.committeechair

• Carlier, Paul R.

Committee members dc:contributor.committeemember

• Santos, Webster L.
• Kingston, David G. I.

• acetylcholinesterase inhibitors
• acetylcholine
• transition-state analogues
• trifluoromethyl ketones
• insecticides
• mosquitocides

Statement dc:rights

• In Copyright

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Dc Identifier Other

vt_gsexam:208

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/54015