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Trifluoromethyl ketones: Potential insecticides towards Anopheles gambiae

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dc.contributor.authorCamerino, Eugeneen
dc.contributor.committeechairCarlier, Paul R.en
dc.contributor.committeememberSantos, Webster L.en
dc.contributor.committeememberKingston, David G. I.en
dc.contributor.departmentChemistryen
dc.date.accessioned2015-07-06T06:00:10Zen
dc.date.available2015-07-06T06:00:10Zen
dc.date.issued2013-01-11en
dc.description.abstractMalaria 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.en
dc.description.degreeMaster of Scienceen
dc.format.mediumETDen
dc.identifier.othervt_gsexam:208en
dc.identifier.urihttp://hdl.handle.net/10919/54015en
dc.publisherVirginia Techen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectacetylcholinesterase inhibitorsen
dc.subjectacetylcholineen
dc.subjecttransition-state analoguesen
dc.subjecttrifluoromethyl ketonesen
dc.subjectinsecticidesen
dc.subjectmosquitocidesen
dc.titleTrifluoromethyl ketones: Potential insecticides towards Anopheles gambiaeen
dc.typeThesisen
thesis.degree.disciplineChemistryen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.levelmastersen
thesis.degree.nameMaster of Scienceen

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