Title page for ETD etd-05122011-181858


Type of Document Dissertation
Author Mutunga, James Mutuku
Author's Email Address jmutunga@vt.edu
URN etd-05122011-181858
Title Molecular, Biochemical, and Toxicological Evaluation of Anticholinesterases for control of the Malaria Mosquito, Anopheles gambiae
Degree PhD
Department Entomology
Advisory Committee
Advisor Name Title
Bloomquist, Jeffrey R. Committee Chair
Myles, Kevin M. Committee Co-Chair
Anderson, Troy Committee Member
Paulson, Sally L. Committee Member
Sharakhov, Igor V. Committee Member
Keywords
  • N-methylcarbamates
  • akron strain
  • tacrine dimers
  • acetylcholinesterase
  • selectivity
  • pyrazoles
  • oximes
  • active site gorge
  • bivalent carbamates
Date of Defense 2011-04-28
Availability unrestricted
Abstract
Pyrethroids are the only class of insecticides approved by the World Health Organization (WHO) for use in insecticide treated nets (ITNs), the first line of malaria vector control. Widespread resistance development to pyrethroids undermines current control efforts, and hence an urgent need for alternative chemistries. I report the evaluation of pharmacological differences between insect and vertebrate acetylcholinesterase (AChE) as well as selectivity and toxicity testing of new carbamate insecticides on Anopheles gambiae, the African malaria mosquito. AChE gorge pharmacology data revealed differences between insect and vertebrate AChE that can be exploited in the design of a bivalent insecticide. Toxicokinetic analysis showed that metabolic detoxication and cuticular penetration affect toxicity of carbamates in a manner dependent on the chemical structure.

Structure activity relationships of side-chain branched N-methylcarbamates emphasized the importance of structural complementarity of ligands to the AChE catalytic active site and the substrate, acetylcholine. Monovalent pyrazoles and acetophenone oxime carbamates were toxic to both susceptible and carbamate-resistant mosquitoes carrying a G119S mutation within the catalytic site. A bivalent phthalimide-pyrazole carbamate and

sulfenylated phenyl N-methyl carbamates were highly toxic when topically applied onto insect but less toxic by treated filter paper assays. In vitro evaluation of a molecular mosquito-selectivity model using AChE peripheral site ligands confirmed that selectivity of PRC 472 was due to presence of I70 in mosquito, which is Y70 in human AChE. The findings presented here are important steps in the on-going search of a mosquito-selective and resistance mitigating carbamate insecticide for control of malaria mosquitoes.

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