Title page for ETD etd-05162011-210932

Type of Document Dissertation
Author Hartsel, Joshua Alan
Author's Email Address jhartsel@vt.edu
URN etd-05162011-210932
Title Revisiting aryl N-methylcarbamate acetylcholinesterase inhibitors as potential insecticides to combat the malaria-transmitting mosquito, Anopheles gambiae
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Carlier, Paul R. Committee Chair
Deck, Paul A. Committee Member
Etzkorn, Felicia A. Committee Member
Gandour, Richard D. Committee Member
Tanko, James M. Committee Member
  • Anopheles gambiae
  • insecticide-treated nets
  • malaria
  • species-selective inhibitors
  • acetylcholinesterase
  • terbam
  • tert-alkylphenol
  • aryl carbamate
  • propoxur
Date of Defense 2011-04-21
Availability unrestricted
My graduate work focused on the syntheses and pharmacology of species-selective aryl methylcarbamate acetylcholinesterase inhibitors to combat the malaria-transmitting mosquito, Anopheles gambiae. We identified six novel carbamates that demonstrated levels of target selectivity exceeding our project milestone of 100-fold. Among the C2-substituted phenylcarbamates examined (class II), 2’-(2-

ethylbutoxy)phenyl N-methylcarbamate (9bd*) was extraordinarily selective (570-fold + 72). The high level of selectivity observed for many of the class II carbamates was attributed to a helical displacement within the active site of An. gambiae

acetylcholinesterase, able to accommodate carbamates with larger C2-substituted secondary β-branching side chains. Conversely, this type of side chain forms unfavorable interactions within the active site of human acetylcholinesterase. The C3-substituted carbamates (class I), such as terbam (9c), were less selective than many of the class II carbamates; however, class I carbamates related to terbam (9c) were highly toxic to An.

gambiae. In particular, the contact toxicity measured for 9c (LC50 = 0.037 mg/mL) was equal to the commonly used agricultural insecticide, propoxur (9a, LC 50 = 0.037 mg/mL). In total, seventy aryl carbamates were screened for their inhibition potency and contact toxicity towards An. gambiae.

The common final step in all of these syntheses was the carbamoylation of a phenol, which normally proceeded in a 70 to 90% yield. Thirty seven novel carbamates are reported out of the seventy two prepared. Although sixteen of the phenols were

commercially available, the others were prepared with known and adapted synthetic methodologies. The emerging structure-activity relationships led us to focus on the synthesis of 3-tert-alkylphenols (Class I) and 2-alkoxy or 2-alkylthio-substituted phenols (Class II). Three methods particularly stand out: First, we applied the methods of Tanaka to prepare 3-tert-alkylphenols wherein a methyl group was replaced by a trifluoromethyl group. Second, we adapted the methods of Tanaka to prepare 3-tert-alkylphenols that lack fluorine substitution. This method is competitive with the little known method of

Reetz to convert aryl ketones to the corresponding 1,1-dimethylalkyl group and allows one to access electron rich tert-alkyl-substituted aromatics that are not accessible by the Friedel-Crafts alkylation (Friedel-Crafts restricted). Third, we found a convenient and high-yielding method for selective S-alkylation of 2-mercaptophenol. In addition to the synthesis of carbamates, the preparation of one hundred three intermediates, phenols, and electron rich tert-alkyl arenes are reported.

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