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dc.contributor.authorHartsel, Joshua Alanen_US
dc.date.accessioned2016-09-22T15:14:43Z
dc.date.available2016-09-22T15:14:43Z
dc.date.issued2011-04-21en_US
dc.identifier.otheretd-05162011-210932en_US
dc.identifier.urihttp://hdl.handle.net/10919/73002
dc.description.abstractMy 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.
dc.language.isoen_USen_US
dc.publisherVirginia Techen_US
dc.rightsI hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Virginia Tech or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.en_US
dc.subjectAnopheles gambiaeen_US
dc.subjectacetylcholinesteraseen_US
dc.subjectaryl carbamateen_US
dc.subjectinsecticide-treated netsen_US
dc.subjectmalariaen_US
dc.subjectpropoxuren_US
dc.subjectspecies-selective inhibitorsen_US
dc.subjectterbamen_US
dc.subjecttert-alkylphenolen_US
dc.titleRevisiting aryl N-methylcarbamate acetylcholinesterase inhibitors as potential insecticides to combat the malaria-transmitting mosquito, Anopheles gambiaeen_US
dc.typeDissertationen_US
dc.contributor.departmentChemistryen_US
dc.description.degreePh. D.en_US
thesis.degree.namePh. D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen_US
thesis.degree.disciplineChemistryen_US
dc.contributor.committeechairCarlier, Paul R.en_US
dc.contributor.committeememberDeck, Paul A.en_US
dc.contributor.committeememberEtzkorn, Felicia A.en_US
dc.contributor.committeememberGandour, Richard D.en_US
dc.contributor.committeememberTanko, James M.en_US
dc.type.dcmitypeTexten_US
dc.identifier.sourceurlhttp://scholar.lib.vt.edu/theses/available/etd-05162011-210932/en_US
dc.date.sdate2011-05-16en_US
dc.date.rdate2012-05-31
dc.date.adate2011-05-31en_US


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