Trypsin Modulating Oostatic Factor (TMOF) and Non-Peptidic Analogs as Novel Insecticides and Arthropod Repellents

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Title: Trypsin Modulating Oostatic Factor (TMOF) and Non-Peptidic Analogs as Novel Insecticides and Arthropod Repellents
Author: Vanderherchen, Matthew Barton
Advisors: Brian M. Wiegmann, Committee Member
Charles S. Apperson, Committee Member
R. Michael Roe, Committee Chair
Randy L. Rose, Committee Member
Abstract: Eight nonpeptidic chemical analogs of trypsin modulating oostatic factor (TMOF), an insect hormone inhibiting trypsin biosynthesis in mosquitoes, were synthesized based on the structure of the native peptide. The median lethal concentration (LC50) for these analogs, TMOF and FDPAP, a peptidic TMOF analog, was estimated for larvae of the northern house mosquito, Culex pipiens, using a static 5-day bioassay. Four of these compounds demonstrated the same larvicidal activity as TMOF, while three of these compounds were 1.2 - 2.5-fold more active than TMOF. There was a relationship found between the lipophilicity of this series of analogs and toxicity to mosquito larvae. All eight TMOF analogs were toxic by injection at some level in fourth instars of the tobacco hornworm (Manduca sexta) while TMOF and FDPAP were non-toxic. Injection of TMOF and FDPAP into fourth stadium and TMOF into second stadium M. sexta had no effect on trypsin activity, larval growth or mortality. Apparently the mosquito hormone is inactive in this species and at the developmental stages examined. Three TMOF analogs (CHEA, PHEA, PHA), demonstrating the highest activity by injection in M. sexta, were also found to be toxic by injection in fourth instars of the tobacco budworm (Heliothis virescens) and the cotton bollworm (Helicoverpa zea) as well as adult male German cockroaches (Blattela germanica). Finally, results of a two-choice feeding bioassay with H. virescens indicated that one of the TMOF analogs, PHEA, has anti-feedant properties. Novel aromatic and aliphatic organic acids, esters and ketone mimics of the mosquito trypsin modulating oostatic factor (TMOF) were synthesized and assayed as repellents for ticks and as an anti-feeding agent for mosquitoes. E-7-(cyclohexyl)hept-4-enoic acid (CHEA), E-7-phenylhept-4-enoic acid (PHEA), ethyl E-7-(cyclohexyl)hept-4-enoate (CHEN) and ethyl E-7-phenylhept-4-enoate (PHEN) had repellent activity against the soft tick, Ornithodorous parkeri (Acari: Argasidae) in a two-choice bioassay. PHEN, an aromatic organic ester, was the most active. Only 15% of the ticks tested selected the surface treated with 5 mg/cm2 of PHEN as compared to the untreated surface. Commercially available 2-undecanone, a natural product found in the trichomes of wild tomatoes, was found to also mimic the structure of TMOF and was active as a repellent at 50 mg/cm2. Since this compound is a natural botanical product with low mammalian toxicity, further tests were conducted to determine its anti-feeding activity against mosquitoes. The median effective dose to prevent 50% of adult yellow fever mosquitoes, Aedes aegypti, from obtaining a blood meal (ED50) was estimated as 91.5 mg/cm2 of human skin as compared to 1.6 mg/cm2 for deet. 2-Undecanone applied as a 30 and 40% solution (vol/vol) in isopropyl alcohol to human skin was 100% active for 15 min in preventing mosquito feeding and 40% provided 93% protection 30 min after application. Persistence is limited by the high volatility of 2-undecanone although it appears that once mosquitoes come into contact with the repellent, host seeking is inhibited more than 2 h
Date: 2003-03-21
Degree: MS
Discipline: Entomology

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