Structure-Activity Relationship Studies on Natural Eremophilanes from Inula helenium as Toxicants Against Aedes aegypti Larvae and Adults

Authors: Cantrell, Charles; Wei Pridgeon, Yuping; FRONCZEK, FRANK - Louisiana Technical University; Becnel, James

Submitted to: Chemistry and Biodiversity
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/8/2010
Publication Date: 6/21/2010
Citation: Cantrell, C.L., Wei Pridgeon, Y., Fronczek, F.R., Becnel, J.J. 2010. Structure-Activity Relationship Studies on Natural Eremophilanes from Inula helenium as Toxicants Against Aedes aegypti Larvae and Adults. Chemistry and Biodiversity. 7:1681-1697.

Interpretive Summary: The yellow fever mosquito, Aedes aegypti (L.) transmits viral pathogens of humans, including yellow fever and dengue, both of which can cause severe human morbidity and mortality. One potential source of new pesticides for controlling arthropods is natural plant chemicals. Not only might certain natural plant products be a source of new pesticides but also botanical derivatives may be more environmentally friendly than synthetic chemicals. This project began by randomly screening previously isolated and identified natural products from our personal repositories. The natural compounds chosen were representative of particular classes of natural products we had previously reported on in the literature. This screening approach led to a previously investigated set of eudesmanolides from Inula helenium which were the subject of a structure-activity investigation. In particular, the two eudesmanolides, alantolactone and isoalantolactone, were the subject of this investigation and the results are reported below. The larvicidal and adulticidal activities of all synthetic isomers and analogs of alantolactone and isoalantolactone against Ae. aegypti and the structure-activity relationships are reported here. None of the synthetic isomers synthesized and screened against Ae aegypti larvae were more active than isoalantolactone itself which had an LC50 of 10.0 ug/mL. This was not the case for analogs of alantolactone for which many of the analogs had larvicidal activity ranging from 12.4 ug/mL to 69.9 ug/mL.

Technical Abstract: An Aedes aegypti larval toxicity bioassay was performed on compounds representing many classes of natural compounds including polyacetylenes, phytosterols, flavonoids, sesquiterpenoids, and triterpenoids. Among these compounds studies, two eudesmanolides, alantolactone and isoalantolactone, showed larcicidal activities against Ae. aegypti and therefore were chosen for further structure-activity relationship study. In this study, structural modifications were performed on both alantolactone and isoalantolactone in an effort to understand the functional groups necessary for maintaining and/or increasing its activity and to possibly lead to more effective insect control agents. All parent compounds and synthetic modification reaction products were evaluated for their toxic activities against Ae. aegypti larvae and adults. Structure modifications included epoxidations, reductions, catalytic hydrogenations, and Michael additions to the a,B-unsaturated lactones. None of the synthetic isomers synthesized and screened against Ae aegypti larvae were more active than isoalantolactone itself which had an LC50 of 10.0 ug/mL. This was not the case for analogs of alantolactone for which many of the analogs had larvicidal activity ranging from 12.4 ug/mL to 69.9 ug/mL. In general, activity trends observed from Ae. aegypti larval screening were not consistent with observations from adulticidal screening. The propyl amine Michael addition analog of alantolactone was the most active adulticide synthesized with an LC50 of 1.07 ug/mosquito. In addition, the crystal structures of both alantolactone and isoalantolactone were determined using CuKa radiation, which allowed their absolute configurations to be determined based on resonant scattering of the light atoms.