Structure-activity relationship studies on derivatives of eudesmanolides from Inula helenium as toxicants against Aedes aegypti larvae and adults.
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, two eudesmanolides, alantolactone, and isoalantolactone showed larvicidal 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 alpha,beta-unsaturated lactones. None of the synthetic isomers synthesized and screened against Ae. aegypti larvae were more active than isoalantolactone itself which had an LC(50) value of 10.0 microg/ml. This was not the case for analogs of alantolactone for which many of the analogs had larvicidal activities ranging from 12.4 to 69.9 microg/ml. In general, activity trends observed from Ae. aegypti larval screening were not consistent with observations from adulticidal screening. The propylamine Michael addition analog of alantolactone was the most active adulticide synthesized with an LC(50) value of 1.07 microg/mosquito. In addition, the crystal structures of both alantolactone and isoalantolactone were determined using CuK(alpha) radiation, which allowed their absolute configurations to be determined based on resonant scattering of the light atoms.
Cantrell
Charles L
CL
USDA-ARS, Natural Products Utilization Research Unit, University, MS 38677, USA. charles.cantrell@ars.usda.gov
Pridgeon
Julia W
JW
Fronczek
Frank R
FR
Becnel
James J
JJ
D000330:Aedes / Q000187:drug effects* / Q000254:growth & development; D000818:Animals; D018360:Crystallography, X-Ray; D007306:Insecticides / Q000737:chemistry / Q000494:pharmacology*; D038143:Inula / Q000737:chemistry*; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology*; D007814:Larva / Q000187:drug effects; D008958:Models, Molecular; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology*; D045787:Sesquiterpenes, Eudesmane / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D007306:Insecticides; D007783:Lactones; D012717:Sesquiterpenes; D045787:Sesquiterpenes, Eudesmane; C032787:isoalantolactone; C004363:alantolactone