Further development of cinnamodial analogues as mosquito (Aedes aegypti) toxicants for vector control.

Aedes aegypti mosquitoes are vectors of deadly arboviruses such as dengue, yellow fever, chikungunya, and Zika which kill millions worldwide. Prior research by our group discovered a drimane-type sesquiterpene cinnamodial (CDIAL, 1), which was isolated from endemic and medicinal Malagasy plants, that showed promising mosquitocidal activities against A. aegypti. Subsequent synthetic medicinal chemistry efforts to develop more stable and potent mosquitocides derived from CDIAL led to the discovery of novel active compounds with drimane or quinone chemotypes. Here we use medicinal chemistry to further explore the toxicity of these chemotypes against mosquitoes. A dihomodrimene 23b and two quinone derivatives 24a & 24b each displayed superior adulticidal potency compared to 1. A preliminary structure-adulticidal activity relationship (SAR) study showed that lipophilic compounds produced by alkylation of the conjugated ketone at C-12 position together with the presence of an aldehyde at C-11 enhance insecticidal activity. For the larvicidal activity of the quinone derivatives, analogs 22a, 24a and 24b were superior in potency compared to CDIAL, with 24a appearing to be the most potent among the active samples.