Neurotoxicity of methoxylated stilbenes and N-Methylbenzamides on mosquitoes

Stilbenes are common phytoestrogen compounds, epitomized by resveratrol, naturally found in peanuts and grapes. Benzamides constitute a diverse synthetic group, some of which are used in human health; such as the insect repellent DEET, used for vector disease control via disruption of insect olfaction. In the present study, synthetic derivatives of these classes were screened for mosquito toxicity.

Compared to analogs, such as 4-methoxystilbene (S880159), and 3,4-dimethoxystilbene (T274844), S943916 had greater toxicity on Anopheles gambiae. At 1 µg/mg topical, S943916 killed 100% mosquitoes, while S880159 and T274844 killed 20% and 0%, respectively. The benzamide 2S-65465 and its 2-hydroxy analog (PRC1358) killed respectively 85% and 77% of the mosquitoes at the same dose. After 24 hours, LD₅₀ values were 540, 488, and 874 ng/mg for S943916, 2S-65465, and PRC1358, respectively. According to 2S-65465 design by Laggner and colleagues (2007), its putative molecular target is a voltage-gated potassium (Kv) channel, because it phenocopied the known inhibitor psora-4. We proceeded to test HEK-293 cells expressing mosquito AgKv2.1 channels through patch-clamp recordings. Potassium currents were inhibited at IC₅₀ = 0.24 µM (2S-65465), 1.14 µM (PRC1358); 22 µM (S943916); and 336 µM (S880159). This is the first report of 2S-65465 inhibitory action on a Kv channel. The relevance of Kv channels as a possible site and a blocking mode of action are discussed. The findings open up interesting leads toward synthetizing new mosquitocides.