Further SAR on the (Phenylsulfonyl)piperazine Scaffold as Inhibitors of the Aedes aegypti Kir1 (AeKir) Channel and Larvicides.

Zika virus (ZIKV), dengue fever (DENV) and chikungunya (CHIKV) are arboviruses that are spread to humans from the bite of an infected adult female Aedes aegypti mosquito. As there are no effective vaccines or therapeutics for these diseases, the primary strategy for controlling the spread of these viruses is to prevent the mosquito from biting humans through the use of insecticides. Unfortunately, the commonly used classes of insecticides have seen a significant increase in resistance, thus complicating control efforts. Inhibiting the renal inward rectifier potassium (Kir) channel of the mosquito vector Aedes aegypti has been shown to be a promising target for the development of novel mosquitocides. We have shown that Kir1 channels play key roles in mosquito diuresis, hemolymph potassium homeostasis, flight, and reproduction. Previous work from our laboratories identified a novel (phenylsulfonyl)piperazine scaffold as potent AeKir channel inhibitors with activity against both adult and larval mosquitoes. Herein, we report further SAR work around this scaffold and have identified additional compounds with improved in vitro potency and mosquito larvae toxicity.

Pharmacological Inhibition of Inward Rectifier Potassium Channels Induces Lethality in Larval Aedes aegypti.

The inward rectifier potassium (Kir) channels play key roles in the physiology of mosquitoes and other insects. Our group, among others, previously demonstrated that small molecule inhibitors of Kir channels are promising lead molecules for developing new insecticides to control adult female mosquitoes. However, the potential use of Kir channel inhibitors as larvicidal agents is unknown. Here we tested the hypothesis that pharmacological inhibition of Kir channels in the larvae of Aedes aegypti, the vector of several medically important arboviruses, induces lethality. We demonstrated that adding barium, a non-specific blocker of Kir channels, or VU041, a specific small-molecule inhibitor of mosquito Kir1 channels, to the rearing water (deionized H2O) of first instar larvae killed them within 48 h. We further showed that the toxic efficacy of VU041 within 24 h was significantly enhanced by increasing the osmolality of the rearing water to 100 mOsm/kg H2O with NaCl, KCl or mannitol; KCl provided the strongest enhancement compared to NaCl and mannitol. These data suggest: (1) the important role of Kir channels in the acclimation of larvae to elevated ambient osmolality and KCl concentrations; and (2) the disruption of osmoregulation as a potential mechanism of the toxic action of VU041. The present study provides the first evidence that inhibition of Kir channels is lethal to larval mosquitoes and broadens the potential applications of our existing arsenal of small molecule inhibitors of Kir channels, which have previously only been considered for developing adulticides.