Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 986125 Nebraska Medical Center, Omaha, NE 68198-6125, USA.
Department of Anesthesiology, Vanderbilt University Medical Center, T-4208 Medical Center North, Nashville, TN 37232, USA.
ChemMedChem. 2021 Jan 19;16(2):319-327. doi: 10.1002/cmdc.202000598. Epub 2020 Oct 28.
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.
寨卡病毒（ZIKV）、登革热（DENV）和基孔肯雅热（CHIKV）是通过受感染的成年雌性埃及伊蚊叮咬传播给人类的虫媒病毒。由于这些疾病目前没有有效的疫苗或治疗方法，因此控制这些病毒传播的主要策略是通过使用杀虫剂来防止蚊子叮咬人类。不幸的是，常用的杀虫剂类别已出现明显的抗药性增加，从而使控制工作变得更加复杂。抑制蚊子传播媒介埃及伊蚊的肾内向整流钾 (Kir) 通道已被证明是开发新型杀蚊剂的有前途的目标。我们已经表明，Kir1 通道在蚊子利尿、血淋巴钾稳态、飞行和繁殖中发挥关键作用。我们实验室的先前工作确定了一种新型（苯磺酰基）哌嗪支架，它是有效的 AeKir 通道抑制剂，对成年和幼虫蚊子均具有活性。在此，我们报告了该支架的进一步 SAR 工作，并确定了具有提高的体外效力和蚊子幼虫毒性的其他化合物。
