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Further SAR on the (phenylsulfonyl)piperazine scaffold as inhibitors of the Aedes aegypti Kir1 (AeKir) channel and larvicides.
ChemMedChem ( IF 3.4 ) Pub Date : 2020-09-14 , DOI: 10.1002/cmdc.202000598
Christopher D Aretz 1 , Sujay V Kharade 2 , Keagan Chronister 2 , Renata Rusconi Trigueros 3 , Erick J Martinez Rodriguez 3 , Peter M Piermarini 3 , Jerod S Denton 2 , Corey R Hopkins 1
Affiliation  

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.

中文翻译:

(苯磺酰基)哌嗪支架上的进一步 SAR 作为埃及伊蚊 Kir1 (AeKir) 通道的抑制剂和杀幼虫剂。

寨卡病毒 (ZIKV)、登革热 (DENV) 和基孔肯雅热 (CHIKV) 是虫媒病毒,通过受感染的成年雌性埃及伊蚊叮咬传播给人类。由于这些疾病没有有效的疫苗或治疗方法,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,常用的杀虫剂类别的抗性显着增加,从而使控制工作复杂化。抑制蚊媒埃及伊蚊的肾脏内向整流钾(Kir)通道已被证明是开发新型杀虫剂的有希望的目标。我们已经证明 Kir1 通道在蚊子利尿、血淋巴钾稳态、飞行和繁殖中起关键作用。我们实验室以前的工作确定了一种新型(苯磺酰基)哌嗪支架作为有效的Ae Kir 通道抑制剂,对成蚊和幼蚊都有活性。在此,我们报告了围绕该支架的进一步 SAR 工作,并确定了其他具有改善体外效力和蚊子幼虫毒性的化合物。
更新日期:2020-09-14
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