The mosquito Aedes aegypti is the vector of arboviruses such as Zika, Chikungunya, dengue and yellow fever. These infectious diseases have a major impact on public health. The unavailability of effective vaccines or drugs to prevent or treat most of these diseases makes vector control the main form of prevention. One strategy to promote mosquito population control is the use of synthetic insecticides to inhibit key enzymes in the metabolic pathway of these insects, particularly during larval stages. One of the main targets of the kynurenine detoxification pathway in mosquitoes is the enzyme 3-hydroxykynurenine transaminase (HKT), which catalyzes the conversion of 3-hydroxykynurenine (3-HK) into xanthurenic acid (XA). In this work, we report eleven newly synthesized oxadiazole derivatives and demonstrate that these compounds are potent noncompetitive inhibitors of HKT from Ae. aegypti. The present data provide direct evidence that HKT can be explored as a molecular target for the discovery of novel larvicides against Ae. aegypti. More importantly, it ensures that structural information derived from the HKT 3D-structure can be used to guide the development of more potent inhibitors.

中文翻译：

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从埃及伊蚊中发现1,2,4-恶二唑衍生物作为3-羟基犬尿氨酸转氨酶（HKT）的新型非竞争性抑制剂。

蚊埃及伊蚊是虫媒病毒的媒介，例如寨卡病毒，基孔肯雅热，登革热和黄热病。这些传染病对公共卫生有重大影响。由于无法获得有效的疫苗或药物来预防或治疗大多数此类疾病，因此病媒控制是预防的主要形式。促进蚊子种群控制的一种策略是使用合成杀虫剂抑制这些昆虫的代谢途径中的关键酶，特别是在幼虫阶段。蚊子中犬尿氨酸的解毒途径的主要目标之一是3-羟基犬尿氨酸转氨酶（HKT），该酶催化3-羟基犬尿氨酸（3-HK）转化为黄嘌呤酸（XA）。在这项工作中，我们报告了11种新合成的恶二唑衍生物，并证明这些化合物是Ae公司HKT的有效非竞争性抑制剂。埃及 目前的数据提供了直接的证据，HKT可以作为发现针对Ae的新型杀幼虫剂的分子靶标进行探索。埃及 更重要的是，它确保从HKT 3D结构获得的结构信息可用于指导开发更有效的抑制剂。