Structure鈥揂ctivity Relationships and Blood Distribution of Antiplasmodial Aminopeptidase-1 Inhibitors

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• 作者：Rebecca Deprez-Poulain ; Marion Flipo ; Catherine Piveteau ; Florence Leroux ; Sandrine Dassonneville ; Isabelle Florent ; Louis Maes ; Paul Cos ; Benoit Deprez
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：December 27, 2012
• 年：2012
• 卷：55
• 期：24
• 页码：10909-10917
• 全文大小：366K
• 年卷期：v.55,no.24(December 27, 2012)
• ISSN：1520-4804

文摘

Malaria is a severe infectious disease that causes between 655鈥?00 and 1.2 million deaths annually. To overcome the resistance to current drugs, new biological targets are needed for drug development. Aminopeptidase M1 (PfAM1), a zinc metalloprotease, has been proposed as a new drug target to fight malaria. Herein, we disclosed the structure鈥揳ctivity relationships of a selective family of hydroxamate PfAM1 inhibitors based on the malonic template. In particular, we performed a 鈥渇luoro-scanning鈥?around hit 1 that enlightened the key positions of the halogen for activity. The docking of the best inhibitor 2 is consistent with in vitro results. The stability of 2 was evaluated in microsomes, in plasma, and toward glutathione. The in vivo distribution study performed with the nanomolar hydroxamate inhibitor 2 (BDM14471) revealed that it reaches its site of action. However, it fails to kill the parasite at concentrations relevant to the enzymatic inhibitory potency, suggesting that killing the parasite remains a challenge for potent and druglike catalytic-site binding PfAM1 inhibitors. In all, this study provides important insights for the design of inhibitors of PfAM1 and the validity of this target.