Carbamoyl Triazoles, Known Serine Protease Inhibitors, Are a Potent New Class of Antimalarials

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• 作者：Matthew McConville ; Jorge Fern谩ndez ; 脥帽igo Angulo-Barturen ; Noemi Bahamontes-Rosa ; Lluis Ballell-Pages ; Pablo Casta帽eda ; Cristina de C贸zar ; Benigno Crespo ; Laura Guijarro ; Mar铆a Bel茅n Jim茅nez-D铆az ; Maria S. Mart铆nez-Mart铆nez ; Jaime de Mercado ; 脕ngel Santos-Villarejo ; Laura M. Sanz ; Micol Frigerio ; Gina Washbourn ; Stephen A. Ward ; Gemma L. Nixon ; Giancarlo A. Biagini ; Neil G. Berry ; Michael J. Blackman ; F茅lix Calder贸n ; Paul M. O鈥橬eill
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：August 27, 2015
• 年：2015
• 卷：58
• 期：16
• 页码：6448-6455
• 全文大小：456K
• ISSN：1520-4804

文摘

Screening of the GSK corporate collection, some 1.9 million compounds, against Plasmodium falciparum (Pf), revealed almost 14000 active hits that are now known as the Tres Cantos Antimalarial Set (TCAMS). Followup work by Calderon et al. clustered and computationally filtered the TCAMS through a variety of criteria and reported 47 series containing a total of 522 compounds. From this enhanced set, we identified the carbamoyl triazole TCMDC-134379 (1), a known serine protease inhibitor, as an excellent starting point for SAR profiling. Lead optimization of 1 led to several molecules with improved antimalarial potency, metabolic stabilities in mouse and human liver microsomes, along with acceptable cytotoxicity profiles. Analogue 44 displayed potent in vitro activity (IC₅₀ = 10 nM) and oral activity in a SCID mouse model of Pf infection with an ED₅₀ of 100 and ED₉₀ of between 100 and 150 mg kg^鈭?, respectively. The results presented encourage further investigations to identify the target of these highly active compounds.