Aminoazabenzimidazoles, a Novel Class of Orally Active Antimalarial Agents

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• 作者：Shahul Hameed P ; Murugan Chinnapattu ; Gajanan Shanbag ; Praveena Manjrekar ; Krishna Koushik ; Anandkumar Raichurkar ; Vikas Patil ; Sandesh Jatheendranath ; Suresh S. Rudrapatna ; Shubhada P. Barde ; Nikhil Rautela ; Disha Awasthy ; Sapna Morayya ; Chandan Narayan ; Stefan Kavanagh ; Ramanatha Saralaya ; Sowmya Bharath ; Pavithra Viswanath ; Kakoli Mukherjee ; Balachandra Bandodkar ; Abhishek Srivastava ; Vijender Panduga ; Jitender Reddy ; K. R. Prabhakar ; Achyut Sinha ; Mar铆a Bel茅n Jim茅nez-D铆az ; Mar铆a Santos Mart铆nez ; I帽igo Angulo-Barturen ; Santiago Ferrer ; Laura Mar铆a Sanz ; Francisco Javier Gamo ; Sandra Duffy ; Vicky M. Avery ; Pamela A. Magistrado ; Amanda K. Lukens ; Dyann F. Wirth ; David Waterson ; V. Balasubramanian ; Pravin S. Iyer ; Shridhar Narayanan ; Vinayak Hosagrahara ; Vasan K. Sambandamurthy ; Sreekanth Ramachandran
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：July 10, 2014
• 年：2014
• 卷：57
• 期：13
• 页码：5702-5713
• 全文大小：460K
• ISSN：1520-4804

文摘

Whole-cell high-throughput screening of the AstraZeneca compound library against the asexual blood stage of Plasmodium falciparum (Pf) led to the identification of amino imidazoles, a robust starting point for initiating a hit-to-lead medicinal chemistry effort. Structure鈥揳ctivity relationship studies followed by pharmacokinetics optimization resulted in the identification of 23 as an attractive lead with good oral bioavailability. Compound 23 was found to be efficacious (ED₉₀ of 28.6 mg路kg^鈥?) in the humanized P. falciparum mouse model of malaria (Pf/SCID model). Representative compounds displayed a moderate to fast killing profile that is comparable to that of chloroquine. This series demonstrates no cross-resistance against a panel of Pf strains with mutations to known antimalarial drugs, thereby suggesting a novel mechanism of action for this chemical class.