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 <b>23b> as an attractive lead with good oral bioavailability. Compound <b>23b> was found to be efficacious (EDb>90b> 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.