Aminoazabenzimidazoles, a Novel Class of Orally Active Antimalarial Agents

作者：Hameed Shahul P; Chinnapattu Murugan; Shanbag Gajanan; Manjrekar Praveena; Koushik Krishna; Raichurkar Anandkumar; Patil Vikas; Jatheendranath Sandesh; Rudrapatna Suresh S; Barde Shubhada P; Rautela Nikhil; Awasthy Disha; Morayya Sapna; Narayan Chandan; Kavanagh Stefan; Saralaya Ramanatha; Bharath Sowmya; Viswanath Pavithra; Mukherjee Kakoli; Bandodkar Balachandra; Srivastava Abhishek; Panduga Vijender; Reddy Jitender; Prabhakar K R; Sinha Achyut

来源：Journal of Medicinal Chemistry, 2014, 57(13): 5702-5713.

DOI：10.1021/jm500535j

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-activity 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.kg(-1)) 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.

• 出版日期2014-7-10