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Aminoazabenzimidazoles, a Novel Class of Orally Active Antimalarial Agents

Journal of Medicinal Chemistry2014Vol. 57(13), pp. 5702–5713

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Shahul Hameed P, Murugan Chinnapattu, Gajanan Shanbag, Praveena Manjrekar, Krishna Koushik, Anandkumar Raichurkar, Vikas Patil, Sandesh Jatheendranath, Suresh Rudrapatna, Shubhada 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 Prabhakar, A M Sinha, Marı́a Belén Jiménez-Dı́az, Maria Santos Martínez, Íñigo Angulo‐Barturen, Santiago Ferrer, Laura M. Sanz, Francisco‐Javier Gamo, Sandra Duffy, Vicky M. Avery, Pamela Magistrado, Amanda K. Lukens, Dyann F. Wirth, David Waterson, V. Balasubramanian, Pravin S. Iyer, Shridhar Narayanan, Vinayak Hosagrahara, Vasan K. Sambandamurthy, Sreekanth A. Ramachandran

Abstract

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.

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Abstract

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