| Autor: |
David Waterson, Stefan Kavanagh, V. Balasubramanian, Vijender Panduga, Francisco-Javier Gamo, María Santos Martínez, Shahul Hameed P, Vinayak Hosagrahara, María Belén Jiménez-Díaz, Shubhada Barde, Kakoli Mukherjee, Sandra Duffy, Santiago Ferrer, Vikas Patil, Balachandra Bandodkar, Ramachandran Sreekanth A, K.R. Prabhakar, Suresh Rudrapatna, Praveena Manjrekar, Iñigo Angulo-Barturen, Pravin Iyer, Vasan K. Sambandamurthy, Nikhil Rautela, Pamela Magistrado, Dyann F. Wirth, Sowmya Bharath, Chandan Narayan, Sapna Morayya, Murugan Chinnapattu, Pavithra Viswanath, Anandkumar Raichurkar, Krishna Koushik, Jitender Reddy, Vicky M. Avery, Achyut Sinha, Amanda K. Lukens, Disha Awasthy, Shridhar Narayanan, Laura M. Sanz, Gajanan Shanbag, Sandesh Jatheendranath, Abhishek Srivastava, Ramanatha Saralaya |
| Rok vydání: |
2014 |
| Předmět: |
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| Zdroj: |
Journal of medicinal chemistry. 57(13) |
| ISSN: |
1520-4804 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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