| Literature DB >> 32248693 |
Sreekanth Kokkonda1, Xiaoyi Deng2, Karen L White3, Farah El Mazouni2, John White1, David M Shackleford3, Kasiram Katneni3, Francis C K Chiu3, Helena Barker3, Jenna McLaren3, Elly Crighton3, Gong Chen3, Inigo Angulo-Barturen4, Maria Belen Jimenez-Diaz4, Santiago Ferrer4, Leticia Huertas-Valentin4, Maria Santos Martinez-Martinez4, Maria Jose Lafuente-Monasterio4, Rajesh Chittimalla5, Shatrughan P Shahi5, Sergio Wittlin6,7, David Waterson8, Jeremy N Burrows8, Dave Matthews8, Diana Tomchick9, Pradipsinh K Rathod1, Michael J Palmer8, Susan A Charman3, Margaret A Phillips2.
Abstract
Malaria puts at risk nearly half the world's population and causes high mortality in sub-Saharan Africa, while drug resistance threatens current therapies. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is a validated target for malaria treatment based on our finding that triazolopyrimidine DSM265 (1) showed efficacy in clinical studies. Herein, we describe optimization of a pyrrole-based series identified using a target-based DHODH screen. Compounds with nanomolar potency versus Plasmodium DHODH and Plasmodium parasites were identified with good pharmacological properties. X-ray studies showed that the pyrroles bind an alternative enzyme conformation from 1 leading to improved species selectivity versus mammalian enzymes and equivalent activity on Plasmodium falciparum and Plasmodium vivax DHODH. The best lead DSM502 (37) showed in vivo efficacy at similar levels of blood exposure to 1, although metabolic stability was reduced. Overall, the pyrrole-based DHODH inhibitors provide an attractive alternative scaffold for the development of new antimalarial compounds.Entities:
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Year: 2020 PMID： 32248693 PMCID： PMC7394244 DOI： 10.1021/acs.jmedchem.0c00311
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446