1. Tetrahydro-2-naphthyl and 2-Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity
- Author
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Jeremy N. Burrows, María Belén Jiménez-Díaz, John H. White, Maria L. Marco, Maria Santos Martinez-Martinez, Sreekanth Kokkonda, Margaret A. Phillips, David Waterson, Laura Fernández de las Heras, Xiaoyi Deng, Iñigo Angulo-Barturen, Farah El Mazouni, Kakali Rani Rudra, Julia Morizzi, Santiago Ferrer Bazaga, Gong Chen, Didier Leroy, Pradipsinh K. Rathod, Diana R. Tomchick, Karen L. White, Eileen Ryan, Jose M. Coteron, Dave Matthews, Werner Kaminsky, Krishne Manjalanagara, and Susan A. Charman
- Subjects
0301 basic medicine ,Oxidoreductases Acting on CH-CH Group Donors ,Pyrimidine ,Plasmodium falciparum ,Dihydroorotate Dehydrogenase ,Mice, SCID ,Pharmacology ,01 natural sciences ,Plasmodium ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Antimalarials ,Mice ,Structure-Activity Relationship ,Parasitic Sensitivity Tests ,Drug Discovery ,parasitic diseases ,medicine ,Potency ,Structure–activity relationship ,Animals ,Humans ,Enzyme Inhibitors ,Malaria, Falciparum ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Plasma levels ,Triazoles ,biology.organism_classification ,medicine.disease ,0104 chemical sciences ,Rats ,Disease Models, Animal ,030104 developmental biology ,Pyrimidines ,chemistry ,Biochemistry ,Dihydroorotate dehydrogenase ,Molecular Medicine ,Malaria - Abstract
Malaria persists as one of the most devastating global infectious diseases. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) has been identified as a new malaria drug target, and a triazolopyrimidine-based DHODH inhibitor 1 (DSM265) is in clinical development. We sought to identify compounds with higher potency against Plasmodium DHODH while showing greater selectivity toward animal DHODHs. Herein we describe a series of novel triazolopyrimidines wherein the p-SF5-aniline was replaced with substituted 1,2,3,4-tetrahydro-2-naphthyl or 2-indanyl amines. These compounds showed strong species selectivity, and several highly potent tetrahydro-2-naphthyl derivatives were identified. Compounds with halogen substitutions displayed sustained plasma levels after oral dosing in rodents leading to efficacy in the P. falciparum SCID mouse malaria model. These data suggest that tetrahydro-2-naphthyl derivatives have the potential to be efficacious for the treatment of malaria, but due to higher metabolic clearance than 1, they most likely would need to be part of a multidose regimen.
- Published
- 2016