Structure-Guided Lead Optimization of Triazolopyrimidine-Ring Substituents Identifies Potent Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors with Clinical Candidate Potential

Drug therapy is the mainstay of antimalarial therapy, yet current drugs are threatened by the development of resistance. In an effort to identify new potential antimalarials, we have undertaken a lead optimization program around our previously identified triazolopyrimidine-based series of Plasmodium...

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Published in:	Journal of medicinal chemistry 2011-08, Vol.54 (15), p.5540-5561
Main Authors:	Coteron, Jose M, Marco, María, Esquivias, Jorge, Deng, Xiaoyi, White, Karen L, White, John, Koltun, Maria, El Mazouni, Farah, Kokkonda, Sreekanth, Katneni, Kasiram, Bhamidipati, Ravi, Shackleford, David M, Angulo-Barturen, Iñigo, Ferrer, Santiago B, Jiménez-Díaz, María Belén, Gamo, Francisco-Javier, Goldsmith, Elizabeth J, Charman, William N, Bathurst, Ian, Floyd, David, Matthews, David, Burrows, Jeremy N, Rathod, Pradipsinh K, Charman, Susan A, Phillips, Margaret A
Format:	Article
Language:	English
Subjects:	60 APPLIED LIFE SCIENCES Animals Antimalarials - chemical synthesis Antimalarials - pharmacology BASIC BIOLOGICAL SCIENCES Chemical Phenomena CHEMISTRY CLEARANCE Crystallography, X-Ray Dihydroorotate Dehydrogenase Drug Resistance HALF-LIFE Humans Mice OPTIMIZATION OXIDOREDUCTASES Oxidoreductases Acting on CH-CH Group Donors - antagonists & inhibitors PLASMODIUM Plasmodium falciparum - enzymology Pyrimidines - chemical synthesis Pyrimidines - chemistry Pyrimidines - pharmacokinetics Pyrimidines - pharmacology Rats RODENTS STRAINS Structure-Activity Relationship THERAPY Triazoles - chemical synthesis Triazoles - chemistry Triazoles - pharmacokinetics Triazoles - pharmacology
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