838094-19-2Relevant academic research and scientific papers
Identification of a metabolically stable triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with antimalarial activity in mice
Gujjar, Ramesh,Marwaha, Alka,Mazouni, Farah El,White, John,White, Karen L.,Creason, Sharon,Shackleford, David M.,Baldwin, Jeffrey,Charman, William N.,Buckner, Frederick S.,Charman, Susan,Rathod, Pradipsinh K.,Phillips, Margaret A.
scheme or table, p. 1864 - 1872 (2009/12/07)
Plasmodium falciparum causes 1-2 million deaths annually. Yet current drug therapies are compromised by resistance. We previously described potent and selective triazolopyrimidine-based inhibitors of P. falciparum dihydroorotate dehydrogenase (PfDHODH) that inhibited parasite growth in vitro; however, they showed no activity in vivo. Here we show that lack of efficacy against P. berghei in mice resulted from a combination of poor plasma exposure and reduced potency against P. berghei DHODH. For compounds containing naphthyl (DSM1) or anthracenyl (DSM2), plasma exposure was reduced upon repeated dosing. Phenyl-substituted triazolopyrimidines were synthesized leading to identification of analogs with low predicted metabolism in human liver microsomes and which showed prolonged exposure in mice. Compound 21 (DSM74), containing p-trifluoromethylphenyl, suppressed growth of P. berghei in mice after oral administration. This study provides the first proof of concept that DHODH inhibitors can suppress Plasmodium growth in vivo, validating DHODH as a new target for antimalarial chemotherapy.
DIHYDROOROTATE DEHYDROGENASE INHIBITORS WITH SELECTIVE ANTI-MALARIAL ACTIVITY
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Page/Page column 50; 52, (2009/07/25)
Compounds according to Formula (I), Formula (II), Formula (III), Formula (V), Formula (VI), or to Formula (VII), and pharmaceutical compositions of compounds that conform to Formula (IV) or (Formula VIII): where R1 through R33 are prescribed, selectively inhibit P. falciparum dihydroorotate dehydrogenase. Accordingly, a method for preventing and treating malaria attaches to such compounds, as well as to pharmaceutically acceptable salts, solvates, stereoisomers, tautomers, and prodrugs thereof.
Cyclocondensation of N-aryl-3-oxobutanethioamides with 1H-1,2,4-triazol-5- amine
Britsun
experimental part, p. 1528 - 1531 (2009/06/28)
Reactions of N-aryl-3-oxobutanethioamides with 1H-1,2,4-triazole-5-amine give mixtures of 7-arylamino-5-methyl[1,2,4]triazolo[1,5-a]pyrimidines, 5-methyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-7-thione, 7-methyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrim
