- DIHYDROOROTATE DEHYDROGENASE INHIBITORS WITH SELECTIVE ANTI-MALARIAL ACTIVITY
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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.
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Page/Page column 50-51
(2009/07/25)
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- Identification of a metabolically stable triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with antimalarial activity in mice
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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.
- 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.
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scheme or table
p. 1864 - 1872
(2009/12/07)
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- Cyclocondensation of N-aryl-3-oxobutanethioamides with 1H-1,2,4-triazol-5- amine
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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
- Britsun
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experimental part
p. 1528 - 1531
(2009/06/28)
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