Optimization of potent inhibitors of P. falciparum dihydroorotate dehydrogenase for the treatment of malaria

Skerlj, R. T. and Bastos, C. M. and Booker, M. L. and Kramer, M. L. and Barker, R. H. and Celatka, C. A. and O'Shea T. J., and Munoz, B. and Sidhu, A. B. and Cortese, J. F. and Wittlin, S. and Papastogiannidis, P. and Angulo-Barturen I., and Jimenez-Diaz M. B., and Sybertz, E.. (2011) Optimization of potent inhibitors of P. falciparum dihydroorotate dehydrogenase for the treatment of malaria. ACS medicinal chemistry letters, Vol. 2, H. 9. pp. 708-713.

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Official URL: http://edoc.unibas.ch/dok/A6002291

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Inhibition of dihydroorotate dehydrogenase (DHODH) for P. falciparum potentially represents a new treatment option for malaria, since DHODH catalyzes the rate-limiting step in the pyrimidine biosynthetic pathway and P. falciparum is unable to salvage pyrimidines and must rely on de novo biosynthesis for survival. We report herein the synthesis and structure-activity relationship of a series of 5-(2-methylbenzimidazol-1-yl)-N-alkylthiophene-2-carboxamides that are potent inhibitors against PfDHODH but do not inhibit the human enzyme. On the basis of efficacy observed in three mouse models of malaria, acceptable safety pharmacology risk assessment and safety toxicology profile in rodents, lack of potential drug-drug interactions, acceptable ADME/pharmacokinetic profile, and projected human dose, 5-(4-cyano-2-methyl-1H-benzo[d]imidazol-1-yl)-N-cyclopropylthiophene-2-carboxamide 2q was identified as a potential drug development candidate
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Wittlin, Sergio
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Chemical Society
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:08 Nov 2012 16:23
Deposited On:08 Nov 2012 16:21

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