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ACS Med Chem Lett DOI:10.1021/ml200143c

Optimization of Potent Inhibitors of P. falciparum Dihydroorotate Dehydrogenase for the Treatment of Malaria.

Publication TypeJournal Article
Year of Publication2011
AuthorsSkerlj, RT, Bastos, CM, Booker, ML, Kramer, ML, Barker, RH, Celatka, CA, O'Shea, TJ, Munoz, B, Sidhu, ABir, Cortese, JF, Wittlin, S, Papastogiannidis, P, Angulo-Barturen, I, Jimenez-Diaz, MBelen, Sybertz, E
JournalACS Med Chem Lett
Date Published2011 Sep 08

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.


Alternate JournalACS Med Chem Lett
PubMed ID24900364
PubMed Central IDPMC4018051