2. Academic Validation
  3. Optimization of Potent Inhibitors of P. falciparum Dihydroorotate Dehydrogenase for the Treatment of Malaria

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

  • ACS Med Chem Lett. 2011 Jul 11;2(9):708-13. doi: 10.1021/ml200143c.
Renato T Skerlj 1,  Cecilia M Bastos 1,  Michael L Booker 1,  Martin L Kramer 1,  Robert H Barker Jr 1,  Cassandra A Celatka 1,  Thomas J O'Shea 1,  Benito Munoz 2,  Amar Bir Sidhu 2,  Joseph F Cortese 2,  Sergio Wittlin 3,  Petros Papastogiannidis 3,  Inigo Angulo-Barturen 4,  Maria Belen Jimenez-Diaz 4,  Edmund Sybertz 1
Affiliations

Affiliations

  • 1 Genzyme Corporation , 153 Second Avenue, Waltham, Massachusetts 02451, United States.
  • 2 Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02141, United States.
  • 3 Swiss Tropical and Public Health Institute , Socinstrasse 57, CH-4002, Basel, Switzerland ; University of Basel , Petersplatz 1, CH-4003, Basel, Switzerland.
  • 4 Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline , c/Severo Ochoa 2, 28760 Tres Cantos, Spain.
PMID: 24900364 DOI: 10.1021/ml200143c
Abstract

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.

Keywords

DHODH; P. falciparum; drug candidate; malaria.

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