Optimization of Potent Inhibitors of P. falciparum Dihydroorotate Dehydrogenase for the Treatment of Malaria
ACS Medicinal Chemistry Letters (Impact Factor: 3.12). 09/2011; 2(9):708-13. DOI: 10.1021/ml200143c
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.
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ABSTRACT: Malaria is currently one of the world’s most severe endemic diseases, responsible for majority of morbidity and mortality. A large number of drugs are available for its treatment; however, the development of resistance has become more widespread with most of the frontline drug therapies. Inhibitors of PfDHODH have proven efficacy for the treatment of malaria. 3D QSAR studies on some 5-(2-methylbenzimidazol-1-yl)-N-alkylthiophene-2-carboxamide derivatives as PfDHODH inhibitors were performed by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods to rationalize the structural requirements responsible for the inhibitory activity of these compounds. The alignment strategy was used for these compounds by means of Distill function defined in SYBYL x 1.2. The best CoMFA and CoMSIA models obtained for the training set were statistically significant with q 2 of 0.669 and 0.727, cross-validated coefficient (r 2cv) of 0.603 and 0.698, and conventional coefficients (r 2) of 0.971 and 0.966, respectively. Both the models were validated by an external test set of five compounds giving satisfactory prediction (r 2pred) of 0.799 and 0.815 for CoMFA and CoMSIA models, respectively. Further the robustness of the model was verified by bootstrapping analysis. Generated CoMFA and CoMSIA models provide useful information for the design of novel inhibitors with better PfDHODH inhibitory activity.Medicinal Chemistry Research 05/2012; 22(5). DOI:10.1007/s00044-012-0216-6 · 1.40 Impact Factor
- Organic Preparations and Procedures International 01/2012; 44(4):340-374. DOI:10.1080/00304948.2012.697708 · 0.96 Impact Factor
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ABSTRACT: A highly diastereoselective protocol for the formal nucleophilic substitution of 2-bromocyclopropylcarboxamides with azoles is described. A wide range of azoles, including pyrroles, indoles, benzimidazoles, pyrazoles, and benzotriazoles, can be efficiently employed as pronucleophiles in this transformation, providing expeditious access to N-cyclopropyl heterocycles.Organic Letters 03/2012; 14(7):1752-5. DOI:10.1021/ol300352z · 6.36 Impact Factor
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