Lead Optimization of Aryl and Aralkyl Amine-Based Triazolopyrimidine Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase with Antimalarial Activity in Mice

Abstract

Malaria is one of the leading causes of severe infectious disease worldwide, yet our ability to maintain effective therapy to combat the illness is continually challenged by the emergence of drug resistance. We previously reported identification of a new class of triazolopyrimidine based P. falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors with antimalarial activity, leading to the discovery of a new lead series and novel target for drug development. Active compounds from the series contained a triazolopyrimidine ring attached to an aromatic group through a bridging nitrogen atom. Herein we describe systematic efforts to optimize the aromatic functionality with the goal of improving potency and in vivo properties of compounds from the series. These studies led to the identification of two new substituted aniline moieties (4-SF5-Ph and 3,5-Di-F-4-CF3-Ph) which, when coupled to the triazolopyrimidine ring showed good plasma exposure and better efficacy in the P. berghei mouse model of the disease, than previously reported compounds from the series.

Assessing drug efficacy against Plasmodium falciparum liver stages in vivo

“…Another important limitation of the rodent model is genetic dissimilarities between model organisms and the human malaria parasites potentially confounding the evaluation of target-specific compounds. For example, analogues of the dihydroorotate dehydrogenase (DHODH) inhibitor DSM265 were 100-fold less potent against P. berghei DHODH compared with P. falciparum DHODH (10).…”

Identification and Validation of Novel Drug Targets for the Treatment of Plasmodium falciparum Malaria: New Insights

“…These differences make PfDHODH a potential species-specific drug target [24], which was extensively explored by a considerable number of studies. Although early research have not yielded effective results, the following studies have led to important achievements in the discovery of PfDHODH inhibitors, such as benzimidazolyl thiophene-2-carboxamides [54][55][56], s-benzyltriazolopyrimidines [57], N-substituted salicylamides [58], trifluoromethyl phenyl butenamide derivatives [59], and triazolopyrimidine-based inhibitors [25,[60][61][62][63][64]. The triazolopyrimidine-based compound DSM265 was shown to be a potent inhibitor of the PfDHODH and Plasmodium vivax DHODH (PvDHODH) with excellent selectivity versus hDHODH [48].…”

Recent advances in novel heterocyclic scaffolds for the treatment of drug-resistant malaria

“…Compounds 82 and 83 are the two new triazolopyrimidines with the substitution of phenyl moieties which results into good plasma exposure and also better efficacy against P. berghei mouse model 46 . Compound 84 was recognized as a preclinical applicant and is presently in the MMV preclinical pipeline 47 .…”