dsm-74 and Malaria

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 Plasmodium 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-SF(5)-Ph and 3,5-Di-F-4-CF(3)-Ph), which, when coupled to the triazolopyrimidine ring, showed good plasma exposure and better efficacy in the Plasmodium berghei mouse model of the disease than previously reported compounds from the series.

Topics: Animals; Antimalarials; Dihydroorotate Dehydrogenase; Disease Models, Animal; Drug Design; Drug Discovery; Enzyme Inhibitors; Humans; Malaria; Mice; Microsomes, Liver; Molecular Structure; Oxidoreductases Acting on CH-CH Group Donors; Plasmodium berghei; Plasmodium falciparum; Protein Binding; Pyrimidines; Solubility; Structure-Activity Relationship; Triazoles

Plasmodium falciparum causes 1-2 million deaths annually. Yet current drug therapies are compromised by resistance. We previously described potent and selective triazolopyrimidine-based inhibitors of P. falciparum dihydroorotate dehydrogenase (PfDHODH) that inhibited parasite growth in vitro; however, they showed no activity in vivo. Here we show that lack of efficacy against P. berghei in mice resulted from a combination of poor plasma exposure and reduced potency against P. berghei DHODH. For compounds containing naphthyl (DSM1) or anthracenyl (DSM2), plasma exposure was reduced upon repeated dosing. Phenyl-substituted triazolopyrimidines were synthesized leading to identification of analogs with low predicted metabolism in human liver microsomes and which showed prolonged exposure in mice. Compound 21 (DSM74), containing p-trifluoromethylphenyl, suppressed growth of P. berghei in mice after oral administration. This study provides the first proof of concept that DHODH inhibitors can suppress Plasmodium growth in vivo, validating DHODH as a new target for antimalarial chemotherapy.

Topics: Administration, Oral; Animals; Antimalarials; Dihydroorotate Dehydrogenase; Humans; In Vitro Techniques; Malaria; Male; Mice; Microsomes, Liver; Models, Molecular; Oxidoreductases Acting on CH-CH Group Donors; Parasitic Sensitivity Tests; Plasmodium berghei; Plasmodium falciparum; Pyrimidines; Structure-Activity Relationship; Thiazoles; Triazoles