Evaluation of 7-arylaminopyrazolo[1,5-a]pyrimidines as anti-Plasmodium falciparum, antimalarial, and Pf-dihydroorotate dehydrogenase inhibitors.

Malaria remains one of the most serious global infectious diseases. An important target for antimalarial chemotherapy is the enzyme dihydroorotate dehydrogenase from Plasmodium falciparum (PfDHODH), which is responsible for the conversion of dihydroorotate to orotate in the de novo pyrimidine biosynthetic pathway. In this study, we have designed and synthesized fifteen 7-arylpyrazolo[1,5-a]pyrimidine derivatives using ring bioisosteric replacement and molecular hybridization of functional groups based on the highly active 5-methyl-N-(naphthalen-2-yl)-2-(trifluoromethyl)- [1,2,4]triazolo[1,5-a]pyrimidin-7-amine. The compounds were tested against Plasmodium falciparum, as antimalarials in mice with P. berghei, and as inhibitors of PfDHODH. Thirteen compounds were found to be active against P. falciparum, with IC