Tetrahydro-1H,5H-pyrazolo[1,2-a]pyrazole-1-carboxylates as inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase

Abstract The reactions between 5-substituted pyrazolidine-3-ones, aldehydes, and methyl methacrylate provided tetrahydropyrazolo[1,2- a ]pyrazole-1-carboxylates as mixtures of syn - and anti -diastereomers. Testing for inhibition of dihydroorotate dehydrogenase of Plasmodium falciparum ( Pf DHODH) revealed high activity of some anti -isomers of the methyl esters, while the corresponding carboxylic acids and carboxamides were not active. The most active representative, methyl (1 S *,3 S *,5 R *)-1,5-dimethyl-7-oxo-3-phenyltetrahydro-1 H ,5 H -pyrazolo[1,2- a ]pyrazole-1-carboxylate (IC 50  = 2.9 ± 0.3 μM), also exhibited very high selectivity of the parasite enzyme vs. the human enzyme, Pf DHODH/ Hs DHODH > 350. According to the molecular docking score, this high activity is explainable by synergic interactions of the methyl, phenyl and the CO 2 Me substituent with the hydrophobic pockets in the active site of the enzyme. The carboxylic acid and carboxamides derived from this compound did not inhibit Pf DHODH.