Regioselective Synthesis of 5- and 3-Hydroxy- N -Aryl-1 H -Pyrazole-4-Carboxylates and Their Evaluation as Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase.

In silico evaluation of various regioisomeric 5- and 3-hydroxy-substituted alkyl 1-aryl-1 H -pyrazole-4-carboxylates and their acyclic precursors yielded promising results with respect to their binding in the active site of dihydroorotate dehydrogenase of Plasmodium falciparum ( Pf DHODH). Consequently, four ethyl 1-aryl-5-hydroxy-1 H -pyrazole-4-carboxylates and their 3-hydroxy regioisomers were prepared by two-step syntheses via enaminone-type reagents or key intermediates. The synthesis of 5-hydroxy-1 H -pyrazoles was carried out using the literature protocol comprising acid-catalyzed transamination of diethyl [(dimethylamino)methylene]malonate with arylhydrazines followed by base-catalyzed cyclization of the intermediate hydrazones. For the synthesis of isomeric methyl 1-aryl-3-hydroxy-1 H -pyrazole-4-carboxylates, a novel two-step synthesis was developed. It comprises acylation of hydrazines with methyl malonyl chloride followed by cyclization of the hydrazines with tert -butoxy-bis(dimethylamino)methane. Testing the pyrazole derivatives for the inhibition of Pf DHODH showed that 1-(naphthalene-2-yl)-5-hydroxy-1 H -pyrazole-4-carboxylate and 1-(naphthalene-2-yl)-, 1-(2,4,6-trichlorophenyl)-, and 1-[4-(trifluoromethyl)phenyl]-3-hydroxy-1 H -pyrazole-4-carboxylates (~30% inhibition) were slightly more potent than a known inhibitor, diethyl α-{[(1 H -indazol-5-yl)amino]methylidene}malonate (19% inhibition).