| Summary: | In silico evaluation of various regioisomeric 5- and 3-hydroxy-substituted alkyl 1-aryl-1<i>H</i>-pyrazole-4-carboxylates and their acyclic precursors yielded promising results with respect to their binding in the active site of dihydroorotate dehydrogenase of <i>Plasmodium falciparum</i> (<i>Pf</i>DHODH). Consequently, four ethyl 1-aryl-5-hydroxy-1<i>H</i>-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<i>H</i>-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<i>H</i>-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 <i>tert</i>-butoxy-bis(dimethylamino)methane. Testing the pyrazole derivatives for the inhibition of <i>Pf</i>DHODH showed that 1-(naphthalene-2-yl)-5-hydroxy-1<i>H</i>-pyrazole-4-carboxylate and 1-(naphthalene-2-yl)-, 1-(2,4,6-trichlorophenyl)-, and 1-[4-(trifluoromethyl)phenyl]-3-hydroxy-1<i>H</i>-pyrazole-4-carboxylates (~30% inhibition) were slightly more potent than a known inhibitor, diethyl α-{[(1<i>H</i>-indazol-5-yl)amino]methylidene}malonate (19% inhibition).
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