Regioselective Synthesis of 5- and 3-Hydroxy--Aryl-1-Pyrazole-4-Carboxylates and Their Evaluation As Inhibitors of Dihydroorotate Dehydrogenase

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2022 Jul 28

PMID 35897941

Authors

Luka Vah

Tadej Medved

Uros Groselj

Marina Klemencic

crtomir Podlipnik

Bogdan Stefane

Jernej Wagger

Marko Novinec

Jurij Svete

Affiliations

Soon will be listed here.

Abstract

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

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