Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia.
Molecules. 2022 Jul 25;27(15):4764. doi: 10.3390/molecules27154764.
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).
通过对各种 5-和 3-羟基取代的烷基 1-芳基-1-吡唑-4-羧酸酯及其非环前体进行计算机评估，发现它们在二氢乳清酸脱氢酶（DHODH）的活性部位结合方面具有良好的效果。因此，通过两步合成法，使用烯胺酮型试剂或关键中间体，制备了四个乙基 1-芳基-5-羟基-1-吡唑-4-羧酸酯及其 3-羟基异构体。5-羟基-1-吡唑的合成采用了文献方案，包括二乙基[(二甲氨基)亚甲基]丙二酸与芳基腙在酸催化下的转氨基反应，然后通过中间体腙的碱催化环化反应进行。为了合成异构的甲基 1-芳基-3-羟基-1-吡唑-4-羧酸酯，开发了一种新的两步合成法。它包括肼与甲基丙二酰氯的酰化反应，然后肼与 -丁氧基-双（二甲氨基）甲烷的环化反应。对吡唑衍生物进行 DHODH 抑制测试表明，1-(萘-2-基)-5-羟基-1-吡唑-4-羧酸酯和 1-(萘-2-基)-、1-(2,4,6-三氯苯基)-和 1-[4-(三氟甲基)苯基]-3-羟基-1-吡唑-4-羧酸酯（抑制率约为 30%）比已知抑制剂二乙基α-[[(1-吲唑-5-基)氨基]甲基]丙二酸盐（抑制率为 19%）稍具活性。
