Abstract：
A series of novel pyrazole-dicarboxamides were synthesized from pyrazole-3,4-dicarboxylic acid chloride and various primary and secondary sulfonamides. The structures of the new compounds were confirmed by FT-IR, 1H-NMR, 13C-NMR, and HRMS. Then the inhibition effects of newly synthesized molecules on human erythrocyte hCA I and hCA II isoenzymes were investigated. Ki values of the compounds were in the range of 0.024-0.496 µM for hCA I and 0.006-5.441 µM for hCA II. Compounds 7a and 7i showed nanomolar level of inhibition of hCA II, and these compounds exhibited high selectivity for this isoenzyme. Molecular docking studies were performed between the most active compounds 7a, 7b, 7i, and the reference inhibitor AAZ and the hCAI and hCAII to investigate the binding mechanisms between the compounds and the isozymes. These compounds showed better interactions than the AAZ. ADMET and drug-likeness analyses for the compounds have shown that the compounds can be used pharmacologically in living organisms.
摘要：
由吡唑-3,4-二羧酸氯化物和各种伯磺酰胺和仲磺酰胺合成了一系列新型吡唑-二甲酰胺。新化合物的结构经FT-IR确证,1H-NMR,13C-NMR,和HRMS。然后研究了新合成的分子对人红细胞hCAI和hCAII同工酶的抑制作用。化合物的Ki值对于hCAI在0.024-0.496µM的范围内，对于hCAII在0.006-5.441µM的范围内。化合物7a和7i显示hCAII的纳摩尔抑制水平，这些化合物对这种同工酶表现出很高的选择性。在最具活性的化合物7a之间进行了分子对接研究，7b,7i,和参考抑制剂AAZ以及hCAI和hCAII来研究化合物与同工酶之间的结合机制。这些化合物显示出比AAZ更好的相互作用。所述化合物的ADMET和药物相似性分析已经表明,所述化合物可以在药理学上用于活生物体中。
