Abstract：
Pyrazoles are unique bioactive molecules with a versatile biological profile and they have gained an important place on pharmaceutical chemistry. Pyrazole compounds containing sulfonamide nuclei also attract attention as carbonic anhydrase (CA) inhibitors. In this study, a library of pyrazole-carboxamides were synthesized and the structures of the synthesized molecules were characterized using 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 0.063-3.368 µM for hCA I and 0.007-4.235 µM for hCA II. Molecular docking studies were performed between the most active compounds 6a, 6b and the reference inhibitor, acetazolamide (AAZ) and the hCA I and hCA II receptors to investigate the binding mechanisms between the compounds and the receptors. These compounds showed better interactions than the AAZ. ADMET analyzes were performed for the compounds and it was seen that the compounds did not show AMES toxicity. The stability of the molecular docking results over time was analysed by 50 ns molecular dynamics simulations. Molecular dynamics simulations revealed that 6a and 6b exhibited good stability after docking to the binding sites of hCA I and hCA II receptors, with minor conformational changes and fluctuations.
摘要：
吡唑是独特的生物活性分子，具有多种生物学特性，在药物化学中占有重要地位。含有磺酰胺核的吡唑化合物作为碳酸酐酶(CA)抑制剂也引起注意。在这项研究中,合成了吡唑-甲酰胺类库，并使用FT-IR表征了合成分子的结构，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0.063-3.368µM的范围内，对于hCAII在0.007-4.235µM的范围内。在最具活性的化合物6a之间进行了分子对接研究，6b和参考抑制剂，乙酰唑胺（AAZ）与hCAI和hCAII受体研究化合物与受体之间的结合机制。这些化合物显示出比AAZ更好的相互作用。对所述化合物进行ADMET分析,发现所述化合物不显示AMES毒性。通过50ns分子动力学模拟分析了分子对接结果随时间的稳定性。分子动力学模拟显示，6a和6b在对接hCAI和hCAII受体的结合位点后表现出良好的稳定性，具有较小的构象变化和波动。
