Synthesis of 1,2,4-triazole-5-on derivatives and determination of carbonic anhydrase II isoenzyme inhibition effects
Synthesis of 1,2,4-triazole-5-on derivatives and determination of carbonic anhydrase II isoenzyme inhibition effects
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DOI：
10.1016/j.bioorg.2018.10.042
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发表时间：
2019-03-01
影响因子：
5.1
通讯作者：
Akatin, Melike Yildirim
中科院分区：
文献类型：
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作者：
Akin, Safak;Ayaloglu, Hasan;Akatin, Melike Yildirim
碳酸酐酶II在调节机体pH值、保护电解质平衡、运输水分和某些代谢途径中起重要作用。因此，CA II抑制剂是非常重要的药物设计分子，具有许多药理学应用。CA II作为靶分子对于消除一些病理状况如青光眼、癌症、癫痫、溃疡和肥胖也是重要的。在这项研究中，一些1，2，4-三唑衍生物的合成和CA II抑制潜力，这些分子进行了检查。已经发现，分子7 c是最有效的抑制剂，在微摩尔水平上具有最低的IC 50值。在新合成的分子以其在反应混合物中可达到的最大浓度存在下，观察到18.41-64.97%范围内的抑制。动力学研究表明，化合物7 c对碳酸酐酶活性的抑制机制是可逆的、非竞争性的。分子对接研究还表明，化合物7 c可与酶的活性位点结合，尤其是与Gln 102、Leu 240、Ala 241和Trp 243的结合较弱。还研究了这些新合成的（3a-e，6，7a-e）的ADME性质，并显示出良好的口服候选药物样性质。
Carbonic anhydrase (CA) II plays major roles in pH regulation of body, protection of electrolyte balance, transportation of water and some metabolic pathways. Therefore, CA II inhibitors are very important molecules for drug design and have many pharmacological applications. CA II as a target molecule is also important for eliminating some pathological conditions such as glaucoma, cancer, epilepsy, ulcer and obesity. In this study, some 1,2,4-triazole derivatives were synthesized and CA II inhibition potentials of these molecules were examined. It has been found that molecule 7c was the most potent inhibitor with the lowest IC50 value at micromolar level among the examined molecules. The inhibition in the range of 18.41-64.97% was seen in the presence of newly synthesized molecules at their reachable maximum concentration in the reaction mixtures. Kinetic studies showed that the inhibition mechanism of compound 7c on carbonic anhydrase activity was reversible and uncompetitive. Molecular docking studies also indicated that compound 7c could bind to the active site of the enzyme by weakly interacting with especially Gln102, Leu240, Ala241 and Trp243. ADME properties of these newly synthesized (3a-e, 6, 7a-e) were also studied and showed good oral drug candidate like properties.