Efeoglu Cagla, Demir Yeliz, Türkeş Cüneyt, Yabalak Erdal, Seferoglu Zeynel, Nural Yahya
Department of Analytical Chemistry, Faculty of Pharmacy, Mersin University, 33169, Mersin, Türkiye.
Department of Pharmacy Services, Nihat Delibalta Gole Vocational High School, Ardahan University, 75700, Ardahan, Türkiye; Department of Chemistry, Faculty of Science, Ataturk University, 25240, Erzurum, Türkiye.
Arch Biochem Biophys. 2025 Sep;771:110515. doi: 10.1016/j.abb.2025.110515. Epub 2025 Jun 20.
In this study, a series of new 1,2,3-triazole derivatives were synthesized in 84-93 % yield using copper-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry and characterized by H/C NMR, FT-IR, and HRMS analyses. The synthesized compounds (4a-h) were evaluated for their inhibitory activities against human carbonic anhydrase isoforms I and II (hCA I and hCA II) and acetylcholinesterase (AChE), which are clinically relevant targets in neurological and metabolic disorders. Among them, compounds 4f and 4g exhibited the most potent dual inhibitory activities. Compound 4f showed K values of 144.30 nM for hCA II and 205.10 nM for AChE, while compound 4g exhibited K values of 239.10 nM for hCA II and 125.90 nM for AChE. These values demonstrate that 4f and 4g are more effective than the reference drugs acetazolamide (hCA II, K = 381.44 nM) and tacrine (AChE, K = 255.44 nM). Structure-activity relationship (SAR) analysis revealed that hydrophobicity, steric bulk, and aromaticity significantly influenced enzyme affinity. In silico docking confirmed strong interactions with key active site residues. Furthermore, ethanol solubility profiling revealed that polar and hydrogen-bonding groups significantly improved solubility, while bulky or aromatic hydrophobic substituents reduced it. The combined biological activity and solubility data emphasize the potential of these triazole derivatives particularly 4f and 4g as promising candidates for multitarget drug design and further preclinical development.
在本研究中，使用铜催化的叠氮化物-炔烃环加成（CuAAC）点击化学合成了一系列新的1,2,3-三唑衍生物，产率为84-93%，并通过氢/碳核磁共振、傅里叶变换红外光谱和高分辨率质谱分析对其进行了表征。对合成的化合物（4a-h）进行了针对人碳酸酐酶同工型I和II（hCA I和hCA II）以及乙酰胆碱酯酶（AChE）的抑制活性评估，这些酶是神经和代谢紊乱中具有临床相关性的靶点。其中，化合物4f和4g表现出最有效的双重抑制活性。化合物4f对hCA II的K值为144.30 nM，对AChE的K值为205.10 nM；而化合物4g对hCA II的K值为239.10 nM，对AChE的K值为125.90 nM。这些值表明4f和4g比参考药物乙酰唑胺（hCA II，K = 381.44 nM）和他克林（AChE，K = 255.44 nM）更有效。构效关系（SAR）分析表明，疏水性、空间位阻和芳香性对酶亲和力有显著影响。计算机模拟对接证实了与关键活性位点残基的强相互作用。此外，乙醇溶解度分析表明，极性和氢键基团显著提高了溶解度，而庞大或芳香疏水取代基则降低了溶解度。综合生物活性和溶解度数据强调了这些三唑衍生物，特别是4f和4g作为多靶点药物设计和进一步临床前开发的有前景候选物的潜力。
