Department of Biochemistry, Faculty of Science, Selçuk University, Konya, Turkey.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eskişehir, Turkey.
Chem Biol Drug Des. 2024 Dec;104(6):e70025. doi: 10.1111/cbdd.70025.
In this study, we propose identifying potential novel compounds targeting carbonic anhydrase I and II. Herein, we have designed and synthesized new benzimidazole-hydrazide-hydrazones derivatives (4a-4r) to investigate the effects of these synthesized compounds on CA isoenzymes. The compounds' H NMR, C NMR, and HRMS spectra were used to confirm their chemical structures. The synthetic derivatives were screened for their inhibitory potential against carbonic anhydrase I and II by in vitro assay. These compounds have IC values of 3.727-1.493 μM (hCA I) and 3.892-1.547 μM (hCA II). Inhibition types and K values of the compounds were determined. The K values of the compounds were 3.006 ± 0.17 μM-0.356 ± 0.0 μM (hCA I) and 2.923 ± 0.15 μM-0.346 ± 0.0 μM (hCA II). Acetazolamide (AAZ) was used as the reference in the study. The most potent derivatives, a 4-methoxy derivative (compound 4k) and 4-(trifluoromethyl) derivative (compound 4g), than AAZ (IC = 2.26 μM) and their IC values were found as 1.493 μM and 1.675 μM, respectively. Compared to AAZ, the other derivatives having more effect on hCA I were compounds 4b, 4e, 4l, 4m, 4n, and 4o. The compounds gave IC values of 1.743, 1.789, 1.933, 1.966, 1.983, and 1.986 μM, respectively. Compounds 4a-4r found no more effective inhibitory activity against hCA II isozyme than AAZ (IC = 1.17 μM). According to the in vitro test results, detailed protein-ligand interactions of the compounds 4b and 4k exhibited considerably low binding energies, suggesting strong interaction affinities against hCA I. In addition, the cytotoxic effects of the compounds on the L929 healthy cell line were evaluated.
在这项研究中，我们提出了鉴定针对碳酸酐酶 I 和 II 的潜在新型化合物的方法。在此，我们设计并合成了新的苯并咪唑-酰肼-腙衍生物（4a-4r），以研究这些合成化合物对 CA 同工酶的影响。通过体外试验筛选化合物对碳酸酐酶 I 和 II 的抑制潜力。这些化合物的 IC 值为 3.727-1.493 μM（hCA I）和 3.892-1.547 μM（hCA II）。测定了化合物的抑制类型和 K 值。化合物的 K 值为 3.006 ± 0.17 μM-0.356 ± 0.0 μM（hCA I）和 2.923 ± 0.15 μM-0.346 ± 0.0 μM（hCA II）。乙酰唑胺（AAZ）在研究中用作参考。最有效的衍生物是 4-甲氧基衍生物（化合物 4k）和 4-（三氟甲基）衍生物（化合物 4g），其活性强于 AAZ（IC = 2.26 μM），IC 值分别为 1.493 μM 和 1.675 μM。与 AAZ 相比，其他对 hCA I 影响更大的衍生物是化合物 4b、4e、4l、4m、4n 和 4o。化合物的 IC 值分别为 1.743、1.789、1.933、1.966、1.983 和 1.986 μM。化合物 4a-4r 对 hCA II 同工酶的抑制活性没有比 AAZ（IC = 1.17 μM）更有效。根据体外试验结果，化合物 4b 和 4k 的详细蛋白-配体相互作用显示出相当低的结合能，表明它们与 hCA I 具有强烈的相互作用亲和力。此外，还评估了化合物对 L929 健康细胞系的细胞毒性作用。
