The β-glucuronidase, a lysosomal enzyme, catalyzes the cleavage of glucuronosyl-O-bonds. Its inhibitors play a significant role in different medicinal therapies as they cause a decrease in carcinogen-induced colonic tumors by reducing the level of toxic substances present in the intestine. Among those inhibitors, bisindole derivatives had displayed promising β-glucuronidase inhibition activity. In the current study, hydrazone derivatives of bisindolymethane (1-30) were synthesized and evaluated for in vitro β-glucuronidase inhibitory activity. Twenty-eight analogs demonstrated better activity (IC50 = 0.50-46.5 µM) than standard D-saccharic acid 1,4-lactone (IC50 = 48.4 ± 1.25 µM). Compounds with hydroxyl group like 6 (0.60 ± 0.01 µM), 20 (1.50 ± 0.10 µM) and 25 (0.50 ± 0.01 µM) exhibited the most potent inhibitory activity, followed by analogs with fluorine 21 (3.50 ± 0.10 µM) and chlorine 23 (8.20 ± 0.20 µM) substituents. The presence of hydroxyl group at the aromatic side chain was observed as the main contributing factor in the inhibitory potential. From the docking studies, it was predicted that the active compounds can fit properly in the binding groove of the β-glucuronidase and displayed significant binding interactions with essential residues.

中文翻译：

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氰基取代的双吲哚腙杂化物的合成、β-葡萄糖醛酸酶抑制和分子对接研究。

β-葡萄糖醛酸酶是一种溶酶体酶，催化葡萄糖醛酸-O-键的裂解。它的抑制剂在不同的药物治疗中发挥着重要作用，因为它们通过降低肠道中存在的有毒物质水平来减少致癌物质诱导的结肠肿瘤。在这些抑制剂中，双吲哚衍生物显示出有希望的 β-葡萄糖醛酸酶抑制活性。在目前的研究中，合成了双吲哚甲烷 (1-30) 的腙衍生物并评估了体外 β-葡萄糖醛酸酶抑制活性。与标准 D-糖精酸 1,4-内酯 (IC50 = 48.4 ± 1.25 µM) 相比，28 种类似物表现出更好的活性 (IC50 = 0.50-46.5 µM)。具有羟基的化合物如 6 (0.60 ± 0.01 µM)、20 (1.50 ± 0.10 µM) 和 25 (0.50 ± 0.01 µM) 表现出最有效的抑制活性，其次是具有氟 21 (3.50 ± 0.10 µM) 和氯 23 (8.20 ± 0.20 µM) 取代基的类似物。观察到芳族侧链上羟基的存在是抑制潜力的主要影响因素。从对接研究中预测，活性化合物可以正确地嵌入 β-葡萄糖醛酸酶的结合槽中，并显示出与必需残基的显着结合相互作用。