Department of Chemistry, Faculty of Arts and Sciences, İstanbul Technical University, İstanbul 34469, Turkey.
Department of Medical Biochemistry, Faculty of Medicine, Kafkas University, Kars 36100, Turkey.
Bioorg Chem. 2021 Dec;117:105473. doi: 10.1016/j.bioorg.2021.105473. Epub 2021 Nov 8.
Aldose reductase (ALR2), one of the metabolically important enzymes, catalyzes the formation of sorbitol from glucose in the polyol pathway. ALR2 inhibition is required to prevent diabetic complications. In the present study, the novel bis-hydrazone compounds bearing isovanillin moiety (GY1-12) were synthesized, and various chromatographic methods were applied to purify the ALR2 enzyme. Afterward, the inhibitory effect of the synthesized compounds on the ALR2 was screened in vitro. All the novel bis-hydrazones demonstrated activity in nanomolar levels as AR inhibitors with IC and K values in the range of 12.55-35.04 nM, and 13.38-88.21 nM, respectively. Compounds GY-11, GY-7, and GY-5 against ALR2 were identified as the highly potent inhibitors, respectively, and were superior to the standard drug, epalrestat. Moreover, a comprehensive ligand-receptor interactions prediction was performed using ADME-Tox, Glide XP, and MM-GBSA modules of Schrödinger Small-Molecule Drug Discovery Suite to elucidate the novel bis-hydrazone derivatives, potential binding modes versus the ALR2. As a result, these compounds with ALR2 inhibitory effects may be potential alternative agents that can be used to treat or prevent diabetic complications.
醛糖还原酶（ALR2）是一种重要的代谢酶，可催化多元醇途径中葡萄糖转化为山梨醇。抑制 ALR2 是预防糖尿病并发症的必要条件。在本研究中，合成了含有异香草醛部分的新型双腙化合物（GY1-12），并应用各种色谱方法纯化 ALR2 酶。随后，在体外筛选了合成化合物对 ALR2 的抑制作用。所有新型双腙均表现出纳米级的 AR 抑制活性，IC 和 K 值范围分别为 12.55-35.04 nM 和 13.38-88.21 nM。化合物 GY-11、GY-7 和 GY-5 对 ALR2 的抑制作用分别被鉴定为高活性抑制剂，优于标准药物依帕司他。此外，使用 Schrödinger Small-Molecule Drug Discovery Suite 的 ADME-Tox、Glide XP 和 MM-GBSA 模块进行了全面的配体-受体相互作用预测，以阐明新型双腙衍生物与 ALR2 的潜在结合模式。因此，这些具有 ALR2 抑制作用的化合物可能是治疗或预防糖尿病并发症的潜在替代药物。
