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Rhodanine-3-acetamide derivatives as aldose and aldehyde reductase inhibitors to treat diabetic complications: synthesis, biological evaluation, molecular docking and simulation studies
BMC Chemistry ( IF 4.3 ) Pub Date : 2021-04-27 , DOI: 10.1186/s13065-021-00756-z
Mohsinul Mulk Bacha , Humaira Nadeem , Sumera Zaib , Sadia Sarwar , Aqeel Imran , Shafiq Ur Rahman , Hafiz Saqib Ali , Muazzam Arif , Jamshed Iqbal

In diabetes, increased accumulation of sorbitol has been associated with diabetic complications through polyol pathway. Aldose reductase (AR) is one of the key factors involved in reduction of glucose to sorbitol, thereby its inhibition is important for the management of diabetic complications. In the present study, a series of seven 4-oxo-2-thioxo-1,3-thiazolidin-3-yl acetamide derivatives 3(a–g) were synthesized by the reaction of 5-(4-hydroxy-3-methoxybenzylidene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl acetic acid (2a) and 5-(4-methoxybenzylidene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl acetic acid (2b) with different amines. The synthesized compounds 3(a–g) were investigated for their in vitro aldehyde reductase (ALR1) and aldose reductase (ALR2) enzyme inhibitory potential. Compound 3c, 3d, 3e, and 3f showed ALR1 inhibition at lower micromolar concentration whereas all the compounds were more active than the standard inhibitor valproic acid. Most of the compounds were active against ALR2 but compound 3a and 3f showed higher inhibition than the standard drug sulindac. Overall, the most potent compound against aldose reductase was 3f with an inhibitory concentration of 0.12 ± 0.01 µM. In vitro results showed that vanillin derivatives exhibited better activity against both aldehyde reductase and aldose reductase. The molecular docking studies were carried out to investigate the binding affinities of synthesized derivatives with both ALR1 and ALR2. The binding site analysis of potent compounds revealed similar interactions as were found by cognate ligands within the active sites of enzymes.

中文翻译:

Rhodanine-3-acetamide衍生物作为醛糖和醛还原酶抑制剂,用于治疗糖尿病并发症:合成,生物学评估,分子对接和模拟研究

在糖尿病中,山梨糖醇的积累增加已通过多元醇途径与糖尿病并发症相关。醛糖还原酶(AR)是葡萄糖还原为山梨糖醇的关键因素之一,因此其抑制对于糖尿病并发症的处理很重要。在本研究中,通过5-(4-羟基-3-甲氧基亚苄基)的反应合成了一系列七个七个4-氧代-2-硫代氧代1,3-噻唑烷-3-基乙酰胺衍生物3(a–g)。 )-4-氧代-2-硫氧代-1,3-噻唑烷-3-基乙酸(2a)和5-(4-甲氧基亚苄基)-4-氧代-2-硫代-1,3-噻唑烷-3-基乙酸(2b)与不同的胺。研究了合成的化合物3(a–g)的体外醛还原酶(ALR1)和醛糖还原酶(ALR2)的酶抑制潜力。化合物3c,3d,3e,3f和3f在较低的微摩尔浓度下显示出对ALR1的抑制作用,而所有化合物均比标准抑制剂丙戊酸更具活性。大多数化合物对ALR2具有活性,但化合物3a和3f的抑制作用要比标准药物舒林酸高。总体而言,最有效的抗醛糖还原酶化合物为3f,抑制浓度为0.12±0.01 µM。体外结果表明,香兰素衍生物对醛还原酶和醛糖还原酶均表现出更好的活性。进行了分子对接研究以研究合成衍生物与ALR1和ALR2的结合亲和力。对有效化合物的结合位点分析揭示了与酶活性位点内的同源配体所发现的相似的相互作用。
更新日期:2021-04-27
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