Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan.
H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan.
Med Chem. 2020;16(4):575-591. doi: 10.2174/1573406415666190212105718.
Advanced glycation end products (AGEs) are known to be involved in the pathophysiology of diabetic complications, neurodegenerative diseases, and aging. Preventing the formation of AGEs can be helpful in the management of these diseases.
Two classes of previously synthesized traizole Schiff's bases (4H-1,2,4-triazole-4- Schiff's bases 1-14, and 4H-1,2,4-triazole-3-Schiff's bases 15-23) were evaluated for their in vitro antiglycation activity.
In vitro fructose-mediated human serum albumin (HSA) glycation assay was employed to assess the antiglycation activity of triazole Schiff's bases. The active compounds were subjected to cytotoxicity analysis by MTT assay on mouse fibroblast (3T3) cell line. Molecular docking and simulation studies were carried out to evaluate the interactions and stability of compounds with HSA. Anti-hyperglycemic and antioxidant activities of selected non-cytotoxic compounds were evaluated by in vitro α-glucosidase inhibition, and DPPH free radical scavenging assays, respectively.
Compound 1 (IC50=47.30±0.38 µM) from 4H-1,2,4-triazole-4-Schiff's bases has exhibited antiglycation activity comparable to standard rutin (IC50=54.5±0.05 µM) along with a stable RMSD profile in MD simulation studies. Compound 1 also exhibited a potent α-glucosidase inhibitory activity, and moderate antioxidant property. Other derivatives showed a weak antiglycation activity with IC50 values between 248.1-637.7 µM. Compounds with potential antiglycation profile were found to be non-cytotoxic in a cellular assay.
The study identifies triazole Schiff's bases active against fructose-mediated glycation of HSA, thus indicates their potential against late diabetic complications due to production of advancedend products (AGEs).
已知糖基化终产物 (AGEs) 参与糖尿病并发症、神经退行性疾病和衰老的病理生理学。防止 AGEs 的形成有助于这些疾病的治疗。
评估先前合成的两类三唑席夫碱（4H-1,2,4-三唑-4-席夫碱 1-14 和 4H-1,2,4-三唑-3-席夫碱 15-23）的体外抗糖基化活性。
采用体外果糖介导的人血清白蛋白 (HSA) 糖化测定法评估三唑席夫碱的抗糖基化活性。通过 MTT 测定法在小鼠成纤维细胞 (3T3) 细胞系上对活性化合物进行细胞毒性分析。进行分子对接和模拟研究，以评估化合物与 HSA 的相互作用和稳定性。通过体外α-葡萄糖苷酶抑制和 DPPH 自由基清除测定法分别评估选定的非细胞毒性化合物的抗高血糖和抗氧化活性。
4H-1,2,4-三唑-4-席夫碱的化合物 1（IC50=47.30±0.38 µM）表现出与标准芦丁（IC50=54.5±0.05 µM）相当的抗糖基化活性，并且在 MD 模拟研究中具有稳定的 RMSD 曲线。化合物 1 还表现出有效的α-葡萄糖苷酶抑制活性和适度的抗氧化性能。其他衍生物表现出较弱的抗糖基化活性，IC50 值在 248.1-637.7 µM 之间。具有潜在抗糖基化特征的化合物在细胞测定中被发现是非细胞毒性的。
该研究鉴定出了对果糖介导的 HSA 糖化具有活性的三唑席夫碱，因此表明它们具有针对晚期糖尿病并发症的潜力，这是由于晚期糖基化终产物（AGEs）的产生所致。
