Design and Synthesis of Ester Linked 1,2,3‐Triazole Quinoline Derivatives with Pancreatic β Cells Protective Activity against Oxidative Stress and Endoplasmic Reticulum Stress for Better Management of Type II Diabetes Mellitus

Abstract

AbstractUnresolved endoplasmic reticulum (ER) stress and oxidative stress lead to the pathogenesis of type II diabetes mellitus (DM). Connecting links between the ER stress and oxidative stress pathways might play an important role in treatment and pathogenesis of diabetes. Here, we used network pharmacology approach to find the target proteins linking the ER stress and oxidative stress pathways. CHOP emerged as a hub protein from our results and was targeted by 16 newly designed and synthesized ester linked 1,2,3‐triazole quinoline derivatives by molecular docking. Drug likeliness prediction studies revealed all compounds as good druggable candidates. Compounds 5b (R = H, R1 = F), 5j (R = CH3, R1 = F), 5m (R = OCH3, R1 = H), and 5n (R = OCH3, R1 = F) were found to have considerable binding energies and active site amino acid interactions with CHOP. We further showed that compounds 5b, 5m, and 5n exhibited low toxicity with more than 50% cell survival and low IC50 values. These were therefore subjected to evaluate their effects on ER stress and oxidative stress. Finally, compound 5n (R = OCH3, R1 = F) was found to alleviate ER stress and is also a good antioxidant. Identification of such targets and compounds effective in improving ER stress and oxidative stress may provide new insights in the development of therapies and management of T2DM.