Indole-linked 1,2,3-triazole derivatives efficiently modulate COX-2 protein and PGE2 levels in human THP-1 monocytes by suppressing AGE-ROS-NF-kβ nexus

AGEs augment inflammatory responses by activating inflammatory cascade in monocytes, and hence lead to vascular dysfunction. The current study aims to study a plausible role and mechanism of a new library of indole-tethered 1,2,3-triazoles 2-13 in AGEs-induced inflammation. Initially, the analogs 2-13 were synthesized by cycloaddition reaction between prop-2-yn-1-yl-2-(1H-indol-3-yl) acetate (1) and azidoacetophenone (1a). In vitro glycation, and metabolic assays were employed to investigate antiglycation and cytotoxicity activities of new indole-triazoles. DCFH-DA, immunostaining, Western blotting, and ELISA techniques were used to study the reactive oxygen species (ROS), and pro-inflammatory mediators levels. Among all the synthesized indole-triazoles, compounds 1-3, and 9-13, and their precursor molecule 1 were found to be active against AGEs production in in vitro glucose- and methylglyoxal (MGO)-BSA models. Compounds 1-2, and 11-13 were also found to be nontoxic against HEPG2, and THP-1 cells. Our results show that pretreatment of THP-1 monocytes with selected lead compounds 1-2, and 11-13, particularly compounds 12, and 13, reduced glucose- and MGO-derived AGEs-mediated ROS production (P