LAUSR

AIMS 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 new library of indole-tethered 1,2,3-triazoles 2-13 in AGEs-induced inflammation. MATERIAL AND METHODS Initially, the analogs were synthesized by cycloaddition reaction between prop-2-yn-1-yl-2-(1H-indol-3-yl) acetate (1) and azidoacetophenone (1a). In vitro antiglycation, and metabolic assays were employed to investigate antiglycation and cytotoxicity activities of indole-triazoles. DCFH-DA, Immunostaining, Western blotting, and ELISA techniques were used to study the reactive oxygen species (ROS) and pro-inflammatory mediators levels. KEY FINDINGS Among all the synthesized indole- triazoles, compounds 1-3, 9-11-13, 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 < 0.001), as compared to standards, PDTC, rutin, and quercetin. They also significantly (P < 0.001) suppressed NF-ĸB translocation in THP-1 monocytes. Moreover, compounds 12, and 13 attenuated the AGEs-induced COX-2 protein levels (P < 0.001), and PGE2 production (P < 0.001) in THP-1 monocytes. SIGNIFICANCE Our data revealed that the indole-triazoles 12, and 13 significantly attenuated the AGEs-induced proinflammatory COX-2 levels, and associated PGE2 production by suppressing AGE-ROS-NF-Kβ nexus in THP-1 monocytes. These compounds can thus serve as candidates for further evaluation as treatment to delay early onset of diabetic vascular complications.