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

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 a new library of indole-tethered 1,2,3-triazoles 2-13 in AGEs-induced inflammation. Material and methods: 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 proinflammatory mediators levels. Key findings: 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)-B SA 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-KB translocation in THP-1 monocytes. Moreover, compounds 12, and 13 attenuated the AGEs-induced COX-2 protein levels (P < 0.001), and PGE(2) production (P < 0.001) in THP-1 monocytes. Significance: Our data revealed that the indole-triazoles 12, and 13 can significantly attenuate the AGEs-induced proinflammatory COX-2 levels, and associated PGE 2 production by suppressing AGE-ROS-NF-K beta nexus in THP-1 monocytes. These compounds can thus serve as leads for further evaluation as treatment to delay early onset of diabetic complications.

Automated summary

This study found that indole-triazole compounds 12 and 13 can attenuate AGEs-induced inflammation by suppressing the AGE-ROS-NF-K beta pathway, suggesting their potential therapeutic value in delaying the early onset of diabetic complications.