Design and synthesis of potent coumarin-1,2,3-triazole conjugates: An approach to docking studies for their therapeutic applications

Abstract

A series of coumarin-1,2,3-triazole conjugates (8a-g) were synthesized via copper(I)-catalyzed azide alkyne cycloaddition (CuAAC) and characterized using spectroscopic techniques. The synthesized compounds were evaluated for their in vitro antibacterial, anti-inflammatory, and antioxidant activities. Among them, compound 8e exhibited the most potent antibacterial activity, with MIC values ranging from 0.5 to 2 mu g/mL, and demonstrated the strongest anti-inflammatory response (IC sub(50) = 28.75 plus-minus 1.02 mu g/mL). The compound 8d displayed superior antioxidant activity (IC sub(50) = 36.17 plus-minus 0.78 mu g/mL), surpassing ascorbic acid. Cytotoxicity studies on HEK293 cells revealed low toxicity across the series, with IC sub(50) values ranging from 113.78 to 143.72 mu g/mL, supporting their biocompatibility. The molecular docking and MM-GBSA analyses confirmed strong binding affinities of 8e and 8c toward prostaglandin D sub(2) synthase (PGDS) and dihydropteroate synthetase (DHPS) respectively. These interactions were further supported by induced fit docking studies and 200 ns molecular dynamics simulations, which confirmed the stability of the 8e-PGDS complex. The ADMET and in silico toxicity predictions indicated that the synthesized compounds possess drug-like properties and bioavailability profiles. Collectively, these results highlight the therapeutic potential of coumarin-triazole hybrids particularly compound 8e as potent candidate for drug like molecule.