Design and Regioselective Synthesis of Triazole–Coumarin–Chalcone Hybrids: Structural Elucidation and Computational Anticancer Evaluation

Abstract

A novel series of triazole–coumarin–chalcone hybrid molecules was synthesized via a copper-catalyzed click reaction between various benzyl azide derivatives and coumarin-based alkynes bearing a chalcone moiety. The required alkyne intermediates were prepared through a base-catalyzed O-alkylation of a pre-synthesized coumarin–chalcone precursor. This synthetic strategy enabled the efficient integration of three distinct pharmacophoric units into a single molecular framework. The structures of the resulting hybrids were comprehensively characterized using one- and two-dimensional NMR spectroscopy. In particular, HSQC and HMBC experiments allowed unambiguous assignment of key proton and carbon resonances and confirmed the regioselective formation of the 1,4-disubstituted triazole ring. These spectroscopic analyses enabled precise signal assignments and conclusively confirmed the regioselective formation of the 1,4-disubstituted triazole moiety. Moreover, the observed long-range correlations allowed clear discrimination between the desired hybrid structure and any possible alternative cycloaddition products. The consistency between synthetic outcomes and spectroscopic data validates the successful formation of the intended hybrid molecules. Molecular docking studies revealed specific and favorable binding interactions between the synthesized compounds and the active site of the target protein, providing valuable insight into the possible mode of action as a breast cancer inhibitor. Furthermore, an in-silico evaluation of absorption, distribution, metabolism, excretion, and toxicity (ADMETox) properties indicated a promising pharmacokinetic and safety profile. These findings suggest that the synthesized hybrid molecules represent an attractive lead candidate for the development of novel anticancer therapeutics.