Computational and Experimental Insights into the Anticancer as Well as Antimicrobial Activity of Coumarin‐1,2,3‐Triazole Derivatives: A Study Based on DFT, Docking, ADME, and In Vitro Assays

Abstract

A novel series of (Z)‐5‐methyl‐N'‐(1‐(2‐oxo‐2H‐chromen‐3‐yl)ethylidene)‐1‐phenyl‐1H‐1,2,3‐triazole‐4‐carbohydrazide derivatives (8a–j) were synthesized in yields ranging from 76%–86% via condensation reaction using Schiff base methodology. Structures of all the synthesized compounds were confirmed by comprehensive spectroscopic analysis (IR, ¹H‐NMR, ¹³C‐NMR, MS). Anticancer evaluation of the synthesized coumarin‐triazole analogues against six human cancer cell lines (NuGC‐3, DLD‐1, HA22T, HepG2, HONEI, and MCF‐7) revealed compound 8c as the most potent derivative with IC₅₀ values of 0.029 µM (NuGC‐3), 0.023 µM (DLD‐1), 1.324 µM (HA22T), 0.025 µM (HepG2), 0.017 µM (HONEI), and 0.031 µM (MCF‐7). Compound 8c demonstrated superior activity compared to CHS‐828 in four cell lines, showing up to 101‐fold improvement in DLD‐1 cells and 50‐fold improvement in HepG2 cells, while showing minimal toxicity against normal WI‐38 cells (IC₅₀ = 0.071 µM). Compound 8c also exhibited a notable antimicrobial activity against Gram‐positive bacteria (S. aureus, MIC = 100 µg/mL; S. pyogenes, MIC = 100 µg/mL), Gram‐negative bacteria (E. coli and K. pneumoniae, MIC = 62.5 µg/mL; P. aeruginosa, MIC = 100 µg/mL), and fungi (C. albicans, A. clavatus, and P. digitatum, MIC = 200 µg/mL; T. rubrum, MIC = 250 µg/mL), with activity comparable to ciprofloxacin against S. pyogenes and superior antifungal activity against T. rubrum compared to griseofulvin. DFT calculations at B3LYP/6‐31G++(d,p) level revealed a HOMO–LUMO energy gap of 3.08 eV for compound 8c with optimal reactivity parameters (η = 1.54 eV, μ = −4.89 eV). Molecular docking studies against carbonic anhydrase (PDB: 4E3D) and tyrosyl‐tRNA synthetase (PDB: 1JIJ) showed compound 8c with high binding affinities (ΔG = −10.3 and −11.7 kcal/mol, respectively). In addition, ADMET profiling predicted excellent drug‐like properties with Lipinski's Rule compliance (MW = 432.29 Da, LogP = 2.8, HBD = 1, HBA = 8) and favorable pharmacokinetic parameters. These quantitative results establish compound 8c as a promising multitarget lead compound for anticancer and antimicrobial drug development.