Structure based designing of potent anticancer pyrrole-triazole chalcone derivatives: synthesis, molecular docking and in silico ADMET evaluation

In this study, pyrrole-triazole chalcone derivatives (3g-3j) have been designed, synthesized, and characterized spectroscopically, with a focus on their anticancer activity. The pyrrole-triazole chalcone derivatives (3g-3j) have been tested against U87-MG (brain cancer), HeLa (cervical cancer), MCF-7 (breast adenocarcinoma), and HEK (normal cell line) to evaluate their potential therapeutic effects. The α- and β-vinylic CH=CH–CO protons of compounds (3g-3j) appeared as doublets at 7.45–8.25 ppm and 7.07–7.52 ppm (J = 13.8–16.8 Hz), respectively, while the corresponding vinylic carbons resonated at 129.53–138.39 ppm (α) and 133.85–138.93 ppm (β), confirming chalcone formation. Computational studies have been conducted to investigate the intermolecular interactions and stability of the dimers formed by these derivatives. Using density functional theory (DFT), the binding energy for the dimers (3i) and (3j) has been calculated to be 10.19 and 11.22 kcal/mol, respectively, after correcting for basis set superposition error (BSSE), while the atoms in molecules (AIM) analysis yielded binding energy of 11.92 kcal/mol for (3i) and (3j) compound. The experimental and theoretical wavenumbers of the dimers were in good agreement, confirming that the dimer formation occurs via hydrogen bonding interactions between the pyrrolic N-H group and the carbonyl C=O group of the ester, resulting in a red shift. The NBO analysis has been performed to evaluate charge transfer and delocalization of electron density. The static first hyperpolarizability (β0) of (3g-3j) has been found to be 72.14 x 10–30, 18.19 x 10–30, 43.00 x 10–30, and 34.14 x 10–30 esu. Compound (3i) showed the highest cytotoxicity among the tested compounds against U87-MG, HeLa and MCF-7 cell lines with IC50 1.5, 170.7, 10.49 μM, respectively, as compared to the standard 5-FU (IC50 = 28.41, 40.65, and 26.86 μM). Molecular docking of pyrrole-triazole chalcone derivatives (3g-3j) study reveals good binding score against targeted proteins. The ADMET study ravels the druglikness of the synthesized compounds. These findings provide valuable insight into the molecular interactions and anticancer potential of the synthesized chalcone derivatives, highlighting their promise as candidates for further development in cancer therapy. Graphical abstract shows the key finding of the research.