Synthesis, QTAIM, anticancer activity analysis of pyrrole-imidazole/ benzimidazole derivatives and investigation of their reactivity properties using DFT calculations and molecular docking

As part of our ongoing investigation into pyrrole derivatives, we here present the synthesis, spectroscopic characterization, QTAIM, reactivity, anticancer activity, and comparative experimental and computational analysis of pyrrole-imidazole ((3l), (3p)) and benzimidazole derivatives ((3h), (3i), (3j), (3k), (3m), (3n), (3o)). All synthesized compounds (3h-3p) have been well characterized by spectroscopic techniques (FT-IR, H-1 and C-13 NMR, Mass spectrometry). The experimental H-1 and C-13 NMR chemical shift values of synthesized pyrrole-imidazole (3l, 3p) and benzimidazole (3h-3o) derivatives have been well corroborated with computed chemical shifts. The vibrational analysis for four derivatives of pyrrole-benzimidazole (3m), (3n), (3o), and pyrrole-imidazole (3p) has the suitability for dimer formation in solid state by intermolecular heteronuclear hydrogen bonding (N-H<middle dot><middle dot><middle dot>O) and the interaction energy of dimers are calculated to be 10.88, 11.70, 9.89 and 10.72 kcal/mol, using DFT. After basis-set superposition error (BSSE) correction, the interaction energies of dimers were found to be 11.12, 12.11, 10.13, and 11.52 kcal/mol. Estimated intermolecular H-bond in (3m-3n) compounds were found to be -13.38, -12.86, -11.02, and -11.28 kJ/mol using QTAIM. All the synthetic pyrrole-imidazole (3l, 3p) and benzimidazole (3h-3o) derivatives exhibit strong antileukemia activity in vitro against the proliferative cell line L1210 leukemia cells. A dataset of investigated compounds was subjected for molecular modelling simulation against three distinct proteins (SYK, PI3K, and BTK), which was found to be highly implicated in the favourable interaction between the compounds and their target proteins in every instance. The synthesized pyrrole-imidazole (3l, 3p) and benzimidazole (3h-3o) derivatives shown favourable interactions with their target proteins, with high activity and binding free energy values falling between 15.22 and 13.43 and -7.4 and -9.8 kcal/mol, respectively. The structure of pyrrole-imidazole (3l, 3p) and benzimidazole (3h-3o) derivatives is thoroughly examined, and several parameters are proposed here to improve their anticancer activity.