Synthesis, crystal structure, DFT, and molecular docking studies of quinazoline-based ML-167 derivatives

Sarcopenia is a chronic disease characterized by loss of skeletal muscle mass and strength, posing a rising societal health challenge among the elderly, leading to increased risks of disability, fractures, falls, and mortality. Despite its clinical significance, there are currently no approved medicinal interventions for this condition. In this study, we used a systems biology framework to uncover potential therapeutic targets for sarcopenia. Based on computational analysis, CYC1 was identified as a key druggable protein. Following bioinformatic screening, ML-167 was selected as a candidate for repurposing. Guided by this insight, we have rationally designed and synthesized a novel series of ML-167-based derivatives, intending to modulate CYC1 activity. For structural validations, comprehensive spectroscopic techniques, including 1 H and 13 C NMR, MS, and, where applicable, single-crystal X-ray crystallography techniques were used. In vitro evaluation of the ML-167 derivatives in C2C12 cells established structure-dependent effects on cell viability. Several derivatives exhibited proliferation levels similar to the control group and indicate differences in biological activity among the derivatives. Computational studies, including molecular docking, density functional theory (DFT) calculations, and analyses of frontier molecular orbitals (FMOs), disclosed favorable electronic features, charge-transfer characteristics, and binding interactions with CYC1. Noncovalent interaction (NCI), reduced density gradient (RDG), electron localization function (ELF), and quantum theory of atoms in molecules (QTAIM) analyses highlighted the role of dispersive forces and hydrogen bonding in stabilizing the ligand-protein complex. Structure–activity relationship (SAR) analysis and in vitro cell proliferation assays identified compounds 3a, 3f, and 5a as the most promising leads, demonstrating optimal binding profiles and favorable biological activity.