Depression is a debilitating neuropsychiatric disorder and a leading cause of disability worldwide, with current therapeutic options often limited by delayed onset of action, inadequate efficacy, and undesirable side effects. The quinoline scaffold, a privileged structure in medicinal chemistry, has been reported to possess a wide spectrum of pharmacological properties, including central nervous system (CNS) modulation.

In this study, two novel 2,4-diphenylquinoline derivatives—CMPD1 [2-(4-methoxyphenyl)-4-phenylquinoline] and CMPD2 [2-(2,4-dichlorophenyl)-4-phenylquinoline]—were rationally designed based on structure–activity relationship (SAR) insights and synthesized via the Friedländer condensation of appropriately substituted anilines with carbonyl precursors. Purification was achieved by recrystallization, and structural confirmation was performed using Fourier-transform infrared (FT-IR) spectroscopy, proton nuclear magnetic resonance (NMR), and carbon-13 NMR spectroscopy, confirming the expected chemical shifts and diagnostic signals for quinoline derivatives.

The pharmacological activity was evaluated using murine models for antidepressant screening: the Forced Swim Test (FST) and Tail Suspension Test (TST). Both compounds produced statistically significant reductions in immobility time compared to the control group (p < 0.05), with CMPD2 showing slightly enhanced activity. The results suggest that electron-donating and electron-withdrawing substituents influence antidepressant potency, potentially through modulation of CNS receptor binding.

These findings validate 2,4-diphenylquinoline derivatives as promising antidepressant leads, meriting further optimization, in vivo pharmacokinetic studies, and mechanistic investigations to establish their clinical translation potential.