Abstract: In an effort to discover novel anti-lung cancer agents, a series of 21 novel 3-phenyl-1H-pyrazole-indole hybrid derivatives were designed and synthesized via a catalyst-free one-pot reaction employing 5-phenyl-2,4-dihydro-3H-pyrazol-3-one, benzaldehyde, and indole as starting materials. All synthesized compounds were fully characterized by 1H NMR, 13C NMR and HRMS. In vitro anti-lung cancer activity screening revealed that most of the target compounds exhibited potent inhibitory effects against both the A549 cell line and the A549/DDP cell line. Notably, compound 4n demonstrated exceptional activity against the resistant A549/DDP cells, with an IC50 value of 0.085±0.003 μmol/L, which was 29-fold more potent than the positive control cisplatin. Mechanistic studies indicated that compound 4n significantly arrested the cell cycle of A549/DDP cells at the G0/G1 phase, induced apoptosis, and suppressed cell migration. Molecular docking results suggested that its antitumor activity may be associated with interactions involving multiple targets, including AKt1, tubulin, and P-gp. Compound 4n represents a promising anti-lung cancer lead candidate for subsequent structural optimization and comprehensive mechanistic investigation.

Key words: Indole, Pyrazole, Derivative, Anti-lung cancer activity