Synthesis of chromone-indole derivatives and evaluation of their antitumor activity

Cancer remains a major global health threat, creating an urgent demand for new, selective small-molecule anticancer agents. To address the paucity of potent, targeted chromone-derived antitumor compounds and fill the knowledge gap in C-2 modified chromone-indole hybrids, we designed, synthesized, and biologically evaluated 24 novel chromone-indole hybrids via C-2 modification of the chromone core and conjugation with indole. All compounds were characterized by ¹H NMR, ¹³C NMR and High-resolution mass spectrometry (HRMS), with single-crystal X-ray diffraction for compound 3 k. In vitro Cell Counting Kit-8 (CCK-8) assays (cisplatin as positive control) identified several potent and selective antiproliferative agents: 3q (IC₅₀ = 14.05 ± 0.95 μM, K562), 3m (IC₅₀ = 13.95 ± 0.98 μM, HeLa) and notably 3h (IC₅₀ = 6.70 ± 0.37 μM, AGS). Network pharmacology and PPI analysis identified MDM2, MAPK1, PGR and AR as core targets; molecular docking confirmed stable binding via hydrogen bonds, π -π stacking and halogen interactions. Label-free surface plasmon resonance(SPR)assays verified direct binding of 3 h to Progesterone receptor (PGR) (KD = 2.41 × 10^-6 M; ka = 70.07 × 10³ M^-1·s^-1, k_d = 16.87 × 10^-2 s^-1, τ = 5.93 s), confirming target engagement.Collectively, this study addresses critical gaps in chromone-indole hybrid research, provides an efficient synthetic strategy, and identifies 3 h as a promising lead candidate for further optimization and in vivo studies.