Synthesis of Novel 4,6-Dimethoxyindole-Based Hydrazones Derived From 2,4-Dimethoxybenzaldehyde: Design, Cytotoxic Activity, Molecular Docking, and ADME-Tox Studies

In this study, a series of indolyl hydrazone derivatives (5–10) were designed and synthesized from 2,4-dimethoxybenzaldehyde (DMBA) (1) as potential chemotherapeutic agents. The structures of the synthesized compounds were confirmed by elemental analysis, FT-IR, 1D, and 2D NMR spectroscopy, and high-resolution mass spectrometry (HRMS). Their cytotoxic activities were evaluated against human breast (MCF-7), liver (HepG2), and colorectal (DLD-1) cancer cell lines. All compounds exhibited cytotoxic effects at micromolar concentrations, with IC50 values ranging from 8.97–26.07 µM for MCF-7, 22.50–70.99 µM for HepG2, and 5.93–66.31 µM for DLD-1 cells. Compound 10 demonstrated the strongest activity against MCF-7 and DLD-1 cells, with IC50 values of 8.97 ± 0.31 and 5.93 ± 0.11 µM, respectively. Compound 7 showed the highest antiproliferative activity against HepG2 cells (22.50 ± 1.23 µM), exceeding the activity of cisplatin (37.27 ± 2.42 µM). Molecular docking studies revealed favorable binding affinities of the most active compounds (7 and 10) toward selected targets. In addition, in silico ADME-toxicity analyses predicted acceptable physicochemical and pharmacokinetic properties, supporting the potential of these derivatives as promising anticancer candidates. © 2026 Wiley-VCH GmbH.