Synthesis of Novel 4,6‐Dimethoxyindole‐Based Hydrazones Derived From 2,4‐Dimethoxybenzaldehyde: Design, Cytotoxic Activity, Molecular Docking, and ADME‐Tox Studies
TL;DR
In silico ADME‐toxicity analyses predicted acceptable physicochemical and pharmacokinetic properties, supporting the potential of these derivatives as promising anticancer candidates.
Abstract
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 IC 50 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 IC 50 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.