Novel Cryptolepine Analogues: Synthesis, Docking, and ADMET Profiling for Anticancer Activity.

In this study, a focused synthetic approach was employed to modify the cryptolepine scaffold at the C-11 position, yielding 7a and 7b that served as versatile platforms for the construction of structurally diverse heterocyclic compounds, including thiazolidinones, sulfonylhydrazides, ureas, and thioureas (compounds 8-15c). All synthesized derivatives were fully characterized by IR and ¹H NMR, and ¹³C NMR spectroscopy. Comprehensive in vitro cytotoxicity screening against MCF-7 (breast), HCT-116 (colon), and HepG-2 (liver) cancer cell lines, alongside with normal human fibroblasts (BJ-1), revealed promising antiproliferative activity across the series. Notably, compounds 6, 11a, 11c, and 15b exhibited high significant IC50 values, with compound 15b demonstrating a superior selectivity index (SI > 11). Structure–activity relationship (SAR) trends highlighted the significance of thiourea functionality and N-methyl substitution in enhancing potency and cellular selectivity. Molecular docking studies against multiple oncogenic targets (cMET, VEGFR-2, EGFR, and ER-α) revealed that selected compounds engage key catalytic residues through hydrogen bonding, π–π stacking, and hydrophobic interactions, often surpassing the binding affinities of the reference drug, doxorubicin. Additionally, in silico ADME and toxicity analyses identified compound 15b as a lead candidate, with favorable pharmacokinetic parameters, high gastrointestinal absorption, acceptable solubility, and a superior drug-likeness profile.