Synthesis, molecular docking, ADMET prediction and cytotoxic activity of novel quinoline‐based chalcones

Abstract

As cancer remains a major human disease, the discovery of new anticancer agents is a crucial priority in drug development. This research centered on the synthesis of novel quinolinyl-chalcones with cytotoxic potential, which were obtained through a Claisen–Schmidt condensation reaction between 1-(6‑chloro-2-methyl-4-phenylquinolin-3-yl)ethan-1-one and various aldehydes. The reaction was carried out in a NaOH/EtOH/H₂O medium. The structures of all the synthesized compounds were confirmed by ^1HNMR , ^13CNMR , and HRMS spectroscopy, the latter used for two newly obtained compounds. The compounds were evaluated for cytotoxic activity against colorectal adenocarcinoma (Caco-2), ovarian carcinoma (SKOV-3), glioblastoma (T98G), and normal fibroblasts (L929). Among them, compound 3h exhibited the highest cytotoxic activity across cancer cell lines (IC₅₀ = 12.21 to 14.92 µM), but with limited selectivity toward normal cells, whereas compound 3c showed a more favorable therapeutic index. Molecular docking studies revealed that the synthesized chalcones engage in strong interactions with the colchicine-binding site of tubulin (PDB ID: 1SA0), with compound 3c displaying the most favorable binding affinity, surpassing the reference colchicine. These results were further supported by molecular dynamics simulations, which confirmed the structural stability of the 3h–tubulin complex over 150 ns under physiological conditions. In silico ADMET predictions (Lipinski’s rules, Pfizer Golden Triangle, and BOILED-Egg model) suggested acceptable oral bioavailability for most derivatives, with 3c and 3h predicted to have good gastrointestinal absorption but limited blood–brain barrier penetration, which is advantageous for reducing central nervous system side effects.