Lonidamine-1,3,4-oxadiazole derivatives with antiproliferative effects on HCT116 colon cancer cell lines: biological evaluation, ADMET, and computational studies.

In recent years, cancer has emerged as a significant challenge for healthcare systems, posing challenges to researchers to develop new treatments. Among various cancers, colorectal cancer is a major cause of death worldwide. To develop novel compounds that strongly inhibit colon cancer cells, lonidamine-1,3,4-oxadiazole derivatives 7(a-h) were designed and synthesized. The prepared compounds were characterized by various spectral techniques, including NMR (1H and 13C), mass spectra, and HPLC. Cytotoxicity tests conducted on a colorectal cancer cell line indicated that compound (7d) demonstrated significant antiproliferative effects, achieving the lowest IC50 value of 12.91 ± 1.58 µM, thereby making it the most effective among the compounds tested. This compound induces apoptosis, as evidenced by Hoechst/PI double staining, and mitigates cell migration, demonstrating its antiproliferative and antimigratory capabilities. Molecular docking, dynamics simulations, and DFT studies helped clarify the structure-activity relationship (SAR) and mechanisms of action. ADME and toxicity predictions also supported its drug-like properties. SAR analysis identified key substituents influencing activity, guiding further optimization. Overall, compound (7d) appears to be a promising candidate for colon cancer therapy, though additional studies are necessary to assess its clinical potential. These findings could be used for designing novel cancer therapeutic or preventive LND-derived agents.