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

Abstract

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.