Design and Synthesis of Novel Lonidamine‐N‐Heterocyclic Derivatives With Potent Anticancer Activity Against Colorectal Cancer Cells

ABSTRACT Colorectal cancer remains a major health concern and the second leading cause of cancer deaths, underscoring the urgent need for advanced early diagnostic methods to improve survival outcomes. In this study, we designed and synthesized a new series of hybrid compounds that incorporate Lonidamine and various N‐heterocycles, such as pyridine, 4‐quinoline, 4,7‐chloroquinoline, and acridine. Synthesized compounds were characterized by various spectral techniques, including NMR ( 1 H and 13 C), mass spectra, and HPLC. The cytotoxicity studies of the conjugates were conducted using the colorectal cancer cell line (HCT116), and compound (22a) exhibited potent antiproliferative activity, with the lowest IC 50 value of 2.59 ± 0.33 µM, indicating that it is the most potent among the screened compounds. The compound effectively induces apoptosis, as demonstrated by Hoechst/PI double staining in HCT116 cells. The treatment group showed reduced migratory capabilities, highlighting the compound′s strong antiproliferative activity and antimigratory propensity against HCT116 cells. Additionally, physicochemical features and ADMET profiles have been investigated to gain a better understanding of their pharmacokinetic and toxicological characteristics. The results demonstrated satisfactory pharmacokinetic behavior and acceptable toxicity profiles, with (22a) emerging as a promising candidate due to its superior bioavailability, enhanced stability, and potent anticancer activity. Molecular docking, dynamics simulations, and DFT studies were used to better understand the SAR and mechanisms of action of potential cancer drugs. This study indicates the promising potential of compound (22a) as a prospective candidate agent for colorectal cancer treatment. Further comprehensive investigations are needed to explore its therapeutic efficacy in greater detail.