Functionalized Indolizines as Potential Anticancer Agents: Synthetic, Biological and In Silico Investigations

Three new series of indolizines (<b>5a</b>-<b>f</b>, <b>6a</b>-<b>f</b> and <b>7a</b>-<b>g</b>), functionalized with bromine or ethyl ester substituents on the pyridine ring, were designed and synthesized as promising anticancer agents. The synthesis of indolizine derivatives was carried out using the 1,3-dipolar cycloaddition of pyridinium <i>N</i>-ylides to ethyl propiolate as a key step. Spectral characterization (using NMR, FT-IR, HRMS and X-ray diffraction) showed that two types of cycloadducts <b>5a</b>-<b>f</b> and <b>6a</b>-<b>f</b> were obtained when the ylides generated by the 3-bromopyridinium salts were used as 1,3-dipoles in Huisgen cycloaddition reactions to ethyl propiolate. The anticancer effect of selected compounds was in vitro assessed against the National Cancer Institute (NCI) panel of 60 human tumor cells, at 10 μM concentration, with three compounds (<b>5c</b>, <b>6c</b> and <b>7g</b>) showing promising inhibitory activity on the growth of several cell lines including lung, brain, renal cancer and melanoma, as well as a cytotoxic effect against HOP-62 non-small cell lung cells (34% for compound <b>5c</b> and 15% for compound <b>7g</b>) and SNB-75 glioblastoma cells (15% for compound <b>5c</b> and 14% for derivative <b>7c</b>). Molecular docking revealed favorable binding affinities for <b>5c</b>, <b>6c</b> and <b>7g</b> (-9.22 to -9.88 kcal/mol) at the colchicine-binding site of tubulin with key interactions involving βASN-258, βALA-317, and βLYS-352 residues for <b>5c</b>, βASN-258 in case of <b>6c</b>, and αVAL-181 and βLYS-254 for derivative <b>7g</b>. According to the in silico ADMET analysis, the active compounds are predicted to exhibit good oral bioavailability, promising drug-like qualities and low toxicity risks.