Facile Synthesis of N-vinylindoles via Knoevenagel Condensation: Molecular Features and Biological Activities

<i>N</i>-vinylindoles have attracted attention for their promising role in medicinal chemistry. Therefore, developing new synthetic methods that enable access to diverse functionalized <i>N</i>-vinylindoles with potential pharmacological properties is highly valuable. 1-[2-aryl-1-(4,5-dihydro-1<i>H</i>-imidazol-2-yl)vinyl]-1<i>H</i>-indoles <b>2a</b>-<b>i</b> were prepared via Knoevenagel condensation promoted by 1<i>H</i>-benzotriazole, and characterized by IR, NMR, and MS spectroscopic data as well as a single-crystal X-ray diffraction-based study of the representative derivative <b>2g</b>. The obtained compounds <b>2a</b>-<b>i</b> were screened for their cytotoxic potency against human cancer cell lines (HeLa, SKOV-3, AGS) and non-cancerous cell line (HaCaT) using the MTT assay. Additional apoptosis analysis and cell cycle assay on SKOV-3 cells were conducted. Their antimicrobial activity was determined using reference strains of <i>S. aureus</i>, <i>E. coli</i>, <i>C. albicans</i>, and <i>C. glabrata</i>. The potent inhibitory activity against AGE2-BSA/sRAGE interaction of selected <i>N</i>-vinylindoles <b>2b</b>, <b>2d</b>-<b>f</b>, and <b>2h</b>-<b>i</b> was evaluated by ELISA assay. A facile approach has been developed for the synthesis of a novel class of <i>N</i>-vinylindoles. The preliminary structure-activity considerations indicated that the presence of substituents R, such as 4-bromophenyl (compound <b>2f</b>) or 2-naphthyl (compound <b>2i</b>) is optimal for anticancer activity and the AGE2-BSA/sRAGE interaction inhibition. The most prominent (<i>Z</i>)-1-[1-(4,5-dihydro-1<i>H</i>-imidazol-2-yl)-2-(naphthalen-2-yl)vinyl]-1<i>H</i>-indole (<b>2i</b>) was found to strongly arrest cell cycle in the SKOV-3 cell line in the subG0 phase, inducing apoptosis. Notably, derivative <b>2i</b> also exhibited the highest activity against <i>S. aureus</i> and <i>C. albicans</i> strains within the tested series. These findings highlight the substantial potential of <i>N</i>-vinylindole derivative <b>2i</b> as a lead compound for the development of anticancer drugs with additional inhibitory activity on the AGE/RAGE interaction.