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

TL;DR

A new method to synthesize N-vinylindoles is developed, and some compounds show strong anticancer and antimicrobial properties.

Contribution

A facile Knoevenagel condensation method for synthesizing functionalized N-vinylindoles with promising pharmacological activity is introduced.

Findings

Compound 2i strongly induces apoptosis and arrests the cell cycle in SKOV-3 cells.

Compound 2i shows high antimicrobial activity against S. aureus and C. albicans.

Selected N-vinylindoles inhibit the AGE2-BSA/sRAGE interaction effectively.

Abstract

N-vinylindoles have attracted attention for their promising role in medicinal chemistry. Therefore, developing new synthetic methods that enable access to diverse functionalized N-vinylindoles with potential pharmacological properties is highly valuable. 1-[2-aryl-1-(4,5-dihydro-1H-imidazol-2-yl)vinyl]-1H-indoles 2a-i were prepared via Knoevenagel condensation promoted by 1H-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 2g. The obtained compounds 2a-i 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 S. aureus, E. coli, C. albicans, and C. glabrata. The potent inhibitory activity against AGE2-BSA/sRAGE interaction of selected N-vinylindoles 2b, 2d-f, and 2h-i was evaluated by ELISA assay. A facile approach has been developed for the synthesis of a novel class of N-vinylindoles. The preliminary structure–activity considerations indicated that the presence of substituents R, such as 4-bromophenyl (compound 2f) or 2-naphthyl (compound 2i) is optimal for anticancer activity and the AGE2-BSA/sRAGE interaction inhibition. The most prominent (Z)-1-[1-(4,5-dihydro-1H-imidazol-2-yl)-2-(naphthalen-2-yl)vinyl]-1H-indole (2i) was found to strongly arrest cell cycle in the SKOV-3 cell line in the subG0 phase, inducing apoptosis. Notably, derivative 2i also exhibited the highest activity against S. aureus and C. albicans strains within the tested series. These findings highlight the substantial potential of N-vinylindole derivative 2i as a lead compound for the development of anticancer drugs with additional inhibitory activity on the AGE/RAGE interaction.

Figures