Design, synthesis, anti-breast cancer and in silico studies of substituted triphenyl imidazole-N-alkyl linked indole derivatives.

Aim: Cancer is an affliction on societies worldwide, chemotherapy, though effective, has its limitations, indicating the need for new therapeutic agents. Imidazole and indole are two important bioactive heterocycles important for developing newer anticancer molecules.We synthesized a series of substituted imidazole-linked indole derivatives and evaluated them for anticancer activity on MCF-7 cells. Further in silico, cell cycle and apoptosis studies was done for the most active compounds.

Materials and methods: Compounds were synthesized by preparing substituted triphenyl imidazoles from benzaldehydes and were further linked to indoles using N-chloroalkyl indoles. The synthesized compounds were characterized and tested for anticancer activity using MTT-assay on MCF-7 cells, followed by a cell-cycle and apoptosis assay of most active compound using flow cytometry. The most active compound was subjected to docking studies using PyRx with the EGFR protein 4HJO, followed by a molecular dynamics simulation using Desmond. Finally, DFT calculations were performed using ORCA 6.0 followed by QSAR analysis of the compounds.

Results: Compounds were confirmed by ¹H NMR, ¹³C NMR, mass spectroscopy, and showed IC₅₀ values of 26.52 to 39.05 µM on MCF-7 cells. The most active compound 11i produced apoptosis at its IC₅₀ in MCF-7 cells and arrested the cell cycle in G2/M phase. 11i also had good interactions with 4HJO which confirmed its stability in both molecular dynamics and DFT studies. QSAR studies predicted the relevant structural features for the biological activity.