Molecular Modeling, Synthesis, and Preliminary Cytotoxicity Evaluation of New Indole-Based Molecules as Possible Sirtuin Inhibitors

Abstract

Sirtuin enzymes are interesting targets for developing new drug candidates. This study aims to design new indole-based sirtuin inhibitors, filtering through molecular docking alongside molecular dynamics and pharmacokinetic property prediction, synthesizing 4 compounds with an evaluation of their cytotoxic activity alongside the sirtuin inhibitor AGK2 against the breast cancer (MCF7) cell line via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The antibacterial activity of these compounds was evaluated by comparing the minimum inhibitory concentration (MIC) with ciprofloxacin against Staphylococcus aureus and Klebsiella pneumoniae using resazurin dye. The docking study showed a higher binding affinity for the synthesized compounds than sirtuin inhibitors AGK2 and selisistat against the sirtuin2 isoform. In addition, the molecular dynamics study showed good stability of the compound with the higher docking score in complex with sirtuin2 over 100 ns. The prediction of pharmacokinetic properties showed adherence to drug-likeness criteria. The MTT assay revealed comparable IC₅₀ values for the compounds with AGK2, as compound AFJ1 showed the highest cytotoxic activity (IC₅₀ = 2.6 μM). Among the synthesized compounds, AFJ2 showed the lowest MIC against K. pneumoniae (125 μg/mL) compared to ciprofloxacin (62.5 μg/mL).