Exploration of novel 3-substituted indole derivatives through multicomponent reaction: In vitro cytotoxicity, in silico docking, and molecular dynamics

[Display omitted] •Catalyst-free synthesis of AAIs and BIMs through one-pot multicomponent reaction.•Inhibition study of 25 indole derivatives AAIs and BIMs on MDA-MB-231 cells.•Proposing components for anticancer activity in 3-substituted indole structures.•Unraveling their interaction with PARP1 aid in designing more effective compounds.•5h shows favorable drug-like properties for anticancer, as per ADMET analysis. This study reports a simple process of synthesizing and separating 3-substituted indole derivatives, which are 3-aminoalkylated indoles (AAIs, (C8H7N)CH(CnH2n+1N) and (C8H7N)CH(CnH2n+1NO)) and bis-(3-indolyl) methanes (BIMs, (C8H7N)2CH(CnHn-1O), (C8H7N)2CH(CnHn-2ClO), and (C8H7N)2CH(CnHn+1O3)), via an efficient one-pot multicomponent reaction under catalyst-free conditions. The structures of all obtained compounds were determined via FT-IR, 1D and 2D NMR, and HRMS. Fourteen novel compounds (4f–p and 5e−g) are reported for the first time in this research. The in vitro anticancer activities of all synthesized indoles were investigated on MDA-MB-231 cell line. The results showed that the inhibitory effect of BIMs was better than that of AAIs, and compound 5h with IC50 of 8.73 μM displayed a remarkable anticancer activity on this cell line. In silico docking, the best docking pose 890 of compound 5h docked to topoisomerase I enzyme (1T8I: PDB) to explain the enzyme inhibition mechanism with the values of Free Gibb energy and inhibition constant of −8.95 Kcal·mol−1 and 0.28 µM, respectively. The molecular dynamic (MD) of the best docking pose 890 and 1T8I has performed in Linux environment and the results of simulation indicated the pharmacophore of compound 5h/pose 890 are more hydrophobic and less hydrophilic. In MD simulation, complex of pose 890-1T8I are more stable and residual amino acids are interacted well with pose 890 via two pi-cation interactions such as Lys 587, Tyr 444. The pharmacokinetic model ADMET of compound 5h has been revealed prediction parameters within permissive ranges, the values of log P and log S suggest that 5h exhibits superior solubility in hydrophobic solvents compared to hydrophilic solvents. Compound 5h has the ability to inhibit the majority of CTP enzymes that are involved in phase I oxidative reactions (CYP 1A2, 2C19, 2C9, 2D6, and 3A4). Additionally, the ADMET study suggests that compound 5h has promising drug-like properties for anticancer purposes.