Design, synthesis, anticancer evaluation, docking and ADMET analysis of novel indole-based thalidomide analogs as promising immunomodulatory agents.

In the present work, novel 16 indole-based thalidomide analogs were designed and synthesized to obtain new effective antitumor immunomodulatory agents. The synthesized compounds were evaluated for their cytotoxic activities against HepG-2, HCT-116, PC3 and MCF-7 cell lines. Generally, the opened analogs of glutarimide ring exhibited higher activities than the closed ones. Compounds and showed strong potencies against all tested cell lines with IC values ranging from 8.27 to 25.20 µM comparable to that of thalidomide (IC values ranging from 32.12 to 76.91 µM). The most active compounds were further evaluated for their immunomodulatory activities estimation of human tumor necrosis factor alpha (TNF-α), human caspase-8 (CASP8), human vascular endothelial growth factor (VEGF), and nuclear factor kappa-B P65 (NF-κB P65) in HCT-116 cells. Thalidomide was used as a positive control. Compounds , and showed remarkable significant reduction in TNF-α. Furthermore, compounds , and showed significant elevation in CASP8 levels. Compounds and significantly inhibited VEGF. In addition, derivatives , and showed significant decrease in level of NF-κB p65. Moreover, our derivatives exhibited good docking and ADMET profile.Communicated by Ramaswamy H. Sarma.