Discovery of New Immunomodulatory Anticancer Thalidomide Analogs: Design, Synthesis, Biological Evaluation and In Silico Studies

New thalidomide analogs have been designed and synthesized by hybridizing the immunomodulatory gutarimide moiety with three antiproliferative nuclei: quinazolinedione, phthalazinedione, and quinoxalinone. The biological results revealed the strong impact of quinazoline derivatives 7 a and 28, and phthalazine based 20 a against HepG-2, MCF-7, PC3, and HCT-116 cell lines, compared to thalidomide. In particular, compound 20 a was the most promising as it had far better biological activity than thalidomide with regard to inhibition of TNF-α, IL-6, caspase 3, COX-I/II, and VEGFR-2, as well as cell cycle arrest, and apoptosis rate enhancement in MCF-7 cells, the most sensitive cell line to the current new molecules. Compound 20 a caused reduction in levels of TNF-α and IL-6 by 75.22 % and 82.51 %, respectively. It elevated the caspase-3 level by 7.21-fold. Furthermore, IC₅₀ against COX-I, COX-II, and VEGFR-2 were 0.65 μM, 0.33 μM, and 232 nM, respectively. In addition, it raised the apoptosis rate from 65.65 % to 99.89 %. Moreover, 20 a was further examined through a docking study and a 200 ns molecular dynamics simulation for its complex with VEGFR-2, along with computational ADME properties. This work suggests the high significance of compounds 20 a, 7 a and 28, as lead compounds for development of new effective immunomodulatory antitumor drugs.