Novel promising benzoxazole/benzothiazole-derived immunomodulatory agents: Design, synthesis, anticancer evaluation, and in silico ADMET analysis

Eleven novel benzoxazole/benzothiazole-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 cells. Generally, the open analogs with semicarbazide and thiosemicarbazide moieties (10, 13a-c, 14, and 17a,b) exhibited higher cytotoxic activities than derivatives with closed glutarimide moiety (8a-d). In particular, compound 13a (IC50 = 6.14, 5.79, 10.26, and 4.71 & mu;M against HepG-2, HCT-116, PC3, and MCF-7, respectively) and 14 (IC50 = 7.93, 8.23, 12.37, and 5.43 & mu;M, respectively) exhibited the highest anticancer activities against the four tested cell lines. The most active compounds 13a and 14 were further evaluated for their in vitro immunomodulatory activities on tumor necrosis factor-alpha (TNF-& alpha;), caspase-8 (CASP8), vascular endothelial growth factor (VEGF), and nuclear factor kappa-B p65 (NF-& kappa;B p65) in HCT-116 cells. Compounds 13a and 14 showed a remarkable and significant reduction in TNF-& alpha;. Furthermore, they showed significant elevation in CASP8 levels. Also, they significantly inhibited VEGF. In addition, compound 13a showed significant decreases in the level of NF-& kappa;B p65 while compound 14 demonstrated an insignificant decrease with respect to thalidomide. Moreover, our derivatives exhibited good in silico absorption, distribution, metabolism, elimination, toxicity (ADMET) profiles.