ABSTRACT
AIM: Simultaneous inhibition of hepatitis C virus (HCV) and hepatocellular carcinoma (HCC) may enhance anti-HCV effects and reduce resistance and side effects. RESULTS/METHODOLOGY: Novel hybrid derivatives were designed and synthesized to exhibit dual activity against HCV and its associated major complication, HCC. The synthesized compounds were screened for their potential activity against HCV and HCC. Compounds 5f, 5j, 5l, 5p, 5q, 5r, 6c and 6d exhibited potential in vitro anticancer activity against HCC cell line HepG2, while compounds 5a, 5l, 5p and 5v showed in vitro anti-HCV activity. Docking studies suggested that the newly synthesized compounds could suppress HCC through VEGFR2 tyrosine kinase inhibition. CONCLUSION: Compounds 5l and 5p exhibited dual activity against HCV and HCC in vitro.
ABSTRACT
AIM: VEGFR2 tyrosine kinase is a main target in suppressing cancer growth and metastasis. Materials & methods: Piperazine-based thiazolidinones were synthesized and screened for their anticancer and VEGFR2 tyrosine kinase inhibitory activity. Results: Compounds 11, 13 and 16 displayed potent anticancer activity against HepG-2 with IC50 values 0.03-0.06 µM. They were safe on normal human fibroblasts with selectivity indices 8.09, 11.40 and 4.37, respectively. Also, these compounds showed VEGFR2 tyrosine kinase inhibitory activities more than the reference staurosporine with IC50 values <0.3 µM. Lineweaver-Burk plot revealed that these compounds behaved as uncompetitive VEGFR2 tyrosine kinase inhibitors. They also induced caspase-dependent apoptosis in HepG-2. In addition, these compounds revealed good binding within VEGFR2 tyrosine kinase enzyme in comparison with sorafenib reference. CONCLUSION: Compounds 11, 13 and 16 comprise a new promising scaffold of selective VEGFR2 tyrosine kinase inhibitors with caspase-dependent apoptotic activities.
Subject(s)
Apoptosis/drug effects , Piperazines/chemistry , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Thiazolidines/chemistry , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Binding Sites , Caspases/metabolism , Cell Line, Tumor , Hep G2 Cells , Humans , Molecular Docking Simulation , Niacinamide/analogs & derivatives , Niacinamide/chemistry , Niacinamide/metabolism , Niacinamide/pharmacology , Phenylurea Compounds/chemistry , Phenylurea Compounds/metabolism , Phenylurea Compounds/pharmacology , Piperazine , Protein Kinase Inhibitors/chemistry , Protein Structure, Tertiary , Sorafenib , Staurosporine/chemical synthesis , Staurosporine/chemistry , Staurosporine/pharmacology , Thiazolidines/chemical synthesis , Thiazolidines/pharmacology , Vascular Endothelial Growth Factor Receptor-2/metabolismABSTRACT
AIM: Simultaneous inhibition of 5-LOX/COX may enhance anti-inflammatory effects and reduce side effects. Hence, synthesis of novel dual inhibitors of 5-LOX/COX is an important strategy for treatment of inflammation. Results/methodology: The target compounds were designed to hybridize benzothiophene scaffold or its bioisostere benzofuran with various anti-inflammatory pharmacophore hetercycles through different atoms spacers. Compounds 4a, 4c, 4d, 5b, 7a, showed significant in vitro LOX inhibitory activity higher than that of meclofenamate sodium. Compounds 4b, 4e, 4f, 5a exhibited significant in vitro COX-2 inhibition higher than celecoxib and in vitro LOX inhibitory activity twice that of reference. These compounds elicited significant in vivo anti-inflammatory activities higher than celecoxib in formalin-induced paw edema test. Compound 4e exhibited gastrointestinal safety profile as celecoxib. The results were also consistent with the docking studies. CONCLUSION: Compound 4e could be considered as structural lead for the development of a new class of anti-inflammatory agents with better safety profile.
