ABSTRACT
Cancer remains a leading cause of death worldwide, often resulting from uncontrolled growth in various organs. Protein kinase inhibitors represent an important class of targeted cancer therapies. Recently, the kinases BRAF and VEGFR-2 have shown synergistic effects on tumor progression. Seeking to develop dual BRAF/VEGFR-2 inhibitors, we synthesized 18 amino-benzothiazole derivatives with structural similarities to reported dual inhibitors. Four compounds-4a, 4f, 4l, and 4r-demonstrated remarkable cytotoxicity, with IC50 values ranging from 3.58 to 15.36 µM, against three cancer cell lines. Furthermore, these compounds showed IC50 values of 38.77-66.22 µM in the case of a normal cell line, which was significantly safer than the reference, sorafenib. Subsequent investigation revealed that compound 4f exhibited the capacity to inhibit the BRAF and VEGFR-2 enzymes, with IC50 values similar to sorafenib (0.071 and 0.194 µM, respectively). Moreover, compound 4f caused G2-M- and S-phase cycle arrest. Molecular modeling demonstrated binding patterns compatible with inhibition for both targets, where 4f exerted the critical interactions in the BRAF site and interacted in the VEGFR-2 site in a manner akin to sorafenib, demonstrating affinity similar to dabrafenib.
Subject(s)
Antineoplastic Agents , Benzothiazoles , Cell Proliferation , Molecular Docking Simulation , Protein Kinase Inhibitors , Proto-Oncogene Proteins B-raf , Thiadiazoles , Vascular Endothelial Growth Factor Receptor-2 , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/metabolism , Humans , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/chemical synthesis , Benzothiazoles/chemistry , Benzothiazoles/pharmacology , Benzothiazoles/chemical synthesis , Thiadiazoles/chemistry , Thiadiazoles/pharmacology , Thiadiazoles/chemical synthesis , Cell Line, Tumor , Cell Proliferation/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Drug Design , Structure-Activity Relationship , Sorafenib/pharmacology , Sorafenib/chemistry , Molecular Structure , Computer Simulation , Drug Screening Assays, AntitumorABSTRACT
This research study describes the development of new small molecules based on 2,4-thiazolidinedione (2,4-TZD) and their aldose reductase (AR) inhibitory activities. The synthesis of 17 new derivatives of 2,4-TZDs hybrids was feasible by incorporating two known bioactive scaffolds, benzothiazole heterocycle, and nitro phenacyl moiety. The most active hybrid (8b) was found to inhibit AR in a non-competitive manner (0.16 µM), as confirmed by kinetic studies and molecular docking simulations. Furthermore, the in vivo experiments demonstrated that compound 8b had a significant hypoglycaemic effect in mice with hyperglycaemia induced by streptozotocin. Fifty milligrams per kilogram dose of 8b produced a marked decrease in blood glucose concentration, and a lower dose of 5 mg/kg demonstrated a noticeable antihyperglycaemic effect. These outcomes suggested that compound 8b may be used as a promising therapeutic agent for the treatment of diabetic complications.
Subject(s)
Aldehyde Reductase , Hypoglycemic Agents , Animals , Mice , Aldehyde Reductase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Hypoglycemic Agents/pharmacology , Kinetics , Molecular Docking Simulation , Thiazolidines/pharmacologyABSTRACT
New series of triazolo[4,3-c]quinazolines were designed, synthesized and their structures were elucidated using different spectroscopic techniques. They were evaluated for their in vitro antitumor activity against HepG2, MCF-7, PC-3, HCT-116 and HeLa cancer cell lines using MTT assay. It was found that all compounds showed variable in vitro cytotoxicity. Distinct derivatives exhibited higher inhibitory activity against the tested cell lines with IC50 values ranging from 8.27 to 10.68 µM using DOX standard (IC50 = 4.17-8.87 µM). In vitro epidermal growth factor receptor (EGFR) inhibition assay was performed. Results revealed that compounds 8, 19 and 21 exhibited worthy EGFR inhibitory activity with IC50 values ranging from 0.69 to1.8 µM in comparison to the reference drug Gefitinib (IC50 = 1.74 µM). Further investigation showed that active candidates 8, 19 and 21 caused cell cycle arrest at the G2/M phase, and interestingly, induced cell death by apoptosis of MCF-7 cells cumulatively with 7.14, 17.52 and 24.88%, respectively, compared with DOX as a positive reference (29.09%). Molecular modeling studies, including docking, flexible alignment and surface mapping, were also done to study the interaction mode into the active site of EGFR kinase domain. There was a good agreement between modeling results and biological results. ADMET analysis and parameters of Lipinski's rule of five were calculated. Pharmacokinetic parameters showed that compound 8 had more expected penetration through blood brain barrier than Gefitinib. The present work displayed new triazoloquinazoline based derivatives with potent cytotoxicity and promising EGFR inhibition activity.