Synthesis, anticancer evaluation and molecular docking of new benzothiazole scaffolds targeting FGFR-1

• Published in: Bioorganic chemistry 2022-02, Vol.119, p.105504-105504, Article 105504
• Main Authors: Abd El-Meguid, Eman A., Mohi El-Deen, Eman M., Moustafa, Gaber O., Awad, Hanem M., Nossier, Eman S.
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Benzothiazole; Benzothiazoles - chemical synthesis; Benzothiazoles - chemistry; Benzothiazoles - pharmacology; Caspase-3/7/9; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; FGFR-1; HepG-2; Humans; MCF-7; Molecular Docking Simulation; Molecular Structure; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Receptor, Fibroblast Growth Factor, Type 1 - antagonists & inhibitors; Receptor, Fibroblast Growth Factor, Type 1 - metabolism; Structure-Activity Relationship
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.105504

[Display omitted] •Synthesis of new 2-aryl benzothiazoles 2–18.•Anticancer activities screened for all novel compounds.•FGFR-1 inhibiting activities evaluated for all new derivatives.•Apoptosis analyses and caspase-3/7/9 activation evaluated for compounds 3 and 8.•Molecular docking study created within ATP-binding pocket of FGFR-1 enzyme. This work deals with the design and synthesis of a series of new substituted 2-arylbenzothiazole compounds attached to 4-oxothiazolidin-2-ylidene ring 2–12 and chain elongation with different amino acids and their corresponding ester derivatives 13–18. All prepared derivatives were screened for their in vitro cytotoxicity activities against two cancer cell lines (HepG-2 and MCF-7) in comparison with doxorubicin; in addition to their safety towards thenormal cell line. Furthermore, all compounds 2–18 were evaluated as FGFR-1 inhibitors using AZD4547 as a reference. The 4-oxothiazolidin-2-ylidene derivatives 3 and 8 exhibited the highest cytotoxic activity (IC50 HepG-2 = 2.06, 2.21 µM and IC50 MCF-7 = 0.73, 0.77 µM, respectively) through their promising FGFR-1 suppression effects (IC50 = 16.31 and 18.08 nM, respectively) in comparison to AZD4547 (IC50 = 21.45 nM). Cell cycle and apoptosis analysis indicated that compounds 3 and 8 induce pronounced increase in the cell percentages at pre-G1 and G2/M phase compared to the untreated MCF-7 cancer cells, in addition to their up regulation of caspase-3/7/9. The molecular docking simulation was created to elucidate the binding modes of benzothiazole derivatives 1–18 bearing various scaffolds within the ATP-binding pocket of FGFR-1 enzyme compared with AZD4547.