Novel 2-(5-Aryl-4,5-Dihydropyrazol-1-yl)thiazol-4-One as EGFR Inhibitors: Synthesis, Biological Assessment and Molecular Docking Insights
Document Type
Article
Publication Date
2022
Abstract
Introduction:Epidermal growth factor receptor (EGFR) regulates several cell functions which include cell growth, survival,multiplication, differentiation, and apoptosis. Currently, EGFR kinase inhibitors are of increasing interest as promising targetedantitumor therapeutic agents.Methods:Different thiazolyl-pyrazoline derivatives (7a-o) were synthesized and were first tested for anti-proliferative effecttowards the A549 lung cancer cell line and the T-47D breast cancer cell line in MTT assay. Thereafter, thiazolyl-pyrazolines (7b,7g, 7l, and7m) were subsequently evaluated for their PK inhibition for EGFR. Moreover, representative promising derivatives(7gand7m) in cytotoxic and PK inhibition assays were tested to investigate their impact on the apoptosis and cell cycle phasesin T-47D cells in order to explore more insights into the antitumor actions of the target thiazolyl-pyrazolines. Furthermore,docking studies were accomplished to evaluate the patterns of binding of thiazolyl-pyrazolines7b, 7g, 7l, and7min the EGFRactive pocket (PDB ID: 1M17).Results:Testing the thiazolyl pyrazoline compounds7a-oon A549 and T-47D cell lines showed IC50arrays between 3.92 and89.03 μM, and between 0.75 and 77.10 μM, respectively. Also, the tested thiazolyl-pyrazolines (7b, 7g, 7l, and7m) demonstratedsignificant sub-micromolar EGFR inhibitory actions with IC50values 83, 262, 171 and 305 nM, respectively, in comparison toerlotinib (IC50=57 nM).Discussion:Generally, it was observed that the tested thiazolyl pyrazolines showed more potent antiproliferative activity towardbreast cancer cells T-47D than toward lung cancer cell lines A549. In particular, thiazolyl pyrazolines7gand7mshowed the bestactivity against A549 cells (IC50= 3.92 and 6.53 μM) and T-47D cells (IC50= 0.88 and 0.75 μM). Compounds7gand7mprovokeda sub-G1 phase arrest and cell apoptosis which are in agreement with the expected outcome of EGFR inhibition. Finally, the moleculardocking of7gand7min the active site of EGFR revealed a common binding pattern similar to that of erlotinib which involves theaccommodation of the 1,3 thiazol-4-one ring and pyrazoline ring of target compounds in the binding region of erlotinib’s quinazolinering and anilino moiety.
Recommended Citation
Albohy, Amgad, "Novel 2-(5-Aryl-4,5-Dihydropyrazol-1-yl)thiazol-4-One as EGFR Inhibitors: Synthesis, Biological Assessment and Molecular Docking Insights" (2022). Pharmacy. 734.
https://buescholar.bue.edu.eg/pharmacy/734