Novel 2-(5-Aryl-4,5-Dihydropyrazol-1-yl)thiazol-4-One as EGFR Inhibitors: Synthesis, Biological Assessment and Molecular Docking Insights

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 targeted antitumor therapeutic agents. Methods Different thiazolyl-pyrazoline derivatives ( 7a-o ) were synthesized and were first tested for anti-proliferative effect towards the A549 lung cancer cell line and the T-47D breast cancer cell line in MTT assay. Thereafter, thiazolyl-pyrazolines ( 7b, 7g, 7l , and 7m ) were subsequently evaluated for their PK inhibition for EGFR. Moreover, representative promising derivatives ( 7g and 7m ) in cytotoxic and PK inhibition assays were tested to investigate their impact on the apoptosis and cell cycle phases in 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-pyrazolines 7b, 7g, 7l , and 7m in the EGFR active pocket (PDB ID: 1M17). Results Testing the thiazolyl pyrazoline compounds 7a-o on A549 and T-47D cell lines showed IC 50 arrays between 3.92 and 89.03 µM, and between 0.75 and 77.10 µM, respectively. Also, the tested thiazolyl-pyrazolines ( 7b, 7g, 7l , and 7m ) demonstrated significant sub-micromolar EGFR inhibitory actions with IC 50 values 83, 262, 171 and 305 nM, respectively, in comparison to erlotinib (IC 50 =57 nM). Discussion Generally, it was observed that the tested thiazolyl pyrazolines showed more potent antiproliferative activity toward breast cancer cells T-47D than toward lung cancer cell lines A549. In particular, thiazolyl pyrazolines 7g and 7m showed the best activity against A549 cells (IC 50 = 3.92 and 6.53 µM) and T-47D cells (IC 50 = 0.88 and 0.75 µM). Compounds 7g and 7m provoked a sub-G1 phase arrest and cell apoptosis which are in agreement with the expected outcome of EGFR inhibition. Finally, the molecular docking of 7g and 7m in the active site of EGFR revealed a common binding pattern similar to that of erlotinib which involves the accommodation of the 1,3 thiazol-4-one ring and pyrazoline ring of target compounds in the binding region of erlotinib’s quinazoline ring and anilino moiety.

Recruitment of hexahydroquinoline as anticancer scaffold targeting inhibition of wild and mutants EGFR (EGFR WT , EGFR T790M , and EGFR L858R )

“…The docking results revealed that our target compounds demonstrated different types of bonds with these amino acids and illustrated the results of the biological evaluation. Looking at the literature, we find that erlotinib binds with the key amino acids in the binding site through H-bonding with Met769 and hydrophobic interactions with other amino acids, including the key amino acid Lys721 and Leu694 98 , 99 . Considering the docking studies, compounds 10c and 10d showed a binding affinity for the active site of EGFR comparable to that found for erlotinib.…”

Machine Learning, Molecular Docking, and Dynamics-Based Computational Identification of Potential Inhibitors against Lung Cancer

“…35 Overall, several studies have documented the selectivity of staurosporine against the T790M/L858R mutation of EGFR over wild-type EGFR ranging from 55 to ∼300 folds. 35−39 Moreover, staurosporine had also demonstrated dose-dependent inhibition of cell proliferation of A549 cells with IC 50 values ranging from 4.29 to 9.50 μM, 40,41 respectively. In addition, staurosporine also inhibits other lung cancer cell lines, such as N417, H209, and Ma-31, with IC 50 values of 54, 29, and 602 nM, 42 respectively, demonstrating its potency.…”

New Thiazolyl-Pyrazoline Derivatives as Potential Dual EGFR/HER2 Inhibitors: Design, Synthesis, Anticancer Activity Evaluation and In Silico Study

“…For compound VI, it displayed antiproliferative activity for the breast cancer T-47D cell line with inhibition activity toward EGFR (IC 50 = 83 nM) [42] (Figure 1). According to the above data and in continuation of our scholarly interest in the chemistry of thiazolyl-pyrazolines and their biological activities [43][44][45], especially as possible anticancer agents [27,46,47], our objective was to enhance and modify a novel series of innovative thiazolyl-pyrazoline derivatives (4a-d, 5a-d, 6a, b, 7a-d, 8a, b, and 10a, b) as According to the above data and in continuation of our scholarly interest in the chemistry of thiazolyl-pyrazolines and their biological activities [43][44][45], especially as possible anticancer agents [27,46,47], our objective was to enhance and modify a novel series of innovative thiazolyl-pyrazoline derivatives (4a-d, 5a-d, 6a, b, 7a-d, 8a, b, and 10a, b) as potential dual-inhibitors against EGFR/HER2 with possible enhancement of their antiproliferative activities depending on introducing bioactive fragments like aryl-diazinyl, arylidene, isatin, or coumarin substitutions into the thiazole-pyrazoline combination as the core center (Figure 1). So, the basis and rationale of the design of target compounds as potential anticancer agents for breast cancer depend on the hybridization of the two bioactive scaffolds thiazole and pyrazoline which give greater anticancer activity by optimization of previous compounds by adding extra hydrophobic binding site and choosing the most active substituents (Cl and OCH 3 ) in the previous work [48] which depends on inhibiting MCF-7 which represent a very important candidate as they are used ubiquitously in research for estrogen receptor (ER)-positive breast cancer cell experiments and many sub-clones, which have been established, represent different classes of ER-positive tumors with varying nuclear receptor expression levels.…”