Rational Design, Synthesis and Biological Evaluation of Novel Pyrazoline-Based Antiproliferative Agents in MCF-7 Cancer Cells

Abstract

Breast cancer is a disease in which cells in the breast divide continuously without control. There are great limitations in cancer chemotherapy. Hence, it is essential to search for new cancer therapeutics. Herein, a novel series of EGFR/HER2 dual inhibitors has been designed based on the hybridization of thiazole and pyrazoline fragments. The synthesized compounds were screened for their anti-proliferative activity against MCF-7 breast cancer cell line and MCF-10 normal breast cell line. Interestingly, synthesized compounds 6e and 6k showed very potent antiproliferative activity towards MCF-7 with IC50 values of 7.21 and 8.02 µM, respectively. Furthermore, enzymatic assay was performed against EGFR and HER2 to prove the dual inhibitory action. Compounds 6e and 6k showed potent inhibitory activity for EGFR with IC50 of 0.009 and 0.051 µM, respectively, and for HER2 with IC50 of 0.013 and 0.027 µM, respectively. Additionally, compounds 6e and 6k significantly stimulated apoptotic breast cancer cell death. Compound 6e was further explored for its anticancer activity in vivo using a Xenograft model. Moreover, computational modeling studies, ADMET studies and toxicity prediction were performed to investigate their potential drug candidates.

Development in the Synthesis of Bioactive Thiazole-Based Heterocyclic Hybrids Utilizing Phenacyl Bromide

“…Fakhry and co-workers 81 communicated the synthesis of 2-(3-(3,4-dimethoxyphenyl)-5-(aryl)-4,5-dihydro-1 H -pyrazol-1-yl)-4-(aryl) thiazoles 59a – 59l . This synthetic procedure involves the chemical interaction between 3-(3,4-dimethoxyphenyl)-5-(4-aryl)-4,5-dihydro-1 H -pyrazole-1-carbothioamide 58 and phenacyl bromide 7 in ethanol, with DMF serving as the catalytic agent.…”

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

“…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. MCF-7 is a commonly used breast cancer cell line that has been propagated for many years by multiple groups and proves to be a suitable model cell line for breast cancer investigations worldwide, including those regarding anticancer [49] and evaluated against MCF-10a cells, which are the most common cell line used as a model for normal human breast cells.…”

“…The aim of this study is to optimize and increase the selectivity of the previous synthesized thiazolyl-pyrazoline series [48] by increasing the bulkiness on C4 or C5 of thiazole to find out the most effective scaffold. The synthesized thiazolyl-pyrazolines were investigated for their anticancer activity toward MCF-7.…”

Synthesis and Anticancer Activities of Pyrazole–Thiadiazole-Based EGFR Inhibitors

“…In the studies on several compounds containing thiazole, a thiadiazole-like heterocyclic ring, and a pyrazole ring, it has been determined that the compounds are anticancer drug candidates with a very high EGFR inhibition potential. − Lazertinib, a third-generation EGFR inhibitor, has had promising results in patients who have not yet started treatment or in patients with Osimertinib resistance. Lazertinib is unique and different from other third-generation EGFR inhibitors in that it contains a pyrazole ring, heterocyclic rings, hydrophobic phenyl, and hydrophilic amine structures.…”