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.…”

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.…”

New pyrazolyl-thiazolidinone/thiazole derivatives as celecoxib/dasatinib analogues with selective COX-2, HER-2 and EGFR inhibitory effects: design, synthesis, anti-inflammatory/anti-proliferative activities, apoptosis, molecular modelling and ADME studies

“…Furthermore, thiazole and thiazolidine pharmacophores occupy an important place in the field of anticancer chemotherapy targeting different proteins 40–42 . Pyrazolyl-thiazole derivative (8) demonstrated promising cytotoxicity through its potent dual inhibitory activity against HER-2 and EGFR with IC 50 of 0.013 μM and 0.009 μM against HER-2 and EGFR respectively, in a comparable way to lapatinib 43 .…”