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

• Main Authors: Mariam M. Fakhry (Author), Kazem Mahmoud (Author), Mohamed S. Nafie (Author), Ahmad O. Noor (Author), Rawan H. Hareeri (Author), Ismail Salama (Author), Safaa M. Kishk (Author)
• Format: Book
• Published: MDPI AG, 2022-10-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/ph15101245; 1424-8247
• Keywords: breast cancer; HER2; EGFR; thiazolyl-pyrazoline; ADMET; docking; Medicine; R; Pharmacy and materia medica; RS1-441
• Source: Pharmaceuticals, Vol 15, Iss 10, p 1245 (2022)

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 <b>6e</b> and <b>6k</b> 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 <b>6e</b> and <b>6k</b> 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 <b>6e</b> and <b>6k</b> significantly stimulated apoptotic breast cancer cell death. Compound <b>6e</b> 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.