Rational Design, Synthesis and Biological Evaluation of Novel Pyrazoline-Based Antiproliferative Agents in MCF-7 Cancer Cells
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 hybridizat...
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MDPI AG
2022-10-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/15/10/1245 |
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| author | Mariam M. Fakhry Kazem Mahmoud Mohamed S. Nafie Ahmad O. Noor Rawan H. Hareeri Ismail Salama Safaa M. Kishk |
| author_facet | Mariam M. Fakhry Kazem Mahmoud Mohamed S. Nafie Ahmad O. Noor Rawan H. Hareeri Ismail Salama Safaa M. Kishk |
| author_sort | Mariam M. Fakhry |
| collection | DOAJ |
| description | 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 IC<sub>50</sub> 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 IC<sub>50</sub> of 0.009 and 0.051 µM, respectively, and for HER2 with IC<sub>50</sub> 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. |
| first_indexed | 2024-03-09T19:36:38Z |
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| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T19:36:38Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-7dabf675638b45bb9c6dea7bf9a44e152023-11-24T01:51:48ZengMDPI AGPharmaceuticals1424-82472022-10-011510124510.3390/ph15101245Rational Design, Synthesis and Biological Evaluation of Novel Pyrazoline-Based Antiproliferative Agents in MCF-7 Cancer CellsMariam M. Fakhry0Kazem Mahmoud1Mohamed S. Nafie2Ahmad O. Noor3Rawan H. Hareeri4Ismail Salama5Safaa M. Kishk6Department of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, EgyptDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr 11829, EgyptDepartment of Chemistry, Faculty of Science, Suez Canal University, Ismailia 41522, EgyptDepartment of Pharmacy Practice, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi ArabiaDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi ArabiaDepartment of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, EgyptDepartment of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, EgyptBreast 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 IC<sub>50</sub> 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 IC<sub>50</sub> of 0.009 and 0.051 µM, respectively, and for HER2 with IC<sub>50</sub> 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.https://www.mdpi.com/1424-8247/15/10/1245breast cancerHER2EGFRthiazolyl–pyrazolineADMETdocking |
| spellingShingle | Mariam M. Fakhry Kazem Mahmoud Mohamed S. Nafie Ahmad O. Noor Rawan H. Hareeri Ismail Salama Safaa M. Kishk Rational Design, Synthesis and Biological Evaluation of Novel Pyrazoline-Based Antiproliferative Agents in MCF-7 Cancer Cells Pharmaceuticals breast cancer HER2 EGFR thiazolyl–pyrazoline ADMET docking |
| title | Rational Design, Synthesis and Biological Evaluation of Novel Pyrazoline-Based Antiproliferative Agents in MCF-7 Cancer Cells |
| title_full | Rational Design, Synthesis and Biological Evaluation of Novel Pyrazoline-Based Antiproliferative Agents in MCF-7 Cancer Cells |
| title_fullStr | Rational Design, Synthesis and Biological Evaluation of Novel Pyrazoline-Based Antiproliferative Agents in MCF-7 Cancer Cells |
| title_full_unstemmed | Rational Design, Synthesis and Biological Evaluation of Novel Pyrazoline-Based Antiproliferative Agents in MCF-7 Cancer Cells |
| title_short | Rational Design, Synthesis and Biological Evaluation of Novel Pyrazoline-Based Antiproliferative Agents in MCF-7 Cancer Cells |
| title_sort | rational design synthesis and biological evaluation of novel pyrazoline based antiproliferative agents in mcf 7 cancer cells |
| topic | breast cancer HER2 EGFR thiazolyl–pyrazoline ADMET docking |
| url | https://www.mdpi.com/1424-8247/15/10/1245 |
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