New Thiazolyl-Pyrazoline Derivatives as Potential Dual EGFR/HER2 Inhibitors: Design, Synthesis, Anticancer Activity Evaluation and In Silico Study
<b>A</b> new series of thiazolyl-pyrazoline derivatives (<b>4a</b>–<b>d</b>, <b>5a</b>–<b>d 6a</b>, <b>b</b>, <b>7a</b>–<b>d</b>, <b>8a</b>, <b>b</b>, and <b>10a</b>, &...
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MDPI AG
2023-11-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/21/7455 |
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| author | Mariam M. Fakhry Amr A. Mattar Marwa Alsulaimany Ebtesam M. Al-Olayan Sara T. Al-Rashood Hatem A. Abdel-Aziz |
| author_facet | Mariam M. Fakhry Amr A. Mattar Marwa Alsulaimany Ebtesam M. Al-Olayan Sara T. Al-Rashood Hatem A. Abdel-Aziz |
| author_sort | Mariam M. Fakhry |
| collection | DOAJ |
| description | <b>A</b> new series of thiazolyl-pyrazoline derivatives (<b>4a</b>–<b>d</b>, <b>5a</b>–<b>d 6a</b>, <b>b</b>, <b>7a</b>–<b>d</b>, <b>8a</b>, <b>b</b>, and <b>10a</b>, <b>b</b>) have been designed and synthesized through the combination of thiazole and pyrazoline moieties, starting from the key building blocks pyrazoline carbothioamides (<b>1a</b>–<b>b</b>). These eighteen derivatives have been designed as anticipated EGFR/HER2 dual inhibitors. The efficacy of the developed compounds in inhibiting cell proliferation was assessed using the breast cancer MCF-7 cell line. Among the new synthesized thiazolyl-pyrazolines, compounds <b>6a</b>, <b>6b</b>, <b>10a</b>, and <b>10b</b> displayed potent anticancer activity toward MCF-7 with IC<sub>50</sub> = 4.08, 5.64, 3.37, and 3.54 µM, respectively, when compared with lapatinib (IC<sub>50</sub> = 5.88 µM). In addition, enzymatic assays were also run for the most cytotoxic compounds (<b>6a</b> and <b>6b</b>) toward EGFR and HER2 to demonstrate their dual inhibitory activity. They revealed promising inhibition potency against EGFR with IC<sub>50</sub> = 0.024, and 0.005 µM, respectively, whereas their IC<sub>50</sub> = 0.047 and 0.022 µM toward HER2, respectively, compared with lapatinib (IC<sub>50</sub> = 0.007 and 0.018 µM). Both compounds <b>6a</b> and <b>10a</b> induced apoptosis by arresting the cell cycle of the MCF-7 cell line at the G1 and G1/S phases, respectively. Molecular modeling studies for the promising candidates <b>6a</b> and <b>10a</b> showed that they formed the essential binding with the crucial amino acids for EGFR and HER2 inhibition, supporting the in vitro assay results. Furthermore, ADMET study predictions were carried out for the compounds in the study. |
| first_indexed | 2024-03-11T11:24:13Z |
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| last_indexed | 2024-03-11T11:24:13Z |
| publishDate | 2023-11-01 |
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| spelling | doaj.art-4fd4316e2b5f4a9398759af2fe2634aa2023-11-10T15:09:03ZengMDPI AGMolecules1420-30492023-11-012821745510.3390/molecules28217455New Thiazolyl-Pyrazoline Derivatives as Potential Dual EGFR/HER2 Inhibitors: Design, Synthesis, Anticancer Activity Evaluation and In Silico StudyMariam M. Fakhry0Amr A. Mattar1Marwa Alsulaimany2Ebtesam M. Al-Olayan3Sara T. Al-Rashood4Hatem A. Abdel-Aziz5Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr 11829, EgyptDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr 11829, EgyptDepartment of Pharmacognosy & Pharmaceutical Chemistry, College of Pharmacy, Taibah University, Medina 42353, Saudi ArabiaDepartment of Zoology, College of Science, King Saud University, Riyadh 11495, Saudi ArabiaDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaApplied Organic Chemistry Department, National Research Center, Cairo 12622, Egypt<b>A</b> new series of thiazolyl-pyrazoline derivatives (<b>4a</b>–<b>d</b>, <b>5a</b>–<b>d 6a</b>, <b>b</b>, <b>7a</b>–<b>d</b>, <b>8a</b>, <b>b</b>, and <b>10a</b>, <b>b</b>) have been designed and synthesized through the combination of thiazole and pyrazoline moieties, starting from the key building blocks pyrazoline carbothioamides (<b>1a</b>–<b>b</b>). These eighteen derivatives have been designed as anticipated EGFR/HER2 dual inhibitors. The efficacy of the developed compounds in inhibiting cell proliferation was assessed using the breast cancer MCF-7 cell line. Among the new synthesized thiazolyl-pyrazolines, compounds <b>6a</b>, <b>6b</b>, <b>10a</b>, and <b>10b</b> displayed potent anticancer activity toward MCF-7 with IC<sub>50</sub> = 4.08, 5.64, 3.37, and 3.54 µM, respectively, when compared with lapatinib (IC<sub>50</sub> = 5.88 µM). In addition, enzymatic assays were also run for the most cytotoxic compounds (<b>6a</b> and <b>6b</b>) toward EGFR and HER2 to demonstrate their dual inhibitory activity. They revealed promising inhibition potency against EGFR with IC<sub>50</sub> = 0.024, and 0.005 µM, respectively, whereas their IC<sub>50</sub> = 0.047 and 0.022 µM toward HER2, respectively, compared with lapatinib (IC<sub>50</sub> = 0.007 and 0.018 µM). Both compounds <b>6a</b> and <b>10a</b> induced apoptosis by arresting the cell cycle of the MCF-7 cell line at the G1 and G1/S phases, respectively. Molecular modeling studies for the promising candidates <b>6a</b> and <b>10a</b> showed that they formed the essential binding with the crucial amino acids for EGFR and HER2 inhibition, supporting the in vitro assay results. Furthermore, ADMET study predictions were carried out for the compounds in the study.https://www.mdpi.com/1420-3049/28/21/7455thiazolyl-pyrazolineanti-cancercell cycleapoptosisEGFRHER2 |
| spellingShingle | Mariam M. Fakhry Amr A. Mattar Marwa Alsulaimany Ebtesam M. Al-Olayan Sara T. Al-Rashood Hatem A. Abdel-Aziz New Thiazolyl-Pyrazoline Derivatives as Potential Dual EGFR/HER2 Inhibitors: Design, Synthesis, Anticancer Activity Evaluation and In Silico Study Molecules thiazolyl-pyrazoline anti-cancer cell cycle apoptosis EGFR HER2 |
| title | New Thiazolyl-Pyrazoline Derivatives as Potential Dual EGFR/HER2 Inhibitors: Design, Synthesis, Anticancer Activity Evaluation and In Silico Study |
| title_full | New Thiazolyl-Pyrazoline Derivatives as Potential Dual EGFR/HER2 Inhibitors: Design, Synthesis, Anticancer Activity Evaluation and In Silico Study |
| title_fullStr | New Thiazolyl-Pyrazoline Derivatives as Potential Dual EGFR/HER2 Inhibitors: Design, Synthesis, Anticancer Activity Evaluation and In Silico Study |
| title_full_unstemmed | New Thiazolyl-Pyrazoline Derivatives as Potential Dual EGFR/HER2 Inhibitors: Design, Synthesis, Anticancer Activity Evaluation and In Silico Study |
| title_short | New Thiazolyl-Pyrazoline Derivatives as Potential Dual EGFR/HER2 Inhibitors: Design, Synthesis, Anticancer Activity Evaluation and In Silico Study |
| title_sort | new thiazolyl pyrazoline derivatives as potential dual egfr her2 inhibitors design synthesis anticancer activity evaluation and in silico study |
| topic | thiazolyl-pyrazoline anti-cancer cell cycle apoptosis EGFR HER2 |
| url | https://www.mdpi.com/1420-3049/28/21/7455 |
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