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New Thiazolyl-Pyrazoline Derivatives as Potential Dual EGFR/HER2 Inhibitors: Design, Synthesis, Anticancer Activity Evaluation and In Silico Study
A new series of thiazolyl-pyrazoline derivatives (4a–d, 5a–d 6a, b, 7a–d, 8a, b, and 10a, b) have been designed and synthesized through the combination of thiazole and pyrazoline moieties, starting from the key building blocks pyrazoline carbothioamides (1a–b). These eighteen derivatives have been d...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10647861/ https://www.ncbi.nlm.nih.gov/pubmed/37959874 http://dx.doi.org/10.3390/molecules28217455 |
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author | Fakhry, Mariam M. Mattar, Amr A. Alsulaimany, Marwa Al-Olayan, Ebtesam M. Al-Rashood, Sara T. Abdel-Aziz, Hatem A. |
author_facet | Fakhry, Mariam M. Mattar, Amr A. Alsulaimany, Marwa Al-Olayan, Ebtesam M. Al-Rashood, Sara T. Abdel-Aziz, Hatem A. |
author_sort | Fakhry, Mariam M. |
collection | PubMed |
description | A new series of thiazolyl-pyrazoline derivatives (4a–d, 5a–d 6a, b, 7a–d, 8a, b, and 10a, b) have been designed and synthesized through the combination of thiazole and pyrazoline moieties, starting from the key building blocks pyrazoline carbothioamides (1a–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 6a, 6b, 10a, and 10b displayed potent anticancer activity toward MCF-7 with IC(50) = 4.08, 5.64, 3.37, and 3.54 µM, respectively, when compared with lapatinib (IC(50) = 5.88 µM). In addition, enzymatic assays were also run for the most cytotoxic compounds (6a and 6b) toward EGFR and HER2 to demonstrate their dual inhibitory activity. They revealed promising inhibition potency against EGFR with IC(50) = 0.024, and 0.005 µM, respectively, whereas their IC(50) = 0.047 and 0.022 µM toward HER2, respectively, compared with lapatinib (IC(50) = 0.007 and 0.018 µM). Both compounds 6a and 10a 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 6a and 10a 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. |
format | Online Article Text |
id | pubmed-10647861 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-106478612023-11-06 New Thiazolyl-Pyrazoline Derivatives as Potential Dual EGFR/HER2 Inhibitors: Design, Synthesis, Anticancer Activity Evaluation and In Silico Study Fakhry, Mariam M. Mattar, Amr A. Alsulaimany, Marwa Al-Olayan, Ebtesam M. Al-Rashood, Sara T. Abdel-Aziz, Hatem A. Molecules Article A new series of thiazolyl-pyrazoline derivatives (4a–d, 5a–d 6a, b, 7a–d, 8a, b, and 10a, b) have been designed and synthesized through the combination of thiazole and pyrazoline moieties, starting from the key building blocks pyrazoline carbothioamides (1a–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 6a, 6b, 10a, and 10b displayed potent anticancer activity toward MCF-7 with IC(50) = 4.08, 5.64, 3.37, and 3.54 µM, respectively, when compared with lapatinib (IC(50) = 5.88 µM). In addition, enzymatic assays were also run for the most cytotoxic compounds (6a and 6b) toward EGFR and HER2 to demonstrate their dual inhibitory activity. They revealed promising inhibition potency against EGFR with IC(50) = 0.024, and 0.005 µM, respectively, whereas their IC(50) = 0.047 and 0.022 µM toward HER2, respectively, compared with lapatinib (IC(50) = 0.007 and 0.018 µM). Both compounds 6a and 10a 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 6a and 10a 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. MDPI 2023-11-06 /pmc/articles/PMC10647861/ /pubmed/37959874 http://dx.doi.org/10.3390/molecules28217455 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Fakhry, Mariam M. Mattar, Amr A. Alsulaimany, Marwa Al-Olayan, Ebtesam M. Al-Rashood, Sara T. Abdel-Aziz, Hatem A. New Thiazolyl-Pyrazoline Derivatives as Potential Dual EGFR/HER2 Inhibitors: Design, Synthesis, Anticancer Activity Evaluation and In Silico Study |
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 | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10647861/ https://www.ncbi.nlm.nih.gov/pubmed/37959874 http://dx.doi.org/10.3390/molecules28217455 |
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