Quinazolin-4(3H)-one based potential multiple tyrosine kinase inhibitors with excellent cytotoxicity
A series of quinazolin-4(3H)-one derivatives were synthesised and evaluated for their cytotoxicity against human Caucasian breast adenocarcinoma (MCF-7) and human ovarian carcinoma (A2780) cell lines. Cytotoxicity of the most tested compounds was 2- to 30-fold more than the positive control lapatini...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2021-01-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
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| Online Access: | http://dx.doi.org/10.1080/14756366.2021.1972992 |
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| author | Tebyan O. Mirgany Ashraf N. Abdalla Md Arifuzzaman A. F. M. Motiur Rahman Huda S. Al-Salem |
| author_facet | Tebyan O. Mirgany Ashraf N. Abdalla Md Arifuzzaman A. F. M. Motiur Rahman Huda S. Al-Salem |
| author_sort | Tebyan O. Mirgany |
| collection | DOAJ |
| description | A series of quinazolin-4(3H)-one derivatives were synthesised and evaluated for their cytotoxicity against human Caucasian breast adenocarcinoma (MCF-7) and human ovarian carcinoma (A2780) cell lines. Cytotoxicity of the most tested compounds was 2- to 30-fold more than the positive control lapatinib (IC50 of 2j = 3.79 ± 0.96; 3j = 0.20 ± 0.02; and lapatinib = 5.9 ± 0.74) against MCF7 cell lines except two compounds (IC50 of 2 b = 15.72 ± 0.07 and 2e = 14.88 ± 0.99). On the other hand, cytotoxicity was 4 − 87 folds (IC50 of 3a = 3.00 ± 1.20; 3 g = 0.14 ± 0.03) more the positive control lapatinib (IC50 = 12.11 ± 1.03) against A2780 cell lines except compound 2e (IC50 = 16.43 ± 1.80). Among the synthesised quinazolin-4(3H)-one derivatives, potent cytotoxic 2f-j and 3f-j were investigated for molecular mechanism of action. Inhibitory activities of the compounds were tested against multiple tyrosine protein kinases (CDK2, HER2, EGFR and VEGFR2) enzymes. As expected, all the quinazolin-4(3H)-one derivatives were showed comparable inhibitory activity against those kinases tested, especially, compound 2i and 3i showed potent inhibitory activity against CDK2, HER2, EGFR tyrosine kinases. Therefore, molecular docking analysis for quinazolin-4(3H)-one derivatives 2i and 3i were performed, and it was revealed that compounds 2i and 3i act as ATP non-competitive type-II inhibitor against CDK2 kinase enzymes and ATP competitive type-I inhibitor against EGFR kinase enzymes. However, in case of HER2, compounds 2i act as ATP non-competitive type-II inhibitor and 3i act as ATP competitive type-I inhibitor. Docking results of known inhibitors were compared with synthesised compounds and found synthesised 2i and 3i are superior than the known inhibitors in case of interactions. In addition, in silico drug likeness properties of quinazolin-4(3H)-one derivatives showed better predicted ADME values than lapatinib. |
| first_indexed | 2024-12-20T10:20:32Z |
| format | Article |
| id | doaj.art-ebf132d88b4243ae891de6fb4714c690 |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2024-12-20T10:20:32Z |
| publishDate | 2021-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-ebf132d88b4243ae891de6fb4714c6902022-12-21T19:43:56ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742021-01-013612055206710.1080/14756366.2021.19729921972992Quinazolin-4(3H)-one based potential multiple tyrosine kinase inhibitors with excellent cytotoxicityTebyan O. Mirgany0Ashraf N. Abdalla1Md Arifuzzaman2A. F. M. Motiur Rahman3Huda S. Al-Salem4Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud UniversityDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Umm Al-Qura UniversityCollege of Pharmacy, Yeungnam UniversityDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud UniversityDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud UniversityA series of quinazolin-4(3H)-one derivatives were synthesised and evaluated for their cytotoxicity against human Caucasian breast adenocarcinoma (MCF-7) and human ovarian carcinoma (A2780) cell lines. Cytotoxicity of the most tested compounds was 2- to 30-fold more than the positive control lapatinib (IC50 of 2j = 3.79 ± 0.96; 3j = 0.20 ± 0.02; and lapatinib = 5.9 ± 0.74) against MCF7 cell lines except two compounds (IC50 of 2 b = 15.72 ± 0.07 and 2e = 14.88 ± 0.99). On the other hand, cytotoxicity was 4 − 87 folds (IC50 of 3a = 3.00 ± 1.20; 3 g = 0.14 ± 0.03) more the positive control lapatinib (IC50 = 12.11 ± 1.03) against A2780 cell lines except compound 2e (IC50 = 16.43 ± 1.80). Among the synthesised quinazolin-4(3H)-one derivatives, potent cytotoxic 2f-j and 3f-j were investigated for molecular mechanism of action. Inhibitory activities of the compounds were tested against multiple tyrosine protein kinases (CDK2, HER2, EGFR and VEGFR2) enzymes. As expected, all the quinazolin-4(3H)-one derivatives were showed comparable inhibitory activity against those kinases tested, especially, compound 2i and 3i showed potent inhibitory activity against CDK2, HER2, EGFR tyrosine kinases. Therefore, molecular docking analysis for quinazolin-4(3H)-one derivatives 2i and 3i were performed, and it was revealed that compounds 2i and 3i act as ATP non-competitive type-II inhibitor against CDK2 kinase enzymes and ATP competitive type-I inhibitor against EGFR kinase enzymes. However, in case of HER2, compounds 2i act as ATP non-competitive type-II inhibitor and 3i act as ATP competitive type-I inhibitor. Docking results of known inhibitors were compared with synthesised compounds and found synthesised 2i and 3i are superior than the known inhibitors in case of interactions. In addition, in silico drug likeness properties of quinazolin-4(3H)-one derivatives showed better predicted ADME values than lapatinib.http://dx.doi.org/10.1080/14756366.2021.1972992quinazolin-4(3h)-onecdk2her2egfrdrug likeness properties |
| spellingShingle | Tebyan O. Mirgany Ashraf N. Abdalla Md Arifuzzaman A. F. M. Motiur Rahman Huda S. Al-Salem Quinazolin-4(3H)-one based potential multiple tyrosine kinase inhibitors with excellent cytotoxicity Journal of Enzyme Inhibition and Medicinal Chemistry quinazolin-4(3h)-one cdk2 her2 egfr drug likeness properties |
| title | Quinazolin-4(3H)-one based potential multiple tyrosine kinase inhibitors with excellent cytotoxicity |
| title_full | Quinazolin-4(3H)-one based potential multiple tyrosine kinase inhibitors with excellent cytotoxicity |
| title_fullStr | Quinazolin-4(3H)-one based potential multiple tyrosine kinase inhibitors with excellent cytotoxicity |
| title_full_unstemmed | Quinazolin-4(3H)-one based potential multiple tyrosine kinase inhibitors with excellent cytotoxicity |
| title_short | Quinazolin-4(3H)-one based potential multiple tyrosine kinase inhibitors with excellent cytotoxicity |
| title_sort | quinazolin 4 3h one based potential multiple tyrosine kinase inhibitors with excellent cytotoxicity |
| topic | quinazolin-4(3h)-one cdk2 her2 egfr drug likeness properties |
| url | http://dx.doi.org/10.1080/14756366.2021.1972992 |
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