Pharmacophore-based virtual screening, synthesis, biological evaluation, and molecular docking study of novel pyrrolizines bearing urea/thiourea moieties with potential cytotoxicity and CDK inhibitory activities
In the current study, virtual screening of a small library of 1302 pyrrolizines bearing urea/thiourea moieties was performed. The top-scoring hits were synthesised and evaluated for their cytotoxicity against three cancer (MCF-7, A2780, and HT29) and one normal (MRC-5) cell lines. The results of the...
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doaj-ff66a1b269f8469b88f7fd2224510c232020-11-25T04:02:14ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742021-01-01361153310.1080/14756366.2020.18371241837124Pharmacophore-based virtual screening, synthesis, biological evaluation, and molecular docking study of novel pyrrolizines bearing urea/thiourea moieties with potential cytotoxicity and CDK inhibitory activitiesAhmed M. Shawky0Nashwa A. Ibrahim1Mohammed A. S. Abourehab2Ashraf N. Abdalla3Ahmed M. Gouda4Science and Technology Unit (STU), Umm Al-Qura UniversityDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Umm Al-Qura UniversityDepartment of Pharmaceutics, Faculty of Pharmacy, Umm Al-Qura UniversityDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Umm Al-Qura UniversityDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Umm Al-Qura UniversityIn the current study, virtual screening of a small library of 1302 pyrrolizines bearing urea/thiourea moieties was performed. The top-scoring hits were synthesised and evaluated for their cytotoxicity against three cancer (MCF-7, A2780, and HT29) and one normal (MRC-5) cell lines. The results of the MTT assay revealed potent cytotoxic activities for most of the new compounds (IC50 = 0.16–34.13 μM). The drug-likeness study revealed that all the new compounds conform to Lipinski’s rule. Mechanistic studies of compounds 18 b, 19a, and 20a revealed the induction of apoptosis and cell cycle arrest at the G1 phase in MCF-7 cells. The three compounds also displayed potent inhibitory activity against CDK-2 (IC50 = 25.53–115.30 nM). Moreover, the docking study revealed a nice fitting of compound 19a into the active sites of CDK-2/6/9. These preliminary results suggested that compound 19a could serve as a promising scaffold in the discovery of new potent anticancer agents.http://dx.doi.org/10.1080/14756366.2020.1837124pyrrolizineurea derivativescytotoxicityapoptosiscell cyclecdk-2 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ahmed M. Shawky Nashwa A. Ibrahim Mohammed A. S. Abourehab Ashraf N. Abdalla Ahmed M. Gouda |
spellingShingle |
Ahmed M. Shawky Nashwa A. Ibrahim Mohammed A. S. Abourehab Ashraf N. Abdalla Ahmed M. Gouda Pharmacophore-based virtual screening, synthesis, biological evaluation, and molecular docking study of novel pyrrolizines bearing urea/thiourea moieties with potential cytotoxicity and CDK inhibitory activities Journal of Enzyme Inhibition and Medicinal Chemistry pyrrolizine urea derivatives cytotoxicity apoptosis cell cycle cdk-2 |
author_facet |
Ahmed M. Shawky Nashwa A. Ibrahim Mohammed A. S. Abourehab Ashraf N. Abdalla Ahmed M. Gouda |
author_sort |
Ahmed M. Shawky |
title |
Pharmacophore-based virtual screening, synthesis, biological evaluation, and molecular docking study of novel pyrrolizines bearing urea/thiourea moieties with potential cytotoxicity and CDK inhibitory activities |
title_short |
Pharmacophore-based virtual screening, synthesis, biological evaluation, and molecular docking study of novel pyrrolizines bearing urea/thiourea moieties with potential cytotoxicity and CDK inhibitory activities |
title_full |
Pharmacophore-based virtual screening, synthesis, biological evaluation, and molecular docking study of novel pyrrolizines bearing urea/thiourea moieties with potential cytotoxicity and CDK inhibitory activities |
title_fullStr |
Pharmacophore-based virtual screening, synthesis, biological evaluation, and molecular docking study of novel pyrrolizines bearing urea/thiourea moieties with potential cytotoxicity and CDK inhibitory activities |
title_full_unstemmed |
Pharmacophore-based virtual screening, synthesis, biological evaluation, and molecular docking study of novel pyrrolizines bearing urea/thiourea moieties with potential cytotoxicity and CDK inhibitory activities |
title_sort |
pharmacophore-based virtual screening, synthesis, biological evaluation, and molecular docking study of novel pyrrolizines bearing urea/thiourea moieties with potential cytotoxicity and cdk inhibitory activities |
publisher |
Taylor & Francis Group |
series |
Journal of Enzyme Inhibition and Medicinal Chemistry |
issn |
1475-6366 1475-6374 |
publishDate |
2021-01-01 |
description |
In the current study, virtual screening of a small library of 1302 pyrrolizines bearing urea/thiourea moieties was performed. The top-scoring hits were synthesised and evaluated for their cytotoxicity against three cancer (MCF-7, A2780, and HT29) and one normal (MRC-5) cell lines. The results of the MTT assay revealed potent cytotoxic activities for most of the new compounds (IC50 = 0.16–34.13 μM). The drug-likeness study revealed that all the new compounds conform to Lipinski’s rule. Mechanistic studies of compounds 18 b, 19a, and 20a revealed the induction of apoptosis and cell cycle arrest at the G1 phase in MCF-7 cells. The three compounds also displayed potent inhibitory activity against CDK-2 (IC50 = 25.53–115.30 nM). Moreover, the docking study revealed a nice fitting of compound 19a into the active sites of CDK-2/6/9. These preliminary results suggested that compound 19a could serve as a promising scaffold in the discovery of new potent anticancer agents. |
topic |
pyrrolizine urea derivatives cytotoxicity apoptosis cell cycle cdk-2 |
url |
http://dx.doi.org/10.1080/14756366.2020.1837124 |
work_keys_str_mv |
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