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

Ahmed M Shawky; Nashwa A Ibrahim; Mohammed A S Abourehab; Ashraf N Abdalla; Ahmed M Gouda

doi:10.1080/14756366.2020.1837124

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

J Enzyme Inhib Med Chem. 2021 Dec;36(1):15-33. doi: 10.1080/14756366.2020.1837124.

Authors

Ahmed M Shawky¹, Nashwa A Ibrahim², Mohammed A S Abourehab³, Ashraf N Abdalla⁴, Ahmed M Gouda^{2

5}

Affiliations

¹ Science and Technology Unit (STU), Umm Al-Qura University, Makkah, Saudi Arabia.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia.
³ Department of Pharmaceutics, Faculty of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia.
⁴ Department of Pharmacology and Toxicology, Faculty of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia.
⁵ Department of Medicinal Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt.

Abstract

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.

Keywords: CDK-2; Pyrrolizine; apoptosis; cell cycle; cytotoxicity; urea derivatives.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cyclin-Dependent Kinase 2 / antagonists & inhibitors*
Cyclin-Dependent Kinase 2 / metabolism
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Drug Screening Assays, Antitumor
Humans
Molecular Docking Simulation*
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrroles / chemical synthesis
Pyrroles / chemistry
Pyrroles / pharmacology*
Structure-Activity Relationship
Urea / analogs & derivatives
Urea / chemistry
Urea / pharmacology*

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyrroles
Urea
CDK2 protein, human
Cyclin-Dependent Kinase 2

Grants and funding

This work was funded by National Science, Technology and Innovation Plan (MAARIFAH), King Abdulaziz City for Science and Technology (KACST), Kingdom of Saudi Arabia, Grant no. 12-MED2304-10-R.