Novel pyrimidines as COX-2 selective inhibitors: synthesis, DFT analysis, molecular docking and dynamic simulation studies

Abstract

Pyrimidine and its derivatives are associated with varieties of biological properties. Therefore, we herein reported the synthesis of four novel pyrimidines (2, 3, and 4a, b) derivatives. The structure of these molecules is confirmed by spectroscopic methods such as IR, NMR, and Mass analysis. The electronic behavior of synthesized compounds 4a, b and in silico drug design 4 c, d was explained by Density Functional Theory estimations at the DFT/B3LYP level via 6-31 G++ (d, p) replicates the structure and geometry. All the synthesized compounds were screened for their in vitro COX-1 and COX-2 inhibitory activity compared to standards Celecoxib and Ibuprofen. Compounds 3 and 4a afforded excellent COX-1 and COX-2 inhibitory activities at IC₅₀ = 5.50 and 5.05 μM against COX-1, 0.85 and 0.65 μM against COX-2, respectively. The standard drugs Celecoxib and Ibuprofen showed inhibitory activity at IC₅₀ = 6.34 and 3.1 μM against COX-1, 0.56 and 1.2 μM against COX-2, respectively. Further, these compounds showed high potential docking with SARS-CoV-2 Omicron protease & COX-2 and predicted drug-likeness for the pyrimidine analogs by using Molinspiration. The protein stability, fluctuations of APO–protein, protein–ligand complexes were investigated through Molecular Dynamics simulations studies using Desmond Maestro 11.3 and potential lead molecules were identified.

Communicated by Ramaswamy H. Sarma

Keywords:

• ADME
• COX-1
• COX-2 activity
• DFT calculations
• molecular docking
• pyrimidine and SARS-CoV-2

Acknowledgment

The authors are grateful to The Directors of IISc, Bengaluru, SAIF Punjab University, and CDRI, Lucknow for spectral data. For biological activities, the authors are grateful to The Director, Skanda Life Sciences Pvt. Ltd., Bengaluru. The thanks are due to Indian Academy Degree College, Bengaluru-560043 for providing necessary facilities to perform research work.

Authors’ contributions

Basavarajaiah: Conceptualization, Methodology, Software, Data curation, Writing—original draft, Visualization, Investigation, Validation, Writing—review & editing. Jeelan Basha: Conceptualization, Methodology, Software, Data curation, Writing—original draft, Visualization, Investigation, Validation, Writing—review & editing. Javeed: Methodology, Software, Data curation, Visualization, Investigation, Validation, Writing—review & editing. Prashantha: Visualization, Investigation, Validation, Writing—review & editing. Venkatesulu: Investigation, Validation, Writing—review & editing. Krishnakanth: Investigation, Validation, Writing—review & editing. Varsha: Writing—review & editing

Date Availability statement

Data will be provided on requests.

Disclosure statement

No potential conflict of interest was reported by the authors.

Ethical approval

Not applicable.

Funding

No funding for this research work.