Related Experiment Video
Updated: Oct 23, 2025
Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
Design, synthesis of pyridine coupled pyrimidinone/pyrimidinthione as anti-MRSA agent: Validation by molecular
S Nanjundaswamy1, S Bindhu1, R R Arun Renganathan2
1Department of Chemistry, SJCE, JSS Science and Technology University, Mysuru, Karnataka, India.
Abstract:
Methicillin Resistant Staphylococcus aureus (MRSA) is a major cause of severe hospital and infections acquired by the population and related morbidity and mortality. In this unique situation, there is a need of dynamic strong drug candidates to control MRSA diseases. Thus, the present work focuses on the synthesis and characterization of pyrimidinones and pyrimidinthiones coupled pyridine derivatives as anti-MRSA agent. The synthesized compounds were characterized by different spectroscopic techniques and evaluated against MRSA strain. Among them, 4e and 4 g possessed better antibacterial activity with MIC values of 10 μg and 8 μg respectively. The key determinant of the wide range beta-lactam resistance in MRSA strains is the Penicillin-Binding Protein 2a (PBP2a) but the gene encodes PBP2a which has a low affinity towards β-lactam antibiotics. Because of this, the present investigation focused on the mechanism of PBP2a protein binding studies by in-silico studies. The synthesized compounds showed very good interactions with PBP2A compared with standard drug Vancomycin, among them compound 4 g showed better interaction with the binding score of -9.8 kcal/mol. Antibacterial activity was validated with molecular docking and molecular dynamic simulation. Simulation results revealed that protein-ligand interactions of 4 g compound stably sustained up to 20,000ps.Communicated by Ramaswamy H. Sarma.
Insights
New pyrimidinone and pyrimidinthione pyridine derivatives show potent activity against Methicillin-Resistant Staphylococcus aureus (MRSA). Compound 4g demonstrates strong antibacterial effects and stable binding to the PBP2a protein, offering a promising anti-MRSA therapeutic candidate.
Area of Science:
- Medicinal Chemistry
- Microbiology
- Computational Chemistry
Background:
- Methicillin-Resistant Staphylococcus aureus (MRSA) presents a significant global health threat due to its resistance to antibiotics.
- There is an urgent need for novel therapeutic agents to combat MRSA infections and associated mortality.
Purpose of the Study:
- To synthesize and characterize novel pyrimidinone and pyrimidinthione pyridine derivatives as potential anti-MRSA agents.
- To investigate the mechanism of action, focusing on interactions with Penicillin-Binding Protein 2a (PBP2a).
Main Methods:
- Chemical synthesis and spectroscopic characterization of novel compounds.
- In vitro antibacterial activity testing against MRSA strains.
- In silico molecular docking and molecular dynamic simulations to assess PBP2a binding affinity and stability.
Main Results:
- Compounds 4e and 4g exhibited significant antibacterial activity, with minimum inhibitory concentrations (MIC) of 10 μg/mL and 8 μg/mL, respectively.
- Compound 4g displayed excellent binding affinity to PBP2a (-9.8 kcal/mol) and stable interactions over 20,000 ps in molecular dynamics simulations.
- The synthesized compounds showed promising interactions with PBP2a compared to Vancomycin.
Conclusions:
- Pyrimidinone and pyrimidinthione pyridine derivatives are effective against MRSA.
- Compound 4g is a highly promising candidate for further development as an anti-MRSA drug, supported by strong in vitro and in silico evidence.
- The study validates the potential of targeting PBP2a for MRSA treatment.
