A Comprehensive Overview of Pyridine and Pyrimidine Derivatives for Anticancer Drug Development
Aakash Sharma, Jagdish Kumar Sahu, Kamal Shah, Shikha SharmaIntroduction:
Pyridine and pyrimidine-based compounds are known to be a part of the structure of DNA and RNA; however, it has been found that these compounds have been incredibly useful in the development of anticancer drugs. The pharmacokinetics of the compounds, along with their potential to target key oncoproteins such as EGFR and VEGFR-2, have made them a subject of research for therapeutic use.
materials and methods:
A systematic search was performed using scientific databases including PubMed, Scopus, Web of Science, and SpringerLink from 2010–2025. Keywords included anticancer agents, kinase inhibitors, pyrimidine derivatives, pyridine scaffolds, SAR analysis, drug resistance, and pharmacokinetics.
Methods:
An extensive literature search (2009-2025) has been conducted to obtain information about anticancer compounds based on the pyridine and pyrimidine ring systems. The authors assessed structure-activity relationships, IC50 values, molecular targets, pharmacokinetics, and resistance of the compounds.
results:
Pyrimidines frequently serve as core scaffolds in ATP-competitive inhibitors (e.g., erlotinib, gefitinib, imatinib analogues). SAR analysis reveals: N1 and N3 positions allow H-bonding critical for anchoring within the hinge region. Electron-donating groups (EDGs) on the aryl substituents improve kinase affinity. Halogen substitutions (Cl, F) enhance lipophilicity and improve membrane permeability. C4/C6 substitutions modulate selectivity for EGFR, VEGFR, and CDKs.
Results:
Pyridine derivatives showed potent inhibitory activity against EGFR, VEGFR-2, and other kinases, with good solubility and metabolic stability, and exhibited secondary pharmacological effects, such as vasodilation. Pyrimidine derivatives, including hetero-fused compounds, showed potent cytotoxic and kinase-inhibitory activity, including against resistant mutants, as well as dual inhibition and scaffold-related benefits.
Discussion:
The results indicate that pyridine and pyrimidine rings are versatile and useful scaffolds for the development of anticancer agents. Their effectiveness in interacting with major molecular targets, overcoming resistance, and having advantageous pharmacokinetic properties makes them promising candidates for addressing unmet medical needs in cancer therapy.
Conclusion:
Pyridines and pyrimidines are privileged structures in anticancer drug discovery because of their high affinity for targets, pharmacokinetic properties, and versatility. SAR and biological information from scientific literature published from 2009 to 2025 have demonstrated potent inhibitory activity against key kinases, including EGFR and VEGFR-2, as well as drug-resistant mutants. Based on this information, both structures are potential candidates for the design of nextgeneration anticancer agents that can overcome drug resistance.