Pyrimidines-Based Heterocyclic Compounds: Synthesis, Cytoxicity Evaluation and Molecular Docking

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Cancer Biology

Background:

• Pyrimidine derivatives are a crucial class of heterocyclic compounds with diverse biological activities.
• Developing novel anti-cancer agents with improved efficacy and safety profiles remains a significant challenge in oncology.

Purpose of the Study:

• To synthesize and characterize novel pyrimidine compounds.
• To evaluate the anti-proliferative activity of these compounds against various human cancer cell lines.
• To identify potential lead compounds for prostate cancer therapy.

Main Methods:

• Synthesis of structurally diverse pyrimidines.
• Structural confirmation using elemental analysis and spectroscopic techniques (FT-IR, 1H NMR, 13C NMR).
• In vitro anti-cancer screening using MTT assay against five human cancer cell lines and one normal cell line.
• In silico assessment of physicochemical properties and drug-likeness (RO5 criteria).

Main Results:

• All synthesized pyrimidines were structurally confirmed.
• Most compounds exhibited anti-proliferative activity against the PC3 prostate cancer cell line.
• Compounds 3b and 3d showed 2-3 fold higher potency than vinblastine sulfate.
• Compounds 3b, 3f, 3g, 3h, and 5 demonstrated superior selectivity index (SI) and safety compared to vinblastine sulfate.
• In silico analysis indicated that the synthesized compounds possess drug-like properties and potential for oral bioavailability.

Conclusions:

• Novel pyrimidine derivatives were successfully synthesized and characterized.
• Compounds 3b and 3d are identified as potent anti-prostate cancer agents, outperforming vinblastine sulfate.
• Several synthesized pyrimidines exhibit enhanced selectivity and safety, suggesting their potential as orally bioavailable anti-cancer drugs.