Novel Amide Functionalized Pyrimidine Derivative as Potential Anticancer Agents: Synthesis, Characterization, Molecular Docking and Invitro Cytotoxicity Evaluation (Research Article)

Author(s): K. Jyothi* and M. Kannadasan

Abstract: A series of amide-functionalized pyrimidine derivatives (6a–6r) were synthesized via a three-step route involving (1) multicomponent assembly of 2-(4-methylpyrimidin-5-yl) acetonitrile (4), (2) LiAlH₄ reduction to the primary amine (5), and (3) DCC/DMAP-mediated coupling with diverse carboxylic acids. The compounds were obtained in good yields (65–92%) and high purity (>95%, NMR/HRMS). Molecular docking studies against EGFR (PDB: 6LUD) and CDK-4 (PDB: 7SJ3) revealed strong binding affinities for hydroxy-substituted derivatives, particularly 6k (EGFR: −7.245 kcal/mol), 6j (CDK-4: −8.72 kcal/mol), and 6l (CDK-4: −9.23 kcal/mol), highlighting the role of hydrogen-bonding interactions. Cytotoxicity screening (MTT assay) against A-549 (lung), HCT-116 (colorectal), PANC-1 (pancreatic), and HaLa (cervical) cancer cells identified 6l (2-hydroxy-4- methoxyphenyl) as the most potent inhibitor (IC₅₀ = 5.87–7.86 μM), with 3–7-fold selectivity over normal HEK-293 cells. Structure-activity relationships demonstrated that electron-donating hydroxy/methoxy groups enhanced activity, while nitro or bulky substituents reduced potency. Notably, 6j (3,4-dihydroxyphenyl) exhibited exceptional activity against HCT-116 (IC₅₀ = 5.67 μM), correlating with its high CDK-4 binding affinity. The combined in silico and in vitro results suggest that these pyrimidine hybrids act via dual EGFR/CDK-4 inhibition, with 6b, 6j, and 6l emerging as promising anticancer leads due to their potent cytotoxicity, kinase selectivity, and favorable safety profiles. This study provides a robust framework for further optimization of pyrimidine-based therapeutics.

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