Novel Amide Functionalized Pyrimidine Derivative as Potential Anticancer Agents: Synthesis, Characterization, Molecular Docking and Invitro Cytotoxicity Evaluation
Authors/Creators
- 1. 1*Research Scholar, Faculty of Pharmaceutical Sciences, Motherhood University, Dehradun Road, Village Karoundi Post - Bhagwanpur, Roorkee Tehsil, Haridwar Distt., Uttarakhand 247661. 2Professor and Principal, Faculty of Pharmaceutical Sciences, Motherhood University, Dehradun Road, Village Karoundi Post - Bhagwanpur, Roorkee Tehsil, Haridwar Distt., Uttarakhand 247661.
Contributors
Researcher:
- 1. 1*Research Scholar, Faculty of Pharmaceutical Sciences, Motherhood University, Dehradun Road, Village Karoundi Post - Bhagwanpur, Roorkee Tehsil, Haridwar Distt., Uttarakhand 247661.
Description
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.
Keywords
Pyrimidine derivatives, Multicomponent synthesis, EGFR, CDK-4, Molecular docking, Anticancer
activity.
Files
164-175-Jyothi K-2.pdf
Files
(741.2 kB)
| Name | Size | Download all |
|---|---|---|
|
md5:b780a15c3e4d9065829c02f405e8e329
|
741.2 kB | Preview Download |
Additional details
Dates
- Available
-
2025-04-01Volume 15 issue 2 2025
References
- 1. Siegel, R.L., Miller, K.D., Wagle, N.S. & Jemal, A. (2023). Cancer statistics, 2023. CA Cancer J Clin., 73(1):17-48. doi: 10.3322/caac.21763. 2. Alafeefy, A.M., Ceruso, M., Al-Tamimi, A.M., Del Prete, S., Capasso, C. & Supuran, C.T. (2014). Quinazoline-sulfonamides with potent inhibitory activity against the α-carbonic anhydrase from Vibrio cholerae. Bioorg Med Chem., 22(19):5133-5140. doi: 10.1016/j.bmc.2014.08.015. 3. Alafeefy, A.M., Ceruso, M., Al-Jaber, N.A., Parkkila, S., Vermelho, A.B. & Supuran, C.T. (2015). A new class of quinazoline-sulfonamides acting as efficient inhibitors against the α-carbonic anhydrase from Trypanosoma cruzi. J Enzyme Inhib Med Chem., 30(4):581-585. doi: 10.3109/14756366.2014.956309. 4. DeMartino, J.K. & Boger, D.L. (2008). Glycinamide ribonucleotide transformylase (GAR Tfase) as a target for cancer therapy. Drugs Fut., 33(11):969. doi: 10.1358/dof.2008.33.11.1247542. 5. Curran, W.J. (2002). New chemotherapeutic agents: update of major chemoradiation trials in solid tumors. Oncology (Williston Park), 63 Suppl 2:29-38. doi: 10.1159/000067145. 6. Nurgali, K., Jagoe, R.T. & Abalo, R. (Eds.). (2018). Adverse effects of cancer chemotherapy: Anything new to improve tolerance and reduce sequelae? Front Pharmacol., 9:245. doi: 10.3389/fphar.2018.00245. 7. El-Messery, S.M., Hassan, G.S., Nagi, M.N., Habib, E.E., Al-Rashood, S.T. & El-Subbagh, H.I. (2016). Synthesis, biological evaluation and molecular modeling study of some new methoxylated 2-benzylthio-quinazoline-4(3H)-ones as nonclassical antifolates. Bioorg Med Chem Lett., 26(19):4815-4823. doi: 10.1016/j.bmcl.2016.08.022. 8. Arteaga, C.L. & Johnson, D.H. (2001). Tyrosine kinase inhibitors—ZD 1839 (Iressa). Curr Opin Oncol., 13(6):491-498. doi: 10.1097/00001622-200111000-00012. 9. Barker, A.J., Gibson, K.H., Grundy, W., Godfrey, A.A., Barlow, J.J., Healy, M.P., et al. (2001). Studies leading to the identification of ZD 1839 (iressa™): an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor targeted to the treatment of cancer. Bioorg Med Chem Lett., 11(14):1911-1914. doi: 10.1016/s0960-894x(01)00344-4. 10. Barker, J. & Johnstone, C. (1997). Preparation of 4-anilino-7-heteroarylquinazolines as tyrosine kinase inhibitors. World Intellectual Property Organization Patent., WO97/30044 A1. 11. El-Azab, A.S., Al-Omar, M.A., Abdel-Aziz, A.A., Abdel-Aziz, N.I., El-Sayed, M.A., Aleisa, A.M., et al. (2010). Design, synthesis and biological evaluation of novel quinazoline derivatives as potential antitumor agents: molecular docking study. Eur J Med Chem., 45(9):4188-4198. doi: 10.1016/j.ejmech.2010.06.013. 12. Tiwari, S., Sachan, S., Mishra, A., Tiwari, S. & Pandey, V. (2015). The anticancer activity of some novel 4-anilino quinazoline derivatives as tyrosine kinase (EGFR) inhibitor and the quantitative structure activity relationships. Int J Pharm Life Sci., 6(12):4819-4828. 13. Al-Suwaidan, I.A., Abdel-Aziz, A.A., Shawer, T.Z., Ayyad, R.R., Alanazi, A.M., El-Morsy, A.M., et al. (2016). Synthesis, antitumor activity and molecular docking study of some novel 3-benzyl-4(3H)quinazolinone analogues. J Enzyme Inhib Med Chem., 31(1):78-89. doi: 10.3109/14756366.2015.1004059. 14. Ammazzalorso, A., Agamennone, M., De Filippis, B. & Fantacuzzi, M. (2021). Development of CDK4/6 Inhibitors: A Five Years Update. Molecules., 26(5):1488. doi: 10.3390/molecules26051488. 15. Suzuki, H., Sakai, N., Iwahara, R., Fujiwaka, T., Satoh, M. & Kakehi, A. (2007). Novel synthesis of 7-fluoro-8-(trifluoromethyl)-1H-1,6-naphthyridin-4-one derivatives: Intermolecular cyclization of an N-Silyl-1-azaallyl anion with Perfluoroalkene and subsequent intramolecular skeletal transformation of the resulting pentasubstituted pyridines. J Org Chem., 72(15):5878-5881. doi: 10.1021/jo070564m. 16. Sakai, N., Aoki, D., Hamajima, T. & Konakahara, T. (2006). Yb(OTf)3-catalyzed cyclization of an N-silylenamine with 2-methylene-1,3-cyclohexanedione to afford a 7,8-dihydroquinolin-5(6H)-one derivative and its application to the one-pot conversion to a 2,3,5-trisubstituted quinoline derivative. Tetrahedron Lett., 47(8):1261-1265. doi: 10.1016/j.tetlet.2005.12.080. 17. Konakahara, T., Sakai, N., Hattori, N., Tomizawa, N. & Abe, N. (2005). New approach to the synthesis of non-benzenoid aromatic compounds, functionalized 1-Azaazulene derivatives: Cyclization reactions of 2-substituted tropones with N-Silylenamine and enamine. Heterocycles., 65(11):2799. doi: 10.3987/COM-05-10537. 18. Stanovnik, B. & Svete, J. (2004). Synthesis of heterocycles from alkyl 3-(dimethylamino)propenoates and related enaminones. Chem Rev., 104(5):2433-2480. doi: 10.1021/cr020093y. 19. House, H.O. (1972). Modern Synthetic Reactions. 2nd ed. Menlo Park: Benjamin/Cummings. 20. Larock, R.C. (1999). Comprehensive Organic Transformations. 2nd ed. New York: Wiley-VCH. 21. Ghosh, A.K. & Shahabi, D. (2021). Synthesis of amide derivatives for electron deficient amines and functionalized carboxylic acids using EDC and DMAP and a catalytic amount of HOBt as the coupling reagents. Tetrahedron Lett., 63:152719. doi: 10.1016/j.tetlet.2020.152719. 22. Meng, X.Y., Zhang, H.X., Mezei, M. & Cui, M. (2011). Current Computer Aided-Drug Design. Curr Comput Aided Drug Des., 7(2):146-157. 23. Riss, T.L., Moravec, R.A., Niles, A.L., Duellman, S., Benink, H.A. & Worzella, T.J. (2016). Cell Viability Assays. In: Assay Guidance Manual [Internet]. Bethesda (MD): National Center for Advancing Translational Sciences. Available from: https://www.ncbi.nlm.nih.gov/books/NBK144065/.