Efficient Synthesis of Densely Functionalized Pyrido[2,3-d]Pyrimidines via Three-component One-pot Domino Knoevenagel aza-Diels Alder Reaction and Induces Apoptosis in Human Cancer Cell Lines via Inhibiting Aurora A and B Kinases

Abstract

The identification of novel aurora kinase inhibitors is one of the most attractive directions in the field of anticancer research and development. In our ongoing efforts to pursue the class of inhibitors, a series of pyrido[2,3-d]pyrimidines were synthesized in DIPEAc/EtOH media. The advantages of the present methodology include a one-pot multicomponent environmentally friendly approach, cost effectiveness, broad substrate scope, operational simplicity, short reaction times, easy workup procedure and high yields. Synthesized compounds were screened against human lung carcinoma A549 cells, human hepatocellular liver carcinoma HepG2 cells and human cervical carcinoma epithelial HeLa cells. Compound 6 b i.e. diethyl 5-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6,7-dicarboxylate was found to be equipotent than the standard drug VX-680 against selected cancer cell lines. The selected compounds (6b, 6d and 6h) exhibit potent inhibition against Aurora A and B with IC₅₀ values (9.4–25 mg/L). Molecular docking model showed that the compounds can bind well to the target by interacting with amino acid residues. It will provide some valuable information for the commercial Aurora Kinase inhibitors.

Graphical Abstract

Keywords:

• Pyrido[2,3-d]pyrimidines
• DIPEAc
• multicomponent
• aurora kinase inhibitor
• molecular docking

Acknowledgments

The authors are thankful to Professor Ramrao A. Mane for his invaluable discussions and guidance. The authors are also thankful to Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad and Central Drug Research Institute (CDRI), Lucknow for providing necessary facilities and spectral analysis, respectively.

Disclosure statement

No potential conflict of interest was reported by the authors.