Synthesis and biological evaluation of new fused Isoxazolo[4',5':4,5] pyrano[2,3-d] Pyrimidines as potent anticancer agents

Abstract

Synthetic chemists have developed efficient and straightforward methods for optimal synthesis to meet the demand for scaffolds critical for medicinal applications. The synthesis of fused isoxazoles, both with and without MWI, was investigated through the [3 + 2] cycloaddition reaction, followed by C–C bond formation. This was achieved using 2-chloro-4-((3-iodoprop-2-yn-1-yl)oxy)-6-methylpyrimidine and substituted nitrile oxides under optimised conditions. The anticancer activity of the synthesized compounds was subsequently assessed in vitro against two cancer cell lines, MCF-7 and A-549. The majority of the tested compounds, specifically 6i, 6j, and 6k, showed notable activity, with compounds 6j and 6k surpassing the standard drug in both cell lines, while 6i displayed comparable activity against the tested cell lines. In silico analyses of more potent compounds (6i, 6j, and 6k) and erlotinib on the EGFR protein indicated that compounds 6i and 6k demonstrate significantly higher binding energies and inhibition constants in comparison to erlotinib.