Microwave-assisted one-pot synthesis of fused isoxazolo[4′,5′:3,4]pyrrolo[1,2-c]pyrimidines as potent anticancer agents: In vitro and in silico study

Microwave-aided one-pot synthesis of certain fused isoxazolo[4′,5′:3,4]pyrrolo[1,2-c] pyrimidine derivatives are synthesized using one-pot Cu(I)-catalyzed [3+2]cycloaddition, followed by Pd-catalyzed CC bond coupling between iodoalkyne and freshly prepared nitrile oxides in a recyclable ionic liquid [Emim]BF₄. The anticancer efficacy of the synthesized isoxazoles was then tested in vitro against A-459 and NCI-H460 cancer cell lines, and some compounds (5k–5n) demonstrated more activity than the others, with 5k and 5l acting more potently than the standard drugs, 5-FU and erlotinib. We also detected EGFR inhibitory activity in the potent compounds 5k, 5l, 5m, and 5n, and the results revealed that compound 5m had the highest inhibitory action compared to the other compounds and was comparable to erlotinib. We also performed in silico tests to assess the molecular interactions of more powerful compounds with EGFR protein (PDB: 4HJO). Our findings indicated that all potent compounds had stronger binding interactions than standard erlotinib (−7.69 kcal/mol), with binding energies ranging from −8.41 to −9.26 kcal/mol.