(Phenylamino)pyrimidine-1,2,3-triazole derivatives as analogs of imatinib: searching for novel compounds against chronic myeloid leukemia

The enzyme tyrosine kinase BCR-Abl-1 is the main molecular target in the treatment of chronic myeloid leukemia and can be competitively inhibited by tyrosine kinase inhibitors such as imatinib. New potential competitive inhibitors were synthesized using the (phenylamino)pyrimidine-pyridine (PAPP) group as a pharmacophoric fragment, and these compounds were biologically evaluated. The synthesis of twelve new compounds was performed in three steps and assisted by microwave irradiation in a 1,3-dipolar cycloaddition to obtain 1,2,3-triazole derivatives substituted on carbon C-4 of the triazole nucleus. All compounds were evaluated for their inhibitory activities against a chronic myeloid leukemia cell line (K562) that expresses the enzyme tyrosine kinase BCRAbl-1 and against healthy cells (WSS-1) to observe their selectivity. Three compounds showed promising results, with IC50 values between 1.0 and 7.3 mu M, and were subjected to molecular docking studies. The results suggest that such compounds can interact at the same binding site as imatinib, probably sharing a competitive inhibition mechanism. One compound showed the greatest interaction affinity for BCR-Abl-1 in the docking studies.

Automated summary

New potential competitive inhibitors targeting the enzyme tyrosine kinase BCR-Abl-1 were synthesized and evaluated for their inhibitory activities against chronic myeloid leukemia. Three compounds showed promising results with IC50 values between 1.0 and 7.3 mu M, suggesting a competitive inhibition mechanism shared with imatinib. One compound exhibited the highest interaction affinity for BCR-Abl-1 in molecular docking studies.