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

Abstract

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 BCR-Abl-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 μM, 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.

Keywords: (phenylamino)pyrimidine-pyridine; 1,2,3-triazole; 1,3-dipolar cycloaddition; chronic myeloid leukemia; imatinib.

Figure 1

Proposed structural modifications to obtain triazole derivatives 1a, b and 2a–j.

Scheme 1

Synthetic route of the triazole derivatives 1a,b, and 2a–j.

Figure 2

Asymmetric unit representation of the 1,2,3-triazole derivative 2b. Displacement ellipsoids are drawn at the 50% probability level.

Figure 3

Screening of the triazole derivatives of imatinib 1a,b, and 2a–j at concentrations of 1 μM and 10 μM against the human K562 cell line. Bars represent the mean ± standard deviation. The standard used was IMT.

Figure 4

Interaction maps of IMT, 2c, 2d, and 2g with the BCR-Abl-1 structure (PDB code: 3PYY), showing steric interactions (red dotted lines) and hydrogen bonds (blue dotted lines).