2-Amino-4,6-diarylpyrimidines as potential chronic myeloid leukemia cell inhibitors targeting anti-ABL1 kinase: microwave-assisted synthesis, biological evaluation, molecular docking, and dynamics studies

Abstract

In this work, a simple and mild process was used to synthesize a series of 2-amino-4,6-diarylpyrimidine derivatives, 1a–1q, whose structures were verified by FTIR, 1D- and 2D-NMR, and HRMS techniques, to investigate and develop anticancer agents. Under microwave irradiation, a two-step process was carried out, consisting of aldol condensation of benzaldehydes and acetophenones to produce intermediate chalcones and ring closure condensation of chalcones and guanidine hydrochloride. Each generated compound's anticancer activity against the human chronic myelocytic leukemia K562 cancer cell line was investigated in vitro to determine the active compounds, which were subsequently evaluated for inhibiting the ABL1 tyrosine kinase. According to these findings, compound 1e demonstrated considerable inhibition against K562 cancer cells and ABL1 tyrosine kinase at IC₅₀ values of 8.77 ± 0.55 μM and 3.35 ± 0.58 μM, respectively. The molecular docking on wild-type and mutant type ABL1 (PDB ID 2HYY and 5MO4) investigation indicated that 1e and 1g interacted with amino acids. It formed stable hydrogen bonds and π–π linkages with crucial residues in the active site of the enzyme. Moreover, the stability of these enzyme–ligand complexes was confirmed using molecular dynamics simulations. These findings suggested that compounds 1e and 1g can be considered promising cancer treatment agents.