Hybrids of Imatinib with Quinoline: Synthesis, Antimyeloproliferative Activity Evaluation, and Molecular Docking

Pharmaceuticals

Anna Cunha¹  Rafael Dantas²  Floriano Junior²  Luiz Pimentel³  Henayle Canzian³  Lucas Hoelz³  Andressa Oliveira³  Monica Bastos³  Debora Marinho³  Nubia Boechat³  Carine Santos³ 

[1] Departamento de Química Orgânica, Campus do Valonguinho, Universidade Federal Fluminense–UFF, Niterói 24020-150, Brazil;Laboratório de Bioquímica Experimental e Computacional de Fármacos, Instituto Oswaldo Cruz FIOCRUZ, Av. Brasil 4365, Manguinhos, Rio de Janeiro 21040-360, Brazil;Laboratório de Sintese de Farmacos-LASFAR, Instituto de Tecnologia em Farmacos-Farmanguinhos, FIOCRUZ, Rua Sizenando Nabuco 100, Manguinhos, Rio de Janeiro 21041-250, Brazil;

关键词: cancer;    imatinib;    PAPP;    quinoline;    1,2,3-triazole;    tyrosine kinase inhibitors;   

DOI  :  10.3390/ph15030309

来源: DOAJ

【 摘 要 】

Imatinib (IMT) is the first-in-class BCR-ABL commercial tyrosine kinase inhibitor (TKI). However, the resistance and toxicity associated with the use of IMT highlight the importance of the search for new TKIs. In this context, heterocyclic systems, such as quinoline, which is present as a pharmacophore in the structure of the TKI inhibitor bosutinib (BST), have been widely applied. Thus, this work aimed to obtain new hybrids of imatinib containing quinoline moieties and evaluate them against K562 cells. The compounds were synthesized with a high purity degree. Among the produced molecules, the inhibitor 4-methyl-N3-(4-(pyridin-3-yl)pyrimidin-2-yl)-N1-(quinolin-4-yl)benzene-1,3-diamine (2g) showed a suitable reduction in cell viability, with a CC₅₀ value of 0.9 µM (IMT, CC₅₀ = 0.08 µM). Molecular docking results suggest that the interaction between the most active inhibitor 2g and the BCR-ABL1 enzyme occurs at the bosutinib binding site through a competitive inhibition mechanism. Despite being less potent and selective than IMT, 2g is a suitable prototype for use in the search for new drugs against chronic myeloid leukemia (CML), especially in patients with acquired resistance to IMT.

【 授权许可】

Unknown