Synthesis, Biological Activities and Docking Studies of Novel 4-(Arylaminomethyl)benzamide Derivatives as Potential Tyrosine Kinase Inhibitors

• Published in: Molecules (Basel, Switzerland) Switzerland), 2019-09, Vol.24 (19), p.3543
• Main Authors: Kalinichenko, Elena, Faryna, Aliaksandr, Kondrateva, Viktoria, Vlasova, Alena, Shevchenko, Valentina, Melnik, Alla, Avdoshko, Olga, Belko, Alla
• Format: Article
• Language: English
• Subjects: 4-(aminomethyl)benzamide; anticancer activity; bcr-abl; Benzamide; Benzamides - chemical synthesis; Benzamides - chemistry; Benzamides - pharmacology; Benzene; Binding Sites; Cell Line, Tumor; Cell lines; Chemistry Techniques, Synthetic; Chromatography; Cytotoxicity; Dose-Response Relationship, Drug; Drug Design; Epidermal growth factor; Epidermal growth factor receptors; ErbB-2 protein; Fusion Proteins, bcr-abl - antagonists & inhibitors; Fusion Proteins, bcr-abl - chemistry; Humans; Hydrogen Bonding; Hydrogen bonds; Isoleucine; Kinases; Leukemia; molecular docking; Molecular Docking Simulation; molecular dynamics; Molecular Dynamics Simulation; Molecular modelling; Molecular Structure; Mutation; Protein Binding; protein kinase inhibitors; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein-tyrosine kinase; Proteins; receptor tyrosine kinases; Structure-Activity Relationship; Tyrosine
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules24193543

A number of new compounds containing the 4-(aminomethyl)benzamide fragment as a linker were designed and synthesized, and their biological activities were evaluated as potential anticancer agents. The cytotoxicity activity of the designed compounds was studied in two hematological and five solid cell lines in comparison with the reference drugs. Targeted structures against eight receptor tyrosine kinases including EGFR, HER-2, HER-4, IGF1R, InsR, KDR, PDGFRa, and PDGFRb were investigated. The majority of the compounds showed a potent inhibitory activity against the tested kinases. The analogues and with the (trifluoromethyl)benzene ring in the amide or amine moiety of the molecule were proven to be highly potent against EGFR, with 91% and 92% inhibition at 10 nM, respectively. The docking of synthesized target compounds for nine protein kinases contained in the Protein Data Bank (PDB) database was carried out. The molecular modeling results for analogue showed that the use of the 4-(aminomethyl)benzamide as a flexible linker leads to a favorable overall geometry of the molecule, which allows one to bypass the bulk isoleucine residue and provides the necessary binding to the active center of the T315I-mutant Abl (PDB: 3QRJ).