Synthesis, Biological Activities and Docking Studies of Novel 4-(Arylaminomethyl)benzamide Derivatives as Potential Tyrosine Kinase Inhibitors
| Autor: | Aliaksandr Faryna, Alla Belko, Elena N. Kalinichenko, Olga Avdoshko, Alena Vlasova, Shevchenko Valentina A, Melnik Alla K, Viktoria Kondrateva |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Molecular model
Protein Data Bank (RCSB PDB) Fusion Proteins bcr-abl Pharmaceutical Science Chemistry Techniques Synthetic Receptor tyrosine kinase Analytical Chemistry chemistry.chemical_compound Drug Discovery Benzamide 0303 health sciences biology receptor tyrosine kinases Molecular Structure Chemistry computer.file_format Molecular Docking Simulation anticancer activity Chemistry (miscellaneous) Benzamides Molecular Medicine Tyrosine kinase Bcr-Abl Protein Binding Stereochemistry 030303 biophysics Molecular Dynamics Simulation Article lcsh:QD241-441 03 medical and health sciences Structure-Activity Relationship lcsh:Organic chemistry Cell Line Tumor Humans Physical and Theoretical Chemistry 030304 developmental biology Binding Sites Dose-Response Relationship Drug Organic Chemistry 4-(aminomethyl)benzamide Hydrogen Bonding molecular docking Protein Data Bank molecular dynamics protein kinase inhibitors Docking (molecular) Drug Design biology.protein computer Linker |
| Zdroj: | Molecules Volume 24 Issue 19 Molecules, Vol 24, Iss 19, p 3543 (2019) |
| ISSN: | 1420-3049 |
| Popis: | 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 11 and 13 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 10 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). |
| Databáze: | OpenAIRE |
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