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

Abstract

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).

Synthesis, In Vitro and In Silico Anticancer Activity of New 4-Methylbenzamide Derivatives Containing 2,6-Substituted Purines as Potential Protein Kinases Inhibitors

“…The synthesis of starting compounds 2 – 4 was carried out according to previously reported methods [ 28 , 29 ]. Compounds 5 and 6 were obtained by reacting chlorobenzoate 4 with 3-(trifluoromethyl) aniline or 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl) aniline, followed by isolation by column chromatography as described in [ 25 ]. Compounds 7 – 12 were synthesized by the condensation of the corresponding chlorine derivative 5 and 6 with the potassium salt of the purine analogue c – e , obtained by treating the corresponding base with potassium carbonate in dimethylformamide at reflux, in high yields ( Scheme 1 ).…”

“…In the 1 H NMR spectra of compounds 12 – 16 , there are chemical shifts in the range 5.45–5.62 ppm, which are typical proton signals of the methylene group connected to the N-9 nitrogen atom of the imidazole ring of purine. In comparison, for related compounds containing a CH 2 group attached not to a purine, but to a secondary amine, the proton signal is shifted to a strong field and is located in the range of 4.54–4.69 ppm [ 25 ]. In the case of analogs containing a CH 2 group at the piperazine ring, an even stronger shift of proton signals in a strong field up to 3.62 ppm is observed [ 25 ].…”

“…In comparison, for related compounds containing a CH 2 group attached not to a purine, but to a secondary amine, the proton signal is shifted to a strong field and is located in the range of 4.54–4.69 ppm [ 25 ]. In the case of analogs containing a CH 2 group at the piperazine ring, an even stronger shift of proton signals in a strong field up to 3.62 ppm is observed [ 25 ]. In the 19 F NMR spectra of compounds 8 and 11 , an additional signal appears at −52.1 ppm, related to the fluorine atom of the purine moiety besides the CF 3 signal at −61.3 ppm.…”

“…In our previous work, we suggested to use a flexible 4-methylbenzamide linker to obtain new chemical compounds capable of inhibiting protein kinases. A number of the obtained derivatives of 4-methylbenzamide showed high biological activity in vitro and in silico [ 25 , 26 ].…”

Synthesis, cytotoxicity and apoptosis‐inducing activity of novel 1H‐benzo[d]imidazole derivatives of dehydroabietic acid

“…[ 17,18 ] In addition, benzamide and benzenesulfonamide are also important pharmacophores frequently used in the design of anticancer agents. [ 19–23 ] The above findings suggest that the incorporation of benzimidazole, benzamide, and/or benzenesulfonamide moieties into the molecule of DAA might be a promising strategy for the discovery of new anticancer agents. Based on this strategy, two series of new N ‐(1 H ‐benzo[ d ]imidazol‐2‐yl)‐benzamide/benzenesulfonamide derivatives were designed and synthesized.…”