Hydrazinecarbonyl-thiazol-2-acetamides with pronounced apoptotic behavior: synthesis, in vitro/in vivo anti-proliferative activity and molecular modeling simulations

A new series of N-[4-(2-substituted hydrazine-1-carbonyl)thiazole-2-yl]acetamides was synthesized and evalu-ated in vitro against six human cell lines as antitumor agents. Compounds 20, 21 and 22 showed remarkable inhibition to HeLa (IC50 values of 1.67, 3.81, 7.92 mu M) and MCF-7 (IC50 values of 4.87, 5.81, 8.36 mu M, respec-tively) cell growth with high selectivity indices and safety profiles. Compound 20 showed significant decreases in both tumor volume and body weight gain compared to vehicle control, in the solid tumor animal model of Ehrlich ascites carcinoma (EAC) with recovered caspase-3 immuno-expression. Flow cytometry cell analysis showed that 20 exerts anti-proliferative activity in mutant Hela and MCF-7 cell lines through arresting the cell growth at the G1/S phase producing cell death via apoptosis rather than necrosis. To explain the antitumor mode of action of the most active compounds, EGFR-TK and DHFR inhibition assays were carried out. Compound 21 conveyed dual EGFR/DHFR inhibition with IC50 0.143 (EGFR) and 0.159 (DHFR) mu M. Compound 20 showed DHFR inhibition with IC50 0.262 mu M. Compound 22 exhibited the best EGFR inhibitory efficacy with IC50 0.131 mu M. Molecular modelling study revealed that 21 and 22 have binding interactions with EGFR amino acid residues Lys745 and Asp855. Compounds 20 and 21 showed affinity toward DHFR amino acid residues Asn64, Ser59 and Phe31. The ADMET profile and Lipinski's rule of five calculated for these compounds were acceptable. Com-pounds 20, 21 and 22 could be regarded as promising prototype antitumor agents for further optimization.

Automated summary

A new series of N-[4-(2-substituted hydrazine-1-carbonyl)thiazole-2-yl]acetamides were synthesized and evaluated for their antitumor activity against six human cell lines. Compounds 20, 21, and 22 showed significant inhibition of HeLa and MCF-7 cell growth with high selectivity and safety. Compound 20 demonstrated the most pronounced antitumor effect in an animal model of Ehrlich ascites carcinoma, inducing cell death through apoptosis.