Tag Archives: inhibition mechanism

Synthesis and investigation of the derivatives of amidinohydrazonelated aromatic compounds as furin inhibitors

T. V. Osadchuk1, A. V. Semyroz1, O. V. Shybyryn1, V. K. Kibirev1,2

1Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Kyiv;
2Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv;
e-mail: osadchuk@bpci.kiev.ua

The proprotein convertase furin plays a crucial role in a variety of pathogenic processes such as cancer, bacterial and viral diseases, neurodegenerative disorders and diabetes. Thus, furin inhibitors are promi­sing therapeutics for the treatment of many diseases. In this study we synthesized some new non-peptide of furin inhibitors, with positively charged amidinohydrazone groups present in ortho-, meta– or para-positions in the benzene rings relative to the linker. From the results of biological testing it followed that the position of amidinohydrazone groups in aromatic rings was significant for the manifestation of antifurin activity. The replacement of linkers containing a propoxy group by a “bridge” with a benzene ring was found to cause an increase in the inhibitory effect of the compounds. The effect of synthesized bisamidinohydrazones on furin also depended on the substitution of the hydrogen atom in the amidinohydrazone group by the methyl group. These compounds were shown to block the enzyme activity mainly by the mechanism of mixed inhibition, and their Ki values were at the micromolar level.