Molecular structures of antiviral agents, 2,3-dihydroxybenzaldehyde 2,4-dinitrophenylhydrazone and 4-[(4-methylpiperazin
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Molecular Structures of Antiviral Agents, 2,3-Dihydroxybenzaldehyde 2,4-Dinitrophenylhydrazone and 4-[(4-Methylpiperazin-1-yl)imino]methyl-1,2-Benzodiol G. V. Gurskayaa, V. E. Zavodnikb, N. E. Zhukhlistovac, and M. V. Kozlova a Engelhardt
Institute of Molecular Biology, Russian Academy of Sciences, ul. Vavilova 32, Moscow, 119991 Russia e-mail: [email protected], [email protected] b Karpov Research Institute of Physical Chemistry, ul. Vorontsovo pole 10, Moscow, 103064 Russia c Shubnikov Institute of Crystallography, Russian Academy of Sciences, Leninskiœ pr. 59, Moscow, 119333 Russia Received August 30, 2007
Abstract—Two antiviral agents, namely, 2,3-dihydroxybenzaldehyde 2,4-dinitrophenylhydrazone and 4-[(4methylpiperazin-1-yl)imino]methyl-1,2-benzodiol, are studied by X-ray diffraction. The stereochemical features of the molecular structures of the compounds under investigation are discussed, and the possible correlation between the structure and biological activity with respect to hepatitis C virus RNA-dependent RNA polymerase is analyzed. PACS numbers: 61.66.Hq DOI: 10.1134/S1063774508040123
INTRODUCTION This study continues the X-ray diffraction investigations of the three-dimensional structure of molecules of antiviral agents [1–5] and is devoted to the inhibitors of reproduction of the hepatitis C virus. Hepatitis C is one of the most dangerous and widespread infectious diseases. At present, more than 170 million people in the world (~3% of the population) are infected with hepatitis C virus (HCV). As a rule, more than 80% of patients suffer the transformation of hepatitis C into the chronic form. In this case, there is a great risk (~15–20%) of the development of cirrhosis of the liver and hepatocellular carcinoma [6]. Effective methods of medical treatment of hepatitis C have not been elaborated. Therefore, the search for new drugs remains an important problem. Hepatitis C virus RNA-dependent RNA polymerase (HCV RdRp, NS5B virus protein) is one of the most suitable objects for the modeling of HCV reproduction inhibitors. This enzyme is of vital importance in the process of reproduction of the virus RNA genome, and its inhibition results in the suppression of the HCV reproduction in infected cells. Moreover, in contrast to nucleic acid polymerases of the human organism, HCV RdRp shows a unique activity, which facilitates the search for selective drugs. It was recently found that some di- and trihydroxybenzaldehyde hydrazones (general structure I, scheme) inhibit the polymerase activity of HCV RdRp in the test system in vitro [7]. On the basis of the molecular modeling of the binding of compounds of this type to the
active center of the enzyme in [8], it was assumed that the mechanism of their action consists in chelating two magnesium cations (which take part in the catalytic act at the stage of transfer of the phosphoryl residue) by the hydroxyl substituents of the benzene ring. However, direct X-ray diffraction data validating this hypothesis have not been ob
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