Fluoroquinolones are an important class of modern and efficient antibacterial
drugs with a broad spectrum of activity. Levofloxacin (the optically active form
of ofloxacin) is one of the most promising fluoroquinolone drugs, and its
antibacterial activity is substantially higher than the activity of other drugs
of the fluoroquinolone family. Earlier, in the Postovsky Institute of Organic
Synthesis, UB RAS, an original method of levofloxacin synthesis was developed,
and now the pilot batch of the drug is being prepared. Bacterial DNA gyrase is a
specific target of fluoroquinolones; hence, the study of the enzyme-drug
interaction is of theoretical and practical importance. Moreover, the parameters
of DNA gyrase inhibition may serve as a criterion for drug quality. Here, we
present the results of studying the interaction of DNA gyrase with a number of
fluoroquinolones and their analogs: intermediates and semi-products of the
levofloxacin synthesis, and also samples from the pilot batches of this drug.
The importance of two structural elements of the levofloxacin molecule for the
efficiency of the inhibition is revealed. The data obtained may be useful for
the design of new drugs derived from levofloxacin.
New synthetic approaches to fluorinated 3-phenyl-1,2,4-benzotriazines for biological testing have been elaborated. 1-(3,4-Difluorophenyl)-3,5-diphenylformazan (IVa) was synthesized via dinitriding of 3,4-difluoroaniline, followed by azo-addition of the resulting azobenzenediazonium chloride with acetaldehyde phenylhydrazone. 6,7-Difluoro-3-phenyl-1,2,4-benzotriazine (Va) was obtained via intramolecular cyclization of formazan IVa in the presence of BF3/AcOH complex. Monofluoro-substituted 6-R-7-fluoro-3-phenyl-1,2,4-benzotriazine derivatives (Vb -Vq) were prepared by substituting fluorine atom with alkoxides in 3,4-difluoronitrobenzene. Conditions for nucleophilic substitution of the second fluorine atom in benzotriazines V have been established. Fluorinated 3-phenyl-1,2,4-benzotriazines have been tested for antiviral and cytotoxic activity on Vero cell cultures and proved to be active against severe diseases caused by smallpox and some other pathogenic viruses.
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