D. N. Sokolov

Novel derivatives of usnic acid effectively inhibiting reproduction of influenza A virus.

Influenza virus is serious human pathogen leading to high morbidity and mortality all over the world. Due to high rate of mutation, it is able to fast development of drug resistance that makes necessary to search novel antivirals with broad range and alternative targets. In the present study we describe synthesis and anti-viral activity of novel derivatives of usnic acid (2,6-diacetyl-7,9-dihydroxy-8,9b-dimethyl-1,3(2H,9bH)-dibenzo-furandione). It is shown that anti-viral activity of usnic acid can be increased by side moieties introduction. The modification with chalcones appeared to be the most effective. Our study revealed that (-)-usnic acid exhibited higher antiviral activity than its (+)-enantiomer, but in the pairs of enantiomer derivatives such as enamines, pyrazoles and chalcones, the (+)-enantiomers were more potent inhibitors of the virus. For other groups of compounds the inhibiting activities of the enantiomers were comparable. Further optimization of the structure could therefore result in development of novel anti-influenza compound with alternative target and mechanism of virus-inhibiting action.

Synthesis and activity of (+)-usnic acid and (−)-usnic acid derivatives containing 1,3-thiazole cycle against Mycobacterium tuberculosis

Abstract New usnic acid (UA) derivatives were investigated in vitro to elucidate their potential inhibitory activities on the growth of Mycobacterium smegmatis and Mycobacterium tuberculosis. Seven pairs of enantiomers of thiazole UA derivatives were tested using the M. smegmatis strain mc2 155 test system, and the “structure–activity” relationship was established. The most active compounds were (+)-3 and (−)-3, and their kinase inhibitory activities were investigated. The results obtained using the Streptomyces lividans APHVIII+ and M. smegmatis APHVIII+ test systems indicated the significant protein kinase activity of these compounds and revealed the species specificity of the actions of the dextro- and levorotatory isomers. Both isomers, (+)-3 and (−)-3, possess similar inhibitory activity against M. tuberculosis H37Rv. The action of the isomers on eukaryotic cells was also investigated, and the results demonstrate that the dextrorotatory isomer (+)-3 leads to the lysis of intact macrophages to a degree higher than that obtained spontaneously and significantly higher than that obtained with the levorotatory isomer.

Synthesis of aurones based on usninic acid

(+)-Usninic acid was brominated at the acetyl group located on the aromatic ring. Aurones were synthesized based on the intramolecular cyclization of monobrominated (+)-usninic acid.

Synthesis and Biological Activity of Usnic Acid Enamine Derivatives

Enamine-derivatives of both enantiomers of usnic acid and the corresponding compounds with a quaternized N atom were synthesized. Compounds3and4exhibited moderate cytotoxic activity. All quaternized compounds were inactive against the tested tumor cell lines. Quaternized compounds7and8showed high antimycobacterial activity against Mycobacterium smegmatis, the primary test species for screening antituberculosis drugs. It was shown that the activity dropped in correlation with an increase of the length of the linker between the N atoms. Compound (+)-8inhibited effectively the growth of pathogenic Grampositive microorganisms Staphylococcus aureus, S. epidermidis, Streptococcus pneumoniae, and Enterococcus faecalis.

Synthesis of Sulfides Based on (+)-Usninic Acid

Sulfides containing the pharmacophore (+)-usninic acid and its methyl ether were synthesized from monobrominated precursors.

Secondary metabolites of the lichen Cladonia stellaris

The composition of slightly polar extracts of the lichen Cladonia stellaris (Opiz.) was studied. The major metabolites of the CHCl3 and Me2CO extracts were isolated. Lichen acids 6 and 7 in addition to 3–5, derivatives of olivetolcarboxylic acid (7), were isolated for the first time from the lichen C. stellaris. The CHCl3 extract was tested for antagonist activity against pathogens of the principal agricultural diseases.

Reduction of (+)-usninic acid and its pyrazole derivative by sodium borohydride

The reaction of (+)-usninic acid and its pyrazole derivative with sodium borohydride was studied. The reduction occurred stereoselectively at the endocyclic carbonyl group. Novel (+)-usninic acid derivatives that were reduction products of the carbonyls were obtained.

Synthesis of new (+)-usnic acid derivatives with the flavone structure

Reactions of a chalcone derivative (synthesized earlier from usnic acid) with various oxidants (hydrogen peroxide, tert-butyl hydroperoxide, and dichlorodicyanobenzoquinone) gave new flavonols, dihydroflavonols, and flavones. Treatment of the starting chalcone with a nucleophilic reagent (NH2NH2·H2O) afforded a dihydropyrazole-containing derivative.

Reaction of (+)-usninic acid and several of its derivatives with diazomethane

New derivatives of (+)-usninic acid including products of ring expansion, methylation of enol and phenol hydroxyls, and formation of an oxirane ring in addition to products with pyran and furan rings annelated to ring A of (+)-usninic acid were prepared by reaction of (+)-usninic acid and its pyrazole derivatives with diazomethane.

Synthesis of Sulfones and Sulfoxides Based on (+)-usnic Acid

Sulfones were produced by meta-chloroperbenzoic-acid oxidation of the corresponding thioethers prepared from (+)-usnic acid. Reaction of the thioethers with H2O2 in the presence of VO(acac)2 formed a mixture of sulfoxide diastereomers. Possible chiral oxidation of the thioethers into sulfoxides was studied.