ABSTRACT
We synthesized fluoro- and hydroxy-containing octahydro-2H-chromenes by the Prins reaction starting from a monoterpenoid (-)-isopulegol and a wide range of aromatic aldehydes in the presence of the BF3âEt2O/H2O system acting as both an acid catalyst and a fluorine source. Activity of the produced compounds against the influenza A/Puerto Rico/8/34 (H1N1) virus was studied. The highest activity was demonstrated by fluoro- (11i) and hydroxy-containing (10i) derivatives of 2,4,6-trimethoxybenzaldehyde. The most pronounced virus-inhibiting effect of compounds 10i and 11i was observed at an early stage of infection. These compounds were supposed to be capable of binding to viral hemagglutinin, which is an agreement with data on the effect of compounds 10i and 11i on the viral fusogenic activity as well as by molecular docking studies.
Subject(s)
Antiviral Agents/pharmacology , Benzopyrans/pharmacology , Cyclohexane Monoterpenes/pharmacology , Influenza A virus/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Benzopyrans/chemical synthesis , Benzopyrans/chemistry , Caco-2 Cells , Cell Death/drug effects , Cyclohexane Monoterpenes/chemical synthesis , Cyclohexane Monoterpenes/chemistry , Dogs , Dose-Response Relationship, Drug , Humans , Madin Darby Canine Kidney Cells/drug effects , Molecular Docking Simulation , Molecular Structure , Structure-Activity RelationshipABSTRACT
A simple and convenient method for the synthesis of new methyl 2-(4-methoxyphenyl)- and 2-(3,4-dimethoxyphenyl)-4-oxo-4H-polyfluorochromen-3-carboxylates as analogs of natural methoxy-containing flavones is proposed. As a result of their directed modification under basic conditions, 7-imidazolyl-substituted derivatives were obtained. In aqueous-organic medium under basic conditions, 5,6,7,8-tetrafluoro-3-(methoxycarbonyl)flavones were transformed into 6,8-difluoro-5-hydroxy-7-(1H-imidazol-1-yl)-3-(methoxycarbonyl)flavones as a result of flavone-5-hydroxyflavone rearrangement, while 6,7,8-trifluorinated analogs underwent a flavone-coumarin rearrangement to give 6,8-difluoro-3-(hydroxyarylidene)-7-(1H-imidazol-1-yl)coumarins under the same conditions. Acid hydrolysis of methyl polyfluoroflavone-3-carboxylates allowed to obtain 2-aryl-4H-polyfluorochromen-4-ones. Evaluation of the antiviral activity of the synthesized compounds against influenza A (H1N1) and Coxsackie B3 viruses showed that 2-(3,4-dimethoxyphenyl)-5,6,8-trifluoro-7-(1H-imidazol-1-yl)-4H-chromene-4-one has the most promising properties.
