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
We previously showed that monoterpenoid (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol 1 alleviates motor manifestations of Parkinson's disease in animal models. In the present study, we designed and synthesized monoepoxides of (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol 1 and evaluated their biological activity in the MPTP mouse model of Parkinson's disease. We also assessed the ability of these compounds to penetrate the blood-brain barrier (BBB). According to these data, we chose epoxide 4, which potently restored the locomotor activity in MPTP-treated mice and efficiently penetrated the BBB, to further explore its potential mechanism of action. Epoxide 4 was found to robustly promote the survival of cultured dopamine neurons, protect dopamine neurons against toxin-induced degeneration, and trigger the mitogen-activated protein kinase (MAPK) signaling cascade in cells of neuronal origin. Meanwhile, neither the survival-promoting effect nor MAPK activation was observed in non-neuronal cells treated with epoxide 4. In the MPTP mouse model of Parkinson's disease, compound 4 increased the density of dopamine neuron fibers in the striatum, which can highlight its potential to stimulate striatal reinnervation and thus halt disease progression. Taken together, these data indicate that epoxide 4 can be a promising compound for further development, not only as a symptomatic but also as a neuroprotective and neurorestorative drug for Parkinson's disease.
Subject(s)
Cell Survival/drug effects , Corpus Striatum/drug effects , Dopaminergic Neurons/drug effects , MPTP Poisoning/drug therapy , Neuroprotective Agents/pharmacology , Animals , Cells, Cultured , Corpus Striatum/metabolism , Dopaminergic Neurons/cytology , Dopaminergic Neurons/metabolism , MPTP Poisoning/metabolism , Mice , Mitogen-Activated Protein Kinases/metabolism , Motor Activity/drug effects , Neuroprotective Agents/therapeutic use , Signal Transduction/drug effects , Tyrosine 3-Monooxygenase/metabolismABSTRACT
The antiviral activity of 4-hydroxy-hexahydro-2H-chromenes and 4-fluorine-hexahydro-2H-chromenes with an aromatic substituent, synthesized from monoterpene (-)-verbenone, was studied for the first time. Five of 11 (45 per cent) of 4-hydroxy-hexahydro-2H-chromene-type compounds have been found to exhibit antiviral activity against influenza A virus of subtype H1N1pdm09. Although a portion of active compounds among 4-fluorine-containing series was fewer, just compound 5i that contains a fluorine substituent exhibited more potent anti-influenza activity along with low cytotoxicity. Thus two new promising types of antiviral compounds were identified.
