Towards a qualitative understanding of the carbonyl reactivity of α-substituted ethyl 5-oxohomoadamantyl-4-carboxylates.

Substituted ethyl 5-oxohomoadamantane-4-carboxylates were subjected to reactions with several nucleophiles to establish some aspects of the carbonyl reactivity. However, only one example of the desired Claisen retro-reaction was observed as 3,7-disubstituted bicyclo[3.3.1]nonane formation. Most of the reactions yielded α-substituted homoadamantan-5-ones or some products of their further transformations. Reductive amination of substituted homoadamantane-5-ones gave several homoadamantane-fused nitrogen heterocycles, which could be considered as GABA- and/or ∂-aminovaleric acid analogues. Reduction products of several substituted ketones were observed as single products when treated with organomagnesium reagents. These deviations from the general chemical reactivity patterns are associated with steric factors and the geometry of the cage unit and could be a particular case, which is reflecting the overall specificity of the chemistry of cage carbonyl compounds.

Catalyst-free formal [3 + 2] cycloaddition of stabilized N,N-cyclic azomethine imines to 3-nitrobenzofurans and 3-nitro-4H-chromenes: access to heteroannulated pyrazolo[1,2-a]pyrazoles.

We have studied the [3 + 2]-cycloaddition of various N,N-cyclic azomethine imines to 3-nitrobenzofurans. This process is a rare example of their dearomatization. We have also extended this process to the related 3-nitro-4H-chromenes as dipolarophiles. Both reactions provide access to benzofuro- and chromeno-condensed pyrazolo[1,2-a]pyrazoles with 100% atom economy in a diastereoselective manner under mild eco-friendly conditions. Finally, on the basis of DFT calculations, the mechanistic insights into the mentioned [3 + 2]-cycloadditions and explanations of the experimentally determined limitations of the method are given. Hirshfeld atomic charge values of push-pull heterocycles were suggested as a criterion for a priori assessment of the possibility of their dipolar cycloaddition with N,N-cyclic azomethine imines.

Adamantane derivatives as potential inhibitors of p37 major envelope protein and poxvirus reproduction. Design, synthesis and antiviral activity.

Currently, smallpox, caused by the variola virus belonging to the poxvirus family, has been completely eradicated according to the WHO. However, other representatives of poxviruses, such as vaccinia virus, cowpox virus, ectromelia virus, monkeypox virus, mousepox virus and others, remain in the natural environment and can infect both animals and humans. The pathogens of animal diseases, belonging to the category with a high epidemic risk, have already caused several outbreaks among humans, and can, in an unfavorable combination of circumstances, cause not only an epidemic, but also a pandemic. Despite the fact that there are protocols for the treatment of poxvirus infections, the targeted design of new drugs will increase their availability and expand the arsenal of antiviral chemotherapeutic agents. One of the potential targets of poxviruses is the p37 protein, which is a tecovirimat target. This protein is relatively small, has no homologs among proteins of humans and other mammals and is necessary for the replication of viral particles, which makes it attractive target for virtual screening. Using the I-TASSER modelling and molecular dynamics refinement the p37 orthopox virus protein model was obtained and its was confirmed by ramachandran plot analysis and superimposition of the model with the template protein with similar function. A virtual library of adamantane containing compounds was generated and a number of potential inhibitors were chosen from virtual library using molecular docking. Several compounds bearing adamantane moiety were synthesized and their biological activity was tested in vitro on vaccinia, cowpox and mousepox viruses. The new compounds inhibiting vaccinia virus replication with IC50 concentrations between 0.133 and 0.515 µM were found as a result of the research. The applied approach can be useful in the search of new inhibitors of orthopox reproduction. The proposed approach may be suitable for the design of new poxvirus inhibitors containing cage structural moiety.

Heterocyclic Inhibitors of Viroporins in the Design of Antiviral Compounds.

Ion channels of viruses (viroporins) represent a common type of protein targets for drugs. The relative simplicity of channel architecture allows convenient computational modeling and enables virtual search for new inhibitors. In this review, we analyze the data published over the last 10 years on known ion channels of viruses that cause socially significant diseases. The effectiveness of inhibition by various types of heterocyclic compounds of the viroporins of influenza virus, hepatitis С virus, human immunodeficiency virus, human papillomaviruses, coronaviruses, and respiratory syncytial virus is discussed. The presented material highlights the promise held by the search for heterocyclic antiviral compounds that act by inhibition of viroporins.

Molecular design, synthesis and biological evaluation of cage compound-based inhibitors of hepatitis C virus p7 ion channels.

The hepatitis C caused by the hepatitis C virus (HCV) is an acute and/or chronic liver disease ranging in severity from a mild brief ailment to a serious lifelong illness that affects up to 3% of the world population and imposes significant and increasing social, economic, and humanistic burden. Over the past decade, its treatment was revolutionized by the development and introduction into clinical practice of the direct acting antiviral (DAA) agents targeting the non-structural viral proteins NS3/4A, NS5A, and NS5B. However, the current treatment options still have important limitations, thus, the development of new classes of DAAs acting on different viral targets and having better pharmacological profile is highly desirable. The hepatitis C virus p7 viroporin is a relatively small hydrophobic oligomeric viral ion channel that plays a critical role during virus assembly and maturation, making it an attractive and validated target for the development of the cage compound-based inhibitors. Using the homology modeling, molecular dynamics, and molecular docking techniques, we have built a representative set of models of the hepatitis C virus p7 ion channels (Gt1a, Gt1b, Gt1b_L20F, Gt2a, and Gt2b), analyzed the inhibitor binding sites, and identified a number of potential broad-spectrum inhibitor structures targeting them. For one promising compound, the binding to these targets was additionally confirmed and the binding modes and probable mechanisms of action were clarified by the molecular dynamics simulations. A number of compounds were synthesized, and the tests of their antiviral activity (using the BVDV model) and cytotoxicity demonstrate their potential therapeutic usefulness and encourage further more detailed studies. The proposed approach is also suitable for the design of broad-spectrum ligands interacting with other multiple labile targets including various viroporins.

Design of Broad-Spectrum Inhibitors of Influenza A Virus M2 Proton Channels: A Molecular Modeling Approach.

BACKGROUND: The influenza A virus M2 proton channel plays a critical role in its life cycle. However, known M2 inhibitors have lost their clinical efficacy due to the spread of resistant mutant channels. Thus, the search for broad-spectrum M2 channel inhibitors is of great importance. OBJECTIVE: The goal of the present work was to develop a general approach supporting the design of ligands interacting with multiple labile targets and to propose on its basis the potential broad-spectrum inhibitors of the M2 proton channel. METHOD: The dynamic dimer-of-dimers structures of the three primary M2 target variants, wild-type, S31N and V27A, were modeled by molecular dynamics and thoroughly analyzed in order to define the inhibitor binding sites. The potential inhibitor structures were identified by molecular docking and their binding was verified by molecular dynamics simulation. RESULTS: The binding sites of the M2 proton channel inhibitors were analyzed, a number of potential broad-spectrum inhibitors were identified and the binding modes and probable mechanisms of action of one promising compound were clarified. CONCLUSION: Using the molecular dynamics and molecular docking techniques, we have refined the dynamic dimer-ofdimers structures of the WT, S31N and V27A variants of the M2 proton channel of the influenza A virus, analyzed the inhibitor binding sites, identified a number of potential broad-spectrum inhibitor structures targeting them, and clarified the binding modes and probable mechanisms of action of one promising compound. The proposed approach is also suitable for the design of ligands interacting with other multiple labile targets.