In recent years, tools for the development of new drugs have been dramatically improved. These include genomic and proteomic research, numerous biophysical methods, combinatorial chemistry and screening technologies. In addition, early ADMET studies are employed in order to significantly reduce the failure rate in the development of drug candidates. As a consequence, the lead finding, lead optimization and development process has gained marked enhancement in speed and efficiency. In parallel to this development, major pharma companies are increasingly outsourcing many components of drug discovery research to biotech companies. All these measures are designed to address the need for a faster time to market. New screening methodologies have contributed significantly to the efficiency of the drug discovery process. The conventional screening of single compounds or compound libraries has been dramatically accelerated by high throughput screening methods. In addition, in silico screening methods allow the evaluation of virtual compounds. A wide range of new lead finding and lead optimization opportunities result from novel screening methods by NMR, which are the topic of this review article.

Drug Discovery Today

Quaternary ammonium-based biomedical materials: State-of-the-art, toxicological aspects and antimicrobial resistance.

The antiviral and antimicrobial activities of licorice, a widely-used Chinese herb.

Tetrazole derivatives are a prime class of heterocycles, very important to medicinal chemistry and drug design due to not only their bioisosterism to carboxylic acid and amide moieties but also to their metabolic stability and other beneficial physicochemical properties. Although more than 20 FDA-approved drugs contain 1 H- or 2 H-tetrazole substituents, their exact binding mode, structural biology, 3D conformations, and in general their chemical behavior is not fully understood. Importantly, multicomponent reaction (MCR) chemistry offers convergent access to multiple tetrazole scaffolds providing the three important elements of novelty, diversity, and complexity, yet MCR pathways to tetrazoles are far from completely explored. Here, we review the use of multicomponent reactions for the preparation of substituted tetrazole derivatives. We highlight specific applications and general trends holding therein and discuss synthetic approaches and their value by analyzing scope and limitations, and also enlighten their receptor binding mode. Finally, we estimated the prospects of further research in this field.

Tetrazoles via Multicomponent Reactions.

Properties of responsible for biological activity tetrazoles are considered. Examples are given of active pharmaceutical ingredients of modern drugs containing the tetrazole ring in the molecular structure. New publications on the synthesis and investigations of biological activity of promising tetrazole-containing compounds are cited.

Medicinal chemistry of tetrazoles

\n\nAdamantane derivatives possess multiple pharmacological activities such\nas antiviral, anticancer, antimycobacterial, antidiabetic, antiparkinsonian and others. The interest of\nmedicinal chemists in adamantane compounds is due to their unique spatial structure, high lipophilicity,\nand carbon cage rigidity. As a result, these molecules can easily penetrate biological lipid\nmembranes and often have unique target-specific activity profile. Another pharmacophore studied in\nthis work is pyridoxine (vitamin B6). Pyridoxine plays highly important roles in living cells as a key\ncofactor of many enzymes. On the other hand, its molecular scaffold is a valuable structural platform\nwhich has led to the development of several launched drugs (Pyritinol, Pirisudanol, Cycletanine,\nMangafodipir) and a wide number of preclinical and clinical drug candidates.\n\n\n\nThe objective of this study is a synthesis of pyridoxine-adamantane and pyridoxinecyclooctane\ndipharmacophore molecules. The underlying idea was to assess the antibacterial and\nantiviral potential of such dipharmacophores, based on multiple examples of promising antiinfective\nagents which have in their structures adamantane and pyridoxine moieties. Another specific reason\nwas to explore the ability of pyridoxine pharmacophore to suppress the potential of microbial pathogens\nto develop resistance to drug molecules.\n\n\n\nIn this study, a series of pyridoxine-adamantane and pyridoxine-cyclooctane dipharmacophore\nmolecules were synthesized based on reactions of three different cycloalkyl amines with the\ncorresponding electrophilic derivatives of pyridoxine aldehydes, chlorides and acetates. All synthesized\ncompounds have been tested for their in vitro activity against M. tuberculosis H37Rv strain and\nH3N2 (A/Aichi/2/68) influenza virus.\n\n\n\nSeries of pyridoxine-adamantane and pyridoxine-cyclooctane dipharmacophore molecules\nwere synthesized based on reactions of three different cycloalkylamines with the corresponding\nelectrophilic derivatives of pyridoxine aldehydes, chlorides and acetates. Reaction of cycloalkylamines\nwith pyridoxine derivatives, in which meta-hydroxyl and ortho-hydroxymethyl groups are\nprotected by acetyl groups, represents a useful alternative to reductive amination of aldehydes and\nnucleophilic substitution of alkyl halides. According to a tentative mechanism, it proceeds via paraand\northo-pyridinone methides which readily react with nucleophiles. None of the synthesized dipharmacophore\ncompounds showed activity against M. tuberculosis H37Rv strain. At the same time,\nthree compounds demonstrated some antiviral activity against H3N2 (A/Aichi/2/68) influenza virus\n(EC50 52-88 µg/mL) that was comparable to the activity of Amantadine, though lower than the activity\nof Rimantadine. The results of this work can be useful in the design of physiologically active\nderivatives of pyridoxine and adamantane.\n\n\n\nThe results of this work can be useful in the design of physiologically active derivatives\nof pyridoxine and adamantane.\n

Synthesis and Antimicrobial Activity of Adamantyl Substituted Pyridoxine Derivatives

New derivatives of dehydroabietylamine were obtained by transformation of primary amino group to pyrrolidine, piperidine, azepane, morpholine, isoindoline, and pyrrole heterocycles. The obtained compounds were tested for antiviral activity against influenza A/California/07/09 (H1N1)pdm09 strain, as well as the activity against some types of bacteria and fungi.

Synthesis of new heterocyclic dehydroabietylamine derivatives and their biological activity

Recent progress of the laboratory in the area of the search and development of novel remedies for prophylaxis and treatment of influenza is reviewed in this work. The data of the study of the anti-viral activity of compounds from the chemical groups of azolo-adamantanes, triterpenes, derivatives of benzimidazole, usnic acid, and other heterocyclic substances are presented. The protective properties of the plant antioxidants at lethal influenza infection of animals are discussed. High virus-inhibiting activity of natural polysaccharides and their complexes with silver ions is shown against influenza virus. The data presented allow listed groups of compounds to be suggested as promising candidates for further development of anti-influenza drugs.

Development of novel drugs against influenza virus based on synthetic and natural compounds

Influenza circulation was substantially reduced after March 2020 in the European region and globally due to the wide introduction of non-pharmaceutical interventions (NPIs) against COVID-19. The virus, however, has been actively circulating in natural reservoirs. In summer 2021, NPIs were loosened in Russia, and influenza activity resumed shortly thereafter. Here, we summarize the epidemiological and virological data on the influenza epidemic in Russia in 2021–2022 obtained by the two National Influenza Centers. We demonstrate that the commonly used baseline for acute respiratory infection (ARI) is no longer sufficiently sensitive and BL for ILI incidence was more specific for early recognition of the epidemic. We also present the results of PCR detection of influenza, SARS-CoV-2 and other respiratory viruses as well as antigenic and genetic analysis of influenza viruses. Influenza A(H3N2) prevailed this season with influenza B being detected at low levels at the end of the epidemic. The majority of A(H3N2) viruses were antigenically and genetically homogenous and belonged to the clade 3C.2a1b.2a.2 of the vaccine strain A/Darwin/9/2021 for the season 2022–2023. All influenza B viruses belonged to the Victoria lineage and were similar to the influenza B/Austria/1359417/2021 virus. No influenza A(H1N1)pdm09 and influenza B/Yamagata lineage was isolated last season.

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Resurgence of Influenza Circulation in the Russian Federation during the Delta and Omicron COVID-19 Era

Novel quinopimaric acid scaffold derivatives were synthesized. Their antiviral activity against influenza A/California/07/09 (H1N1) was studied. It was found that several of the synthesized quinopimaric acid scaffold derivatives were potentially active etiotropic antiviral compounds.

Anna A. Shtro

Papers

Synthesis and Antimicrobial Activity of Adamantyl Substituted Pyridoxine Derivatives

Synthesis of new heterocyclic dehydroabietylamine derivatives and their biological activity

Development of novel drugs against influenza virus based on synthetic and natural compounds

Resurgence of Influenza Circulation in the Russian Federation during the Delta and Omicron COVID-19 Era

Search for Antiviral Agents Among Quinopimaric Acid Scaffold Derivatives