New Adamantane Derivatives Can Overcome Resistance of Influenza A(H1N1)pdm2009 and A(H3N2) Viruses to Remantadine

Шибнев, В. А.; Garaev, T. M.; Финогенова, М. П.; Shevchenko, Ekaterina S.; Burtseva, Elena

doi:10.1007/s10517-012-1684-x

Cited by 17 publications

(6 citation statements)

References 6 publications

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“…A method was proposed to overcome the resistance of influenza A viruses to adamantane series drugs by introducing new functional groups (carboxyl, hydroxyl, imidazole, indole, etc.) into the aminoadamantane carbocycle using amino acids, peptides, or other physiologically important compounds [ 28 ]. The resulting series of carbocyclic derivatives of amino acids and peptides is capable of inhibiting highly pathogenic strains of influenza A viruses, including A/H1N1pdm09, A/H5N1, A/H3N2, etc.…”

Section: Adamantane-type Derivatives With Anti-viral Activitymentioning

confidence: 99%

Physiologically Active Compounds Based on Membranotropic Cage Carriers–Derivatives of Adamantane and Polyhedral Boron Clusters (Review)

Авдеева

Garaev

Малинина

et al. 2022

Russ. J. Inorg. Chem.

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Data on compounds based on cage structures―boron clusters (polyhedral boron hydrides, carboranes, metallacarboranes) and compounds of the adamantane series, which possess physiological activity, have been generalized. The main emphasis is placed on the antiviral activity of the compounds. The mechanism of the possible action of the replication inhibitors of influenza A virus strains is considered, the molecular model of viroporin inhibitors is discussed. The proposed model consists of a cage hydrophobic core that performs the function of a membranotropic carrier (a boron cluster or adamantane fragment), into which physiologically active functional groups are introduced. The relationship between the structure of the cage compound with the introduced substitute and the biologically active properties of this molecular structure has been analyzed.

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Section: Adamantane-type Derivatives With Anti-viral Activitymentioning

confidence: 99%

Physiologically Active Compounds Based on Membranotropic Cage Carriers–Derivatives of Adamantane and Polyhedral Boron Clusters (Review)

Авдеева

Garaev

Малинина

et al. 2022

Russ. J. Inorg. Chem.

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“…Аминокислоты обладают достаточно широким спектром боковых групп, которые могут привнести необходимые свойства будущей молекуле ингибитора. Более того, использование пептидов и некоторых других биологических молекул, введённых в адамантановый карбоцикл методами пептидного синтеза, может в значительной мере расширить поиск наиболее подходящего блокатора канала М2 вируса гриппа [7].…”

Section: оригинальные исследованияunclassified

Adamantan derivatives capable of inhibiting the reproduction of a Rimantadine resistant strain of influenza A(H1N1)pdm09 virus <i>(Influenza A virus, Alphainfluenzavirus, Orthomyxoviridae)</i>

Garaev¹,

Odnovorov

Кириллова³

et al. 2020

Problems of Virology

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Introduction. Adamantanthane-type drugs such as rimantadine and amantadine have long been used to treat diseases caused by influenza A virus. However, as a result of the mutations, influenza viruses have become resistant to aminoadamantans. The target for these drugs was the protein channel M2. Influenza A virus M2 viroporin in the protein shell forms fairly specific ion channels with a diameter of about 11 Å, specializing in transporting protons inside the viral particle (virion). Restoration of the antiviral properties of adamantanthane-type drugs consists in the selection of advanced functional groups bound by the carbocycle to find new sites of binding to the protein target M2.The рurpose of the study is to identify the antiviral properties of new adamantanum derivatives to the pandemic strain of influenza A virus in vitro.Material and methods. Compounds of aminoadamantans with amino acids and other organic molecules were obtained by classical peptide synthesis methods. The structure of the compound was tested by means of physical and chemical methods. Antiviral properties of synthetic compounds were studied in vitro on monolayer MDCK cells infected with pandemic strain of influenza A/California/07/2009 virus in two schemes of administration of investigated compounds and virus.Results. The reference strain of the influenza virus A/California/07/2009(H1N1) was sensitive to the compounds under test in varying degrees. The antiviral activity of the compounds was expressed in a 50% inhibitory concentration (IС50) ranging from 0.5 to 2.5 мкM, which is generally a good indicator for the Rimantadine/Amantadine resistant strain.Discussion. The values of the IС50 for compounds introduced two hours before contact with the virus were slightly higher than those for single-moment introduction of the substance and virus. The effect of increasing the inhibitory concentration in the prophylactic scheme of compounds was valid for all compounds of the experiment.Conclusion. The presented synthetic compounds are active against the variant of influenza A virus resistant to Rimantadine and Amantadine preparations. The obtained compounds can be used as model structures for creation of a new drug of direct action against advanced strains of influenza A virus.

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“…Preclinical in vitro and in vivo studies demonstrated the pronounced activity of the new substance against rimantadine and amantadine resistant strains of influenza A virus in comparison with other analogs [12,13], which served as the basis for further clinical trials of H-His-Rim•2HCl•H2O. The identification of the new substance and the determination of its properties are crucial for further testing.…”

Section: Fig 1: Structural Formula Of L-histidyl-1-adamantylethylamin...mentioning

confidence: 99%

Physicochemical Properties and Biological Activity of the New Antiviral Substance

Odnovorov

GREBENNIKOVA²,

Pleteneva³

et al. 2020

Int J App Pharm

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Objective: To develop a set of quality control procedures for the promising antiviral pharmaceutical substance L-histidyl-1-adamantylethylamine dihydrochloride monohydrate, a derivative of rimantadine. Methods: Substances and solvents: synthesized in laboratory L-histidyl-1-adamantylethylamine dihydrochloride monohydrate (H-His-Rim•2HCl•H2O), rimantadine hydrochloride (Rim•HCl), 99%, ethanol 96%, N, N-dimethylformamide (DMF) anhydrous, 99.8% and n-hexane anhydrous, 95%, deionized high-resistance water (18.2 MΩ•cm at 25 °C, Milli-Q system), silver nitrate. Infrared (IR) Spectroscopy–Cary 630 Fourier Transform IR Spectrometer, elemental analysis–elemental composition analyzer CHNS-O EuroEA3000, ultraviolet (UV) spectrometry–Cary-60 spectrophotometer, polarimetry–POL-1/2 polarimeter with an external Peltier module, granulometric analysis by optical microscopy (Altami BIO 2 microscope) and low-angle laser light scattering (LALLS)–Master Sizer 3600, measurement of potential for hydrogen–potentiometer PB-11, Spirotox method–the study of temperature dependences of Spirostomum ambiguum lifetime to characterize the biological activity of the studied compounds. Results: The substance H-His-Rim•2HCl•H2O is an amorphous yellowish powder, slightly soluble in water, soluble in ethanol, freely soluble in N, N-dimethylformamide, and practically insoluble in n-hexane. A study of the elemental composition has confirmed the authenticity of H-His-Rim•2HCl•H2O. Comparison of the spectral characteristics of H-His-Rim•2HCl•H2O and Rim•HCl by IR spectroscopy and UV spectrometry confirmed the authenticity of the substance. The racemic form of the substance Rim•HCl with an insignificant amount of impurity of the levorotatory enantiomer was proved polarimetrically: α =-0.0126±0.0003 (1% aqueous solution, 20±0.5 °С). The specific optical rotation of 1% aqueous solution H-His-Rim•2HCl•H2O . In 1% ethanol solution -10.32±0.12. Using the method of laser light diffraction for a substance H-His-Rim•2HCl•H2O, the dimensional spectra «fraction of particles, %-d, μm» were characterized, the maximum of which in hexane is in the region of 40–50 μm. Arrhenius’s kinetics on the Spirotox model established statistically significant differences in ligand-receptor interactions, which are characterized by values of observed apparent activation energy °bsEa, kJ/mol: 132.36±1.55 for H-His-Rim•2HCl•H2O and 176.15±0.48 for Rim•HCl. Conclusion: The developed set of methods for assessment of physical and chemical properties and biological activity of a new antiviral substance H-His-Rim•2HCl•H2O is the basis for establish of regulatory documentation.

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New Adamantane Derivatives Can Overcome Resistance of Influenza A(H1N1)pdm2009 and A(H3N2) Viruses to Remantadine

Cited by 17 publications

References 6 publications

Physiologically Active Compounds Based on Membranotropic Cage Carriers–Derivatives of Adamantane and Polyhedral Boron Clusters (Review)

Physiologically Active Compounds Based on Membranotropic Cage Carriers–Derivatives of Adamantane and Polyhedral Boron Clusters (Review)

Adamantan derivatives capable of inhibiting the reproduction of a Rimantadine resistant strain of influenza A(H1N1)pdm09 virus <i>(Influenza A virus, Alphainfluenzavirus, Orthomyxoviridae)</i>

Physicochemical Properties and Biological Activity of the New Antiviral Substance

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