KFU. Card publication. Synthesis and antimicrobial activity of adamantyl substituted pyridoxine derivatives

KAZAN
FEDERAL UNIVERSITY

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SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF ADAMANTYL SUBSTITUTED PYRIDOXINE DERIVATIVES

Form of presentation

Articles in international journals and collections

Year of publication

2019

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Authors, employees of KFU

Pavelev Roman Sergeevich, author

Bibliographic description in the original language

Khaziev R. Synthesis and antimicrobial activity of adamantyl substituted pyridoxine derivatives / R. Khaziev, N. Shtyrlin, R. Pavelyev, R. Nigmatullin, R. Gabbasova, D. Grishaev, A. Shtro, A. Galochkina, Y. Nikolaeva, T. Vinogradova, O. Manicheva, M. Dogonadze, O. Gnezdilov, E. Sokolovich, P. Yablonskiy, K. Balakin, Y. Shtyrlin // Letters in Drug Design & Discovery. – 2019. – V 16 (12). – R. 1360 – 1369.

Annotation

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

Keywords

Pyridoxine, adamantane derivatives, antimycobacterial activity, antiviral activity, M. tuberculosis, dipharmacophore molecules.

The name of the journal

Letters in Drug Design and Discovery

URL

http://www.eurekaselect.com/174810/article

Please use this ID to quote from or refer to the card

https://repository.kpfu.ru/eng/?p_id=233320&p_lang=2

Full metadata record

Field DC	Value	Language
dc.contributor.author	Pavelev Roman Sergeevich	ru_RU
dc.date.accessioned	2019-01-01T00:00:00Z	ru_RU
dc.date.available	2019-01-01T00:00:00Z	ru_RU
dc.date.issued	2019	ru_RU
dc.identifier.citation	Khaziev R. Synthesis and antimicrobial activity of adamantyl substituted pyridoxine derivatives / R. Khaziev, N. Shtyrlin, R. Pavelyev, R. Nigmatullin, R. Gabbasova, D. Grishaev, A. Shtro, A. Galochkina, Y. Nikolaeva, T. Vinogradova, O. Manicheva, M. Dogonadze, O. Gnezdilov, E. Sokolovich, P. Yablonskiy, K. Balakin, Y. Shtyrlin // Letters in Drug Design & Discovery. – 2019. – V 16 (12). – �. 1360 – 1369.	ru_RU
dc.identifier.uri	https://repository.kpfu.ru/eng/?p_id=233320&p_lang=2	ru_RU
dc.description.abstract	Letters in Drug Design and Discovery	ru_RU
dc.description.abstract	Adamantane derivatives possess multiple pharmacological activities such as antiviral, anticancer, antimycobacterial, antidiabetic, antiparkinsonian and others. The interest of medicinal chemists in adamantane compounds is due to their unique spatial structure, high lipophilicity, and carbon cage rigidity. As a result, these molecules can easily penetrate biological lipid membranes and often have unique target-specific activity profile. Another pharmacophore studied in this work is pyridoxine (vitamin B6). Pyridoxine plays highly important roles in living cells as a key cofactor of many enzymes. On the other hand, its molecular scaffold is a valuable structural platform which has led to the development of several launched drugs (Pyritinol, Pirisudanol, Cycletanine, Mangafodipir) and a wide number of preclinical and clinical drug candidates. Objective: The objective of this study is a synthesis of pyridoxine-adamantane and pyridoxinecyclooctane dipharmacophore molecules. The underlying idea was to assess the antibacterial and antiviral potential of such dipharmacophores, based on multiple examples of promising antiinfective agents which have in their structures adamantane and pyridoxine moieties. Another specific reason was to explore the ability of pyridoxine pharmacophore to suppress the potential of microbial pathogens to develop resistance to drug molecules. Methods: In this study, a series of pyridoxine-adamantane and pyridoxine-cyclooctane dipharmacophore molecules were synthesized based on reactions of three different cycloalkyl amines with the corresponding electrophilic derivatives of pyridoxine aldehydes, chlorides and acetates. All synthesized compounds have been tested for their in vitro activity against M. tuberculosis H37Rv strain and H3N2 (A/Aichi/2/68) influenza virus. Results: Series of pyridoxine-adamantane and pyridoxine-cyclooctane dipharmacophore molecules were synthesized based on reactions of three different cycloalkylamines with the corresponding electrophilic derivatives of pyridoxine aldehydes, chlorides and acetates. Reaction of cycloalkylamines with pyridoxine derivatives, in which meta-hydroxyl and ortho-hydroxymethyl groups are protected by acetyl groups, represents a useful alternative to reductive amination of aldehydes and nucleophilic substitution of alkyl halides. According to a tentative mechanism, it proceeds via paraand ortho-pyridinone methides which readily react with nucleophiles. None of the synthesized dipharmacophore compounds showed activity against M. tuberculosis H37Rv strain. At the same time, three compounds demonstrated some antiviral activity against H3N2 (A/Aichi/2/68) influenza virus (EC50 52-88 μg/mL) that was comparable to the activity of Amantadine, though lower than the activity of Rimantadine. The results of this work can be useful in the design of physiologically active derivatives of pyridoxine and adamantane.	ru_RU
dc.language.iso	ru	ru_RU
dc.subject	Pyridoxine	ru_RU
dc.subject	adamantane derivatives	ru_RU
dc.subject	antimycobacterial activity	ru_RU
dc.subject	antiviral activity	ru_RU
dc.subject	M. tuberculosis	ru_RU
dc.subject	dipharmacophore molecules.	ru_RU
dc.title	Synthesis and antimicrobial activity of adamantyl substituted pyridoxine derivatives	ru_RU
dc.type	Articles in international journals and collections	ru_RU