Synthesis and Antimicrobial Activity of Adamantyl Substituted Pyridoxine Derivatives
Authors: Khaziev Rail , Shtyrlin Nikita , Pavelyev Roman , Nigmatullin Raushan , Gabbasova Raylya , Grishaev Denis , Shtro Anna , Galochkina Anastasia , Nikolaeva Yulia , Vinogradova Tatiana , Manicheva Olga , Dogonadze Marine , Gnezdilov Oleg , Sokolovich Evgenii , Yablonskiy Petr , Balakin Konstantin , Shtyrlin Yurii 
Published: September 2019

Background:

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.

Conclusion:

The results of this work can be useful in the design of physiologically active derivatives
of pyridoxine and adamantane.