Mendeleev
Communications
Mendeleev Commun., 2020, 30, 347–349
Synthesis of new physiologically active (2-oxoimidazolidin-5-yl)indoles
Lyudmila A. Sviridova,a Polina S. Protopopova,b Mikhail G. Akimov,c Maria S. Dudina,c
Elizaveta K. Melnikovaa,b and Konstantin A. Kochetkov*b,d
a Department of Chemistry, M. V. Lomonosov Moscow State University, 119991 Moscow, Russian Federation
b A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. E-mail: const@ineos.ac.ru
c M. M. Shemyakin–Yu. A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences,
117997 Moscow, Russian Federation. E-mail: akimovmike@yandex.ru
d D. I. Mendeleev University of Chemical Technology of Russia, 125047 Moscow, Russian Federation
DOI: 10.1016/j.mencom.2020.05.029
H
N
Boron trifluoride-catalyzed amidoalkylation of indole
R'
O
Ph
N
R'
derivatives with 5-hydroxy-1-phenylimidozolidin-2-one
affords new biheterocycles with a direct C–C bond. Among
them, 3- or 2-(2-oxoimidazolidin-5-yl)indoles manifest anti-
inflammatory activity with relatively low toxicity.
N
N
N
O
Ph
N
R
N
H
R'
R
R
6 examples
2 examples
Keywords: amidoalkylation, biheterocycles, 3- or 2-(2-oxoimidazolidin-5-yl)indoles, anti-inflammatory activity, indoles,
imidazolylindoles.
Heterocyclic compounds containing a 2- or 3-substituted
indole moiety are the most widespread constituents of natural
and synthetic bioactive molecules.1 In most cases, the
biological activity of a compound is directly related to the
presence of an indole core2 in the molecule. Nowadays, the
therapeutic potential of indole pharmaceuticals (Indomethacin,
Roxindole, Indalpine, Delavirdine, Perindopril, Ondansetron,
Sumatriptan, Tadalafil, Fluvastatin, etc.) has been exhausted.
Therefore, a search for new analogues is underway, and their
efficiency as anti-inflammatory,3 anti-HIV,4 antituberculous,5
anti-malarial6 and anticonvulsant drugs7 is being estimated.
In addition, indole-containing compounds with antidiabetic,8
However, this approach is still not widely used to obtain
biheterocycles in which two heterocyclic moieties are directly
bound by a carbon–carbon bond, and which belong to new
pharmacologically oriented heterocyclic ensembles. At the
same time, in terms of anti-inflammatory drug design based
on 2- or 3-substituted indoles, direct incorporation of the
imidazolidin-2-one group into this heterocyclic scaffold to
give 2- or 3-(2-oxoimidazolidin-5-yl)indoles can ensure its
interaction with the hydrophobic pockets of the target protein,
in particular, due to acceptors and hydrogen bond donors in
functional derivatives at positions 1 and 5.
The purpose of this work was to synthesize such new
3- or 2-(2-oxoimidazolidin-5-yl)indoles 1 and 2, respectively,
using amidoalkylation reaction with 5-hydroxy-1-phenyl-
imidazolidin-2-one 3 as the key reactant (Scheme 1). The
possibility of using available 5-hydroxyimidazolidin-2-ones as
amidoalkylating agents for the preparation of biheterocyclic
compounds was not studied to date. One of the probable reasons
is that their hydroxy group is eliminated rather readily under acid
and alkaline catalysis conditions. Compound 3 was obtained by
chemoselective reduction22 of the amide moiety of the
corresponding hydantoin derivative (see Scheme 1).
The next amidoalkylation step (see Scheme 1) was carried
out under Lewis acid catalysis. Performing the reaction in THF
in the presence of catalytic amounts of boron trifluoride
etherate provided satisfactory results to afford desired
biheterocycles 1a–f and 2a,b in 11–32% yields.
Comparative analysis of isomeric amidoalkylation products,
namely, 1b vs. 2a and 1e vs. 2b, showed that such isomers had
different physicochemical properties and their 1H NMR spectra
were different.† The aliphatic parts of these spectra retain the
antimicrobial,9
antitumor,10,11
antifungal,12,13
anti-
dyslipidemic14 and other valuable properties are known.
However, the potential of indole-based small molecules as
anti-inflammatory agents has been studied rather poorly.
In turn, incorporation of a heterocyclic moiety into the
indole molecule may be promising in terms of adjusting the
existing biological activity, improving the pharmacological
properties and finding its new types, as well as creating new
drugs.14–17 Incorporating an additional heterocycle into
bioactive molecules can affect their pKa, construct
conformational hindrance, vary the hydrophilic-hydrophobic
balance or increase lipophilicity. Moreover, these parameters
can be modulated both separately and in various
combinations.18 Substituted imidazolylindoles also exhibit a
wide range of physiological activity, in particular, as C protein
kinase inhibitors.19 Two heterocyclic moieties, imidazolidin-
2-one and indole, are combined in Sertindole, an antipsychotic
drug used in the treatment of schizophrenia.20 Thus,
incorporation of an additional heterocyclic core allows one to
obtain compounds that are superior in activity to the currently
used drugs.21
†
For details, see Online Supplementary Materials.
© 2020 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
– 347 –
Akimov, Mikhail G.
