New Adamantane Derivatives with NO-Generating Fragment

Article abstract of DOI:10.1134/S0012500818010044

An approach to the synthesis of adamantane derivatives with NO-generating fragment containing nitroxy group has been developed. 1-Aminoadamantane, memantine, and adamantanecarboxylic acid have been used as initial compounds. The prepared compounds have shown ability to generate nitric oxide in a system mimicking biological reactions of nitro group reduction.

Full text of DOI:10.1134/S0012500818010044

ISSN 0012-5008, Doklady Chemistry, 2018, Vol. 478, Part 1, pp. 9–11. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © I.V. Serkov, A.N. Proshin, A.K. Ustinov, B.V. Lednev, E.V. Fomina-Ageeva, A.M. Ashba, V.V. Bezuglov, S.O. Bachurin, 2018, published in Doklady
Akademii Nauk, 2018, Vol. 478, No. 2, pp. 168–171.
CHEMISTRY
New Adamantane Derivatives with NO-Generating Fragment
I. V. Serkova,*, A. N. Proshina, A. K. Ustinova, B. V. Ledneva, E. V. Fomina-Ageevab, A. M. Ashbab,
V. V. Bezuglovb, and Corresponding Member of the RAS S. O. Bachurina
Received August 21, 2017
Abstract—An approach to the synthesis of adamantane derivatives with NO-generating fragment containing
nitroxy group has been developed. 1-Aminoadamantane, memantine, and adamantanecarboxylic acid have
been used as initial compounds. The prepared compounds have shown ability to generate nitric oxide in a sys-
tem mimicking biological reactions of nitro group reduction.
DOI: 10.1134/S0012500818010044
Compounds based on adamantane, a saturated tri- imino group, which according to literature data also
cyclic bridged hydrocarbon, attract considerable scru- can behave as a donor of nitric oxide [10]. Initial com-
tiny as promising candidates for pharmaceuticals. pounds were 1-aminoadamantane (1a), memantine
These compounds exhibit various biological activity, (1b), and adamantanecarboxylic acid (10).
including antiviral [1, 2], antibacterial [3], antifungal
[4], etc. Adamantane derivatives found practical
application as pharmaceuticals, for example, 1-
amino-3,5-dimethyladamantane (Memantine) is one
of few drugs used for the treatment of Alzheimer’s dis-
ease [5], while Rimantadine (α-methyltricy-
clo[3.3.1.1.7]decan-1-methanamine hydrochloride) is
known as a remedy to treat and prevent influenza. At
present, a strategy to design new efficient drugs based
on multitarget pharmaceuticals affecting simultane-
ously several biological targets is under development.
A search for multipharmacophoric agents on adaman-
tane basis is in progress in recent years [6, 7].
One of the approaches to extend the spectrum of
biological targets is the introduction into molecule of
biologically active compound of additional fragment
capable of releasing nitric oxide (NO) participating in
regulation of different signaling routes [8, 9].
The aim of this work is to develop approaches to
the synthesis of new bifunctional adamantane deriva-
tives with an NO-releasing fragment containing
nitroxy group (Schemes 1 and 2).
1-Aminoadamantane (1a) and memantine (1b)
were converted by reacting with phosgene into corre-
sponding isocyanates (2a, 2b). Obtained isocyanates 2a
and 2b were condensed with nitroethanolamine to give
adamantane derivatives of urea containing NO-gener-
ating fragment (3a and 3b, Scheme 1).
Compound 6 with hydroxyimino group was syn-
thesized in the same manner. Initially, 1-aminoada-
mantane (1a) was condensed with 3-acetylphenyl iso-
cyanate (4) to give urea (5), which was reacted with
hydroxylamine to afford hydroxyimino derivative of
adamantane (6, Scheme 1). Compound 9 was
obtained from aminoadamantane (1a) by alkylation
with 3-bromopropanol (7) followed by esterification
of the resultant alcohol (8) with concentrated nitric
acid (Scheme 1).
Another approach to the synthesis of NO-generat-
ing hybrid compounds is based on the use of adamantan-
ecarboxylic acid (10) as initial compound (Scheme 2),
which was reacted with thionyl chloride to form acid
chloride (11). The latter compound was condensed
with 2-aminoethyl nitrate and glycerol 1,3-dinitrate to
give N-(2-nitroethyl)(1-adamantyl)carboxamide (12)
and glycerol 1,3-dinitrate-2-(1-adamantyl)carboxyl-
ate (13). Table 1 displays 1H NMR spectra.
All obtained compounds showed the ability to pro-
duce NO in a system mimicking biological reactions of
nitro group reduction. L-Cysteine and granulated
cadmium metal were used as reducing agents. The
generating ability was assessed from the amount of the
formed nitrite ion using Griess test by a modified pro-
cedure [11]. The reaction with L-cysteine (10 mM) or
cadmium metal was conducted in a phosphate salt
buffer (pH 7.4) at ambient temperature for 3 h. All
These compounds related to organic nitrates can
release nitric oxide in the presence of biological reduc-
ing agents. To compare NO-generating activity, we
prepared adamantane derivative containing hydroxy-
aInstitute of Physiologically Active Substances,
Russian Academy of Sciences, Chernogolovka,
Moscow oblast, 142432 Russia
bShemyakin–Ovchinnikov Institute of Bioorganic Chemistry,
Russian Academy of Sciences, Moscow, 117997 Russia
*e-mail: serkoviv@mail.ru
9

10
SERKOV et al.
H
N
H
N
vi
OH
ONO2
8
9
v
Br
OH
(R = H)
7
O
H
N
HCl
NH2
R
R
R
R
ii
i
NCO
N
H
ONO2
H2N
ONO2
HCl
R
R
1a R = H;
1b R = Me
2a R = H;
2b R = Me
3a R = H;
3b R = Me
O
iii
(R = H)
NCO
4
H
N
H
N
iv
O
N OH
N
H
N
H
O
O
5
6
i ―COCl2, CHCl3, Et3N, 0°C, 30 min; ii―CHCl3, Et3N, 25°C, 2 h; iii―CHCl3, Et3N, 4, 25°C, 18 h;
iv ―MeOH, NH2OH · HCl, AcONa, 25°C, 2 h; v―MeCN, K2CO3, 7, sealed ampule, 80°C, 48 h;
vi―CHCl3, 100% HNO3, 0°C, 30 min
Scheme 1.
O
ii
N
H
ONO2
O
O
i
12
OH
Cl
10
11
O
iii
ONO2
ONO2
O
13
i ―COCl2, CHCl3, 50°C, 3 h; ii―CHCl3, O2NOCH2CH2NH2 · HNO3, Et3N, 25°C, 5 h;
iii―CHCl3, glycerol 1,3-dinitrate, Et3N, 25°C, 18 h
Scheme 2.
compounds were preliminary dissolved in ethanol, ali- compounds spontaneously evolved nitric oxide and
quots were taken to determine the generating ability in the determined concentration of nitrite ion was the
such a manner that the concentration of the tested same as in the blank test. The comparison of the NO
compound in the reaction solution was 156 μM. In generation intensity under the action of cysteine and
control experiments, we found that none of the tested cadmium metal showed that the amount of the formed
DOKLADY CHEMISTRY
Vol. 478
Part 1
2018

NEW ADAMANTANE DERIVATIVES
11
Table 1. 1H NMR spectral data
NO generation,
μM/156 μM of substance,
1H NMR spectrum (CDCl3), δ, ppm
Compound
n = 3
3a
3b
6
4.71 (1H, t, J = 5.0 Hz, NH), 4.51 (2H, t, J = 5.0 Hz, CH2ONO2), 4.35 (1H,
br s, NH), 3.59 (2H, q, J = 5.3 Hz, NCH2), 2.05 (3H, s, 3 × CH), 1.93 (6H,
m, 3 × CH2), 1.66 (6H, s, 3 × CH2)
4.56 (1Н, brs, NH), 4.53 (2H, t, J = 5.1 Hz, CH2ONO2), 4.35 (1Н, brs, NH),
3.59 (2H, q, J = 5.1 Hz, NCН2), 2.09 (1Н, m, СН), 1.91 (2Н, d, CH2), 1.72
(4Н, s, 2'CH2), 1.43 (4Н, m, 2'CH2), 1.24 (2Н, s, СН2), 0.93 (6Н, s, 2'CH3)
7.80 (2H, m, Harom), 7.59 (1H, m, Harom), 7.38 (1H, m, Harom), 6.67 (1H, s,
NH), 4.75 (1H, s, NH), 2.66 (3Н, s, СН3), 2.10 (3H, s, 3 × CH), 2.04 (6H,
m, 3 × CH2), 1.69 (6H, s, 3 × CH2)
89.8 3.5
68.4 2.2
26.5 0.6
57.6 0.4
9
9.11 (1H, br s, NH), 4.56 (2H, t, J = 5.9 Hz, CH2ONO2), 2.93 (2H, m,
NCH2), 2.33 (2H, m, CH2), 2.13 (3H, s, 3 × CH), 1.95 (6H, s, 3 × CH2), 1.64
(6H, s, 3 × CH2)
12
13
4.53 (2H, t, J = 5.1 Hz, CH2ONO2), 3.59 (2H, m, NCH2), 1.90 (3H, s, 3 × CH),
1.83 (6H, m, 3 × CH2), 1.70 (6H, s, 3 × CH2)
4.54 (4H, m, 2 × CH2ONO2), 4.26 (1H, m, CH), 2.03 (3H, s, 3 × CH), 1.87
(6H, m, 3 × CH2), 1.71 (6H, s, 3 × CH2)
63.9 1.1
119.0 1.6
nitrite ion is by an order of magnitude higher in sam-
ples where cadmium was used as a reducing agent.
Thus, the concentration of nitrite ion in an incubation
medium (3 h, 37°C) for nitro ester (9) was 3.28 and
52.15 μM on the use of L-cysteine and cadmium,
respectively. Therefore, we used cadmium metal
reduction to compare generating activity of the
obtained compounds. Glycerol 1,3-dinitrate-2-(1-
adamantyl)carboxylate (13) showed the highest gener-
ating activity, monoesters were less active almost two-
fold. Among ureas 3a and 3b, adamantane derivative 3a
was a reliably more active donor of nitric oxide by a
factor of 1.3. Hydroxyimino derivative 6 showed the
least NO-generating activity (Table 1).
ACKNOWLEDGMENTS
The synthetic portion of the work was supported by
the Russian Science Foundation (grant no. 14–23–
00160P).
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Translated by I. Kudryavtsev
DOKLADY CHEMISTRY Vol. 478 Part 1 2018