Antimicrobial activity of imidazo[1,5-a]quinoxaline derivatives with pyridinium moiety

Article abstract of DOI:10.1016/j.ejmech.2013.05.038

3-Phenyl(methyl)-5-alkyl-1-(pyridin-3-yl)imidazo[1,5-a]quinoxalin-4-ones (2a-f) and their N-alkyl-pyridinium salts (3a-o), including 1,n-bis{3-(3- phenylimidazo[1,5-a]quinoxalin-4(5H)-on-1-yl)pyridinium}alkane dibromides (4a-d, 5, 6) have been synthesized. It has been established that the antimicrobial properties of imidazo[1,5-a]quinoxaline derivatives are connected with the presence of various alkyl substituents in the position 1 of the pyridine ring and in the position 5 of the imidazo[1,5-a]quinoxaline system. Chlorides and iodides are more active towards bacteria than fungi. Compounds 3d, 3e, 3m and 3n showed an effective bacteriostatic activity. Compound showed not only well defined bacteriostatic activities but also good fungistatic activities, with the MIC values comparable with the reference drugs. Toxicity of more effective (imidazo[1,5-a]quinoxalin-4-on-1-yl)-1-pyridinium halides was examined in mice.

Full text of DOI:10.1016/j.ejmech.2013.05.038

European Journal of Medicinal Chemistry 66 (2013) 345e354
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Antimicrobial activity of imidazo[1,5-a]quinoxaline derivatives with
pyridinium moietyq
,
b
Alexey A. Kalinin a, Alexandra D. Voloshina a, Nataliya V. Kulik a, Vladimir V. Zobov a
,
,
Vakhid A. Mamedova
*
a A.E. Arbuzov Institute of Organic and Physical Chemistry of the Russian Academy of Sciences, Arbuzov Str. 8, Kazan 420088, Russian Federation
b Kazan State University, Kazan 420008, 18 Kremlyovskaya str., Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
3-Phenyl(methyl)-5-alkyl-1-(pyridin-3-yl)imidazo[1,5-a]quinoxalin-4-ones (2aef) and their N-alkyl-
pyridinium salts (3aeo), including 1,n-bis{3-(3-phenylimidazo[1,5-a]quinoxalin-4(5H)-on-1-yl)pyr-
idinium}alkane dibromides (4aed, 5, 6) have been synthesized. It has been established that the anti-
microbial properties of imidazo[1,5-a]quinoxaline derivatives are connected with the presence of various
alkyl substituents in the position 1 of the pyridine ring and in the position 5 of the imidazo[1,5-a]qui-
noxaline system. Chlorides and iodides are more active towards bacteria than fungi. Compounds 3d, 3e,
3m and 3n showed an effective bacteriostatic activity. Compound showed not only well defined
bacteriostatic activities but also good fungistatic activities, with the MIC values comparable with the
reference drugs.
Received 31 March 2013
Received in revised form
8 May 2013
Accepted 25 May 2013
Available online 7 June 2013
Keywords:
Imidazo[1,5-a]quinoxalines
Pyridinium salt
Toxicity of more effective (imidazo[1,5-a]quinoxalin-4-on-1-yl)-1-pyridinium halides was examined in
mice.
Bacteriostatic activity
Fungistatic activity
Ó 2013 Elsevier Masson SAS. All rights reserved.
1. Introduction
GABAa receptor ligands or prodrugs and selective GABA agonists,
antagonists or inverse agonists of GABA receptors [16e20]. They are
Heterocyclic systems containing quinoxaline moiety exhibit
important biological activities. Many of them possess anticancer
[1,2], antiviral [3], antibacterial [4], antiinflammatory [5] properties
and serve as inhibitor of enzymes by catalyzing the transport of the
phosphate group from ATP (kinase inhibitor) [6]. Quinoxalines are
used as antibiotics [7,8], DNA-binding agents [9], building blocks in
the synthesis of anion receptors [10], etc. Imidazoquinoxaline is one
of the important classes of heterocycles that are often found in
biologically active and pharmacologically useful agents such as
Dazoquinast (antiallergic), FG 10571, NNC 14-0571, Panadiplon, U-
78875 anxiolytic (benzodiazepine receptor partial agonist), U-8044
(antidepressant, anxiolytic), U-97775 (anxiolytic (GABAA receptor
ligand)) and LU 73068 (anticonvulsant glycine/NMDA) but not in
the NMDA receptor antagonist (Fig. 1) [11].
also used for the treatment of anxiety, sleep disorders, seizure
disorders or for memory enhancement [20]. Many of these com-
pounds contain substituents in various positions of 1,2,4-oxadiazol-
3-yl [3,8,9,11,12,15], 1,2,4-oxadiazol-5-yl [14], 1,2-oxazol-3-yl [13],
2-oxazol-5-yl [13], imidazol-1-yl [21e23], pyrrolidin-1-yl [15,23]
and morpholin-4-yl [21,23] moieties. This affects the manifesta-
tion of one or the other kind of properties. There is only one patent
with the imidazo[1,5-a]quinoxaline derivatives containing a pyr-
idinyl moiety in their structure as useful in treatment of central
nervous system diseases such as psychosis and also in treatment of
obesity, type 2 diabetes, metabolic syndrome, glucose intolerance,
and pain [24].
The introduction of a pyridyl moiety with the free nitrogen atom
into imidazoquinoxalines is assumed to greatly enhance their
possibilities in synthesis and also in searching for physiologically
active compounds. We assumed that due to the additional binding
with the biotarget the efficiency of a specific moiety connected
with imidazo[1,5-a]quinoxaline and pyridyl units would dramati-
cally increase. The latter can be caused by the more rigid framework
of the bis-heterocyclic systems with two quaternized nitrogen
atoms in comparison with their mono counterparts. The bis-
heterocyclic system involves complementary with the biotarget,
Some of the derivatives of imidazoquinoxalines are used in the
treatment of central nervous system ailments [12,13] such as
anticonvulsant, anxiolytic, hypnotic, and sedative/hypnotic prop-
erties [13e15]. Imidazoquinoxalines are proved to be useful as
q
Dedicated to the 75th anniversary of Professor Vladimir Savich Reznik.
* Corresponding author.
E-mail address: mamedov@iopc.ru (V.A. Mamedov).
0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2013.05.038

346
A.A. Kalinin et al. / European Journal of Medicinal Chemistry 66 (2013) 345e354
Fig. 1. Some quinoxaline derivatives of pharmacolical interest.
particularly with the bis-heterocyclic systems with two pyridyl
moieties and can exhibit activity due to the macrocyclic framework
as a specific target.
to display the potency. As new infectious diseases appear time to
time, it has become especially important to search for absolutely
new agents for their remedy.
To our knowledge, in spite of advances in imidazo[1,5-a]qui-
noxalines chemistry, the biological activity for these compounds
have so far not been investigated. The possible explanation might
be due to the insolubility of almost all the known imidazo[1,5-a]
quinoxalines in water, which prevents testing their biological
properties. A wide screening of various kinds of biological activity is
possible for imidazoquinoxalines of this type.
2. Chemistry
We have recently reported the synthesis of imidazo[1,5-a]
quinoxalines by the reaction of 3-aroylquinoxalin-2(1H)-ones and
their N-alkyl analogues with benzylamines in DMSO. The reaction
It is known that quaternary ammonium salts in combination
with lipophilic residues display nonspecific activity through inter-
action with cell walls and cell membranes of microorganisms. The
use of organic cations as disinfectants in agriculture, food pro-
cessing industry and clinics is particularly important because they
possess a high antibacterial activity and a broad spectrum of anti-
microbial activity. Taking into account of the above points and
considering the imidazoquinoxaline framework as a specific target
to interfere with the main biochemical pathways (cell wall syn-
thesis, DNA and RNA synthesis, protein formation) we have pre-
pared a series of 1-(pyridin-3-yl)imidazo[1,5-a]quinoxalin-4-ones,
and quaternized them by benzyl and alkyl halides. This preliminary
communication demonstrates the in vitro antibacterial and anti-
fungal activities of the imidazo[1,5-a]quinoxalinones and their
toxicity, which have so far not been studied. We have also syn-
thesized and tested a new type of imidazo[1,5-a]quinoxalinaphane
with two 1-(pyridin-3-yl)imidazo[1,5-a]quinoxalin-4-one units
and two spacers. One of them is the decamethylene fragment
which connects the N4 and N40 of the carbamoyl function of pyr-
azinone ring systems, and another one is the m-xylylene fragment
which connects N and N0 of the pyrimidine rings. Besides, we tested
the 1-(pyridin-3-yl)imidazo[1,5-a]quinoxalin-4-ones with the
structural features of the examined bis-compounds and imidazo
[1,5-a]quinoxalinaphane. The imidazo[1,5-a]quinoxalin-4-ones are
subjected to screening in an attempt to determine the units
responsible for antimicrobial activity and to evaluate the impor-
tance of ring-closure for efficiency. The objective of our study is to
generate novel bioactive compounds and to optimize the structure
proceeds through an intermediate formation of N-(a-quinox-
alinylbenzylydene)benzylamine, which when subjected to oxida-
tive cyclocondensation gives imidazo[1,5-a]quinoxalines [25]. The
same synthetic protocol was used for the preparation of pyridyl
containing imidazo[1,5-a]quinoxalin-4-ones. The use of 3-
acylquinoxalin-2(1H)-ones 1a, g and N-alkyl derivatives 1beh,
and aminomethylpyridines make it possible to develop funda-
mentally new methods of imidazoannulation and lead to 1-
pyridylimidazo[1,5-a]quinoxalin-4(5H)-ones 2g, h and their N-
alkylated derivatives 2bef (Scheme 1). The 1-pyridylimidazo[1,5-
a]quinoxalin-4(5H)-ones 2a, g, h were synthesised from ketones
1a, b, g and picolylamines under heating conditions in DMSO in
good yields [25]. In the cases of cef a modified procedure
involving alkylation of compound 1a with alkylbromide was used
with subsequent imidazoannulation of the crude N-bromalkyl
derivatives 1bef with the 3-picolylamine. The products 2bef
were readily isolated in pure form by filtration and the overall
yield of the two-stage process 1a / 1bef / 2bef is 44e57%
(Scheme 1).
The reaction of 1-(pyridin-3-yl)imidazo[1,5-a]quinoxalin-
4(5H)-ones with various types of alkyl halides gave rise to water-
soluble derivatives 3, 4, 6 with a quaternized nitrogen atom in
the pyridine ring system. Reaction conditions were optimised to
obtain compounds 4 in which they were precipitated in their pure
form from the reaction mixture. The synthesis of compounds 4a, b,
containing the NH group, were carried out in DMF, whereas syn-
thesis of compounds 4c, d with N-alkylated fragment in acetonitrile
(Table 1).
N
R3
R2
N
N
R2
N
N
N
R1
1b-h
N
N
R3CH2NH2
DMSO,
N
R1Br (I)
3-PyCH2NH2
O
O
DMSO,
KOH, Ä,
dioxane
R2 = Ph
N
H
O
O
O
N
H
O
4 h, 150 o
C
8 h, 150 oC
R1
2b-f
1a, g
2a,g,h
R2 = Ph (a),
Me (g)
R3
R2
Yieldb,
1, 2
2
a
R1
76 (65)a
51 (32)a
57 (42)a
51 (35)a
Ph
3-Py
3-Py
b
c
Me
g
h
Me
Ph
Pr
C6H13
C9H19
d
e
2-Py
a drop out of the reaction mixture in analytically pure form
b in case c-f for 2 steps (alkylation and annulation)
44 (30)a
C18H37
f
Scheme 1. The synthesis of imidazo[1,5-a]quinoxalin-4-ones 2aeh.

A.A. Kalinin et al. / European Journal of Medicinal Chemistry 66 (2013) 345e354
347
Table 1
absolutely inactive towards Gram-negative bacteria E. coli,
P. aeruginosa and moulds A. niger and T. mentagrophytes.
The imidazo[1,5-a] quinoxaline derivatives which have been
studied can be divided into three groups depending on the counter-
ions.
The synthesis of 3-(imidazo[1,5-a]quinoxalin-4-on-1-yl)pyridinium halides 3aeo
and 4aed.
The first group contains chlorine as the counter-ion (3aeg), the
second one contains bromine (3i, l, n) and the third one contains
iodine (3h, j, k, m, o). It was established that the main criteria for
evaluating the antimicrobial activity of imidazo[1,5-a]quinoxaline
derivatives were the introduction of various substituents into posi-
tion 1 of the pyridine ring and in position 5 of the imidazo[1,5-a]
quinoxaline system and the presence of the charge in the molecule.
This assumption was confirmed by the experiments determining the
antimicrobial activity of hydrochlorides of compounds 2a and 2h [25]
(Fig. 2), which represent uncharged molecules with unsubstituted
nitrogen atoms at the position 1 of the pyridine ring and at position 5
of the imidazoquinoxaline system. From the data outlined inTable 2 it
is evident that these compounds do not possess any antimicrobial
activity against all the microorganisms used in the tests.
In the first group of imidazo[1,5-a]quinoxaline derivatives a
comparative analysis of compounds with an unsubstituted nitrogen
atom in the position 5 of the imidazo[1,5-a]quinoxaline system 3a,
with compounds containing a variety of alkyl groups in this posi-
tion were carried out. As can be seen from the data in Table 2 the
introduction of the methyl group in the position 5 does not affect
the antimicrobial activity of 3b. While the presence of the propyl
(C3H7) group in 3c leads to a sharp decrease in the fungistatic ac-
tivity, as well as reduction of the bacteriostatic activity by two times
against Gram-positive bacteria S. aureus. Compound 3d, which
contains the hexyl (C6H13) group in the position 5 is the best both in
its bacteriostatic and its fungistatic activities in the first group. This
compound has a low antibacterial activity against S. aureus as
compared with the antibiotic Ciprofloxacin, but exhibits an inhib-
Entry
Compound
R1
R2
R3
Z
X
Yield, %
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
4a
4b
4c
4d
H
Me
Pr
C6H13
C9H19
Ph
Ph
Ph
Ph
Ph
Ph
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
e
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bu
C6H13
C6H13
C6H13
C9H19
C9H19
C9H19
C9H19
e
e
Cl
Cl
Cl
Cl
Cl
Cl
Cl
I
Br
I
I
Br
I
Br
I
87
71
70
79
69
74
64
95
87
72
69
65
68
64
75
51
55
72
68
e
e
e
e
C
18H37
e
H
H
H
e
e
9
e
10
11
12
13
14
15
16
17
18
19
C6H13
C9H19
C6H13
C6H13
C9H19
C9H19
H
H
C6H13
C9H19
e
e
e
e
e
e
(CH2)2
(CH2)4
m-C6H4
m-C6H4
Br
Br
Br
Br
e
e
e
e
e
e
Reagents and conditions: (i) 1.5 equiv of R3X, DMF, 120 ꢀC, 16 h (3a,b,g,h,i); (ii)
1.5 equiv of R3X, CH3CN, reflux, 24 h (3cef, 3jeo); (iii) 0.5 equiv of BrCH2ZCH2Br,
DMF, 120 ꢀC, 16 h (for 4a,b); (iv) 0.5 equiv of m-xylene dibromide, CH3CN, reflux,
24 h (4c,d).
Macrocycle 6 was obtained under similar conditions like 4ce
d but from a considerably more diluted (40 times or 1 mg/mL or
w1 mmol/L) solution (Scheme 2).
itory effect at 0.97
similar to the MIC of the antibiotic Ofloxacin, but much better than
Norfloxacin (at MIC 2.42 g/ml).
mg/ml against Gram-positive bacteria S. aureus,
m
The increase in the lipophilicity of the carbon chain up to nonyl
(C9H19) 3e led to a decrease in the bacteriostatic activity by two
times and increase in the fungistatic activity by two as compared
with the compound 3d. Introducing an even longer chain such as
octadecanyl (C18H37) 3f resulted in completely loss of the antimi-
crobial activity of imidazo[1,5-a]quinoxaline derivatives.
Replacement of the phenyl by methyl in the imidazo[1,5-a]
quinoxaline derivative dramatically reduces the antimicrobial ac-
tivity in the compound 3g.
The second group of compounds containing hexyl (C6H13) and
nonyl (C9H19) groups were studied. The most active compound was
3l with the nonyl (C9H19) group in the position 1 of the pyridine
ring and the hexyl (C6H13) group in the position 5 of the imidazo
[1,5-a]quinoxaline system. The antimicrobial activity is lower than
Ciprofloxacin and Clotrimazole but it possesses a bacteriostatic and
fungistatic activity against Gram-positive bacteria and yeast, com-
parable to the known drugs e Ofloxacin and Amphotericin B.
3. Biological results and discussion
The antibacterial and antifungal activity of the imidazo[1,5-a]
quinoxaline derivatives with pyridinium salts were investigated
in vitro against several pathogenic representative Gram-negative
bacteria (Pseudomonas aeruginosa 9027 and Escherichia coli F-50),
Gram-positive bacteria (Staphylococcus aureus 209p and Bacillus
cereus 8035), and pathogenic fungi (Aspergillus niger BKMF-1119,
Trichophyton mentagrophytes) and yeast (Candida albicans 885-
653). The results are summarized in Tables 2e4.
The screened compounds exhibit bacteriostatic and fungistatic
activity in the regions of 0.78e500
mg/mL and 0.97e500 mg/mL
concentrations, respectively. As evident from antibacterial data,
imidazo[1,5-a]quinoxalines 3a, b, j, k are showing a slight bacte-
riostatic and fungistatic activity against Gram-positive bacteria
S. aureus and B. cereus and pathogenic yeast C. albicans but are
Scheme 2. The synthesis of diimidazo[1,5-a]quinoxalinapyridinabenzenacyclophane 6.

348
A.A. Kalinin et al. / European Journal of Medicinal Chemistry 66 (2013) 345e354
3l and 3n. Bacteriostatic properties vary slightly. The introduction
of the hexyl (C6H13) group into position 1 of the pyridine ring and
the nonyl (C9H19) group into position 5 of the imidazo[1,5-a]qui-
noxaline system (compound 3k) resulted in a decrease in the
bacteriostatic activity by 80 and an increase in the fungistatic
activity by 20 as compared with the compound 3m. In this
connection, it can be assumed that the introduction of the hexyl
(C6H13) group in the position 5 of the imidazo[1,5-a]quinoxaline
system leads to the improvement of the bacteriostatic properties
of imidazo[1,5-a]quinoxaline derivatives, and its presence in the
position 1 of the pyridine ring contributes to the fungistatic
properties.
Compounds 4aed, 6 consist of two N-alkyl-pyridine moieties
(Fig. 3). The data in Table 3 show that these substances are inferior
to the antimicrobial activity than the compounds listed in Table 2.
Compounds 4a and 4b contain connecting bridges at positions 1,
with the nitrogen atoms of the pyridine rings of each of the frag-
ments. As can be seen from the data in Table 3 both compounds are
inactive against bacteria. However, if the number of the methylene
groups in the connecting bridges decreases from 6 as in compound
4b to 4 as in compound 4a, the fungistatic activity increases against
the yeast C. albicans. Imidazo[1,5-a]quinoxaline compounds 4c and
4d containing hexyl (C6H13) and nonyl (C9H19) groups at position 5,
respectively, exhibit bacteriostatic (against Gram-positive bacteria)
as well as fungistatic activity (against the yeast C. albicans). The
cyclophane 6 examined in this group exhibits a low antimicrobial
activity against Gram-positive bacteria and yeast.
Fig. 2. The hydrochlorides of 1-(pyridin-3-yl)- (2a) and 1-(pyridin-4-yl)- (2h) imidazo
[1,5-a]quinoxalin-4-ones without any alkyl groups at the position 1 of the pyridine ring
and at the position 5 of the imidazoquinoxaline system.
The introduction of the nonyl (C9H19) group in the position 5
(compound 3n) decreased its both bacteriostatic properties by 1.5e
6 times, and the fungistatic factor by 50 times as compared with the
compound 3l.
Compound 3i, with an unsubstituted nitrogen atom in the po-
sition 5 of the imidazoquinoxaline system ranks considerably
below the compound 3l containing various alkyl (C6H13, C9H19
groups and the compound 3n, containing the same alkyl (C9H19
groups in its activity.
)
)
The analysis of the test results of the compounds of group 3
showed that the introduction of the butyl (C4H9) group in position 1
of the pyridine ring (compound 3h) leads to a sharp decrease in the
antimicrobial activity. The introduction of the hexyl (C6H13) group
in the position 1 of the pyridine ring and in the position 5 of the
imidazo[1,5-a]quinoxaline system (compound 3j) leaded to the
increase in the fungistatic activity against the yeast C. albicans by 16
times as compared with the compound 3i, containing the hexyl
(C6H13) group only in position 1 of the pyridine ring.
Compounds with the highest bacteriostatic and fungistatic ef-
ficacy were further screened for their bactericidal and fungicidal
activities (Table 4). The screened compounds exhibit bactericidal
Compound 3m exhibits a lower antimicrobial activity than the
and fungicidal activities in the regions of 5e500
500 g/ml concentrations, respectively.
mg/ml and 50e
antibiotics Ciprofloxacin, but shows an inhibitory effect at 0.78
ml against Gram-positive bacteria, similar to the MIC as the anti-
m
g/
m
Compound 3l ranks bellow the bactericidal and fungicidal ac-
tivities of the drug Ciprofloxacin and Clotrimazole, but also reveals
bionic Ofloxacin, but much better then Norfloxacin (MIC at 2.42
ml).
mg/
an inhibitory effect at 5
S. aureus, similar to the MBC as the antibionic Norfloxacin. Its
fungicidal activity at 50 g/ml against yeast C. albicans and at
250 g/ml against the T. mentagrophytes, is the same MBC as the
antifungal drug Amphotericin B.
mg/ml against Gram-positive bacteria
The compounds 3m and 3o have structures similar to those of
compounds 3l and 3n from the second group. A comparative
analysis of the data showed that the change of the counter-ion
from bromine to iodine leads to a sharp decrease in the fungi-
static properties of compounds 3m and 3o as compared with the
m
m
Table 2
Antibacterial and antifungal activity of imidazo[1,5-a]quinoxaline derivatives 3 in vitro.
Entry
Compound
R1
R2
R3
Xꢁ
Minimal inhibitory concentration (MICs) mg/mL
Sa
Bc
Ec
Pa
An
Tm
Ca
1
2
3
4
5
6
7
8
2a$HCl
2h$HCl
3a
3b
3c
3d
3e
3f
3g
3i
3l
3n
3h
3j
3k
3m
H
H
H
CH3
C3H7
C6H13
C9H19
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CH3
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
e
>500
>500
31.3
31.3
62.5
0.97
1.95
500
>500
>500
125
125
125
6.3
12.5
>500
>500
125
0.97
6.3
>500
62.5
125
0.78
7.8
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
500
>500
>500
>500
0.5
3.1
3.0
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
500
500
>500
500
>500
>500
62.5
62.5
>500
7.8
e
Bn
Bn
Bn
Bn
Bn
Bn
Bn
C6H13
C9H19
C9H19
C4H9
C6H13
C6H13
C9H19
C9H19
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
I
500
3.9
C18H37
>500
>500
>500
250
>500
>500
250
0.97
50
>500
15.6
25
9
H
H
500
10
11
12
13
14
15
16
17
18
19
20
21
22
62.5
0.97
1.5
C6H13
C9H19
H
C6H13
C9H19
C6H13
C9H19
>500
>500
250
500
500
>500
>500
>500
>500
>500
I
I
I
I
62.5
62.5
0.78
7.8
0.25
0.97
2.42
250
>500
>500
0.5
0.5
1.5
500
>500
3o
Ciprofloxacin
Ofloxacin
Norfloxacin
Clotrimazole
Amphotericin B
0.25
1.5
7.8
3.13
3.13
0.39
0.97
20
The tests were performed in duplicate and repeated twice; Pa, Pseudomonas aeruginosa; Ec, Escherichia coli; Sa, Staphylococcus aureus; Bc, Bacillus cereus; An, Aspergillus niger;
Tm, Trichophyton mentagrophytes; Ca, Candida albicans.

A.A. Kalinin et al. / European Journal of Medicinal Chemistry 66 (2013) 345e354
349
N
N
+
_
Br
+
N
N
N
N
_
N
N
Ph
O
Ph
O
Ph
_
Ph
_
Br
N
N
N
N
Br
Br
O
O
N
N
N
N
4a
R1
R1
4d
C9H19
C9H19
N
N
+
N
N
_
Br
Ph
O
Ph
_
Br
N
N
O
HN
NH
_
Br
4b
_
Br
N
N
N
N
Ph
Ph
N
N
N
N
N
N
Ph
_
Ph
_
Br
N
N
Br
O
O
N
N
O
O
N
N
4c
C6H13
C6H13
6
Fig. 3. Imidazo[1,5-a]quinoxalines with the two N-alkylpyridine fragments.
Table 3
Table 4
Antibacterial and antifungal activity of imidazo[1,5-a]quinoxaline derivatives 4 with
two N-alkylpyridine fragments in vitro.
Bactericidal and fungicidal activity of imidazo[1,5-a]quinoxaline derivatives in vitro.
Compound
MBC
Sa
m
g/ml MFC
m
g/mL
Ec
Entry Compound Minimal inhibitory concentration (MICs)
Sa Bc Ec Pa An
>500 >500 >500 >500 >500
m
g/ml
Bc
Pa
An
Tm
Ca
Tm
Ca
3d
3e
3l
50
50
5
>500 >500 >500 >500 >500 500
>500 >500 >500 >500 >500 500
1
2
3
4
5
4a
4b
4c
4d
6
250 3.9
>500 >500 >500 >500 >500 >500
500
12.5
3.9
50
500
>500 >500 250
50
62.5
15.6
>500 >500 >500 >500 15.6
500 >500 >500 500 7.8
3m
3n
3o
5
500
500
>500 >500 >500 >500 500
>500 >500 >500 >500 500
50
500
0.25
5
125
>500 >500 >500 >500 >500 250
>500 >500 >500 >500 >500 >500
0.25
12.5
Ciprofloxacin
Norfloxacin
Clotrimazole
Amphotericin B
0.5
5
0.5
5
The tests were performed in duplicate and repeated twice; Pa, Pseudomonas aeru-
ginosa; Ec, Escherichia coli; Sa, Staphylococcus aureus; Bc, Bacillus cereus; An, Asper-
gillus niger; Tm, Trichophyton mentagrophytes; Ca, Candida albicans.
3.13
250 250
0.39
50
Toxicity of more effective (imidazo[1,5-a]quinoxalin-4-on-1-yl)-
1-pyridinium halides was determined in mice (Table 5).
It should be pointed out that the levels of acute toxicity for
Gramicidin S by the intraperitoneal introductions is 26e30 mg/kg,
while for Amphotericin B is 27.74 mg/kg. Thus according to the
levels of acute toxicity for mammals the (imidazo[1,5-a]quinoxalin-
4-on-1-yl)-1-pyridinium halides can be considered as moderately
toxic compounds.
MBC, minimum bactericidal concentration; MFC, minimum fungicidal concentra-
tion. The tests were performed in duplicate and repeated twice; Pa, Pseudomonas
aeruginosa; Ec, Escherichia coli; Sa, Staphylococcus aureus; Bc, Bacillus cereus; An,
Aspergillus niger; Tm, Trichophyton mentagrophytes; Ca, Candida albicans.
5. Experimental
5.1. Chemistry
5.1.1. Materials
The melting points were determined on a Boetius hot-stage
apparatus and are uncorrected. Infrared (IR) spectra were recor-
ded on a Bruker Vector-22 spectrometer. NMR experiments were
carried out with Bruker spectrometers AVANCE-400 (400.1 MHz
4. Conclusions
The antibacterial and antifungal activity of a series of imidazo
[1,5-a]quinoxaline derivatives has been described. The data ob-
tained have disclosed the dependence of the antimicrobial ac-
tivity on the number of N-alkyl-pyridine moieties and on the
nature of the substituents both in the position 1 of a pyridine
ring and in the position 5 of an imidazo[1,5-a]quinoxaline sys-
tem. It has been established that the compounds with one N-
alkyl-pyridine fragment are most active. The introduction of the
alkyl chain (C6H13) in the position 1 of the pyridine ring increases
the fungistatic activity of imidazo[1,5-a]quinoxaline derivatives,
and its presence in the 5 position of the imidazo[1,5-a]quinoxa-
line system tends to improve the bacteriostatic properties. Imi-
dazo[1,5-a]quinoxaline, with bromine as a counter-ion, with the
substituent (C9H19) in position 1 of the pyridine ring and the
substituent (C6H13) in position 5 of the imidazoquinoxaline sys-
tem (3l) is the best for bacteriostatic, bactericidal, fungistatic, and
fungicidal properties. In this case, the antibacterial and anti-
fungal activities of this compound is comparable to the antimi-
crobial activity of the known drugs e Ofloxacin, Norfloxacin and
Amphotericin B.
(1H), 100.6 MHz
(
13C)) and AVANCE-600 (600.1 MHz (1H),
(ppm)
150.9 MHz (13C)). Chemical shifts were reported on the
d
scale and are relative to the residual 1H and 13H signal of DMSO-d6
and CDCl3. The MALDI mass spectra were obtained on a Bruker
UltraFlex III MALDI TOF/TOF instrument with p-nitroaniline as a
matrix. The elemental analyses were carried out at the micro-
analysis laboratory of the Arbuzov Institute of Organic and Physical
Chemistry, Russian Academy of Sciences. The 3-imidazo[1,5-a]
quinoxalin-4-ones 2a, b, g, h were synthesized according to the
reported methods [25].
5.1.2. General procedure for the synthesis of imidazo[1,5-a]
quinoxaline (2cef)
A suspension of 3-benzoylquinoxaline-2(1H)-one (1a) (1.0 g,
4.0 mmol), KOH (0.50 g, 8.9 mmol), appropriate alkylbromide
(4.8 mmol), and dioxane (50 mL) was refluxed for 12 h. After
cooling to room temperature, the reaction mixture was poured into
water (150 mL). The mixture was washed with CH2Cl2 (3ꢂ 40 mL),

350
A.A. Kalinin et al. / European Journal of Medicinal Chemistry 66 (2013) 345e354
nmax, cmꢁ1, KBr): 3102, 3053, 2921, 2848, 1655, 1610, 1592, 1567,
Table 5
(
Toxicity of (imidazo[1,5-a]quinoxalin-4-on-1-yl)-1-pyridinium
halides 3a, 3d, 3h, 3i, 3l, 3m and 4d.
1501, 1485, 1469, 1412, 1396, 1355, 1326, 1300, 1280, 1250, 1183,
1119, 1025, 1025, 813, 783, 751, 727, 715, 697, 670. 1H NMR
(400 MHz, CDCl3) dH: 0.88 (t, 3H, J ¼ 6.8 Hz, CH3), 1.20e1.32 (m, 8H,
CH2), 1.33e1.42 (m, 2H, CH2), 1.42e1.52 (m, 2H, CH2), 1.72e1.86 (m,
2H, CH2), 4.23 (t, 2H, J ¼ 7.8 Hz, NCH2), 6.94 (ddd, 1H, J 8.4, 6.8, 1.6,
H8-Q), 7.30 (d, 1H, J ¼ 8.6 Hz, H9-Q), 7.32e7.43 (m, 3H, H6,7-Q, p-
Ph), 7.47 (dd, 2H, J ¼ 7.6, 7.3 Hz, m-Ph), 7.52 (dd, 1H, J ¼ 7.9, 5.0 Hz,
H5-Py), 8.07 (d, 1H, J ¼ 7.9 Hz, H4-Py), 8.13 (d, 2H, J ¼ 7.3 Hz, o-Ph),
8.82 (br d, 1H, J ¼ 5.0 Hz, H6-Py), 8.97 (br s, 1H, H2-Py). 13C NMR
(100.6 MHz, CDCl3) dc: 14.25, 22.82, 27.24, 27.46, 29.40, 29.55, 29.71,
32.01, 42.15, 116.22, 118.06, 118.89, 122.43, 122.78, 124.01, 127.60,
128.11, 128.82, 128.92, 130.13, 130.71, 132.86, 137.63, 141.31, 146.20,
150.09, 150.76, 155.39. MS (MALDI TOF) ¼ 465 [MH]þ. Found: C,
77.47; H, 6.79; N, 12.15. C30H32N4O requires: C, 77.56; H, 6.94;
N,12.06%.
Compound
LD50, mice, mg/kg
3a
3d
3h
3i
3l
3m
4d
65.7 (47.3O79.7)
61.1 (47.7O78.5)
63.2 (52.1O75.3)
75.8 (65.2O87.1)
120.5 (39.3O69.2)
52.5 (36.4O65.7)
108.2 (86.7O140.2)
and the combined organic phases were then washed with water
(3ꢂ 10 mL), dried over anhydrous Na2SO4, filtered, and evaporated
to dryness. Hexane (15 mL) was added to the residue. The reaction
mixture was left overnight. The solution was separated from the
residue. The crude product 2cef was dried. A solution of 3-
picolylamine (4.2 mmol) in DMSO (10 mL) was added to the res-
idue. The reaction mixture was stirred for 8 h at 150 ꢀC, and left
overnight at room temperature, wherein the crystals of the product
were precipitated out. The crystals were collected by suction
filtration, washed with EtOH (10 mL) and dried. The mother solu-
tion was poured into water (20 mL), the product extracted with
methylene chloride (3ꢂ 7 mL). The combined methylene chloride
solutions were washed with water (3ꢂ 3 mL), dried over anhydrous
Na2SO4, filtered, and evaporated to dryness. The crude product was
recrystallized from acetonitrile and the additional amount of
compound 2 was obtained.
5.1.2.4. 5-Octadecyl-3-phenyl-1-(pyridin-3-yl)imidazo[1,5-a]quinox-
alin-4-one (2f). Yield 44%. White powder, mp 134e137 ꢀC (CH3CN).
IR (nmax, cmꢁ1, KBr): 2956, 2848, 1655, 1610, 1593, 1501, 1484, 1467,
1412, 1396, 1326, 1300, 1252, 1182, 1119, 1025, 751, 716, 697. 1H NMR
(400 MHz, CDCl3) dH: 0.88 (t, 3H, J ¼ 6.8 Hz, CH3), 1.20e1.32 (m,
26H, CH2),1.33e1.42 (m, 2H, CH2),1.42e1.52 (m, 2H, CH2),1.74e1.84
(m, 2H, CH2), 4.23 (t, 2H, J ¼ 7.8 Hz, NCH2), 6.99 (d, 1H, J ¼ 8.3, 7.0,
1.4 Hz, H8-Q), 7.25e7.44 (m, 4H, H6,7,9-Q, p-Ph), 7.47 (dd, 2H,
J ¼ 7.6, 7.1 Hz, m-Ph), 7.69 (dd, 1H, J ¼ 7.9, 5.2, H5-Py), 8.13 (dd, 2H,
J ¼ 7.9, 1.4, o-Ph), 8.30 (ddd, 1H, J ¼ 7.9, 1.6, 1.5 Hz, H4-Py), 8.85 (dd,
1H, J ¼ 5.2,1.5 Hz, H6-Py), 9.02 (br d, 1H, J ¼ 1.6 Hz, H2-Py). 13C NMR
(100.6 MHz, CDCl3) dc: 14.27, 22.85, 27.25, 27.46, 29.53, 29.56,
29.70e29.55 (10C), 32.10, 42.15, 116.18, 118.06, 118.85, 122.39,
122.81, 123.90, 127.55, 128.10, 128.78, 129.79, 130.13, 130.70, 132.89,
137.39, 141.45, 146.17, 150.34, 151.02, 155.39. MS (MALDI TOF) ¼ 591
[MH]þ. Found: C, 79.43; H, 8.69; N, 9.55. C39H50N4O requires: C,
79.28; H, 8.53; N, 9.48%.
5.1.2.1. 3-Phenyl-5-propyl-1-(pyridin-3-yl)imidazo[1,5-a]quinoxalin-
4-one (2c). Yield 51%. White powder, mp 182e184 ꢀC (CH3CN). IR
(
nmax, cmꢁ1, KBr): 3105, 3071, 2958, 2929, 2871, 1658, 1611, 1595,
1502, 1484, 1467, 1416, 1393, 1301, 1242, 1114, 1025, 748, 727, 697,
670. 1H NMR (400 MHz, CDCl3) dH: 1.07 (t, 3H, J ¼ 7.4 Hz, CH3), 1.75e
1.90 (m, 2H, CH2), 4.21 (t, 2H, J ¼ 7.9 Hz, NCH2), 6.94 (ddd, 1H,
J ¼ 8.5, 6.7, 1.9 Hz, H8-Q), 7.28e7.49 (m, 6H, ArH), 7.50 (ddd, 1H,
J ¼ 7.9, 4.9, 0.8 Hz, H5-Py), 8.05 (ddd, 1H, J ¼ 7.9, 2.2, 1.7 Hz, H4-Py),
8.10e8.15 (m, 2H, o-Ph), 8.82 (dd, 1H, J ¼ 4.9, 1.7 Hz, H6-Py), 8.98
5.1.3. General procedure for the synthesis of imidazo[1,5-a]
quinoxaline derivatives with the pyridinium salt fragments (3, 4)
A mixture of imidazo[1,5-a]quinoxaline 2 (0.40 mmol) and
alkylhalide R3X (0.60 mmol) or dibromoalkane BrCH2ZCH2Br
(0.19 mmol) a. in DMF (2.5 mL) was stirred for 16 h at 125 ꢀC (for
synthesizing 3a, gei and 4a, b) b. in acetonitrile (10 mL) was
refluxed for 24 h (for synthesizing 3bef, jeo and 4c, d).
(dd, 1H, J ¼ 2.2, 0.8 Hz, H2-Py). 13C NMR (150.9 MHz, CDCl3) dc
:
11.50, 20.77, 43.58, 116.21, 118.08, 118.84, 122.44, 122.83, 123.90,
127.55, 128.11, 128.81, 128.83, 130.15, 130.73, 132.91, 137.36, 141.52,
146.23, 150.41, 151.10, 155.48. MS (MALDI TOF) ¼ 381 [MH]þ, 403
[M þ Na]þ, 419 [M þ K]þ. Found: C, 75.90; H, 5.23; N, 14.62.
When synthesizing 3a, 3g the reaction mixture was left over-
night at room temperature, while the crystals of the product were
precipitated, collected by suction filtration, washed with CH3CN
(5 mL) and solvent was evaporated and ether (20 mL) was added to
the residue. The resulting precipitate was filtered off and washed
with Et2O (2 ꢂ 10 mL). When synthesizing 3h, i after cooling to
room temperature and standing overnight, Et2O (20 mL) was
poured into the reaction mixture. After collection by filtration the
product was washed with Et2O (20 mL) and dried in vacuum. When
synthesizing 3bef, jeo the solvent was removed in vacuum and the
residue was purified by flash column chromatography on Silicagel
(EtOH:CH2Cl2 ¼ 1:30 / 1:10) (Table 1). When synthesizing 4a, b,
4c, d the reaction mixture was left overnight at room temperature,
while the crystals of the product were precipitated, collected by
suction filtration, washed with CH3CN (5 mL) and dried in vacuum.
C
24H20N4O requires: C, 75.77; H, 5.30; N,14.73%.
5.1.2.2. 5-Hexyl-3-phenyl-1-(pyridin-3-yl)imidazo[1,5-a]quinoxalin-
4-one (2d). Yield 57%. White powder, mp 164e166 ꢀC (CH3CN). IR
(
nmax, cmꢁ1, KBr): 3104, 3053, 2952, 2922, 2863, 2846, 1655, 1610,
1592, 1567, 1484, 1461, 1447, 1412, 1396, 1355, 1325, 1300, 1249,
1198, 1182, 1118, 1052, 1025, 751, 728, 715, 697, 670. 1H NMR
(400 MHz, CDCl3) dH: 0.91 (t, 3H, J ¼ 6.8 Hz, CH3), 1.30e1.40 (m, 4H,
CH2), 1.43e1.53 (m, 2H, CH2), 1.74e1.84 (m, 2H, CH2), 4.23 (t, 2H,
J ¼ 7.8 Hz, NCH2), 6.94 (ddd, 1H, J ¼ 8.3, 6.8, 1.4 Hz, H8-Q), 7.30 (d,
1H, J ¼ 7.9 Hz, H9-Q), 7.32e7.42 (m, 3H, H6,7-Q, p-Ph), 7.47 (dd, 2H,
J ¼ 7.6, 7.6 Hz, m-Ph), 7.50 (dd, 1H, J ¼ 8.1, 5.0 Hz, H5-Py), 8.06 (ddd,
1H, J ¼ 8.1, 1.6, 1.6 Hz, H4-Py), 8.13 (dd, 2H, J ¼ 7.9, 1.3 Hz, o-Ph), 8.82
(br dd, 1H, J ¼ 5.0, 1.6 Hz, H6-Py), 8.97 (br d, 1H, J ¼ 1.6 Hz, H2-Py).
13C NMR (100.6 MHz, CDCl3) dc: 14.16, 22.76, 26.88, 27.40, 31.70,
42.11, 116.15, 118.04, 118.83, 122.39, 122.78, 123.89, 127.54, 128.07,
128.09, 128.77, 130.11, 130.67, 132.87, 137.39, 141.42, 146.13, 150.30,
150.99, 155.37. MS (MALDI TOF) ¼ 423 [MH]þ. Found: C, 76.87; H,
6.29; N, 13.12. C27H26N4O requires: C, 76.75; H, 6.20; N,13.26%.
5.1.3.1. 1-Benzyl-3-(3-phenylimidazo[1,5-a]quinoxalin-4(5H)-on-1-
yl)pyridinium chloride (3a). Yield 87%. White powder, mp 333e
335 ꢀC (dec.). IR (nmax, cmꢁ1, Nujol mull): 3220e2500, 1666, 1618,
1508, 1484, 1396, 1329, 1301, 1274, 1248, 1157, 1075, 1032, 851, 815,
739, 698, 523. 1H NMR (400 MHz, DMSO-d6) dH: 5.99 (s, 2H, CH2Ph),
6.92 (dd, 1H, J ¼ 8.5, 7.5 Hz, H8-Q), 7.20 (d, 1H, J ¼ 8.5 Hz, H9-Q),
7.36e7.53 (m, 8H, ArH), 7.60e7.66 (m, 2H, CH2Ph-o), 8.19 (d, 2H,
5.1.2.3. 5-Nonyl-3-phenyl-1-(pyridin-3-yl)imidazo[1,5-a]quinoxalin-
4-one (2e). Yield 51%. White powder, mp 148e150 ꢀC (CH3CN). IR

A.A. Kalinin et al. / European Journal of Medicinal Chemistry 66 (2013) 345e354
351
J ¼ 7.5 Hz, C3-Ph-o), 8.42 (dd, 1H, J ¼ 7.8, 6.2 Hz, H5-Py), 9.02 (d, 1H,
J ¼ 7.8 Hz, H4-Py), 9.49 (d,1H, J ¼ 6.2 Hz, H6-Py), 9.79 (s,1H, H2-Py),
11.70 (s, 1H, NH). 13C NMR (100.6 MHz, DMSO-d6) dc: 63.66, 116.94,
117.48, 119.91, 120.63, 122.30, 127.62, 127.73, 128.42, 128.73, 129.05,
129.16, 129.39, 129.46, 129.71, 131.92, 132.25, 133.83, 137.69, 144.17,
145.24, 145.85, 145.92, 154.83. MS (MALDI TOF) ¼ 429 [M ꢁ Clꢁ]þ.
Found: C, 72.18; H, 4.39; N, 12.02; Cl, 7.59. C28H21N4OCl requires: C,
72.33; H, 4.55; N,12.05; Cl, 7.63%.
1485, 1458, 1402, 1376, 1300, 1256, 1216, 1155, 1116, 755, 746, 702,
692, 667. 1H NMR (400 MHz, CDCl3) dH: 0.87 (t, 3H, J ¼ 6.8 Hz, CH3),
1.22e1.30 (m, 8H, CH2), 1.30e1.40 (m, 2H, CH2), 1.40e1.50 (m, 2H,
CH2), 1.70e1.80 (m, 2H, CH2), 4.15 (t, 2H, J ¼ 7.8 Hz, NCH2), 6.38 (s,
2H, CH2Ph), 7.10 (dd, 1H, J 8.6, 7.6 Hz, H8-Q), 7.32 (d, 1H, J ¼ 8.6 Hz,
H9-Q), 7.40e7.70 (m, 10H, ArH), 8.03 (dd, 2H, J ¼ 8.1, 1.4 Hz, C3-Ph-
o), 8.23 (dd, 1H, J 7.9, 5.6 Hz, H5-Py), 8.60 (d, 1H, J ¼ 7.9, Hz, H4-Py),
9.27 (br s, 1H, H2-Py), 10.06 (br d, 1H, J ¼ 5.6 Hz, H6-Py). 13C NMR
(100.6 MHz, CDCl3) dc: 14.22, 22.78, 27.20, 27.42, 29.35, 29.48, 29.67,
31.97, 42.29, 61.31, 116.43, 118.78, 120.20, 121.43, 123.82, 128.16,
128.55,128.66,129.22,130.03,130.26,130.38,130.83,131.24,132.02,
132.30, 132.51, 136.48, 144.17, 144.70, 146.69, 146.80, 154.82. MS
(MALDI TOF) ¼ 555 [M ꢁ Clꢁ]þ. Found: C, 75.06; H, 6.59; N, 9.57; Cl,
5.87. C37H39N4OCl requires: C, 75.17; H, 6.65; N,9.48; Cl, 6.00%.
5.1.3.2. 1-Benzyl-3-(5-methyl-3-phenylimidazo[1,5-a]quinoxalin-4-
on-1-yl)pyridinium chloride (3b). Yield 71%. White powder,
mp > 205 ꢀC (dec.). IR (nmax, cmꢁ1, KBr): 3022, 2990, 1647, 1612,
1590, 1522, 1487, 1447, 1400, 1368, 1330,1300, 1260, 1162, 1105, 980,
756, 705, 671. 1H NMR (400 MHz, CDCl3) dH: 3.55 (s, 3H, CH3), 6.35
(s, 2H, CH2Ph), 7.05 (ddd, 1H, J ¼ 8.6, 7.3, 1.4 Hz, H8-Q), 7.32 (dd, 1H,
J ¼ 8.6, 1.4 Hz, H9-Q), 7.30e7.45 (m, 7H, ArH), 7.63 (dd, 1H, J ¼ 8.3,
1.6 Hz, H6-Q), 7.66e7.70 (m, 2H, ArH), 7.97e8.02 (m, 2H, C3-Ph-o),
8.20 (dd, 1H, J ¼ 8.2, 6.0 Hz, H5-Py), 8.58 (d, 1H, J ¼ 8.2 Hz, H4-Py),
9.33 (s, 1H, H2-Py), 10.08 (d, 1H, J ¼ 6.0 Hz, H6-Py). 13C NMR
(100.6 MHz, DMSO-d6) dc: 28.88, 63.55, 116.72, 117.88, 119.36,
121.30, 122.70, 127.66, 127.90, 128.48, 128.80, 129.05, 129.15, 129.39,
129.59, 130.81, 131.76, 132.22, 133.81, 137.46, 144.51, 145.15, 145.67,
145.76, 154.79. MS (MALDI TOF) ¼ 443 [M ꢁ Clꢁ]þ. Found: C, 72.58;
H, 4.69; N, 11.82; Cl, 7.38. C29H23N4OCl requires: C, 72.72; H, 4.84;
N,11.70; Cl, 7.40%.
5.1.3.6. 1-Benzyl-3-(5-octadecyl-3-phenylimidazo[1,5-a]quinoxalin-
4-on-1-yl)pyridinium chloride (3f). Yield 74%. White powder, mp
225e227 ꢀC (dec.). IR (nmax, cmꢁ1, KBr): 3059, 2989, 2919, 2850,
1667, 1611, 1591, 1486, 1468, 1458, 1403, 1376, 1300, 1253, 1179, 1115,
756, 744, 702, 692. 1H NMR (400 MHz, CDCl3) dH: 0.88 (t, 3H,
J ¼ 6.6 Hz, CH3), 1.22e1.30 (m, 26H, CH2), 1.30e1.40 (m, 2H, CH2),
1.40e1.50 (m, 2H, CH2), 1.70e1.82 (m, 2H, CH2), 4.19 (t, 2H,
J ¼ 7.5 Hz, NCH2), 6.30 (s, 2H, CH2Ph), 7.13e7.22 (m, 1H, H8-Q), 7.34
(d, 1H, J ¼ 8.4 Hz, H9-Q), 7.40e7.50 (m, 7H, ArH), 7.65 (d, 1H,
J ¼ 7.7 Hz, H6-Q), 7.65e7.75 (m, 2H, ArH), 8.07 (d, 2H, J ¼ 7.3, C3-Ph-
o), 8.17 (dd, 1H, J ¼ 8.0, 5.6 Hz, H5-Py), 8.60 (d, 1H, J ¼ 8.0 Hz, H4-
Py), 9.34 (br s, 1H, H2-Py), 9.81 (br s, 1H, H6-Py). 13C NMR
(150.9 MHz, CDCl3) dc: 14.29, 22.87, 27.26, 27.47, 29.53, 29.54,
29.70e29.55 (10C), 32.11, 42.47, 65.94, 116.52,118.97, 120.33, 121.36,
124.00, 128.27, 128.62, 128.75, 129.40, 129.69, 130.08, 130.11, 130.39,
130.54, 130.59, 130.60, 131.94, 136.24, 136.27, 144.15, 144.63, 146.75,
154.79. MS (MALDI TOF) ¼ 681 [M ꢁ Clꢁ]þ. Found: C, 77.12; H, 8.05;
N, 7.87; Cl, 4.84. C46H57N4OCl requires: C, 77.01; H, 8.01; N,7.81; Cl,
4.94%.
5.1.3.3. 1-Benzyl-3-(5-propyl-3-phenylimidazo[1,5-a]quinoxalin-4-
on-1-yl)pyridinium chloride (3c). Yield 70%. White powder, mp
193e196 ꢀC (dec.). IR (nmax, cmꢁ1, KBr): 3079, 3037, 2960, 2932,
2874, 1648, 1608, 1589, 1555, 1520, 1486, 1450, 1401, 1324, 1299,
1258, 1185, 1165, 1118, 1058, 785, 752, 706, 674. 1H NMR (400 MHz,
CDCl3) dH: 1.06 (t, 3H, J ¼ 7.4 Hz, CH3), 1.75e1.85 (m, 2H, CH2), 4.15
(t, 2H, J ¼ 7.9 Hz, NCH2), 6.36 (s, 2H, CH2Ph), 7.11 (dd, 1H, J ¼ 8.2,
7.4 Hz, H8-Q), 7.33 (d, 1H, J ¼ 8.2 Hz, H9-Q), 7.36e7.47 (m, 7H, ArH),
7.49 (d, 1H, J ¼ 8.0 Hz, H6-Q), 7.62e7.70 (m, 2H, ArH), 8.04 (d, 2H,
J ¼ 7.0 Hz, C3-Ph-o), 8.21 (dd, 1H, J ¼ 7.7, 6.1, H5-Py), 8.59 (d, 1H,
J ¼ 7.7 Hz, H4-Py), 9.20 (s, 1H, H2-Py), 10.04 (br d, 1H, J ¼ 6.1 Hz, H6-
Py). 13C NMR (100.6 MHz, DMSO-d6) dc: 11.04, 20.18, 42.54, 63.74,
116.70, 118.21, 119.20, 121.42, 122.59, 127.69, 127.98, 128.48, 128.76,
129.00, 129.19, 129.41, 129.62, 129.79, 131.93, 132.28, 133.80, 137.37,
144.52, 145.20, 145.72, 145.83, 154.34. MS (MALDI TOF) ¼ 471
[M ꢁ Clꢁ]þ. Found: C, 73.56; H, 5.49; N, 11.07; Cl, 6.88. C31H27N4OCl
requires: C, 73.44; H, 5.37; N,11.05; Cl, 6.99%.
5.1.3.7. 1-Benzyl-3-(3-methylimidazo[1,5-a]quinoxalin-4(5H)-on-1-
yl)pyridinium chloride (3g). Yield 64%. White powder, mp 326e
328 ꢀC (dec.). IR (nmax, cmꢁ1, Nujol mull): 3220e2500, 1669, 1617,
1571,1519,1503,1412,1325,1269,1246,1203,1161,1140,1098,1030,
930, 843, 820, 746, 736, 709, 682, 629, 584. 1H NMR (400 MHz,
DMSO-d6) dH: 2.66 (s, 3H, Me), 5.97 (s, 2H, CH2Ph), 6.89 (dd, 1H,
J ¼ 8.4, 7.9 Hz, H8-Q), 7.19 (d, 1H, J ¼ 8.4 Hz, H9-Q), 7.30e7.43 (m,
2H, H6,7-Q), 7.47e7.55 (m, 3H, m,p-Ph), 7.60e7.66 (m, 2H, o-Ph),
8.38 (ddd, 1H, J ¼ 8.2, 6.2, 1.7 Hz, H5-Py), 8.93 (d, 1H, J ¼ 8.2 Hz, H4-
Py), 9.45 (d, 1H, J ¼ 6.2 Hz, H6-Py), 9.73 (s, 1H, H2-Py), 11.55 (s, 1H,
NH). 13C NMR (100.6 MHz, DMSO-d6) dc: 13.93, 63.64, 117.10, 117.11,
120.23, 120.87, 122.22, 125.40, 128.61, 128.96, 129.17, 129.39, 129.87,
132.04, 133.85, 136.47, 142.56, 145.10, 145.54, 145.73, 155.53. MS
(MALDI TOF) ¼ 367 [M ꢁ Clꢁ]þ. Found: C, 68.52; H, 4.66; N, 13.87;
Cl, 8.85. C23H19N4OCl requires: C, 68.57; H, 4.75; N,13.91; Cl, 8.80%.
5.1.3.4. 1-Benzyl-3-(5-hexyl-3-phenylimidazo[1,5-a]quinoxalin-4-
on-1-yl)pyridinium chloride (3d). Yield 79%. White powder, mp
232e234 ꢀC (dec.). IR (nmax, cmꢁ1, KBr): 3058, 2988, 2956, 2854,
1666,1611,1591,1486,1457,1448,1402,1376,1323,1299,1253,1176,
1154, 1114, 755, 744, 692. 1H NMR (400 MHz, CDCl3) dH: 0.90 (t, 3H,
J ¼ 7.0 Hz, CH3), 1.28e1.38 (m, 4H, CH2), 1.40e1.50 (m, 2H, CH2),
1.70e1.80 (m, 2H, CH2), 4.15 (t, 2H, J ¼ 7.9 Hz, NCH2), 6.38 (s, 2H,
CH2Ph), 7.09 (dd, 1H, J ¼ 8.2, 7.4 Hz, H8-Q), 7.33 (e, 1H, J ¼ 8.2 Hz,
H9-Q), 7.35e7.48 (m, 8H, ArH), 7.65e7.72 (m, 2H, ArH), 8.03 (dd, 2H,
J ¼ 8.2, 1.5 Hz, C3-Ph-o), 8.21 (dd, 1H, J ¼ 7.9, 6.0 Hz, H5-Py), 8.58 (d,
1H, J ¼ 7.9 Hz, H4-Py), 9.24 (s,1H, H2-Py),10.13 (br d,1H, J ¼ 6.0, H6-
Py). 13C NMR (150.9 MHz, CDCl3) dc: 14.15, 22.76, 26.88, 27.39, 31.66,
42.43, 65.59, 116.34, 118.78, 120.17, 121.44, 123.89, 128.18, 128.58,
128.73, 129.29, 129.98, 130.07, 130.32, 130.40, 130.47, 131.95, 132.33,
132.44, 136.46, 144.19, 144.69, 146.67, 146.84, 154.81. MS (MALDI
TOF) ¼ 513 [M ꢁ Clꢁ]þ. Found: C, 74.46; H, 6.19; N, 10.17; Cl, 6.29.
5.1.3.8. 1-Butyl-3-(3-phenylimidazo[1,5-a]quinoxalin-4(5H)-on-1-yl)
pyridinium iodide (3h). Yield 95%. Light-yellow powder,
mp > 215 ꢀC (dec.). IR (nmax, cmꢁ1, Nujol mull): 3220e2500, 1667,
1616, 1580, 1547, 1522, 1484, 1421, 1395, 1329, 1302, 1275, 1247,
1202, 1159, 786, 766, 753, 722, 698, 682, 673. 1H NMR (600 MHz,
DMSO-d6) dH: 0.96 (t, 3H, J ¼ 7.2 Hz, CH3), 1.35e1.44 (m, 2H,
CH3CH2), 1.97e2.04 (m, 2H, NCH2CH2), 4.70 (t, 2H, J ¼ 7.2 Hz,
NCH2CH2), 6.99e7.04 (m, 1H, H8-Q), 7.28 (d, 1H, J ¼ 8.5 Hz, H9-Q),
7.40e7.46 (m, 3H, H6,7-Q, p-Ph), 7.47e7.52 (m, 2H, m-Ph), 8.21 (dd,
2H, J ¼ 7.5, 1.3 Hz, o-Ph), 8.39 (dd, 1H, J ¼ 8.1, 6.3 Hz, H5-Py), 8.99 (d,
1H, J 8.1 Hz, H4-Py), 9.33 (d, 1H, J ¼ 6.3 Hz, H6-Py), 9.66 (s, 1H, H2-
Py), 11.66 (s, 1H, NH). 13C NMR (100.6 MHz, DMSO-d6) dc: 13.32,
18.78, 32.49, 61.10, 116.90, 117.68, 119.91, 120.69, 122.32, 127.73,
127.74, 128.33, 128.45, 129.47, 129.73, 131.62, 132.27, 137.82, 144.19,
C
34H33N4OCl requires: C, 74.37; H, 6.06; N,10.20; Cl, 6.46%.
5.1.3.5. 1-Benzyl-3-(5-nonyl-3-phenylimidazo[1,5-a]quinoxalin-4-
on-1-yl)pyridinium chloride (3e). Yield 69%. White powder, mp
182e184 ꢀC. IR (nmax, cmꢁ1, KBr): 2929, 2848, 2723,1669,1613,1591,

352
A.A. Kalinin et al. / European Journal of Medicinal Chemistry 66 (2013) 345e354
145.11, 145.37, 145.76, 154.90. MS (MALDI TOF) ¼ 395 [M ꢁ Iꢁ]þ.
Found: C, 57.52; H, 4.48; N, 10.77; I, 24.19. C25H23N4OI requires: C,
57.48; H, 4.44; N, 10.73; I, 24.29%.
555. 1H NMR (400 MHz, CDCl3) dH: 0.86 (t, 3H, J ¼ 7.0 Hz, CH3), 0.90
(t, 3H, J ¼ 7.0 Hz, CH3), 1.20e1.32 (m, 8H, CH2), 1.32e1.42 (m, 6H,
CH2), 1.42e1.52 (m, 4H, CH2), 1.72e1.83 (m, 2H, CH2), 2.09e2.22 (m,
2H, CH2), 4.18 (t, 2H, J ¼ 7.8 Hz, NCH2), 5.02 (t, 2H, J ¼ 7.4 Hz,
NþCH2), 7.22 (dd, 1H, J ¼ 8.3, 7.0 Hz, H8-Q), 7.34 (d, 1H, J ¼ 8.3 Hz,
H9-Q), 7.36e7.48 (m, 4H, H7-Q, m,p-Ph), 7.61 (d, 1H, J ¼ 8.1 Hz, H6-
Q), 8.06 (dd, 2H, J ¼ 8.1, 1.4 Hz, o-Ph), 8.31 (dd, 1H, J ¼ 7.6, 6.0 Hz,
H5-Py), 8.59 (d, 1H, J ¼ 7.6 Hz, H4-Py), 9.11 (s, 1H, H2-Py), 9.88 (br d,
1H, J ¼ 6.0, Hz, H6-Py). 13C NMR (100.6 MHz, CDCl3) dc: 14.17, 14.23,
22.76, 22.77, 26.46, 26.89, 27.42, 29.21, 29.30, 29.47, 31.62, 31.68,
31.94, 42.40, 63.49, 116.49, 119.14, 120.38, 121.45, 124.02, 128.24,
128.72, 128.99, 129.29, 130.03,130.52,132.10, 132.72,136.42, 143.96,
144.24, 146.66, 146.94, 154.90. MS (MALDI TOF) ¼ 549 [M ꢁ Brꢁ]þ.
Found: C, 68.60; H, 7.31; N, 8.77; Br, 12.53. C36H45N4OBr requires: C,
68.67; H, 7.20; N, 8.90; Br, 12.69%.
5.1.3.9. 1-Hexyl-3-(3-phenylimidazo[1,5-a]quinoxalin-4(5H)-on-1-
yl)pyridinium bromide (3i). Yield 87%. White powder, mp 173e
175 ꢀC (dec.). IR (nmax, cmꢁ1, Nujol mull): 3220e2500, 1671, 1616,
1556, 1524, 1504, 1486, 1427, 1400, 1326, 1304, 1275, 1247, 1162,
1009, 818, 769, 746, 698, 688, 675, 526. 1H NMR (600 MHz, DMSO-
d6) dH: 0.89 (t, 3H, J ¼ 7.0 Hz, CH3), 1.29e1.41 (m, 6H, CH3CH2), 1.96e
2.05 (m, 2H, NCH2CH2), 4.70 (t, 2H, J ¼ 7.4 Hz, NCH2), 6.97e7.03 (m,
1H, H8-Q), 7.28 (d, 1H, J ¼ 8.6 Hz, H9-Q), 7.40e7.45 (m, 3H, H6,7-Q,
p-Ph), 7.47e7.52 (m, 2H, m-Ph), 8.20e8.23 (m, 2H, Hz, o-Ph), 8.39
(dd, 1H, J ¼ 8.1, 6.1 Hz, H5-Py), 8.99 (d, 1H, J ¼ 8.1 Hz, H4-Py), 9.34
(uz. d, 1H, J ¼ 6.1 Hz, H6-Py), 9.66 (s, 1H, H2-Py), 11.66 (s, 1H, NH).
13C NMR (100.6 MHz, DMSO-d6) dc: 13.75, 21.76, 25.03, 30.53, 34.21,
61.26, 116.92, 117.66, 119.90, 120.70, 122.30, 127.74, 127.75, 128.32,
128.45, 129.47, 129.75, 131.59, 132.28, 137.83, 144.17, 145.12, 145.36,
145.80, 154.89. MS (MALDI TOF) ¼ 423 [M ꢁ Brꢁ]þ. Found: C, 64.50;
H, 5.47; N, 11.00; Br, 15.78. C27H27N4OBr requires: C, 64.42; H, 5.41;
N,11.13; Br, 15.87%.
5.1.3.13. 3-(5-Hexyl-3-phenylimidazo[1,5-a]quinoxalin-4-on-1-yl)-1-
nonylpyridinium iodide (3m). Yield 68%. Yellow powder, mp 100e
102 ꢀC. IR (nmax, cmꢁ1, Nujol mull): 1646, 1610, 1590, 1521, 1486,
1402, 1299, 1258, 1166, 1148, 1112, 1026, 981, 754. 1H NMR
(400 MHz, CDCl3) dH: 0.87 (t, 3H, J ¼ 7.0 Hz, CH3), 0.90 (t, 3H,
J ¼ 7.0 Hz, CH3), 1.20e1.32 (m, 8H, CH2), 1.31e1.42 (m, 6H, CH2),
1.42e1.52 (m, 4H, CH2), 1.72e1.82 (m, 2H, CH2), 2.10e2.22 (m, 2H,
CH2), 4.17 (t, 2H, J 7.8, NCH2), 4.91 (t, 2H, J ¼ 7.7 Hz, NþCH2), 7.28 (dd,
1H, J ¼ 8.0, 7.3 Hz, H8-Q), 7.33 (d, 1H, J ¼ 8.0 Hz, H9-Q), 7.36e7.48
(m, 4H, H7-Q, m,p-Ph), 7.72 (d, 1H, J ¼ 8.4 Hz, H6-Q), 8.07 (br d, 2H,
J ¼ 7.8 Hz, o-Ph), 8.30 (dd, 1H, J ¼ 8.2 6.1 Hz, H5-Py), 8.58 (d, 1H,
J ¼ 8.2, H4-Py), 9.09 (s, 1H, H2-Py), 9.58 (d, 1H, J ¼ 6.1 Hz, H6-Py).
13C NMR (100.6 MHz, CDCl3) dc: 14.14, 14.20, 22.73, 22.74, 26.40,
26.86, 27.38, 29.18, 29.28, 29.45, 31.28, 31.64, 31.91, 42.39, 63.57,
116.39, 119.39, 120.29, 121.34, 124.20, 128.16, 128.60, 129.08, 129.21,
130.03, 130.39, 132.11, 132.68, 136.55, 144.06, 144.30, 146.05, 146.78,
154.87. MS (MALDI TOF) ¼ 549 (M ꢁ Iꢁ)þ. Found: C, 63.85; H, 6.66;
N, 8.30; I, 18.65. C36H45N4OI requires: C, 63.90; H, 6.70; N, 8.28; I,
18.75%.
5.1.3.10. 1-Hexyl-3-(5-hexyl-3-phenylimidazo[1,5-a]quinoxalin-4-
on-1-yl)pyridinium iodide (3j). Yield 72%. Yellow powder, mp 113e
115 ꢀC. IR (nmax, cmꢁ1, KBr): 3043, 2954, 2928, 2855, 1649, 1610,
1589, 1487, 1460, 1447, 1404, 1372, 1300, 1256, 1119, 754, 695, 670.
1H NMR (400 MHz, CDCl3) dH: 0.85e0.95 (m, 6H, CH3), 1.30e1.40
(m, 8H, CH2), 1.40e1.52 (m, 4H, CH2), 1.72e1.82 (m, 2H, CH2), 2.10e
2.20 (m, 2H, CH2), 4.16 (t, 2H, J ¼ 7.6 Hz, NCH2), 4.92 (t, 2H,
J ¼ 7.9 Hz, NþCH2), 7.22e7.30 (m, 1H, H8-Q), 7.33 (dd, 1H, J ¼ 8.6,
1.0 Hz, H9-Q), 7.35e7.48 (m, 4H, H7-Q, m,p-Ph), 7.70 (dd, 1H, J ¼ 8.3,
1.0 Hz, H6-Q), 8.06 (dd, 2H, J ¼ 8.2,1.4 Hz, o-Ph), 8.30 (dd,1H, J ¼ 8.1,
6.2 Hz, H5-Py), 8.57 (d, 1H, J ¼ 8.1 Hz, H4-Py), 9.10 (s, 1H, H2-Py),
9.61 (d, 1H, J ¼ 6.2 Hz, H6-Py). 13C NMR (100.6 MHz, CDCl3) dc
:
14.06, 14.14, 22.52, 22.74, 26.05, 26.86, 27.38, 31.24, 31.25, 31.64,
42.40, 63.54, 116.41, 119.35, 120.29, 121.35, 124.17, 128.17, 128.61,
129.08, 129.22, 130.04, 130.40, 132.11, 132.67, 136.55, 144.07, 144.29,
146.12, 146.79, 154.88. MS (MALDI TOF) ¼ 507 [M ꢁ Iꢁ]þ. Found: C,
62.58; H, 6.22; N, 8.86; I, 19.87. C33H39N4OI requires: C, 62.46; H,
6.19; N, 8.83; I, 20.00%.
5.1.3.14. 1-Nonyl-3-(5-nonyl-3-phenylimidazo[1,5-a]quinoxalin-4-
on-1-yl)pyridinium bromide (3n). Yield 64%. White powder, mp
165e167 ꢀC (dec.). IR (nmax, cmꢁ1, KBr): 3052, 2954, 2924, 2852,
1650, 1611, 1487, 1462, 1447, 1404, 1372, 1299, 1251, 1117, 754, 695,
671. 1H NMR (400 MHz, CDCl3) dH: 0.83e0.90 (m, 6H, CH3), 1.20e
1.32 (m, 14H, CH2), 1.33e1.41 (m, 4H, CH2), 1.42e1.51 (m, 4H, CH2),
1.70e1.82 (m, 4H, CH2), 2.09e2.19 (m, 2H, CH2), 4.18 (t, 2H,
J ¼ 7.8 Hz, NCH2), 5.02 (t, 2H, J ¼ 7.6 Hz, NþCH2), 7.23 (ddd, 1H,
J ¼ 8.3, 7.3, 1.1 Hz, H8-Q), 7.34 (dd, 1H, J ¼ 8.3, 0.6 Hz, H9-Q), 7.36e
7.48 (m, 4H, H7-Q, m,p-Ph), 7.63 (dd, 1H, J ¼ 8.4, 1.0 Hz, H6-Q), 8.06
(dd, 2H, J ¼ 8.2, 1.3 Hz, o-Ph), 8.31 (dd, 1H, J ¼ 8.0, 6.1 Hz, H5-Py),
8.58 (d, 1H, J ¼ 8.0 Hz, H4-Py), 9.10 (s, 1H, H2-Py), 9.87 (d, 1H,
J ¼ 6.1 Hz, H6-Py). 13C NMR (150.9 MHz, CDCl3) dc: 14.16, 14.17,
22.71, 22.74, 26.39, 27.17, 27.40, 29.19, 29.26, 29.32, 29.43, 29.44,
29.64, 31.58, 31.89, 31.94, 42.34, 63.22, 116.36, 119.10, 120.16, 121.45,
123.89, 128.12, 128.55, 129.06, 129.16, 130.00, 130.40, 132.10, 132.46,
136.61, 144.05, 144.31, 146.61, 146.66, 154.83. MS (MALDI
TOF) ¼ 591 [M ꢁ Brꢁ]þ. Found: C, 69.56; H, 7.61; N, 8.49; Br, 11.73.
5.1.3.11. 1-Hexyl-3-(5-nonyl-3-phenylimidazo[1,5-a]quinoxalin-4-
on-1-yl)pyridinium iodide (3k). Yield 69%. Yellow powder, mp 97e
99 ꢀC. IR (nmax, cmꢁ1, KBr): 3046, 2954, 2923, 2852, 1648, 1609,
1589, 1521, 1486, 1459, 1402, 1374, 1298, 1258, 1169, 1120, 694, 671.
1H NMR (400 MHz, CDCl3) dH: 0.87 (t, 3H, J ¼ 7.0 Hz, CH3), 0.89 (t,
3H, J ¼ 7.0 Hz, CH3),1.20e1.53 (m,18H, CH2),1.70e1.80 (m, 2H, CH2),
2.10e2.20 (m, 2H, CH2), 4.16 (t, 2H, J ¼ 7.9 Hz, NCH2), 4.91 (t, 2H,
J ¼ 7.6 Hz, NþCH2), 7.22e7.30 (m, 1H, H8-Q), 7.30 (d, 1H, J ¼ 8.2 Hz,
H9-Q), 7.35e7.48 (m, 4H, H7-Q, m,p-Ph), 7.70 (d, 1H, J ¼ 8.1 Hz, H6-
Q), 8.07 (dd, 2H, J ¼ 7.7,1.5 Hz, o-Ph), 8.30 (dd,1H, J ¼ 7.7, 6.1 Hz, H5-
Py), 8.58 (d, 1H, J ¼ 8.2 Hz, H4-Py), 9.10 (s, 1H, H2-Py), 9.57 (br d, 1H,
J ¼ 6.1 Hz, H6-Py). 13C NMR (100.6 MHz, CDCl3) dc: 14.08, 14.25,
22.55, 22.81, 26.12, 27.24, 27.47, 29.39, 29.52, 29.71, 31.27, 31.30,
32.00, 42.44, 63.80, 116.51, 119.39, 120.49, 121.35, 124.27, 128.25,
128.74, 129.04, 129.30, 130.05, 130.51, 132.12, 132.95, 136.41, 144.05,
144.25, 146.09, 147.00, 154.91. MS (MALDI TOF) ¼ 549 [M-Iꢁ]þ.
Found: C, 63.84; H, 6.70; N, 8.32; I, 18.67. C36H45N4OI requires: C,
63.90; H, 6.70; N, 8.28; I, 18.75%.
C39H51N4OBr requires: C, 69.73; H, 7.65; N, 8.34; Br, 11.89%.
5.1.3.15. 1-Nonyl-3-(5-nonyl-3-phenylimidazo[1,5-a]quinoxalin-4-
on-1-yl)pyridinium iodide (3o). Yield 75%. Yellow powder, mp 96e
99 ꢀC (dec.). IR (nmax, cmꢁ1, Nujol mull): 1649, 1610, 1487, 1408,
1343, 1301, 1255, 1198, 1168, 1118, 1072, 968, 923, 754, 695, 671. 1H
NMR (400 MHz, CDCl3) dH: 0.82e0.92 (m, 6H, CH3), 1.20e1.32 (m,
14H, CH2),1.33e1.42 (m, 4H, CH2),1.42e1.52 (m, 4H, CH2),1.72e1.82
(m, 4H, CH2), 2.10e2.20 (m, 2H, CH2), 4.18 (t, 2H, J ¼ 7.8 Hz, NCH2),
4.92 (t, 2H, J ¼ 7.7 Hz, NþCH2), 7.28 (dd, 1H, J ¼ 8.0, 7.3 Hz, H8-Q),
7.34 (d, 1H, J ¼ 8.0 Hz, H9-Q), 7.37e7.49 (m, 4H, H7-Q, m,p-Ph), 7.73
5.1.3.12. 3-(5-Hexyl-3-phenylimidazo[1,5-a]quinoxalin-4-on-1-yl)-
1-nonylpyridinium bromide (3l). Yield 65%. White powder, mp 99e
100 ꢀC. IR (nmax, cmꢁ1, KBr): 3049, 2953, 2925, 2854, 1646, 1610,
1589, 1522, 1503, 1487, 1463, 1447, 1403, 1374, 1339, 1322, 1299,
1259, 1203, 1178, 1148, 1116, 1072, 985, 785, 755, 718, 695, 671, 579,

A.A. Kalinin et al. / European Journal of Medicinal Chemistry 66 (2013) 345e354
353
(d, 1H, J ¼ 8.3 Hz, H6-Q), 8.07 (dd, 2H, J ¼ 7.0 Hz, o-Ph), 8.30 (ddd,
1H, J ¼ 8.0, 6.0, 0.5 Hz, H5-Py), 8.58 (d, 1H, J ¼ 8.0 Hz, H4-Py), 9.10
(br s, 1H, H2-Py), 9.59 (d, 1H, J ¼ 6.0, H6-Py). 13C NMR (100.6 MHz,
CDCl3) dc: 14.21, 14.22, 22.76, 22.79, 26.43, 27.22, 27.45, 29.19, 29.29,
29.37, 29.46, 29.50, 29.69, 31.32, 31.93, 31.98, 42.41, 63.64, 116.43,
119.40, 120.35, 121.35, 124.23, 128.19, 128.63, 129.07, 129.24, 130.04,
130.43, 132.12, 132.76, 136.51, 144.04, 144.28, 146.12, 146.86, 154.89.
MS (MALDI TOF) ¼ 591 [M ꢁ Iꢁ]þ. Found: C, 65.25; H, 7.10; N, 7.80; I,
17.60. C39H51N4OI requires: C, 65.17; H, 7.15; N,7.79; I, 17.66%.
5.1.3.19. 1,3-Bis{3-(5-nonyl-3-phenylimidazo[1,5-a]quinoxalin-4-on-
1-yl)pyridinium}xylene dibromide (4d). Yield 68%. White powder,
mp 242e245 ꢀC (dec.). IR (nmax, cmꢁ1, Nujol mull): 3200e2500,
1666, 1610, 1589, 1524, 1485, 1403, 1297, 1258, 1169, 1114, 836, 783,
752, 721, 701, 672. 1H NMR (400 MHz, CDCl3) dH: 0.86 (t, 6H,
J ¼ 6.8 Hz, CH3), 1.20e1.45 (m, 24H, CH2), 1.70e1.85 (m, 4H, CH2),
4.10 (t, 4H, J ¼ 6.8 Hz, NCH2), 6.29 (s, 4H, CH2-xyl), 7.04 (dd, 2H,
J ¼ 7.5, 7.5 Hz, H8-Q), 7.22e7.35 (m, 10H, ArH), 7.40 (dd, 1H, J ¼ 7.8,
7.8 Hz, H5-xyl), 7.50 (d, 2H, J ¼ 8.5 Hz, H9-Q or H6-Q), 7.74 (d, 2H,
J ¼ 7.2 Hz, H4,6-xyl), 7.99 (d, 4H, J ¼ 7.2 Hz, o-Ph), 8.13 (dd, 2H,
J ¼ 7.8, 5.8 Hz, H5-Py), 8.38 (d, 2H, J ¼ 7.8 Hz, H4-Py), 8.54 (s,1H, H2-
xyl), 9.69 (s, 2H, H2-Py), 10.02 (br d, 2H, J ¼ 5.8 Hz, H6-Py). 13C NMR
(150.9 MHz, CDCl3) dc: 14.25, 22.81, 27.25, 27.45, 29.39, 29.52, 29.73,
32.00, 42.44, 64.14, 116.18, 119.19, 120.09, 121.26, 123.87, 128.10,
128.53, 129.12, 129.24, 130.04, 130.28, 130.61, 131.34, 131.89, 132.18,
132.34, 133.97, 136.46, 144.59, 144.95, 145.96, 146.62, 154.70. MS
5.1.3.16. 1,4-Bis{3-(3-phenylimidazo[1,5-a]quinoxalin-4(5H)-on-1-
yl)pyridinium}butane dibromide (4a). Yield 51%. White powder, mp
273e275 ꢀC (dec.). IR (nmax, cmꢁ1, KBr): 3049, 2917, 1670, 1617,
1485, 1447, 1424, 1399, 1328, 1302, 1275, 1161, 785, 756, 746, 698,
679, 666. 1H NMR (400 MHz, DMSO-d6) dH: 2.14 (br s, 4H,
NCH2CH2), 4.82 (br s, 4H, NCH2CH2), 6.84 (ddd, 2H, J ¼ 8.4, 7.3,
1.1 Hz, H8-Q), 7.17 (d, 2H, J ¼ 8.4 Hz, H9-Q), 7.31 (d, 2H, J ¼ 8.1,
7.3 Hz, H7-Q), 7.35 (dd, 2H, J ¼ 8.1, 1.1 Hz, H6-Q), 7.41e7.53 (m, 6H,
ArH), 8.18 (dd, 4H, J ¼ 8.4, 1.4 Hz, o-Ph), 8.39 (dd, 2H, J ¼ 8.1, 6.0 Hz,
H5-Py), 8.94 (d, 2H, J ¼ 8.1 Hz, H4-Py), 9.36 (d, 2H, J ¼ 6.0 Hz, H6-
Py), 9.64 (s, 2H, H2-Py), 11.62 (s, 2H, NH). 13C NMR (100.6 MHz,
DMSO-d6) dc: 27.17, 60.46, 116.83, 117.57, 120.00, 120.51, 122.12,
127.52, 127.77, 128.33, 128.47, 129.43, 129.68, 131.59, 132.24,
137.66, 144.13, 145.02, 145.48, 146.00, 154.85. MS (MALDI
TOF) ¼ 813 [M ꢁ Brꢁ]þ, 811 [M ꢁ Brꢁ]þ, 731 [M4ꢁ HBr ꢁ Brꢁ]þ.
Found: C, 61.73; H, 4.01; N, 12.70; Br, 17.78. C46H36N8O2Br2 re-
quires: C, 61.89; H, 4.06; N,12.55; Br, 17.90%.
(MALDI TOF)
¼
1113 [M
ꢁ
Brꢁ]þ, 1111 [M
ꢁ
Brꢁ]þ, 1031
[M ꢁ HBr ꢁ Brꢁ]þ. Found: C, 68.56; H, 6.21; N, 9.49; Br, 13.23.
C68H72N8O2Br2 requires: C, 68.45; H, 6.08; N, 9.39; Br, 13.39%.
5.1.4. 1,10-Bis-{3-phenyl-1-(pyridin-3-yl)imidazo[1,5-a]quinoxalin-
4-on-5-yl}decane (5)
A solution of b-picolylamine (0.52 g, 4.8 mmol) in DMSO (3 mL)
was added to a solution of 1,10-bis-(3-benzoyquinoxalin-2-on-1-yl)
decane [26] (1.0 g, 1.6 mmol) in DMSO (7 mL). The reaction mixture
was stirred for 8 h at 150 ꢀC, and left overnight at room tempera-
ture, while the crystals of the product were precipitated, collected
by suction filtration, washed with EtOH (10 mL) and dried. The yield
5.1.3.17. 1,6-Bis{3-(3-phenylimidazo[1,5-a]quinoxalin-4(5H)-on-1-
yl)pyridinium}hexane dibromide (4b). Yield 55%. White powder, mp
321e323 ꢀC (dec.). IR (nmax, cmꢁ1, KBr): 3035, 2950, 2918, 2874,
2839, 2744, 2674, 1665, 1615, 1484, 1448, 1397, 1328, 1302, 1276,
1259, 1155, 812, 783, 765, 697, 671. 1H NMR (400 MHz, DMSO-d6)
was 60%. White powder, mp 235e237 ꢀC (DMSO). IR (nmax, cmꢁ1
,
KBr): 3052, 2923, 2852, 1656, 1610, 1592, 1567, 1499, 1485, 1469,
1447, 1394, 1336, 1323, 1299, 1252, 1183, 1120, 1025, 969, 745, 717,
692, 671. 1H NMR (400 MHz, CDCl3) dH: 1.20e1.50 (m, 12H, CH2),
1.70e1.85 (m, 4H, NCH2CH2), 4.22 (t, 4H, J ¼ 7.9 Hz, NCH2), 6.97 (dd,
2H, J ¼ 7.8, 6.5 Hz, H8-Q), 7.26e7.42 (m, 8H, ArH), 7.46 (d, 4H, J ¼ 7.7,
7.1 Hz, m-Ph), 7.63 (dd, 2H, J ¼ 7.8, 5.6 Hz, H5-Py), 8.12 (d, 4H,
J ¼ 7.2 Hz, o-Ph), 8.21 (d, 2H, J ¼ 7.8 Hz, H4-Py), 8.84 (dd, 2H, J ¼ 5.6,
0.7 Hz, H6-Py), 9.0 (d, 2H, J ¼ 0.7 Hz, H2-Py). 13C NMR (100.6 MHz,
CDCl3) dc: 27.17, 27.42, 29.44, 29.58, 42.09, 116.15, 118.05, 118.81,
122.41, 122.78, 123.88, 127.56, 128.07, 128.75, 128.76, 130.11, 130.64,
132.88, 137.33, 141.47, 146.12, 150.36, 151.07, 155.38. MS (MALDI
TOF) ¼ 815 [MH]þ. Found: C, 76.51; H, 5.75; N, 13.65. C52H46N8O2
requires: C, 76.64; H, 5.69; N,13.75%.
dH
:
1.42e1.48 (m, 4H, N(CH2)2CH2), 1.98e2.07 (m, 4H,
NCH2CH2CH2), 4.73 (t, 4H, J ¼ 7.5 Hz, NCH2(CH2)2), 6.96e7.02 (m,
2H, H8-Q), 7.27 (d, 2H, J ¼ 8.4 Hz, H9-Q), 7.37e7.52 (m, 10H, ArH),
8.17e8.21 (m, 4H, o-Ph), 8.40 (dd, 2H, J ¼ 8.1, 6.2 Hz, H5-Py), 8.98 (d,
2H, J ¼ 8.1, H4-Py), 9.37 (d, 2H, J ¼ 6.2 Hz, H6-Py), 9.66 (s, 2H, H2-
Py), 11.67 (s, 1H, NH). 13C NMR (100.6 MHz, DMSO-d6) dc: 24.85,
30.32, 61.10, 116.94, 117.65, 119.94, 120.69, 122.30, 127.75, 127.76,
128.30, 128.47, 129.46, 129.79, 131.63, 132.25, 137.79, 144.19, 145.09,
145.44, 145.80, 154.89. MS (MALDI TOF) ¼ 841 [M ꢁ Brꢁ]þ, 839
[M ꢁ Brꢁ]þ, 759 [M ꢁ HBr ꢁ Brꢁ]þ. Found: C, 62.50; H, 4.53; N,
12.32; Br, 17.16. C48H40N8O2Br2 requires: C, 62.62; H, 4.38; N,12.17;
Br, 17.36%.
5.1.5. 13,73-Diphenyl,-14,74-dioxa-1,7(1,5)-diimidazo[1,5-a]
qunoxalina,-2(3,1),6(1,3)-dipyridina,-4(1,3)-
benzenacycloheptadecaphane-21,61,-ylium dibromide (6)
5.1.3.18. 1,3-Bis{3-(5-hexyl-3-phenylimidazo[1,5-a]quinoxalin-4-on-
1-yl)pyridinium}xylene dibromide (4c). Yield 72%. White powder,
mp 252e254 ꢀC (dec.). IR (nmax, cmꢁ1, KBr): 3050, 3001, 2951,
2927, 2853, 1663, 1609, 1589, 1486, 1450, 1446, 1402, 1371, 1339,
1320, 1296, 1255, 1195, 1178, 1112, 987, 752, 698, 671. 1H NMR
(400 MHz, CDCl3) dH: 0.90 (t, 6H, J ¼ 6.6 Hz, CH3), 1.25e1.38 (m, 8H,
CH2), 1.38e1.48 (m, 4H, CH2), 1.65e1.77 (m, 4H, CH2), 4.00e4.15
(m, 4H, NCH2), 6.29 (s, 4H, CH2-xyl), 6.96 (dd, 2H, J ¼ 7.7, 7.5 Hz,
H8-Q), 7.15e7.45 (m, 13H, ArH), 7.74 (d, 2H, J ¼ 7.7 Hz, H4,6-xyl),
7.94 (d, 4H, J ¼ 7.5 Hz, o-Ph), 8.13 (br dd, 2H, J ¼ 7.2, 6.6, H5-Py),
8.31 (d, 2H, J ¼ 8.1, H4-Py), 8.50 (s, 1H, H2-xyl), 9.63 (br s, 2H, H2-
A solution of bisimidazo[1,5-a]quinoxaline 5 (0.24 g, 0.3 mmol)
and m-dibromoxylene (77.8 mg, 0.3 mmol) in acetonitrile (240 mL)
was refluxed for 24 h. The solvent was removed in vacuum and the
residue was purified by recrystallization from CHCl3 and then from
the mixture CHCl3:CH3CN ¼ 4:1. Yield 25%. White powder, mp 228e
230 ꢀC (dec.). IR (nmax, cmꢁ1, Nujol mull): 3089, 2927, 2852, 1657,
1612, 1590, 1522, 1486, 1462, 1447, 1406, 1370, 1324, 1299, 1253,
1177, 1122, 1074, 1053, 993, 926, 813, 752, 696, 671. 1H NMR
(400 MHz, DMSO-d6) dH: 1.35e1.44 (m, 4H, CH2), 1.45e1.52 (m, 8H,
CH2), 1.75e1.85 (m, 4H, CH2), 4.05e4.15 (m, 4H, NCH2), 6.03 (s, 4H,
CH2-xyl), 6.66 (dd, 2H, J ¼ 8.3, 7.2 Hz, H8-Q), 7.09 (d, 2H, J ¼ 8.3 Hz,
H9-Q), 7.21 (dd, 2H, J ¼ 8.3, 7.2 Hz, H7-Q), 7.30e7.40 (m, 6H, m,p-
Ph), 7.44 (d, 2H, J ¼ 8.4 Hz, H6-Q), 7.68 (dd, 1H, J ¼ 7.8, 7.8 Hz, H5-
xyl), 7.76 (s, 1H, H2-xyl), 7.78 (d, 2H, J ¼ 8.0 Hz, H4,6-xyl), 7.98 (d,
4H, J ¼ 7.6 Hz, o-Ph), 8.33 (dd, 2H, J ¼ 7.7, 6.3 Hz, H5-Py), 8.60 (br s,
Py), 9.93 (br d, 2H, J ¼ 5.3, H6-Py). 13C NMR (150.6 MHz, CDCl3) dc
:
14.18, 22.79, 26.91, 27.40, 31.68, 42.44, 62.25, 116.22, 119.22,
120.10, 121.25, 123.91, 128.12, 128.58, 129.16, 129.30, 130.05,
130.28, 130.65, 131.39, 131.83, 132.15, 132.42, 133.93, 136.44,
144.60, 144.94, 145.97, 146.67, 154.70. MS (MALDI TOF) ¼ 1029
[M ꢁ Brꢁ]þ, 1027 [M ꢁ Brꢁ]þ, 947 [M ꢁ HBr ꢁ Brꢁ]þ. Found: C,
67.00; H, 5.41; N, 10.22; Br, 14.48. C62H60N8O2Br2 requires: C,
67.15; H, 5.45; N, 10.10; Br, 14.41%.
2H, H4-Py), 9.48 (br d, 2H, J ¼ 6.3 Hz, H6-Py), 9.50 (s, 2H, H2-Py). 13
C
NMR (100.6 MHz, DMSO-d6) dc: 24.79, 26.67, 27.13, 41.66, 63.30,
116.27, 118.08, 119.29, 121.01, 122.00, 127.36, 127.50, 128.33, 128.49,
129.16, 129.58, 129.80, 129.98, 130.98, 131.62, 131.90, 134.90, 136.81,

354
A.A. Kalinin et al. / European Journal of Medicinal Chemistry 66 (2013) 345e354
144.08, 144.37, 145.27, 146.00, 154.16. MS (MALDI TOF) ¼ 999
[M ꢁ Brꢁ]þ, 997 [M ꢁ Brꢁ]þ, 917 [M ꢁ HBr ꢁ Brꢁ]þ. Found: C, 66.70;
H, 4.96; N,10.45; Br,14.85. C60H54N8OBr2 requires: C, 66.79; H, 5.04;
N,10.39; Br, 14.81%.
Appendix A. Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.ejmech.2013.05.
038. These data include MOL files and InChiKeys of the most
important compounds described in this article.
5.2. Biological evaluation
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bacteria and after incubation during 14 days for fungi. The bacte-
ricidal and fungicidal activities were determined as follows. Assay
tubes were filled with 1 mL of test compound solution in nutrient
agar. Concentrations of test compounds were varied from 5 to
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Acknowledgements
This work was supported by the Russian Foundation for Basic
Research (Grant No 13-03-00123-a) and Federal Agency of Science
and Innovation (the state contract No 02.740.11.0633).
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