Azaanalogues of ebselen as antimicrobial and antiviral agents: Synthesis and properties

Article abstract of DOI:10.1016/j.farmac.2004.07.003

The different analogues of ebselen - unsubstituted benzisoselenazol-3(2H)- one (2a) 2-pyridylbenzisoselenazol-3(2H)-ones (2b-h) and 7-azabenzisoselenazol- 3(2H)-ones (3a-j) were designed as new selenium-containing antiviral and antimicrobial agents and synthesized. Some of them were found in the antiviral assay in vitro to be strong inhibitors of cythopatic activity of herpes simplex virus type 1 - HSV-1 (compounds 2a,b,f,h, 3a-j) and encephalomyocarditis virus - EMCV (compounds 2a,h, 3a-f,k,l). The compounds 2a,h and 3a-e,j were found to have an appreciable activity against Gram-positive bacteria (Staphylococcus aureus and Bacillus) in vitro, some of them inhibited growth of pathogenic yeasts (Candida albicans) (3a,b) and filamentous fungi (3a-e,f).

Full text of DOI:10.1016/j.farmac.2004.07.003

IL FARMACO 59 (2004) 863–868
http://france.elsevier.com/direct/FARMAC/
Azaanalogues of ebselen as antimicrobial and antiviral agents:
synthesis and properties
H. Wójtowicz a, K. Kloc a, I. Maliszewska a, J. Młochowski a,*,
M. PiVtka a, E. Piasecki b
a Institute of Organic Chemistry, Biochemistry and Biotechnology, Wrocław University of Technology, Wyb, Wyspian´skiego 27, 50-375 Wroclaw, Poland
b Laboratory of Virology, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, R. Weigla 12, 53-114 Wroclaw, Poland
Received 28 May 2004; accepted 16 July 2004
Available online 11 September 2004
Abstract
The different analogues of ebselen—unsubstituted benzisoselenazol-3(2H)-one (2a) 2-pyridylbenzisoselenazol-3(2H)-ones (2b–h) and
7-azabenzisoselenazol-3(2H)-ones (3a–j) were designed as new selenium-containing antiviral and antimicrobial agents and synthesized.
Some of them were found in the antiviral assay in vitro to be strong inhibitors of cythopatic activity of herpes simplex virus type 1—HSV-1
(compounds 2a,b,f,h, 3a–j) and encephalomyocarditis virus—EMCV (compounds 2a,h, 3a–f,k,l). The compounds 2a,h and 3a–e,j were
found to have an appreciable activity against Gram-positive bacteria (Staphylococcus aureus and Bacillus) in vitro, some of them inhibited
growth of pathogenic yeasts (Candida albicans) (3a,b) and filamentous fungi (3a–e,f).
© 2004 Elsevier SAS. All rights reserved.
Keywords: Ebselen; Organoselenium compounds; Bactericides; Fungicides; Virucides
1. Introduction
little attention has only been paid for their activity toward
pathogenic viruses, bacteria and fungi [6]. In the previous
works we reported that some of them were inhibitors of viral
cytopathogenicity and replication [13–15] and that ebselen,
some other benzisoselenazolones and diaryl diselenides ex-
hibited inhibitory activity against selected strains of bacteria
and fungi [15,16]. These findings opened a question: could a
replacement of condensed benzene ring of parent benzisose-
lenazolone system or phenyl substituent by pyridine moiety
result in enhancement of biological activity against pathoge-
nic bacteria and fungi in comparison to ebselen and other
benzisoselenazol-3(2H)-ones.
In this work ebselen (1) and unsubstituted benziso-
selenazol-3(2H)-one (2a), were obtained as reference com-
pounds. Then, two groups of their azaanalogues were synthe-
sized. There were 2-(2-pyridyl)benzisoselenazol-3(2H)-ones
(2b–f), also 2-(3-pyridyl)benzisoselenazol-3(2H)-one me-
thiodide (2h), 7-azabenzisoselenazol-3(2H)-ones (3a–j) and
methiodides 3k,l. All these compounds were screened in the
antiviral, antibacterial, and antifungal assay in vitro and most
of them exhibited expected high activity depending on the
molecular structure.
Two decades ago it was revealed that the simple, synthe-
ticallyavailableorganoseleniumcompound2-phenylbenziso-
selenazol-3(2H)-one named ebselen (1) could act against
oxidative stress in a similar way as common enzyme gluta-
thione peroxidase [1,2]. More recently extensive studies on
the chemistry and biology of ebselen and its analogues de-
monstrated their antiinflammatory, antisclerotic and cytopro-
tective properties [3–6].
In our previous papers we reported that various
2-substituted benzisoselenazol-3(2H)-ones and related dia-
ryl diselenides exhibited high activity as immunostimulants
inducing cytokines such as interferons, tumor necrosis factor
and interleukin (IL-2) in human peripheral blood leukocytes
[7–9]. Moreover some of them were found as potent and
selective inhibitors of endothelial nitric oxide synthase
[10–12].
In contrast to broad interest focused on the glutathione
peroxidase like activity of these compounds as antioxidants a
* Corresponding author. Tel.: +48-71-3202419; fax: +48-71-3284064.
E-mail address: jacek.mlochowski@pwr.wroc.pl (J. Młochowski).
0014-827X/$ - see front matter © 2004 Elsevier SAS. All rights reserved.
doi:10.1016/j.farmac.2004.07.003

864
H. Wójtowicz et al. / IL FARMACO 59 (2004) 863–868
Scheme 1
.
2. Chemistry
Ebselen (1) and unsubstituted benzisoselenazol-3(2H)-
one (2a) were prepared by treatment of 2-chloro-
selenobenzoyl chloride (4), obtained in four-step synthesis
starting from anthranilic acid, with aniline or aqueous ammo-
nia, respectively, in the same way as reported in our earlier
works [8,12]. The same chloride 4 reacting with various
2-aminopyridines produced 2-(2-pyridyl)benzisoselenazol-
3(2H)-ones (2b–f) and with 3-aminopyridine gave 2-(3-
pyridyl)benzisoselenazol-3(2H)-one (2g) as it is shown in
Scheme 1. The compound 2g heated with iodomethane, used
in excess, gave methiodide 2h. N-Methylation of its
2-pyridyl analogue 2b was unsuccessful, most probably be-
cause of steric hindrance of the lone electron pair of the
nitrogen atom. Possible methylation of selenium atom was
not observed. 4-Amino pyridine reacted with chloride in
another way then its 2- and 3-isomer. In this case instead of
tandem acylation-selenenylation of the primary amino group
both of the electrophilic centers, localized on the carbonyl
carbon and selenium, reacted separately and N-pyridin-4-yl-
2-(N-pyridin-4-yl-aminoseleno)benzamide reported in our
earlier work [8] was produced.
The strategy for synthesis of 7-azabenzisoselenazol-
3(2H)-ones (3), presented in Scheme 2, was based on the
conversion of 2-chloronicotinic acid (5) into 2-(chloro-
Scheme 2
.

H. Wójtowicz et al. / IL FARMACO 59 (2004) 863–868
865
Table 1
Virucidal activity of organoselenium compounds 1–3, acyclovir and dideoxycytidine
Compound
Cytotoxicity a
EMCV
MIC b
10.0
HSV-1
MIC b
4.0
VSV
Index c
1.5
Index c
0.8
MIC b
>1000
600.0
>1000
>1000
>1000
>1000
500.0
>1000
80.0
Index c
<0.01
0.005
<0.12
<0.20
<0.23
<0.10
0.08
1
2a
2b
2c
2d
2e
2f
2g
2h
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
Acyclovir
DdCd
15.0
3.0
0.4
7.5
1.0
3.0
120.0
200.0
230.0
100,0
40.0
3.0
>1000
>1000
>1000
>1000
500.0
>1000
20.0
<0.12
<0.20
<0.23
<0.10
0.08
<0.03
4.00
4.02
2.10
1.30
2.50
1.50
5.00
0.10
0.01
0.14
0.80
7.80
15.60
NAe
<4.0
2.0
60.0
<0.20
<0.23
<0.10
8.0
>1000
>1000
>1000
5.0
>1000
20.0
0.4
<0.03
4.0
<0.03
1.00
80.0
25.0
8.5
6.0
62.5
14.0
12.5
10.0
7.5
>1000
>1000
400.0
>1000
>1000
>1000
500.0
500.0
500.0
>1000
>1000
>1000
>1000
>1000
<0.02
<0.08
0.01
4.0
0.6
5.0
4.0
0.4
10.0
6.0
4.0
1.0
<0.01
<0.06
<0.02
0.10
4.0
0.8
20.0
50.0
7.5
4.0
0.6
33.5
50.0
7.5
500.0
500.0
500.0
100.0
2.0
1.0
1.0
0.01
70.0
80.0
15.6
31.2
>2500
4000
2.0
35.0
80.0
<0.02
<0.02
NAe
<4.0
0.14
1.0
<0.08
<0.02
0.03
800.0
400.0
>1000
>1000
2.0
>1000
>1000
NAe
<4.0
a Cytotoxicity on human A549 cells (µg/ml).
b Minimal virus inhibiting concentration (µg/ml).
c Index = cytotoxicity/MIC.
d Dideoxycytidine.
e Not applicable.
seleno)nicotinoyl chloride (10) and finally on the tandem
acylation-selenenylation of the primary amino group of ami-
noalkanes and aminoarenes with this reagent. For this
purpose acid 5 was converted into chloride 6 which treated
with potassium tert-butoxylate in dry tetrahydrofurane gave
ester 7. In the next step diselenide 8 was obtained by substi-
tution of chlorine atom in ester 7 by diselenide group with
dilithium diselenide generated in situ from elemental lithium
and selenium. Acid hydrolysis of carboxyester group in dise-
lenide 8 lead to 2,2′-diselenobisnicotinic acid 9 which treated
with thionyl chloride in the presence of catalytic amounts of
dimethylformamide gave 2-(chloroseleno)nicotinoyl chlo-
ride (10). The reaction of chloride 10 and ammonia or corres-
ponding primary amines in dry dichloromethane at ca –15 °C
resulted in formation of desired 7-azabenziso-
selenazol-3(2H)-ones (3). For this synthesis the procedures
elaborated recently in our laboratory were applied [17]. From
3b and 3i methiodides 3k and 3l were obtained by heating
with iodomethane.
Contrary to previously tested alkyl and aryl diselenides
which mostly were inactive or only moderately active against
HSV-1 virus [15], activity in a range of 0.4–2.0 µg/ml, seve-
ral times higher than activity of ebselen (1), was observed for
unsubstituted benzisoselenazol-3(2H)-one (2a) and different
7-azabenzisoselenazol-3(2H)-ones
(3a–j).
Among
2-(pyridyl)benzisoselenazol-3(2H)-ones high activity was
observed for the 2b,f substituted with 2-pyridyl. Presence of
3-pyridyl as a substituent made the compound 2g inactive
although its methiodide 2b was active. Methiodides 3k and 3l
derived from 7-azabenzisoselenazol-3(2H)-ones, were inac-
tive toward HSV-1 virus. Strong anti-EMCV activity, higher
that activity of ebselen (1) was found for unsubstituted
benzisoselenazol-3(2H)-one (2a), its 7-azaanalogue 3a,
7-azabenzisoselenazol-3(2H)-ones substituted with alkyl
groups 3b–f, and methiodides 3k and 3l.
To our knowledge the compounds 2a,h and 3a–j are the
most potent selenium-containing compounds active toward
both these viruses. VSV virus remained resistant toward
tested organoselenium compounds, except active methiodide
2h.
3. Results and discussion
To compare with organoselenium compounds two antivi-
ral drugs (acyclovir and dideoxycytidine) were tested in
similar conditions. The drugs were inactive against viruses
used in the virocidal assays (Table 1). Dideoxycytidine is an
anti-HIV drug, specific inhibitor of retroviral reverse trans-
criptase only. Although acyclovir is widely used as a potent
All compounds 2 and 3 were tested as inhibitors of cyto-
pathic activity of encephalomyocarditis virus (EMCV, non-
enveloped RNA virus), herpes simplex virus type 1 (HSV-1
enveloped DNA virus) and vesicular stomatitis virus (VSV,
enveloped RNA virus). The results are presented in Table 1.

866
H. Wójtowicz et al. / IL FARMACO 59 (2004) 863–868
Table 2
Antimicrobial activity of organoselenium compounds 1–3 against bacteria, yeasts and filamentous fungi characterized by values of MIC (µg/ml)
Compound
Bacteria
E. coli
n.a. b
32.0
n.a.
Yeasts
C. albicans
128.0
256.0
n.a.
Filamentous fungi
S. marcescens S. aureus a
B. subtilis
32.0
64.0
128
B. cereus
32.0
64.0
n.a.
A. niger
256.0
256.0
n.a.
P. chrysogenumP. citrinum
1
512.0
64.0
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
64.0
32.0
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
256.0
n.a.
n.a.
128.0
16.0
n.a.
256.0
256.0
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
32.0
2.0
128.0
256.0
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
32.0
2.0
2a
2b
2c
2d
2e
2f
2g
2h
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
128.0
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
16.0
256.0
32.0
512.0
n.a.
8.0
64.0
8.0
4.0
4.0
4.0
2.0
256.0
n.a.
64.0
8.0
4.0
4.0
4.0
4.0
128.0
n.a.
n.a.
n.a.
16.0
16.0
128.0
n.a.
128.0
64.0
512.0
n.a.
32.0
2.0
2.0
4.0
4.0
8.0
4.0
8.0
n.a.
64.0
512.0
n.a.
n.a.
32.0
n.a.
32.0
n.a.
n.a.
n.a.
n.a.
32.0
n.a.
n.a.
n.a.
32.0
n.a.
n.a.
n.a.
n.a.
32.0
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
64.0
128.0
32.0
128.0
16.0
256.0
16.0
512
16.0
256.0
128.0
n.a.
n.a.
32.0
n.a.
256.0
n.a.
n.a.
128.0
n.a.
n.a.
3m
n.a.
n.a.
a The literature data for: oxacillin MIC ≤0.03 µg/ml [18].
b Non-active MIC >500 µg/ml.
antiherpetic drug, it has no direct virocidal activity against
HSV-1.
active toward filamentous fungi strains Aspergillus niger,
Penicillium chrysogenum and Penicillium citrinum more
resistant toward ebselen.
Generally, antibacterial activity of the tested compounds
is far from being interesting (for example activities against
Staphylococcus aureus of two antibiotics Oxacillin and Peni-
cillin G, taken from Ref. [18], are given in Table 2) contrary
to their appreciable activity against filamentous fungi (Ta-
ble 2).
According to known hypothesis saying that mechanism of
biological action of benzisoselenazol-3(2H)-ones involves
interactions of selenenamide Se–N moiety with sulfhydryl
groups of biomolecules present in the living cells [3,4,6] it
seems to be possible that biological action of all tested
compounds on the molecular level should be similar. Proba-
bly observed differences in the biological response result
from different polarity and shape of the inhibitor molecule.
It may be concluded that the structural modifications of
parent ebselen structure lead to substantial enhancement of
the antiviral and antimicrobial activity of its azaanalogues.
Some of them, particularly 7-azabenzisoselenazol-3(2H)-
ones (3) were found to be strong inhibitors of cytopathic
activity of encephalomyocarditis virus EMCV (compounds
3a–f,k,l) and herpes simplex virus HSV-1 (compounds
3a–j), and to have appreciable activity against broad spec-
trum of microorganisms (particularly compound 3b). These
results make evidence that replacement of condensed ben-
zene ring in benzisoselenazol-3(2H)-one by pyridine ring
and introduction of small non-polar alkyl group in 2-position
plays a crucial role in strong enhancement of antiviral and
Cytotoxicity of the compounds reported in this work,
determined on human A 549 cells, presented in Table 1, falls
in a broad range from 3.0 µg/ml for 2a,g to 230 µg/ml for the
lowest toxic compound 2d. For EMCV, because of cytotoxi-
city, only ebselen (1) and compounds 2a,h,3a–f have appre-
ciable indices >1.0 (inhibitory dose is lower than cytotoxic
dose). Among these compounds unsubstituted benziso-
selenazol-3(2H)-one (2a) and azaanalogue of ebselen 3f ha-
ving index values 7.5 and 5.0 are most interesting.
Most of the compounds tested against HSV-1 have index
values substantially higher than ebselen. The indices for 2b,
3a,f,g,i,j falls in a range 30.0–80.0.
Cytotoxicity of acyclovir and dideoxycytidine were found
to be considerably lower than that of the organoselenium
compounds.
All azaanalogues of ebselen (2b–g, 3a–j) and methiodides
(2h, 3k and 3l) were tested against pathogenic bacteria,
yeasts and filamentous fungi. The results, expressed as mini-
mum inhibitory dose (MIC) values, are shown in Table 2,
together with those obtained for the same strains for ebselen
(1) and unsubstituted benzisoselenazol-3(2H)-one (2a). The
broadest spectrum of activity against tested microorganisms
was observed for 2-methyl-7-azabenzisoselenazol-3(2H)-
one (3b) having MIC values in the range 2.0–32.0 µg/ml. The
biological response for the Gram-positive and Gram-
negative bacteria, and yeasts Candida albicans was substan-
tially stronger to that established for ebselen (1) and its
unsubstituted analogue 2a. The same compound 3b was

H. Wójtowicz et al. / IL FARMACO 59 (2004) 863–868
867
antimicrobial activity. On the contrary, introduction of pyri-
dine moiety as a substituent generally does not enhance of
the biological response or even made the compound inactive.
4.1.2.3. 2-[6-Methyl(2-pyridyl)]benzisoselenazol-3(2H)-one
(2d) (81%). m.p. 238–239 °C: IR m 3060 cm–1 (C–Har),
2959 cm–1 (C–Haliph), 1627, 1573 cm–1 (C=O amide), 1590,
1445 cm–1 (C–Car), 1308, 739 cm–1 (C–N amide), 675 cm–1
(Py): 1H NMR d 2.42 (s, 3H, CH3), 7.07 (d, 1H, J = 7.4 Hz,
PyH), 7.43 (t, 1H, J = 7.4 Hz, ArH), 7.66 (t, 1H, J = 7.3 Hz,
ArH), 7.78 (t, 1H, J = 7.9 Hz, PyH), 7.88 (d, 1H, J = 7.6 Hz,
ArH), 8.03 (d, 1H, J = 7.6 Hz, ArH), 8.37 (d, 1H, J = 8.1 Hz,
PyH):
4. Experimental
4.1. Chemistry
All reagents and solvents were purchased from Aldrich
and Fluka. Melting points were determined with a digital
melting point apparatus Electrothermal IA 9100. IR spectra
were measured on a Perkin-Elmer 200 FT spectrometer in
KBr pellets. 1H NMR spectra were recorded in DMSO-d6 on
a Bruker DRX spectrometer 300 MHz. Chemical shifts are
reported in ppm relative to TMS. Reaction progress was
monitored by thin layer chromatography (TLC) on silica gel
60F254 coated aluminium TLC plates from Merck. Elemental
analyses were performed in our analytical laboratory and
agreed with theoretical values to within 0.3%.
4.1.2.4. 2-[5-Chloro(2-pyridyl)]benzisoselenazol-3(2H)-one
(2e) (68%). m.p. 269–271 °C: IR m 3073 cm–1 (C–Har), 1667,
1579 cm–1 (C=O amide), 1598, 1446 cm–1 (C–Car), 1282,
1
731 cm–1 (C–N amide), 671 cm–1 (Py): H NMR d 7.42 (t,
1H, J = 7.5 Hz, ArH) 7.65 (t, 1H, J = 7.6 Hz, ArH), 7.87 (d,
1H, J = 7.1 Hz, ArH) 7.98 (dd, 1H, J = 9.0 and J = 2.5 Hz,
PyH) 8.02 (d, 1H, J = 8.0 Hz, ArH) 8.46 (d, 1H, J = 2.0 Hz,
PyH) 8.59 (d, 1H, J = 9.2 Hz, PyH).
4.1.2.5. 2-[5-Nitro(2-pyridyl)]benzisoselenazol-3(2H)-one
(2f) (78%). m.p. 337–340 °C: IR m 3081 cm–1 (C–Har), 1670,
1577 cm–1 (C=O amide), 1593, 1460 cm–1 (C–Car), 1502,
1340, 844 cm–1 (NO2), 1272, 732 cm–1 (C–N amide),
671 cm–1 (Py): 1H NMR d 7.45 (t, 1H, J = 7.4 Hz, ArH), 7.70
(t, 1H, J = 7.8 Hz, ArH), 7.93 (d, 1H, J = 7.7 Hz, ArH), 8.05
(d, 1H, J = 7.9 Hz, ArH), 8.65 (dd, 1H, J = 9.3 and 2.7 Hz,
PyH), 8.74 (d, 1H, J1 = 9.3 Hz, PyH), 9.2 (d, 1H, J2 = 2.6 Hz,
PyH).
4.1.1. Ebselen (1) and benzisoselenazol-3(2H)-one (2a)
These compounds were prepared from 2-(chloroseleno)
benzoyl chloride (4) following the synthetic route described
in our previous work [8].
4.1.2. 2-Pyridylbenzisoselenazol-3(2H)-ones (2b–g).
General procedure
The solution of 2-(chloroseleno)benzoyl chloride (4)
(1.27 g, 5 mmol) in acetonitrile (25 ml) was added dropwise
at room temperature with stirring to the solution of the
corresponding aminopyridine (16.5 mmol) in acetonitrile
(25 ml) during 30 min and the reaction was continued for
24 h (2b–d,f,g) or 2 h (2e).After the reaction was finished the
solvent was evaporated in vacuo. To the crystalline residue
water (100 ml) was added and the mixture was stirred for
24 h at room temperature. Unsoluble product was filtered off,
washed with water, dried and recrystallized from methanol.
4.1.2.6. 2-(3-Pyridyl)benzisoselenazol-3(2H)-one (2g)
(88%). m.p. 274–275 °C: IR m 3064 cm–1 (C–Har), 1630,
1578 cm–1 (C=O amide), 1477, 1446 cm–1 (C–Car), 1314,
739 cm–1 (C–N amide), 674 cm–1 (Py): 1H NMR d 7.42–7.51
(m, 2H, ArH, PyH), 7.70 (t, 1H, J = 7.2 Hz, ArH) 7.91 (d, 1H,
J = 7.7 Hz, ArH), 8.05–8.11 (m, 2H, ArH, PyH), 8.45 (d, 1H,
J = 4.6 Hz, PyH), 8.87 (s, 1H, PyH).
4.1.3. 7–Azabenzisoselenazol-3(2H)-ones (3a–j).
General procedure
Were prepared from 2-(chloroseleno)nicotinoyl chloride
and ammonia (3a), alkyl amine (3b,c), phenylamine (3f–h)
or aminopyridine (3i,j), respectively, following the synthetic
route described in our recent work [17].
4.1.2.1. 2-(2-Pyridyl)benzisoselenazol-3(2H)-one (2b)
(82%). m.p. 233–234 °C (decomp.): IR m 3053 cm–1 (C–Har),
1617, 1568 cm–1 (C=O amide), 1586, 1461 cm–1 (C–Car),
1290, 743 cm–1 (C–N amide), 678 cm–1 (Py): 1H NMR d 7.21
(t, 1H, J = 6.0 Hz, PyH), 7.45 (t, 1H, J = 7.5 Hz,ArH), 7.68 (t,
1H, 7.5 Hz, ArH), 7.87 (t, 1H, J = 6.9 Hz, PyH), 7.90 (d, 1H,
J = 7.4 Hz, ArH), 8.06 (d, 1H, J = 7.9 Hz, ArH), 8.41 (d, 1H,
J = 3.4 Hz, PyH), 8.64 (d, 1H, J = 8.5 Hz, PyH).
4.1.4. Methiodides 2h, 3k and 3l
A mixture of 2-(3-pyridyl)benzisoselenazol-3(2H)-one
(2g) or 2-substituted 7–azabenzisoselenazol-3(2H)-ones
(3b,i) (2.5 mmol) and methyl iodide (5 ml, 80 mmol) was
heated at 120 °C for during 3 h for 2 g or 24 h 3b and i in
hermetically closed tube. After this time the yellow solid
precipitated. It was filtered, washed with dichloromethane
and dried in the air. Compound 2h (91%): m.p. 268–269 °C:
IR m 3073 cm–1 (C–Har), 2996 cm–1 C–Haliph), 1640 cm–1
(C=O amide), 1608, 1498 cm–1 (C–Car), 1280, 748 cm–1
(C–N amide), 664 cm–1 (Py): 1H NMR d 4.41 (s, 3H, CH3)
7.52 (t, 1H, J = 7.5 Hz, PyH), 7.74 (t, 1H, J = 7.7 Hz, ArH),
4.1.2.2. 2-[4-Methyl(2-pyridyl)]benzisoselenazol-3(2H)-one
(2c) (78%). m.p. 268–269 °C (decomp.): IR m 3065 cm–1
(C–Har), 2920 cm–1 (C–Haliph), 1622, 1557 cm–1 (C=O
amide), 1589, 1445 cm–1 (C–Car), 1286, 737 cm–1 (C–N
amide), 676 cm–1 (Py): 1H NMR d 2.48 (s, 3H, CH3), 7.05 (d,
1H, J = 4.7 Hz, PyH), 7.44 (t, 1H, J = 7.4 Hz, ArH), 7.67 (t,
1H, J = 7.5 Hz, ArH), 7.9 (d, 1H, J = 7.4 Hz, ArH), 8.05 (d,
1H, J = 7.9 Hz, ArH), 8.25 (d, 1H, J = 5.1 Hz, PyH), 8.45 (s,
1H, PyH).

868
H. Wójtowicz et al. / IL FARMACO 59 (2004) 863–868
7.79 (d, 1H, J = 7.7 Hz, ArH) 8.16 (dd, 1H, J = 6.0 and
2.58 Hz, PyH), 8.76 (t, 2H, J = 6.2 Hz, PyH), 9.15 (s, 1H,
PyH): compound 3k (99%): m.p. 192–194 °C: IR m
3008 cm–1 (C–Har), 2925 cm–1 C–Haliph), 1668, 1615 cm–1
(C=O amide), 1584, 1451 cm–1 (C–Car), 1312, 742 cm–1
(C–N amide), 668 cm–1 (Py): 1H NMR d 3.46 (s, 3H, CH3),
4.37 (s, 3H, CH3), 8.14 (dd, 1H, J = 7.6 and 6.2 Hz, PyH),
8.81 (d, 1H, J = 7.8 Hz, PyH), 9.18 (d, 1H, J = 6.0 Hz, PyH):
compound 3l (95%): m.p. 309–310 °C: IR m 3063 cm–1
(C–Har), 2965 cm–1 (C–Haliph), 1676, 1585 cm–1 (C=O
amide), 1569, 1430 cm–1 (C–Car), 1308, 743 cm–1 (C–N
amide), 1086, 667 cm–1 (Py): 1H NMR d 4.41 (s, 3H, CH3),
7.41 (dd, 1 H, J = 6.9 and J = 1.5 Hz, PyH), 8.08 (dt,
J = 7.6 and J = 1.6 Hz, PyH), 8.18 (dd, 1H, J = 7.9 and
J = 1.7 Hz, PyH), 8.45 (d, 1H, J = 8.3 Hz, PyH), 8.50 (1H,
J = 4.84 Hz, PyH), 8.89 (d, 1H, J = 7.4 Hz, PyH), 9.34 (d, 1H,
J = 5.9 Hz, PyH).
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