Novel substituted quinoxaline 1,4-dioxides with in vitro antimycobacterial and anticandida activity

Article abstract of DOI:10.1016/S0223-5234(02)01346-6

Thirty-six 6(7)-substituted-3-methyl- or 3-halogenomethyl-2-phenylthio-phenylsulphonyl-chloro-quinoxaline 1,4-dioxides belonging to series 3-6 were synthesised and submitted to a preliminary in vitro evaluation for antimycobacterial, anticandida and antibacterial activities. Antitubercular screening showed a generally good activity of 3-methyl-2-phenylthioquinoxaline 1,4-dioxides (3d,e,h-j) against Mycobacterium tuberculosis, and exhibited MIC between 0.39 and 0.78 μg mL^-1 (rifampicin MIC=0.25 μg mL^-1), whereas in compounds 4d,e, 5a,b,d,e,l and 6b-e,j,l MIC ranged between 1.56 and 6.25 μg mL^-1. Results of the antibacterial and anticandida screening showed that 6e and 6l exhibited MIC=0.4 and 1.9 μg mL^-1, respectively, against Candida krusei (miconazole MIC=0.9 μg mL^-1), and 4i, 5b,d, 6e, MIC=3.9 μg mL^-1 against Candida glabrata (miconazole MIC=0.4 μg mL^-1), while compounds 3d,l, 5e,l, and 6b,d,e,l showed MIC=15.6 μg mL^-1 against Vibrio alginolyticus.

Full text of DOI:10.1016/S0223-5234(02)01346-6

Eur. J. Med. Chem. 37 (2002) 355–366
www.elsevier.com/locate/ejmech
Original article
Novel substituted quinoxaline 1,4-dioxides with in vitro
antimycobacterial and anticandida activity
Antonio Carta a, Giuseppe Paglietti a, Mohammad E. Rahbar Nikookar a,
Paolo Sanna a,*, Leonardo Sechi b, Stefania Zanetti b
a Dipartimento Farmaco Chimico Tossicologico, 6ia Muroni 23/a, 07100 Sassari, Italy
b Dipartimento di Scienze Biomediche, 6iale S. Pietro, 07100 Sassari, Italy
Received 11 October 2001; received in revised form 29 January 2002; accepted 29 January 2002
Abstract
Thirty-six 6(7)-substituted-3-methyl- or 3-halogenomethyl-2-phenylthio–phenylsulphonyl–chloro-quinoxaline 1,4-dioxides be-
longing to series 3–6 were synthesised and submitted to a preliminary in vitro evaluation for antimycobacterial, anticandida and
antibacterial activities. Antitubercular screening showed a generally good activity of 3-methyl-2-phenylthioquinoxaline 1,4-dio-
xides (3d,e,h–j) against Mycobacterium tuberculosis, and exhibited MIC between 0.39 and 0.78 mg mL−1 (rifampicin MIC=0.25
mg mL−1), whereas in compounds 4d,e, 5a,b,d,e,l and 6b–e,j,l MIC ranged between 1.56 and 6.25 mg mL−1. Results of the
antibacterial and anticandida screening showed that 6e and 6l exhibited MIC=0.4 and 1.9 mg mL−1, respectively, against
Candida krusei (miconazole MIC=0.9 mg mL−1), and 4i, 5b,d, 6e, MIC=3.9 mg mL−1 against Candida glabrata (miconazole
MIC=0.4 mg mL−1), while compounds 3d,l, 5e,l, and 6b,d,e,l showed MIC=15.6 mg mL−1 against Vibrio alginolyticus. © 2002
´
Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
Keywords: Quinoxaline 1,4-dioxides; Antimycobacterial; Anticandida; Antibacterial activity
activities of various 2-methylquinoxaline 1,4-dioxides,
confirming that the presence of methyl (or
1. Introduction
a
halogenomethyl) group at 2(3) position of this ring, as
previously reported also by other authors [6,8,9,17,18],
is favourable for antimicrobial activity. Interestingly,
The quinoxaline derivatives show very interesting
biological properties (antibacterial, antiviral, anti-
cancer, antifungal, anthelmintic, insecticidal) and their
interest in medicinal chemistry is far to come to an end
[1,2]. In the last two decades, many mono- and di-N-oxi-
des and 2-oxo derivatives of this heterocyclic system
have appeared and their biological activities reported.
Thus, for some quinoxalin-2-ones it was evidenced anti-
fungal activity [3,4], whereas the quinoxaline 1-oxides
have shown antibacterial activity [5]. Oxidation of both
ring nitrogen of quinoxaline enormously widens the
diversity of the biological properties, among these an-
tibacterial activity [6–9], animal growth promoting in
feed additives [10–12], hypoxia-selective activity [13],
genotoxycity against Escherichia coli and S. ty-
phimurium [14], etc. Recently, some researchers have
reported antibacterial [15] and antimycobacterial [16]
some
2-sulphonylquinoxalines
[19]
and
3-
[(alkylthio)methyl]quinoxaline 1-oxide derivatives [5]
were reported to be endowed with antibacterial and
antifungal activities.
In this context as contribution in the development of
quinoxaline derivatives, some of us have recently re-
ported the preparation and in vitro antitumoral and
antifungal activities of a large series of variously substi-
tuted quinoxalines [20–23] as well as the synthesis and
anticancer, antibacterial and antifungal activities of a
series of 2(3)-oxo-quinoxalines [4,24,25], and antibacte-
rial activity of quinoxaline-N-oxides [26]. Now, as a
further contribution in this field, we have designed the
series of 6(7)-substituted-3-methyl(halogenomethyl)-2-
phenylthio(sulphonyl)(chloro)quinoxaline 1,4-dioxides
(3–6) summarised in Fig. 1. Substituent at 6 and/or 7
positions in the benzene moiety, was chosen in order to
* Correspondence and reprints.
E-mail address: psanna@ssmain.uniss.it (P. Sanna).
´
0223-5234/02/$ - see front matter © 2002 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
PII: S0223-5234(02)01346-6

356
A. Carta et al. / European Journal of Medicinal Chemistry 37 (2002) 355–366
respectively. The 3-bromomethyl-2-phenylthioquinoxa-
line 1,4-dioxides (4a–e,h–l) were obtained in good yield
(83–88%), starting from 3a–e,h–l by addition of a
solution of bromine in ethyl acetate and heating the
mixture at reflux temperature [28]. The 3-methyl-2-
phenylsulphonylquinoxaline 1,4-dioxides (5a–e,g,j,l)
were in turn obtained, generally in good yield, by
oxidation of the 2-phenylthio derivatives (3a–e,g,j,l)
Fig. 1. Quinoxaline 1,4-dioxides (3–6).
with
a
solution of 3-chloroperoxybenzoic acid
evaluate the effect of an electron-withdrawing group
(CF3, Cl, diF) or electron-releasing group (CH3, EtO)
on the biological activities.
(MCPBA) in chloroform according to a described
method [29]. Conversion of the sulphonylquinoxaline
derivatives 5a–e,j,l into the 2-chloro-3-methylquinoxa-
line 1,4-dioxides (6a–e,j,l) was performed, with good
yield (78–93%), carrying out the reaction in concen-
trated hydrochloric acid, under stirring at 70 °C for 15
min.
2. Chemistry
The synthetic approach for the preparation of the
quinoxalines 1,4-dioxides (3–6) is depicted in Fig. 2.
The 3-methyl-2-phenylthioquinoxaline 1,4-dioxides
(3a–e,g–l) were obtained according to the known
Beirut reaction, by condensation of benzofuroxan
derivatives 2a,c,e,f,i–k with acetonylphenyl sulphide in
the presence of methanolic ammonia. Formation of
isomeric quinoxaline 1,4-dioxides was observed in the
case of monosubstituted benzofuroxans 2c,e,f,i and of
the non-symmetrical disubstituted compound 2k. Ac-
cording to previous reports by Abushanab and Alteri
for similar cases [27], we have observed that when an
electron-releasing substituent is present on benzo-
furoxan ring the 7-substituted-quinoxaline 1,4-dioxides
(3c,l) were prevailing over the 6-isomers 3b,k or the
only isomer formed was 3g. These results were reversed
when electron-withdrawing substituents were present.
Compounds 3d,h were prevailing over the isomers 3e,i,
Preparation of the benzofuroxan intermediates
2a,c,e,f,i,k was achieved, following the procedure pre-
viously described by Mallory [30], by means of a
sodium hypochlorite solution added to a suspension of
the appropriate o-nitroaniline 1a,c,e,f,i,j in a mixture of
potassium hydroxide and absolute ethanol. In the case
of 4,5-difluoro-2-nitroaniline (1j), the reaction afforded
the 5-ethoxy-6-fluorobenzofuroxan (2k), in 84% yield,
instead of the desired 5,6-difluorobenzofuroxan (2j).
This behaviour clearly indicates that a nucleophilic
displacement of fluorine atom at C-5 of the compound
1j by ethoxyde, was taking place during cyclisation to
2k. Conversion of the intermediate 1j into 2j was
obtained following a previous described alternative
route [31]. Compound 1j, in glacial acetic acid, was first
diazotised with nitrosyl sulphuric acid and the resulting
diazonium salt was added to an aqueous solution of
sodium azide (Fig. 2) to give 2j in 67% yield.
Fig. 2. Method of preparation of quinoxaline 1,4-dioxides (3–6).

A. Carta et al. / European Journal of Medicinal Chemistry 37 (2002) 355–366
357
3. Microbiology
Tables 1–4. These data show that various compounds
possess an interesting activity against several tested
strains. In general, compounds of the series 3, 5 and 6
resulted more active against M. tuberculosis, V. algi-
nolyticus and various strains of Candida compared with
those of the series 4.
With regard to antibacterial activity, the obtained
results mainly indicate that most of tested compounds
exhibited scarce activity against Gram positive and
-negative bacteria showing MIC values ranging from
62.5 to 500 mg mL−1 with a few exceptions. Com-
pounds 4a, 5a,b and 6d (MIC=31.25 mg mL−1) and 5c
and 5d (MIC=15.6 mg mL−1) were the most active
against S. aureus, while only compounds 5a (MIC=7.8
mg mL−1 against E. coli ) and 4j (MIC=31.25 mg
mL−1 against P. aeruginosa), display significant acti-
vity versus the mentioned Gram negative bacteria.
However, the titled compounds 3d,l, 5e,l and 6b,d,e,l
exhibited significant activity against environment Gram
Microbiological screening of the described com-
pounds was performed against mycobacteria (Mycobac-
terium tuberculosis), Gram positive (Staphylococcus
aureus) and Gram negative (E. coli, Vibrio alginolyticus,
Klebsiella pneumoniae and Pseudomonas aeruginosa)
bacteria, and yeasts (Candida albicans, Candida
glabrata, Candida krusei and Candida parapsilosis).
4. Results and discussion
Quinoxaline 1,4-dioxides (3a–e,g–l, 4a–e,h–l, 5a–
e,g,j,l and 6a–e,j,l) were evaluated in vitro for antibac-
terial (S. aureus, E. coli, V. alginolyticus, K. pneumoniae
and P. aeruginosa), antifungal (C. albicans, C. glabrata,
C. krusei and C. parapsilosis), and antimycobacterial
(M. tuberculosis) activities and results are reported in
Table 1
In vitro evaluation of anticandida activity on 24 clinical isolated strains of C. albicans of tested compounds (3d,e,i, 4a, 5a,e,l, 6e,l) MIC (mg mL−1),
miconazole MIC=3.9 mg mL−1
Strains
3d
3e
3i
4a
5a
5e
5l
6e
6l
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
62.5
15.6
15.6
15.6
31.25
62.5
62.5
31.25
31.25
15.6
31.25
31.25
62.5
15.6
15.6
15.6
31.25
31.25
31.25
31.25
62.5
31.25
15.6
15.6
15.6
15.6
31.25
15.6
7.8
7.8
15.6
62.5
15.6
31.25
15.6
31.25
31.25
31.25
31.25
31.25
31.25
15.6
31.25
31.25
62.5
31.25
31.25
7.8
62.5
15.6
62.5
15.6
62.5
15.6
15.6
15.6
15.6
15.6
15.6
15.6
15.6
31.25
15.6
15.6
15.6
31.25
15.6
15.6
31.25
7.8
15.6
15.6
15.6
15.6
7.8
31.25
7.8
15.6
15.6
7.8
7.8
7.8
7.8
31.25
15.6
7.8
31.25
7.8
62.5
15.6
62.5
15.6
31.25
15.6
15.6
15.6
62.5
15.6
62.5
62.5
62.5
62.5
62.5
62.5
62.5
7.8
15.6
31.25
31.25
31.25
31.25
31.25
15.6
31.25
31.25
31.25
31.25
62.5
62.5
31.25
7.8
62.5
62.5
31.25
31.25
31.25
31.25
31.25
31.25
62.5
31.25
31.25
62.5
62.5
31.25
7.8
31.25
15.6
62.5
15.6
15.6
15.6
31.25
31.25
31.25
31.25
31.25
15.6
15.6
15.6
15.6
31.25
31.25
7.8
15.6
31.25
7.8
31.25
31.25
31.25
31.25
15.6
15.6
15.6
31.25
31.25
15.6
15.6
7.8
15.6
31.25
15.6
31.25
31.25
31.25
31.25
15.6
31.25
7.8
15.6
15.6
7.8
15.6
7.8
7.8
15.6
15.6
15.6
15.6
7.8
7.8
7.8
7.8
15.6
15.6
15.6
15.6
31.25
31.25
15.6
31.25
15.6
7.8
7.8
15.6
15.6
15.6
31.25
15.6
31.5
15.6
31.25
31.25
31.25
31.25
31.25
Table 2
In vitro evaluation of anticandida activity on C. glabrata, C. krusei and C. parapsilosis (clinical isolated) of tested compounds (3d,k,j, 4b,i, 5b,d,l,
6e,l) MIC (mg mL−1
)
3d
3k
3j
4b
4i
3.9
31.25
31.25
5b
3.9
31.25
62.5
5d
3.9
7.8
15.6
5l
7.8
31.25
62.5
6e
3.9
0.4
15.6
6l
Miconazole
C. glabrata
C. krusei
C. parapsilosis
31.25
31.25
62.5
62.5
62.5
62.5
62.5
31.25
62.5
31.25
62.5
62.5
15.6
1.9
62.5
0.4
0.9
0.4

358
A. Carta et al. / European Journal of Medicinal Chemistry 37 (2002) 355–366
Table 3
In vitro evaluation of antitubercular activity as % growth inhibition at 6.25 mg mL−1 of concentration against M. tuberculosis of compounds
3a–e,h–l, 4a–e,h–j, 5a–e,j,l and 6b–e,j,l
Compound MIC (mg
mL−1
% Inhibition
Compound MIC (mg
mL−1
% Inhibition
Compound MIC (mg
mL−1
% Inhibition
)
)
)
3a
3b
3c
3d
3e
3h
3i
3j
3k
3l
\6.25
\6.25
\6.25
B6.25
B6.25
B6.25
B6.25
B6.25
\6.25
\6.25
\6.25
88
19
27
100
100
100
100
100
0
4b
4c
4d
4e
4h
4i
\6.25
\6.25
B6.25
B6.25
\6.25
\6.25
\6.25
B6.25
B6.25
\6.25
B6.25
0
17
96
99
88
77
48
100
99
79
5e
5j
5l
6b
6c
6d
6e
6j
B6.25
\6.25
B6.25
B6.25
B6.25
B6.25
B6.25
B6.25
B6.25
100
27
100
100
100
99
100
100
99
4j
5a
5b
5c
5d
6l
19
28
4a
100
Table 4
Actual MIC against M. tuberculosis (rifampicin MIC=0.25 mg mL−1) of compounds exhibiting \95% growth inhibition at 6.25 mg mL−1 of
compounds 3d,e,h–j, 4d,e, 5a,b,d,e,l and 6b–e,j,l
Compound
Actual MIC against M.
Compound Actual MIC against M.
Compound Actual MIC against M.
tuberculosis (mg mL−1
)
tuberculosis (mg mL−1
)
tuberculosis (mg mL−1
)
Rifampicin
0.25
0.78
0.39
0.39
0.78
0.78
6.25
4e
5a
5b
5d
5e
5l
3.13
6.25
3.13
6.25
6.25
6.25
3.13
6c
6d
6e
6j
3.13
6.25
1.56
1.56
3.13
3d
3e
3h
3i
3j
4d
6l
6b
negative bacterium V. alginolyticus with a MIC=15.6
mg mL−1 compared with ciprofloxacin (MIC=0.5 mg
mL−1).
general good activity. Among these compounds, the
derivatives 6e and 6l resulted the most active exhibiting
MIC=0.4 and 1.9 mg mL−1, respectively against C.
krusei (miconazole MIC=0.9 mg mL−1), whereas 4i,
5b,d and 6e recorded MIC=3.9 mg mL−1 against C.
glabrata (miconazole MIC=0.4 mg mL−1).
The in vitro anticandida activity was first tested
against a clinically isolated strains of C. albicans, using
miconazole as reference drug (MIC=3.9 mg mL−1).
The result of this preliminary test shows that none of
the tested compounds exhibited a better activity than
that of miconazole, even if several compounds showed
MIC values in the range 7.8–15.6 mg mL−1. In particu-
lar, among these compounds 3i, 4b,i and 5d exhibited
MIC=7.8 mg mL−1, and 3d,e,j,k, 4a, 5a,b,e and 6e,l
MIC=15.6 mg mL−1. In Table 1, we have reported the
results of a screening carried out over nine of these
derivatives (3d,e,i, 4a, 5a,e,l and 6e,l) against an addi-
tional 24 clinically isolated strains of C. albicans. The
data reported seem to confirm that the quinoxaline
1,4-dioxide derivatives have in general a good activity
against C. albicans. Of these compounds 5l and 6e
exhibited MIC515.6 mg mL−1 (miconazole MIC=3.9
mg mL−1) versus several strains. In the light of these
results the compounds 5l and 6e, along with 3d,j,k, 4b,i,
5b,d,l and 6e,l were tested against other clinically iso-
lated species of Candida (C. glabrata, C. krusei and C.
parapsilosis). The results reported in Table 2 show a
In Table 3, we have reported the results of an in vitro
antitubercular screening of 31 derivatives that showed a
general good activity against M. tuberculosis. In parti-
cular, the compounds 3d,e,h–j, 4d,e, 5a,b,d,e,l and 6b–
d,e,j,l exhibited at 6.25 mg mL−1 a growth inhibition in
the range 96–100%. For these derivatives, a confirma-
tory advanced screening was performed in order to
determine their actual MICs, that are reported in Table
4. Among these, 3-methyl-2-phenylthioquinoxaline 1,4-
dioxides (3d,e,h,i,j) exhibited the best activity with MIC
between 0.39 and 0.78 mg mL−1 (rifampicin MIC=
0.25 mg mL−1), whereas for compounds 4d,e, 5a,b,d,e,l
and 6b–d,e,j,l MIC ranged between 1.56 and 6.25 mg
mL−1
.
In conclusion, the overall biological data allowed us
to make some observations on structure–activity rela-
tionships. Antitubercular assays seem to confirm that
the quinoxaline 1,4-dioxide system is a good scaffold
for this type of activity. This resulted very high when

A. Carta et al. / European Journal of Medicinal Chemistry 37 (2002) 355–366
359
the phenylthio group in C-2 was associated with the
presence of an electron-withdrawing group in the ben-
zene moiety (CF3, Cl, diF), while combination of the
phenylthio group with a ring electron-releasing group
(CH3, EtO), as well as with the bromomethyl sub-
stituent at C-3, reduces this activity. Both oxidation of
the sulphide bridge to sulphonyl derivative and replace-
ment of phenylthio group with a chlorine generally
decreases the antitubercular activity, although in these
cases the type of the substituent in the benzene moiety
was generally not significant. On the contrary, the
results of antibacterial tests seem to put in evidence that
the highest activity is exhibited from those derivatives
bearing a chlorine or a phenylsulphonyl group at C-2
beside a methyl group in C-3, while the position and
the type of the substituents in the benzene moiety were
generally not relevant. As regards the anticandida test,
we can notice that the presence of chlorine atom at
position 2 (compounds 6e and 6l) favourably increases
the activity against these fungi.
multiplicities are represented by: s (singlet), d (doublet),
dd (double doublet), m (multiplet), and br s (broad
singlet). Column chromatographies were performed
using 230–400 mesh silica gel (Merck silica gel 60).
Light petroleum refers to the fraction with b.p. 40–
60 °C. Elemental analyses were performed by the Lab-
oratorio di Microanalisi, Dipartimento di Scienze
Farmaceutiche, Universita` di Padova (Italy). The ana-
lytical results for C, H, N, and halogen (Cl, Br), when
present, were within 90.4% of the theoretical values.
6.1.1. Starting materials
The o-nitroaniline derivatives 1a,c,e,i,j were commer-
cially available, 1f was known [32] but it was now
prepared, in 85% yield, by an alternative route by
nucleophilic displacement of the chlorine by EtONa–
EtOH starting from commercial 5-chloro-2-nitroaniline,
(m.p. 102–103 °C; literature [32]: m.p. 105–106 °C).
Acetonylphenyl sulphide was prepared following the
procedure previously described [33].
5. Conclusions
6.1.2. Intermediate benzofuroxans
(i) The benzofuroxan derivatives 2a,c,e,f,i,k were pre-
pared following the procedure previously described by
Mallory [30]. To a suspension of the appropriate o-ni-
troaniline 1a,c,e,f,i,j (28.9–72.7 mmol), in a mixture of
KOH (32–80 mmol) and absolute EtOH (25–60 mL)
cooled at 0 °C, was slowly added under vigorous stir-
ring a freshly prepared NaClO solution. After the addi-
tion was complete, the reaction mixture was stirred at
0 °C for an additional 1–2 h and then allowed to reach
room temperature (r.t.). The resulting precipitate was
filtered off and crystallised from EtOH.
(ii) Compound 2j was in turn obtained following the
procedure described by Ghosh et al. [31] for the mono-
fluoro derivative. The o-nitroaniline (1j) (57.4 mmol) in
glacial AcOH (50 mL) was added dropwise to ice-
cooled stirred nitrosyl sulphuric acid (4.26 g of NaNO2
in 50 mL of concd. H2SO4). When the addition was
complete, stirring was continued for an additional 1 h
at 0 °C and the resulting solution was poured onto
crushed ice (100 g). Then the reaction mixture was
added to a solution of NaN3 (4.10 g of NaN3 in 100
mL of H2O) under stirring for 30 min, the resulting
precipitate was filtered off, added of glacial AcOH (50
mL) and refluxed under stirring for 2 h. Eventually, the
AcOH was removed in vacuo and the remaining solu-
tion poured onto H2O. The precipitate obtained was
filtered off and thoroughly dried.
The screening on the in vitro antimicrobial activity
of these novel series of 6(7)-substituted-3-methyl- or
3 - halogenomethyl - 2 - phenylthio–phenylsulphonyl–
chloro-quinoxaline 1,4-dioxides has evidenced that the
3-methyl-2-phenylthioquinoxaline 1,4-dioxides (3d, 3e,
3h, 3i, 3j) have emerged as new compounds endowed
with antitubercular activity exhibiting MIC between
0.39 and 0.78 mg mL−1 (rifampicin MIC=0.25 mg
mL−1). This result is most encouraging for the develop-
ment of some compounds as antitubercular agents. In
addition, the quinoxaline 1,4-dioxide derivatives have a
general good anticandida activity. In particular, com-
pounds 6e and 6l were the most active against C. krusei
exhibiting MIC=0.4 and 1.9 mg mL−1, respectively,
(miconazole MIC=0.9 mg mL−1).
6. Experimental
6.1. Chemistry
M.p.s were determined by a Kofler hot stage or
Digital Electrothermal apparatus, and are uncorrected.
IR spectra are in nujol mulls and were recorded using a
Perkin–Elmer 781 spectrophotometer. UV spectra are
qualitative and were recorded in nm for solutions in
EtOH with a Perkin–Elmer Lambda 5 spectrophoto-
meter. 1H-NMR spectra were recorded on a Varian
XL-200 (200 MHz) instrument, using TMS as internal
standard. The chemical shift values are reported in ppm
(l) and coupling constants (J) in Hertz (Hz). Signal
6.1.2.1. Benzofuroxan (2a). This compound was ob-
tained in 74% yield; m.p. 69–70 °C (from EtOH),
(literature [30,34]: m.p. 72–73 °C).

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A. Carta et al. / European Journal of Medicinal Chemistry 37 (2002) 355–366
6.1.2.2. 6-Methylbenzofuroxan (2c). This compound
was obtained in 72% yield; m.p. 95–96 °C (from
EtOH), (literature [34]: m.p. 98 °C).
after stirring for 16 h and crystallisation from MeOH;
m.p. 159–161 °C; IR (cm−1): w 1620, 1600, 1350, 1310;
UV: umax 378, 296, 268, 242, 200 nm; 1H-NMR
(CDCl3): l 8.44 (1H, d, J=9.0, H-8), 8.41 (1H, s, H-5),
7.60 (1H, d, J=9.0, H-7), 7.32 (5H, m, 5 phenyl-H),
2.87 (3H, s, 3-CH3), 2.61 (3H, s, 6-CH3). Anal.
C16H14N2O2S (C, H, N).
6.1.2.3. 6-Chlorobenzofuroxan (2e). This compound was
obtained in 79% yield; m.p. 47–48 °C (from EtOH),
(literature [34]: m.p. 48 °C).
6.1.2.4. 5-Ethoxybenzofuroxan (2f). This is a new com-
pound and was obtained in 56% yield; m.p. \300 °C
(from EtOH); IR (cm−1): w 1620, 1600, 1520; UV: umax
6.1.3.3. 3,7-Dimethyl-2-phenylthioquinoxaline 1,4-dio-
xide (3c). This compound was obtained in 34% yield
after stirring for 16 h and crystallisation from MeOH;
m.p. 137–139 °C; IR (cm−1): w 1620, 1600, 1340, 1310;
UV: umax 381, 297, 268, 242, 202 nm; 1H-NMR
(CDCl3): l 8.51 (1H, d, J=8.8, H-5), 8.34 (1H, d,
J=1.8, H-8), 7.65 (1H, dd, J=8.8 and 1.8, H-6), 7.33
(5H, m, 5 phenyl-H), 2.85 (3H, s, 3-CH3), 2.58 (3H, s,
7-CH3). Anal. C16H14N2O2S (C, H, N).
1
372, 323, 309, 219 nm; H-NMR (DMSO-d6): l 7.49
(1H, d, J=8.8, H-5), 7.37 (1H, s, H-7), 6.98 (1H, d,
J=8.8, H-4), 4.13 (2H, q, J=7.0, CH2), 1.36 (3H, t,
J=7.0, CH3). Anal. C8H8N2O3 (C, H, N).
6.1.2.5. 6-Trifluoromethylbenzofuroxan (2i). This com-
pound was obtained in 80% yield; m.p. 108–110 °C
(from EtOH), (literature [31]: b.p. 118–120 °C/1
mmHg).
6.1.3.4. 6-Chloro-3-methyl-2-phenylthioquinoxaline 1,4-
dioxide (3d). This compound was obtained in 29% yield
after stirring for 12 h and chromatography on silica gel
column (eluent Et2O–light petroleum 70:30); m.p. 134–
136 °C (from MeOH); IR (cm−1): w 1620, 1350, 1310;
UV: umax 387, 304, 274, 243, 203 nm; 1H-NMR
(CDCl3): l 8.64 (1H, d, J=2.2, H-5), 8.48 (1H, d,
J=9.2, H-8), 7.72 (1H, dd, J=9.2 and 2.2, H-7), 7.34
(5H, m, 5 phenyl-H), 2.86 (3H, s, CH3). Anal.
C15H11ClN2O2S (C, H, Cl, N).
6.1.2.6. 5,6-Difluorobenzofuroxan (2j). This compound
was obtained in 67% yield; m.p. 55–56 °C (from
EtOH), (literature [35]: m.p. 56–58 °C).
6.1.2.7. 6-Fluoro-5-ethoxybenzofuroxan (2k). This is a
new compound and was obtained in 84% yield; m.p.
75–76 °C (from EtOH); IR (cm−1): w 1600, 1520, 1330;
1
UV: umax 352, 320, 306, 214 nm; H-NMR (CDCl3): l
7.25 (1H, d, J=10.4, H-7), 6.70 (1H, d, J=7.4, H-4),
4.17 (2H, q, J=7.0, CH2), 1.54 (3H, t, J=7.0, CH3).
Anal. C8H7FN2O3 (C, H, N).
6.1.3.5. 7-Chloro-3-methyl-2-phenylthioquinoxaline 1,4-
dioxide (3e). This compound was obtained in 26% yield
after stirring for 12 h and chromatography on silica gel
column (eluent Et2O–light petroleum 70:30); m.p. 152–
154 °C (from MeOH); IR (cm−1): w 1620, 1600, 1340,
6.1.3. General procedure for preparation of
3-methyl-2-phenylthioquinoxaline 1,4-dioxides
1
1310; UV: umax 389, 300, 272, 242, 202 nm; H-NMR
(3a–e,g–l)
(CDCl3): l 8.56 (1H, d, J=9.2, H-5), 8.53 (1H, d,
J=2.2, H-8), 7.75 (1H, dd, J=9.2 and 2.2, H-6), 7.34
(5H, m, 5 phenyl-H), 2.85 (3H, s, CH3). Anal.
C15H11ClN2O2S (C, H, Cl, N).
The title compounds were prepared following the
known Beirut reaction. Equimolar amounts (3.0–117.0
mmol) of the appropriate benzofuroxan 2a,c,e,f,i,j,k
and acetonylphenyl sulphide in MeOH (10–150 mL)
were bubbled in with ammonia gas for 10 min. Then,
the reaction mixture was stirred at r.t. for an additional
time, as indicated below. The resulting precipitate was
filtered off, washed with Et2O and dried. Separation of
the couple of two isomers, when present in the crude
mixture, was achieved by fractional crystallisation (3b/
3c) or by chromatography (3d/3e, 3h/3i and 3k/3l), as
indicated below.
6.1.3.6. 7-Ethoxy-3-methyl-2-phenylthioquinoxaline 1,4-
dioxide (3g). This compound was obtained in 49% yield
after stirring for 16 h and crystallisation from MeOH;
m.p. 250–251 °C; IR (cm−1): w 1620, 1580, 1330, 1320;
UV: umax 389, 306, 284, 253, 205 nm; 1H-NMR
(CDCl3): l 8.41 (1H, d, J=9.6, H-5), 7.69 (1H, d,
J=2.2, H-8), 7.55 (1H, dd, J=9.6 and 2.2, H-6), 7.33
(5H, m, 5 phenyl-H), 4.22 (2H, q, J=7.0, CH2), 2.68
(3H, s, 3-CH3), 1.41 (3H, t, J=7.0, CH3ꢀCH2). Anal.
C17H16N2O3S (C, H, N).
6.1.3.1. 3-Methyl-2-phenylthioquinoxaline 1,4-dioxide
(3a). This compound was obtained in 69% yield; m.p.
154–156 °C (from MeOH), (literature [29]: m.p. 153–
154 °C).
6.1.3.7. 6-Trifluoromethyl-3-methyl-2-phenylthioquino-
xaline 1,4-dioxide (3h). This compound was obtained in
12% yield after stirring for 11 h and chromatography
on silica gel column (eluent Et2O–light petroleum
50:50); m.p. 144–145 °C (from MeOH); IR (cm−1): w
6.1.3.2. 3,6-Dimethyl-2-phenylthioquinoxaline 1,4-dio-
xide (3b). This compound was obtained in 21% yield

A. Carta et al. / European Journal of Medicinal Chemistry 37 (2002) 355–366
361
1600, 1330, 1310, 1150, 1040; UV: umax 389, 300, 272,
236, 204 nm; H-NMR (CDCl3): l 8.85 (1H, d, J=2.2,
H-5), 8.76 (1H, d, J=9.2, H-8), 8.00 (1H, dd, J=9.2
and 2.2, H-7), 7.35 (5H, m, 5 phenyl-H), 2.89 (3H, s,
CH3). Anal. C16H11F3N2O2S (C, H, N).
quinoxaline 1,4-dioxide (3a–e,h–l) (1.5–2.0 mmol) in
EtOAc (50 mL) was heated to reflux temperature, when
a solution of Br (2.25–3.0 mmol) in EtOAc (5 mL) was
slowly (30–230 min) added dropwise. After the addi-
tion was complete, the reaction mixture was stirred
under reflux for an additional 15 min. The volume of
the solution was then concentrated in vacuo, to 5 mL,
and the solid precipitate was filtered off, washed with
Et2O, dried and crystallised from a suitable solvent.
1
6.1.3.8. 7-Trifluoromethyl-3-methyl-2-phenylthioquino-
xaline 1,4-dioxide (3i). This compound was obtained in
2.4% yield after stirring for 11 h and chromatography
on silica gel column (eluent Et2O–light petroleum
50:50); m.p. 128–129 °C (from MeOH); IR (cm−1): w
1620, 1330, 1300; UV: umax 396, 342, 300, 270, 235, 207
6.1.4.1. 3-Bromomethyl-2-phenylthioquinoxaline 1,4-
dioxide (4a). This compound was obtained in 87% yield
(after addition of Br solution within 75 min); m.p.
167–169 °C (from EtOAc); IR (cm−1): w 1610, 1350,
1
nm; H-NMR (CDCl3): l 8.95 (1H, d, J=1.6, H-8),
8.66 (1H, d, J=8.8, H-5), 7.97 (1H, dd, J=8.8 and
1.6, H-6), 7.35 (5H, m, 5 phenyl-H), 2.86 (3H, s, CH3).
Anal. C16H11F3N2O2S (C, H, N).
1
1320; UV: umax 382, 309, 274, 242, 205 nm; H-NMR
(CDCl3): l 8.66 (1H, dd, J=8.4 and 2.2, H-5), 8.51
(1H, dd, J=8.4 and 2.2, H-8), 7.84 (2H, m, H-6+H-
7), 7.51 (2H, m, 2 phenyl-H), 7.35 (3H, m, 3 phenyl-H),
5.20 (2H, s, CH2). Anal. C15H11BrN2O2S (C, H, Br, N).
6.1.3.9. 6,7-Difluoro-3-methyl-2-phenylthioquinoxaline
1,4-dioxide (3j). This compound was obtained in 82%
yield after stirring for 12 h and crystallisation from
MeOH; m.p. 186–187 °C; IR (cm−1): w 1620, 1340,
6.1.4.2. 3-Bromomethyl-6-methyl-2-phenylthioquinoxa-
line 1,4-dioxide (4b). This compound was obtained in
87% yield (after addition of Br solution within 70 min);
m.p. 165–166 °C (from EtOAc); IR (cm−1): w 1600,
1350, 1320; UV: umax 381, 312, 275, 246, 203 nm;
1H-NMR (CDCl3): l 8.45 (1H, d, J=2.2, H-5), 8.40
(1H, d, J=8.6, H-8), 7.64 (1H, dd, J=8.6 and 2.2,
H-7), 7.49 (2H, m, 2 phenyl-H), 7.33 (3H, m, 3 phenyl-
H), 5.22 (2H, s, CH2), 2.63 (3H, s, CH3). Anal.
C16H13BrN2O2S (C, H, Br, N).
1
1320; UV: umax 386, 298, 270, 236, 213 nm; H-NMR
(CDCl3): l 8.39 (2H, m, H-5+H-8), 7.34 (5H, m, 5
phenyl-H), 2.85 (3H, s, CH3). Anal. C15H10F2N2O2S (C,
H, N).
6.1.3.10.
6-Ethoxy-7-fluoro-3-methyl-2-phenylthio-
quinoxaline 1,4-dioxide (3k). This compound was ob-
tained in 13% yield after stirring for 16 h and
chromatography on silica gel column (eluent CHCl3–
light petroleum–EtOAc 50:20:30); m.p. 168–169 °C
(from MeOH); IR (cm−1): w 1620, 1500, 1400, 1330,
6.1.4.3. 3-Bromomethyl-7-methyl-2-phenylthioquinoxa-
line 1,4-dioxide (4c). This compound was obtained in
83% yield (after addition of Br solution within 110
min); m.p. 186–187 °C (from EtOAc); IR (cm−1): w
1600, 1330, 1310; UV: umax 382, 311, 275, 246, 202 nm;
1H-NMR (CDCl3): l 8.55 (1H, d, J=8.8, H-5), 8.32
(1H, d, J=2.2, H-8), 7.68 (1H, dd, J=8.8 and 2.2,
H-6), 7.52 (2H, m, 2 phenyl-H), 7.35 (3H, m, 3 phenyl-
H), 5.21 (2H, s, CH2), 2.58 (3H, s, CH3). Anal.
C16H13BrN2O2S (C, H, Br, N).
1
1310; UV: umax 378, 305, 271, 249, 204 nm; H-NMR
(CDCl3): l 8.21 (1H, d, J=10.8, H-8), 8.02 (1H, d,
J=7.4, H-5), 7.32 (5H, m, 5 phenyl-H), 4.32 (2H, q,
J=7.0, CH2), 2.88 (3H, s, 3-CH3), 1.57 (3H, t, J=7.0,
CH3ꢀCH2). Anal. C17H15FN2O3S (C, H, N).
6.1.3.11.
7-Ethoxy-6-fluoro-3-methyl-2-phenylthio-
quinoxaline 1,4-dioxide (3l). This compound was ob-
tained in 47% yield after stirring for 16 h and
chromatography on silica gel column (eluent CHCl3–
light petroleum–EtOAc 50:20:30); m.p. 157–158 °C
(from MeOH); IR (cm−1): w 1620, 1500, 1410, 1330,
6.1.4.4. 3-Bromomethyl-6-chloro-2-phenylthioquinoxa-
line 1,4-dioxide (4d). This compound was obtained in
85% yield (after addition of Br solution within 60 min);
m.p. 188–190 °C (from EtOAc); IR (cm−1): w 1600,
1340, 1320; UV: umax 387, 317, 280, 245, 203 nm;
1H-NMR (CDCl3): l 8.64 (1H, d, J=2.2, H-5), 8.44
(1H, d, J=9.2, H-8), 7.74 (1H, dd, J=9.2 and 2.2,
H-7), 7.49 (2H, m, 2 phenyl-H), 7.34 (3H, m, 3 phenyl-
H), 5.17 (2H, s, CH2). Anal. C15H10BrClN2O2S (C, H,
Br, Cl, N).
1
1320; UV: umax 396, 382, 303, 268, 246, 204 nm; H-
NMR (CDCl3): l 8.28 (1H, d, J=10.8, H-5), 7.94 (1H,
d, J=7.8, H-8), 7.32 (5H, m, 5 phenyl-H), 4.26 (2H, q,
J=7.0, CH2), 2.86 (3H, s, 3-CH3), 1.54 (3H, t, J=7.0,
CH3ꢀCH2). Anal. C17H15FN2O3S (C, H, N).
6.1.4. General procedure for preparation of
3-bromomethyl-2-phenylthioquinoxaline 1,4-dioxides
(4a–e,h–l)
The title compounds were prepared following the
procedure previously described by Haddadin et al. [28].
A solution of the appropriate 3-methyl-2-phenylthio-
6.1.4.5. 3-Bromomethyl-7-chloro-2-phenylthioquinoxa-
line 1,4-dioxide (4e). This compound was obtained in
86% yield (after addition of Br solution within 60 min);

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A. Carta et al. / European Journal of Medicinal Chemistry 37 (2002) 355–366
m.p. 198–199 °C (from EtOAc); IR (cm−1): w 1600,
1350, 1330; UV: umax 388, 314, 278, 245, 202 nm;
1H-NMR (CDCl3): l 8.59 (1H, d, J=9.2, H-5), 8.49
(1H, d, J=2.4, H-8), 7.77 (1H, dd, J=9.2 and 2.4,
H-6), 7.53 (2H, m, 2 phenyl-H), 7.34 (3H, m, 3 phenyl-
H), 5.17 (2H, s, CH2). Anal. C15H10BrClN2O2S (C, H,
Br, Cl, N).
(cm−1): w 1600, 1330; UV: umax 382, 319, 274, 253, 204
nm; H-NMR (CDCl3): l 8.30 (1H, d, J=10.4, H-5),
7.90 (1H, d, J=7.8, H-8), 7.51 (2H, m, 2 phenyl-H),
7.35 (3H, m, 3 phenyl-H), 5.19 (2H, s, CH2Br), 4.24
(2H, q, J=7.0, CH2O), 1.53 (3H, t, J=7.0, CH3).
Anal. C17H14BrFN2O3S (C, H, Br, N).
1
6.1.5. General procedure for preparation of
6.1.4.6. 3-Bromomethyl-6-trifluoromethyl-2-phenylthio-
quinoxaline 1,4-dioxide (4h). This compound was ob-
tained in 86% yield (after addition of Br solution within
30 min); m.p. 185–186 °C (from EtOAc); IR (cm−1): w
1610, 1330, 1310; UV: umax 394, 276, 237, 203 nm;
1H-NMR (CDCl3): l 8.81 (1H, d, J=2.2, H-5), 8.79
(1H, d, J=8.8, H-8), 8.02 (1H, dd, J=8.8 and 2.2,
H-7), 7.58 (2H, m, 2 phenyl-H), 7.38 (3H, m, 3 phenyl-
H), 5.20 (2H, s, CH2). Anal. C16H10BrF3N2O2S (C, H,
Br, N).
3-methyl-2-phenylsulphonylquinoxaline 1,4-dioxides
(5a–e,g,j,l)
The title compounds were prepared following the
procedure previously described by Abushanab [29]. To
a solution of the appropriate 3-methyl-2-phenylthio-
quinoxaline 1,4-dioxide (3a–e,g,j,k) (6.25–18.5 mmol)
in CHCl3 (50–100 mL) a solution of 3-chloroperoxy-
benzoic acid (MCPBA) (12.5–37.0 mmol) in CHCl3
(30–60 mL) was slowly added. After the addition was
complete, the reaction mixture was stirred at r.t. for an
additional 16 h, then the CHCl3 solution was washed
with 10% NaHCO3 aq. solution, dried over MgSO4,
filtered off and evaporated. A solid was obtained and
purified as indicated below.
6.1.4.7. 3-Bromomethyl-7-trifluoromethyl-2-phenylthio-
quinoxaline 1,4-dioxide (4i). This compound was ob-
tained in 85% yield (after addition of Br solution within
30 min); m.p. 175–176 °C (from EtOAc); IR (cm−1): w
1600, 1350, 1310; UV: umax 389, 277, 237, 202 nm;
1H-NMR (CDCl3): l 8.97 (1H, d, J=2.2, H-8), 8.62
(1H, d, J=8.8, H-5), 7.99 (1H, dd, J=8.8 and 2.2,
H-6), 7.52 (2H, m, 2 phenyl-H), 7.37 (3H, m, 3 phenyl-
H), 5.18 (2H, s, CH2). Anal. C16H10BrF3N2O2S (C, H,
Br, N).
6.1.5.1. 3-Methyl-2-phenylsulphonylquinoxaline 1,4-
dioxide (5a). This compound was obtained in 94% yield;
m.p. 158–160 °C (from CHCl3), (literature [29]: m.p.
180–181 °C).
6.1.5.2. 3,6-Dimethyl-2-phenylsulphonylquinoxaline 1,4-
dioxide (5b). This compound was obtained in 77% yield;
m.p. 179–180 °C (from CHCl3); IR (cm−1): w 1600,
6.1.4.8.
3-Bromomethyl-6,7-difluoro-2-phenylthio-
1
quinoxaline 1,4-dioxide (4j). This compound was ob-
tained in 87% yield (after addition of Br solution within
30 min); m.p. 181–182 °C (from EtOAc); IR (cm−1): w
1600, 1340, 1310; UV: umax 384, 306, 275, 236, 203 nm;
1H-NMR (CDCl3): l 8.46 (1H, t, J=8.6, H-5), 8.31
(1H, t, J=8.6, H-8), 7.52 (2H, m, 2 phenyl-H), 7.36
(3H, m, 3 phenyl-H), 5.17 (2H, s, CH2). Anal.
C15H9BrF2N2O2S (C, H, Br, N).
1350, 1310; UV: umax 398, 274, 247, 201 nm; H-NMR
(CDCl3): l 8.40 (1H, d, J=2.2, H-5), 8.28 (1H, d,
J=8.8, H-8), 8.15 (1H, dd, J=8.8 and 2.2, H-7), 7.63
(5H, m, 5 phenyl-H), 3.21 (3H, d, J=2.2, 3-CH3), 2.60
(3H, s, 6-CH3). Anal. C16H14N2O4S (C, H, N).
6.1.5.3. 3,7-Dimethyl-2-phenylsulphonylquinoxaline 1,4-
dioxide (5c). This compound was obtained in 74% yield;
m.p. 180–181 °C (from CHCl3); IR (cm−1): w 1600,
1350, 1300; UV: umax 410, 362, 272, 240, 201 nm;
1H-NMR (CDCl3): l 8.49 (1H, d, J=8.8, H-5), 8.14
(2H, m, H-6+H-8), 7.65 (5H, m, 5 phenyl-H), 3.20
(3H, s, 3-CH3), 2.53 (3H, s, 7-CH3). Anal. C16H14N2O4S
(C, H, N).
6.1.4.9. 3-Bromomethyl-6-ethoxy-7-fluoro-2-phenylthio-
quinoxaline 1,4-dioxide (4k). This compound was ob-
tained in 84% yield (after addition of Br solution within
120 min); m.p. 165–166 °C (from EtOAc); IR (cm−1):
w 1610, 1330; UV: umax 378, 316, 273, 250, 204 nm;
1H-NMR (CDCl3): l 8.19 (1H, d, J=10.2, H-8), 8.06
(1H, d, J=8.0, H-5), 7.48 (2H, m, 2 phenyl-H), 7.33
(3H, m, 3 phenyl-H), 5.22 (2H, s, CH2Br), 4.32 (2H, q,
J=6.8, CH2O), 1.57 (3H, t, J=6.8, CH3). Anal.
C17H14BrFN2O3S (C, H, Br, N).
6.1.5.4. 6-Chloro-3-methyl-2-phenylsulphonylquinoxa-
line 1,4-dioxide (5d). This compound was obtained in
72% yield; m.p. 148–150 °C (from CHCl3); IR (cm−1):
w 1600, 1330, 1310; UV: umax 396, 281, 244, 203 nm;
1H-NMR (CDCl3): l 8.61 (1H, d, J=2.0, H-5), 8.43
(1H, d, J=9.0, H-8), 8.14 (1H, dd, J=9.0 and 2.0,
H-7), 7.73 (2H, m, 2 phenyl-H), 7.54 (3H, m, 3 phenyl-
H), 3.21 (3H, s, CH3). Anal. C15H11ClN2O4S (C, H, Cl,
N).
6.1.4.10. 3-Bromomethyl-7-ethoxy-6-fluoro-2-phenyl-
thioquinoxaline 1,4-dioxide (4l). This compound was
obtained in 88% yield (after addition of Br solution
within 230 min); m.p. 180–181 °C (from EtOAc); IR

A. Carta et al. / European Journal of Medicinal Chemistry 37 (2002) 355–366
363
6.1.5.5. 7-Chloro-3-methyl-2-phenylsulphonylquinoxa-
line 1,4-dioxide (5e). This compound was obtained in
80% yield; m.p. 158–160 °C (from CHCl3); IR (cm−1):
w 1600, 1330, 1310; UV: umax 403, 282, 237, 202 nm;
1H-NMR (CDCl3): l 8.53 (1H, d, J=8.8, H-5), 8.49
(1H, d, J=2.2, H-8), 8.08 (2H, m, 2 phenyl-H), 7.78
(1H, dd, J=8.8 and 2.2, H-6), 7.54 (3H, m, 3 phenyl-
H), 2.95 (3H, s, CH3). Anal. C15H11ClN2O4S (C, H, Cl,
N).
6.1.6.1. 2-Chloro-3-methylquinoxaline 1,4-dioxide (6a).
This compound was obtained in 87% yield; m.p. 132–
133 °C (from ether–EtOH), (literature [29]: m.p. 166–
68 °C).
6.1.6.2. 2-Chloro-3,6-dimethylquinoxaline 1,4-dioxide
(6b). This compound was obtained in 91% yield; m.p.
153–154 °C (from ether–EtOH); IR (cm−1): w 1600,
1320, 1260; UV: umax 379, 363, 266, 240, 216 nm;
1H-NMR (CDCl3): l 8.51 (1H, d, J=8.8, H-8), 8.41
(1H, d, J=2.0, H-5), 7.67 (1H, dd, J=8.8 and 2.0,
H-7), 2.84 (3H, s, 3-CH3), 2.63 (3H, s, 6-CH3). Anal.
C10H9ClN2O2 (C, H, Cl, N).
6.1.5.6. 7-Ethoxy-3-methyl-2-phenylsulphonylquinoxa-
line 1,4-dioxide (5g). This compound was obtained in
5% yield; m.p. 146–148 °C (from CHCl3); IR (cm−1):
w 1620, 1330, 1310; UV: umax 402, 280, 230, 211 nm;
1H-NMR (CDCl3): l 8.06 (1H, d, J=2.0, H-8), 7.97
(1H, d, J=8.4, H-5), 7.91 (1H, dd, J=8.4 and 2.0,
H-6), 7.64 (2H, m, 2 phenyl-H), 7.48 (3H, m, 3 phenyl-
H), 4.42 (2H, q, J=7.0, CH2), 2.28 (3H, s, 3-CH3), 1.41
(3H, t, J=7.0, CH3ꢀCH2). Anal. C17H16N2O5S (C, H,
N).
6.1.6.3. 2-Chloro-3,7-dimethylquinoxaline 1,4-dioxide
(6c). This compound was obtained in 92% yield; m.p.
152–153 °C (from ether–EtOH); IR (cm−1): w 1600,
1320, 1260; UV: umax 379, 361, 266, 240, 216 nm;
1H-NMR (CDCl3): l 8.50 (1H, d, J=8.8, H-5), 8.41
(1H, d, J=2.0, H-8), 7.67 (1H, dd, J=8.8 and 2.0,
H-6), 2.83 (3H, s, 3-CH3), 2.63 (3H, s, 7-CH3). Anal.
C10H9ClN2O2 (C, H, Cl, N).
6.1.5.7. 6,7-Difluoro-3-methyl-2-phenylsulphonylquino-
xaline 1,4-dioxide (5j). This compound was obtained in
74% yield; m.p. 179–180 °C (from CHCl3); IR (cm−1):
w 1610, 1340, 1310; UV: umax 405, 368, 274, 230 nm;
1H-NMR (CDCl3): l 8.43 (1H, t, J=8.6, H-8), 8.21
(1H, t, J=8.6, H-5), 8.14 (2H, m, 2 phenyl-H), 7.62
(3H, m, 3 phenyl-H), 3.20 (3H, s, CH3). Anal. C15H10
F2N2O4S (C, H, N).
6.1.6.4. 2,6-Dichloro-3-methylquinoxaline 1,4-dioxide
(6d). This compound was obtained in 84% yield; m.p.
151–153 °C (from ether–EtOH); IR (cm−1): w 1620,
1320, 1270; UV: umax 382, 370, 272, 230, 205 nm;
1H-NMR (CDCl3): l 8.61 (1H, d, J=2.0, H-5) 8.58
(1H, d, J=9.2, H-8), 7.79 (1H, dd, J=9.2 and 2.0,
H-7), 2.84 (3H, s, CH3). Anal. C9H6Cl2N2O2 (C, H, Cl,
N).
6.1.5.8.
7-Ethoxy-6-fluoro-3-methyl-2-phenylsulpho-
nylquinoxaline 1,4-dioxide (5l). This compound was ob-
tained in 89% yield; m.p. 150–152 °C (from CHCl3);
IR (cm−1): w 1620, 1330, 1320; UV: umax 402, 367, 318,
6.1.6.5. 2,7-Dichloro-3-methylquinoxaline 1,4-dioxide
(6e). This compound was obtained in 88% yield; m.p.
178–179 °C (from ether–EtOH); IR (cm−1): w 1600,
1
1
274, 245, 208 nm; H-NMR (CDCl3): l 8.28 (1H, d,
1310, 1250; UV: umax 368, 272, 240, 212 nm; H-NMR
J=10.2, H-5), 7.84 (1H, d, J=7.6, H-8), 7.66 (5H, m,
5 phenyl-H), 4.29 (2H, q, J=7.0, CH2), 3.20 (3H, s,
3-CH3), 1.56 (3H, t, J=7.0, CH3ꢀCH2). Anal.
C17H15FN2O5S (C, H, N).
(CDCl3): l 8.63 (1H, d, J=2.0, H-8), 8.57 (1H, d,
J=9.2, H-5), 7.80 (1H, dd, J=9.2 and 2.0, H-6), 2.83
(3H, s, CH3). Anal. C9H6Cl2N2O2 (C, H, Cl, N).
6.1.6.6. 2-Chloro-6,7-difluoro-3-methylquinoxaline 1,4-
dioxide (6j). This compound was obtained in 78% yield;
m.p. 202–203 °C (from ether–EtOH); IR (cm−1): w
1620, 1600, 1320, 1270; UV: umax 379, 268, 231 nm;
1H-NMR (CDCl3): l 8.44 (2H, m, H-5+H-8), 2.83
(3H, s, CH3). Anal. C9H5ClF2N2O2 (C, H, Cl, N).
6.1.6. General procedure for preparation of
2-chloro-3-methylquinoxaline 1,4-dioxides (6a–e,j,l)
The title compounds were prepared by an adaptation
of the procedure described by Abushanab [29]. A mix-
ture of the appropriate sulphonylquinoxaline derivative
5a–e,j,l (3.1–15.8 mmol) in concd. HCl (6–32 mL) was
warmed up at 70 °C under stirring for 15 min. After
the excess of the acid was removed in vacuo, the aq.
solution was poured onto ice (about 20 g) and extracted
with CHCl3. The CHCl3 extracts were dried over
MgSO4, filtered off and evaporated. The solid residue
obtained was chromatographed on silica gel, eluting by
ethyl ether–EtOH 90:10, to give the desired
compounds.
6.1.6.7. 2-Chloro-7-ethoxy-6-fluoro-3-methylquinoxa-
line 1,4-dioxide (6l). This compound was obtained in
93% yield; m.p. 180–181 °C (from ether–EtOH); IR
(cm−1): w 1610, 1310, 1260; UV: umax 384, 362, 300,
1
267, 244, 202 nm; H-NMR (CDCl3): l 8.26 (1H, d,
J=10.4, H-5), 7.99 (1H, d, J=7.6, H-8), 4.33 (2H, q,
J=7.0, CH2), 2.81 (3H, s, 3-CH3), 1.58 (3H, t, J=7.0,
CH3ꢀCH2). Anal. C11H10ClFN2O3 (C, H, Cl, N).

364
A. Carta et al. / European Journal of Medicinal Chemistry 37 (2002) 355–366
6.2. Microbiological assays
6.2.3. Antimycobacterial assay
The described compounds were tested in vitro for
their antitubercular activity at Southern Research Insti-
tute, GWL Hansen’s Disease Center (Colorado State
University) within the Tuberculosis Antimicrobial Ac-
quisition and Coordinating Facility (TAACF) screening
program for the discovery of novel drugs for treatment
of tuberculosis.
All the synthetised compounds were evaluated in
vitro for their antimicrobial activity against Gram posi-
tive (S. aureus) and Gram negative (E. coli, V. algi-
nolyticus, K. pneumoniae and P. aeruginosa) bacteria,
yeasts (C. albicans, C. glabrata, C. krusei and C. parap-
silosis), and mycobacteria (M. tuberculosis).
Primary screening was conducted at 6.25 mg mL−1
for 3a–e,h–l, 4a–e,h–j, 5a–e,j,l, and 6b–e,j,l, against
the virulent strain M. tuberculosis H37Rv (ATCC
27294) in BACTEC 12B medium using a broth mi-
crodilution assay, the Microplate Alamar Blue assay
(MABA). Compounds exhibiting fluorescence were
tested in the Bactec 460 radiometric system. The MIC is
defined as the lowest concentration effecting a reduc-
tion in fluorescence of 90% relative to controls. Com-
pounds showing at least 90% inhibition in the primary
screen are re-tested at lower concentration againt M.
tuberculosis H37Rv to determine the actual minimum
inhibitory concentration in a broth microdilution Ala-
mar Blue assay (MABA) [36]. Compounds effecting
B90% inhibition in the primary screening (MIC\6.25
mg mL−1) were not evaluated further. The standard
compound used in this primary assay was rifampicin
(MIC=0.25 mg mL−1).
6.2.1. Antibacterial assays
The strains used in these tests were from American
Type Culture Collection (ATCC): S. aureus ATCC
2913, E. coli ATCC 25922, K. pneumoniae ATCC
700603, and P. aeruginosa ATCC 27853, or are envi-
ronmental isolate (V. alginolyticus). A logarithmic
phase culture of each bacterial strain was diluted with
Luria broth in order to obtain a density of 106 CFU
mL−1. The test was performed in a 96 well microtitre
plate in a final volume of 100 mL. Test compounds were
dissolved in dimethyl sulphoxide at an initial concentra-
tion of 1000 mg mL−1 and serially diluted in the plate
(500–7.8 mg mL−1) using Luria broth. Each well was
then inoculated with the standardised bacterial suspen-
sion and incubated at 37 °C for 18–24 h. One well
containing bacteria without sample (growth control),
and one well containing broth only (sterility control)
were also used. After the incubation the growth (or its
lack) of the bacteria was determined visually in both
containing compound well and control well. The lowest
concentration at which there was no visible growth
(turbidity) was taken as the MIC. In addition 5 mL of
suspension from each well was inoculated in a Mueller
Hinton agar plate to control bacterial viability.
Acknowledgements
We acknowledge the support of Southern Research
Institute, GWL Hansen’s Disease Center and Colorado
State University, USA; and Dr J.A.M
collaboration.
., for his kind
6.2.2. Antimycotic assay
Antifungal activity was determined by the tube dilu-
tion method on clinical isolates of C. glabrata, C.
krusei, C. parapsilosis and C. albicans (24 strains).
These clinical isolates were from a variety of patient
types including patients with AIDS, candidaemia, and
tissue disease. Yeast inocula were obtained by properly
diluting cultures incubated at 35 °C for 48 h in
Sabouraud Dextran agar to obtain a density of 106
Appendix A. Analytical data
5-Ethoxybenzofuroxan (2f): Anal. Calc. for
C8H8N2O3: C, 53.33; H, 4.48; N, 15.55. Found: C,
53.11; H, 4.63; N, 15.32%.
6-Fluoro-5-ethoxybenzofuroxan (2k): Anal. Calc. for
C8H7FN2O3: C, 48.49; H, 3.56; N, 14.14. Found: C,
48.37; H, 3.48; N, 14.02%.
CFU mL−1
. Test compounds were dissolved in
dimethyl sulphoxide at an initial concentration of 1000
mg mL−1 and then were serially diluted in culture
medium to 15.6 mg mL−1. Then, 0.5 mL of the above
serial dilutions of test compounds were added, in sterile
polystirene tubes, with an equal volume of fungal sus-
pension and incubated at 35 °C for 48 h. The MIC
determination was performed in duplicate, and defined
as the lowest concentration of the compound which
produced no visible growth. A sample of compound
free growth control and a set of tubes with sample
alone for monitoring contamination of the medium
were used.
3,6-Dimethyl-2-phenylthioquinoxaline
(3b): Anal. Calc. for C16H14N2O2S: C, 64.41; H, 4.73;
N, 9.39. Found: C, 64.32; H, 4.63; N, 9.24%.
3,7-Dimethyl-2-phenylthioquinoxaline
(3c): Anal. Calc. for C16H14N2O2S: C, 64.41; H, 4.73;
N, 9.39. Found: C, 64.33; H, 4.66; N, 9.23%.
6-Chloro-3-methyl-2-phenylthioquinoxaline 1,4-diox-
ide (3d): Anal. Calc. for C15H11ClN2O2S: C, 56.51; H,
3.48; Cl, 11.12; N, 8.79. Found: C, 56.43; H, 3.39; Cl,
11.07; N, 8.62%.
1,4-dioxide
1,4-dioxide
7-Chloro-3-methyl-2-phenylthioquinoxaline 1,4-diox-
ide (3e): Anal. Calc. for C15H11ClN2O2S: C, 56.51; H,

A. Carta et al. / European Journal of Medicinal Chemistry 37 (2002) 355–366
365
3.48; Cl, 11.12; N, 8.79. Found: C, 56.34; H, 3.35; Cl,
11.02; N, 8.64%.
3-Bromomethyl-6-ethoxy-7-fluoro-2-phenylthio-
quinoxaline 1,4-dioxide (4k): Anal. Calc. for
C17H14BrFN2O3S: C, 48.01; H, 3.32; Br, 18.79; N, 6.59.
Found: C, 47.86; H, 3.57; Br, 18.62; N, 6.33%.
3-Bromomethyl-7-ethoxy-6-fluoro-2-phenylthio-
quinoxaline 1,4-dioxide (4l): Anal. Calc. for
C17H14BrFN2O3S: C, 48.01; H, 3.32; Br, 18.79; N, 6.59.
Found: C, 47.93; H, 3.29; Br, 18.83; N, 6.47%.
3,6-Dimethyl-2-phenylsulphonylquinoxaline 1,4-diox-
ide (5b): Anal. Calc. for C16H14N2O4S: C, 58.17; H,
4.27; N, 8.48. Found: C, 58.06; H, 4.19; N, 8.41%.
3,7-Dimethyl-2-phenylsulphonylquinoxaline 1,4-diox-
ide (5c): Anal. Calc. for C16H14N2O4S: C, 58.17; H,
4.27; N, 8.48. Found: C, 58.11; H, 4.34; N, 8.37%.
6-Chloro-3-methyl-2-phenylsulphonylquinoxaline
1,4-dioxide (5d): Anal. Calc. for C15H11ClN2O4S: C,
51.36; H, 3.16; Cl, 10.11; N, 7.99. Found: C, 51.29; H,
3.11; Cl, 9.98; N, 7.87%.
7-Chloro-3-methyl-2-phenylsulphonylquinoxaline
1,4-dioxide (5e): Anal. Calc. for C15H11ClN2O4S: C,
51.36; H, 3.16; Cl, 10.11; N, 7.99. Found: C, 51.18; H,
3.28; Cl, 10.03; N, 7.84%.
7-Ethoxy-3-methyl-2-phenylsulphonylquinoxaline
1,4-dioxide (5g): Anal. Calc. for C17H16N2O5S: C,
56.65; H, 4.48; N, 7.77. Found: C, 56.41; H, 4.74; N,
7.51%.
6,7-Difluoro-3-methyl-2-phenylsulphonylquinoxaline
1,4-dioxide (5j): Anal. Calc. for C15H10F2N2O4S: C,
51.13; H, 2.86; N, 7.95. Found: C, 51.06; H, 2.72; N,
7.84%.
7-Ethoxy-6-fluoro-3-methyl-2-phenylsulpho-
nylquinoxaline 1,4-dioxide (5l): Anal. Calc. for
C17H15FN2O5S: C, 53.96; H, 4.00; N, 7.40. Found: C,
53.89; H, 3.97; N, 7.31%.
2-Chloro-3,6-dimethylquinoxaline 1,4-dioxide (6b):
Anal. Calc. for C10H9ClN2O2: C, 53.46; H, 4.04; Cl,
15.78; N, 12.47. Found: C, 53.39; H, 3.96; Cl, 15.66; N,
12.36%.
2-Chloro-3,7-dimethylquinoxaline 1,4-dioxide (6c):
Anal. Calc. for C10H9ClN2O2: C, 53.46; H, 4.04; Cl,
15.78; N, 12.47. Found: C, 53.26; H, 3.99; Cl, 15.51; N,
12.32%.
7-Ethoxy-3-methyl-2-phenylthioquinoxaline 1,4-diox-
ide (3g): Anal. Calc. for C17H16N2O3S: C, 62.17; H,
4.91; N, 8.53. Found: C, 62.07; H, 5.19; N, 8.32%.
6-Trifluoromethyl-3-methyl-2-phenylthioquinoxaline
1,4-dioxide (3h): Anal. Calc. for C16H11F3N2O2S: C,
54.54; H, 3.15; N, 7.95. Found: C, 54.49; H, 16.12; N,
7.84%.
7-Trifluoromethyl-3-methyl-2-phenylthioquinoxaline
1,4-dioxide (3i): Anal. Calc. for C16H11F3N2O2S: C,
54.54; H, 3.15; N, 7.95. Found: C, 54.38; H, 3.09; N,
7.80%.
6,7-Difluoro-3-methyl-2-phenylthioquinoxaline 1,4-
dioxide (3j): Anal. Calc. for C15H10F2N2O2S: C, 56.24;
H, 3.15; N, 8.75. Found: C, 56.17; H, 3.02; N, 8.67%.
6-Ethoxy-7-fluoro-3-methyl-2-phenylthioquinoxaline
1,4-dioxide (3k): Anal. Calc. for C17H15FN2O3S: C,
58.94; H, 4.37; N, 8.09. Found: C, 58.83; H, 4.29; N,
7.96%.
7-Ethoxy-6-fluoro-3-methyl-2-phenylthioquinoxaline
1,4-dioxide (3l): Anal. Calc. for C17H15FN2O3S: C,
58.95; H, 4.36; N, 8.09. Found: C, 58.87; H, 4.27; N,
8.02%.
3-Bromomethyl-2-phenylthioquinoxaline 1,4-dioxide
(4a): Anal. Calc. for C15H11BrN2O2S: C, 49.60; H, 3.06;
Br, 22.00; N, 7.71. Found: C, 49.57; H, 2.98; Br, 21.93;
N, 7.64%.
3-Bromomethyl-6-methyl-2-phenylthioquinoxaline
1,4-dioxide (4b): Anal. Calc. for C16H13BrN2O2S: C,
50.94; H, 3.47; Br, 21.18; N, 7.42. Found: C, 50.86; H,
3.39; Br, 21.07; N, 7.69%.
3-Bromomethyl-7-methyl-2-phenylthioquinoxaline
1,4-dioxide (4c): Anal. Calc. for C16H13BrN2O2S: C,
50.94; H, 3.47; Br, 21.18; N, 7.42. Found: C, 50.77; H,
3.42; Br, 21.02; N, 7.30%.
3-Bromomethyl-6-chloro-2-phenylthioquinoxaline
1,4-dioxide (4d): Anal. Calc. for C15H10BrClN2O2S: C,
45.30; H, 2.53; Br, 20.10; Cl, 8.92; N, 7.05. Found: C,
45.24; H, 2.48; Br, 19.93; Cl, 8.83; N, 6.97%.
3-Bromomethyl-7-chloro-2-phenylthioquinoxaline
1,4-dioxide (4e): Anal. Calc. for C15H10BrClN2O2S: C,
45.30; H, 2.53; Br, 20.10; Cl, 8.92; N, 7.05. Found: C,
45.16; H, 2.41; Br, 19.90; Cl, 8.78; N, 6.91%.
3-Bromomethyl-6-trifluoromethyl-2-phenylthio-
quinoxaline 1,4-dioxide (4h): Anal. Calc. for
C16H10BrF3N2O2S: C, 44.56; H, 2.34; Br, 18.53; N,
6.50. Found: C, 44.27; H, 2.42; Br, 18.44; N, 6.36%.
3-Bromomethyl-7-trifluoromethyl-2-phenylthio-
quinoxaline 1,4-dioxide (4i): Anal. Calc. for
C16H10BrF3N2O2S: C, 44.56; H, 2.34; Br, 18.53; N,
6.50. Found: C, 44.48; H, 2.28; Br, 18.39; N, 6.47%.
3-Bromomethyl-6,7-difluoro-2-phenylthioquinoxaline
1,4-dioxide (4j): Anal. Calc. for C15H9BrF2N2O2S: C,
45.13; H, 2.27; Br, 20.02; N, 7.02. Found: C, 44.79; H,
2.42; Br, 19.73; N, 6.84%.
2,6-Dichloro-3-methylquinoxaline 1,4-dioxide (6d):
Anal. Calc. for C9H6Cl2N2O2: C, 44.11; H, 2.47; Cl,
28.93; N, 11.43. Found: C, 44.07; H, 2.41; Cl, 28.89; N,
11.36%.
2,7-Dichloro-3-methylquinoxaline 1,4-dioxide (6e):
Anal. Calc. for C9H6Cl2N2O2: C, 44.11; H, 2.47; Cl,
28.93; N, 11.43. Found: C, 43.93; H, 2.53; Cl, 28.88; N,
11.27%.
2-Chloro-6,7-difluoro-3-methylquinoxaline 1,4-diox-
ide (6j): Anal. Calc. for C9H5ClF2N2O2: C, 43.83; H,
2.04; Cl, 14.38; N, 11.36. Found: C, 43.76; H, 1.99; Cl,
14.32; N, 11.29%.
2-Chloro-7-ethoxy-6-fluoro-3-methylquinoxaline 1,4-
dioxide (6l): Anal. Calc. for C11H10ClFN2O3: C, 48.45;

366
A. Carta et al. / European Journal of Medicinal Chemistry 37 (2002) 355–366
XVIth International Symposium on Medicinal Chemistry,
Bologna, Italy, 18–22 September, p. 550.
[17] R.R. Shaffer, US Patent 3,560,616, 1971; Chem. Abstr. 75 (1971)
47839u.
H, 3.70; Cl, 13.00; N, 10.28. Found: C, 48.37; H, 3.68;
Cl, 12.94; N, 10.23%.
[18] C.H. Issidorides, M.J. Haddadin, US Patent 4,343,942, 1982;
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