Synthesis and antibacterial activity of novel quinoxalinone derivatives

Article abstract of DOI:10.3184/030823409X12510409044803

The reaction of 3-hydrazinocarbonylmethylquinoxalin-2(1H)-one with phthalic anhydride, certain aromatic aldehydes, isocyanates and phenyl isothiocyanate furnished corresponding imide, Schiff's, semi- and thiosemicabazide derivatives. Treatment of 3-[2 (ph

Full text of DOI:10.3184/030823409X12510409044803

574 RESEARCH PAPER
SEPTEMBER, 574–578
JOURNAL OF CHEMICAL RESEARCH 2009
Synthesis and antibacterial activity of novel quinoxalinone derivatives
Mohamed A. Shaabana, Omneya M. Khalila, Khaled R. Ahmedb and Phoebe F. Lamieb
aPharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
bOrganic Chemistry Department, Faculty of Pharmacy, Beni-Swief University, Beni-Swief, Egypt
The reaction of 3-hydrazinocarbonylmethylquinoxalin-2(1H)-one with phthalic anhydride, certain aromatic
aldehydes, isocyanates and phenyl isothiocyanate furnished corresponding imide, Schiff's, semi- and
thiosemicabazide derivatives. Treatment of 3-[2-(phenylcarbamoyl)hydrazinocarbonylmethyl]quinoxalin-2(1H)-
one with chloroacetic acid, sulfuric acid and sodium hydroxide yielded cyclised derivatives. Moreover, 3-[2-
bromobenzylidenehydrazinocarbonyl-methyl]quinoxalin-2(1H)-one was cyclised to oxadiazolinyl derivative using
acetic anhydride. Furthermore, 3-[5-sulfanylidene-4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl]quinoxalin-2(1H)-one
was employed as a precursor in the synthesis of some novel 2(1H)-quinoxalinones. Some of the newly prepared
compounds were evaluated for in vitro antibacterial activity using ofloxacin as the reference standard.
Keywords: quinoxalinones, synthesis, antibacterial activity
Among the various classes of nitrogen containing heterocyclic
compounds, quinoxaline derivatives have been shown to
display a diverse array of pharmacological activities, among
which are antibacterial,1 antiviral,2 antifungal,3 antiprotozoal,4
and anti-inflammatory activities.5
oxadiazol-2-yl)methyl]quinoxalin-2(1H)-one (7). Oxidation of
compound 7 with hydrogen peroxide in acetic acid afforded 3-
[(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl]quinoxalin-
2(1H)-one (8). Furthermore, compounds 9a,b were prepared
by the reaction of 512 with formaldehyde and diethylamine or
morpholine under Mannich conditions (Scheme 1).
Moreover, five-membered heterocyclic compounds6-9 act as
highly functionalised scaffolds and are known pharmacophores
of a number of biologically active and medicinally useful
molecules.
When the acid hydrazide
1
was refluxed with
phenylisocyanate in absolute ethanol for 6 hours 3-[2-
(phenylcarbamoyl)hydrazinecarbonylmethyl]quinoxalin-
2(1H)-one (10) was obtained. On the other hand, refluxing
compound 1 with certain isocyanates for 24 hours yielded
triazole derivatives 11a,b. Cyclisation of the thiosemicarbazide
derivative 1213 was achieved by the action of chloroacetic acid
and sulfuric acid to yield 1,3-thiazolidin-4-one 13, and 1,3,4-
thiadiazole 14 derivatives respectively. Finally, the reaction of
the reported cyclised compound 1513 with certain alkyl halides
afforded the desired thioethers 16a,b (Scheme 2).
Meanwhile, resistance to antimicrobial agents is now
recognised as a major global public health problem. With the
emergence of new bacterial strains to many currently available
treatments, there is increasing interest in the discovery of
novel antibacterial agents.10
Hence, it was considered worthwhile to prepare molecules
having quinoxaline and oxadiazole/thiadiazole/triazole/
thiazolidinone rings in an attempt to find an effective
antibacterial agent.
The starting material, 3-hydrazinocarbonylmethyl-
quinoxalin-2(1H)-one (1), was prepared via hydrazinolysis
of 3-ethoxycarbonylmethylquinoxalin-2(1H)-one adopting
a reported procedure.11 Treatment of 1 with certain aromatic
aldehydes gave 3-[3-arylidenehydrazinocarbonylmethyl]
quinoxalin-2(1H)-ones 2a,b. Cyclisation of compound 2a
with acetic anhydride yielded the corresponding 3-[(4-acetyl-
5-(2-bromophenyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl]
quinoxalin-2(1H)-one (3) and was substantiated by spectral
Experimental
Melting points were obtained on a Griffin apparatus and are
uncorrected. Microanalyses for C,H and N were carried out at the
Microanalytical Centre, Cairo University. IR spectra were recorded
on a Shimadzu 435 spectrometer, using KBr discs. H NMR spectra
were performed on a Joel NMR FXQ-200 MHz spectrometer, using
TMS as the internal standard.
Mass spectra were recorded on a GCMP-QP1000 EX Mass
spectrometer. Progress of the reactions were monitored by TLC using
precoated aluminium sheet silica gel MERCK 60F 254 and was
visualised by UV lamp.
1
1
evidence. Thus, the H NMR spectra revealed the absence
of the two signals corresponding to azomethine (CH=N) and
(CO–NH) protons of its precursors. Moreover, the appearance
of a signal at d 2.35 ppm corresponding to an acetyl group, in
addition to a singlet signal at d 7.20 ppm corresponding to the
proton at position 2- of the oxadiazoline ring, were indicative
of successful formation of the title compound 3.
In addition, compound 1 was allowed to react with phthalic
anhydride to afford 3-(N-imidocarbamoylmethyl)quinoxalin-
2(1H)-one 4.
Conversely,heatingtheacidhydrazide1withcarbondisulfide
in alcoholic potassium hydroxide gave 3-[5-sulfanylidene-
4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl]quinoxalin-2(1H)-
one (5) as reported.12 Attempted alkylation of 5 with benzyl
chloride furnished 3-[(5-benzylsulfanyl-1,3,4-oxadiazol-2-
yl)methyl]quinoxalin-2(1H)-one (6). Its 1H NMR spectra
showed the appearance of a singlet at d 4.53 ppm integrating
for two protons of SCH2. Also, its mass spectrum showed a
molecular ion peak at m/z 350. Meanwhile, alkylation of 5 with
chloroacetic acid yielded 3-[(5-carboxymethylsulfanyl-1,3,4-
General procedure for the synthesis of compounds 2a,b
To a solution of compound 1 (2.18 g, 0.01 mol) in hot ethanol
(20 mL), the appropriate aromatic aldehyde (0.01 mol) was added.
The mixture was heated under reflux for 3 h, then allowed to cool
to room temperature. The solid obtained was filtered, washed with
ethanol and crystallised from dimethylformamide.
3-[2-Bromobenzylidenehydrazinocarbonylmethyl]quinoxalin-
2(1H)-one (2a): Yield: 98%; m.p. 295–297°C; IR: 3447–3196
(NH), 1678, 1630 (2C=O), 1603 (C=N); 1H NMR (DMSO-d6):
4.12 (s, 2H, CH2), 5.73 (s, 1H, vinylic =CH), 6.50–7.31 (m, 8H,
8 ArH), 7.95, 8.04 (2 s, 1H, syn, anti isomers of azomethine N=CH),
9.57, 9.64 (2 s, 1H, CONH, D2O exchangeable), 11.10 (s, 1H, N4H,
D2O exchangeable), 11.66, 12.06 (2 s, 1H, N1H, OH, tautomers of
quinoxaline, D2O exchangeable), MS: m/z 386 (M + 2, 4.95%), 384
(M+, 4.97%). Anal. Calcd for C17H13BrN4O2: C, 53.00; H, 3.40; N,
14.54. Found: C, 53.00; H, 3.20; N, 14.50%.
3-[4-Hydroxybenzylidenehydrazinocarbonylmethyl]quinoxalin-
2(1H)-one (2b): Yield: 69%; m.p. 279–281°C; IR: 3447–3200 (NH),
1678, 1640 (2C=O), 1610 (C=N); 1H NMR (DMSO-d6): 4.11 (s, 2H,
CH2), 5.78 (s, 1H, vinylic =CH), 6.50–7.53 (m, 8H, 8ArH), 7.87,
7.96 (2 s, 1H, syn, anti isomers of azomethine N=CH), 9.88 (s, 1H,
CONH, D2O exchangeable), 11.02 (s, 1H, OH, D2O exchangeable),
11.28 (s, 1H, N4H, D2O exchangeable), 11.67, 12.07 (2 s, 1H, N1H,
OH, tautomers of quinoxaline, D2O exchangeable). Anal. Calcd for
* Correspondent. E-mail: omneyafawzy@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2009 575
R
H
CHO
N
O
R
N
N
2a, R= 2-Br-C6H4
2b, R= 4-OH-C6H4
O
N
H
2a,b
H
N
(CH3CO)2O
2a
O
H
N
N
O
NH2
O
N
H
N
1
O
N
N
Br
O
O
CH3
3
H
N
N
Phthalic anhydride
CS2
O
NH
N
O
O
4
H
N
C6H5CH2Cl
O
N
N
O
N
CH2C6H5
S
H
H
N
N
O
O
6
N
ClCH2COOH
H2O2
N
N
N
O
O
N
HN
O
S
S
OH
5
H
7
N
O
N
N
HN
O
8
O
H
N
O
HCHO/ HNRR'
9a, R,R'=C2H5, C2H5
9b, R,R'=
N
O
N
O
N
N
R
N
S
R'
9a,b
Scheme 1
1
C17H14N4O3: C, 63.35; H, 4.37; N, 17.38. Found: C, 63.55; H, 4.31;
N, 17.35%.
1625 (C=N); H NMR (DMSO-d6): 2.35 (s, 3H, COCH3), 3.77 (s,
2H, CH2), 5.73 (s, 1H, vinylic =CH), 6.94–7.72 (m, 9H, 8ArH and
one oxadiazoline H); 10.42 (s,1H, N4H, D2O exchangeable) and
11.56, 12.31 (2 s, 1H, N1H, OH, tautomers of quinoxaline, D2O
exchangeable); MS: m/z 428 (M + 2, 2.15%), 427 (M + 1, 0.59%),
426 (M+, 2.18%). Anal. Calcd for C19H15BrN4O3: C, 53.41; H, 3.53;
N, 13.11. Found: C, 53.64; H, 3.62; N, 13.14%.
3-[(4-Acetyl-5-(2-bromophenyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl)
methyl] quinoxalin-2(1H)-one (3):Amixture of compound 2a (3.84 g,
0.01 mole) and acetic anhydride (6 mL) was heated under reflux
for 2 h. The excess acetic anhydride was distilled off under reduced
pressure, the obtained residue was triturated with petroleum ether
(25 mL). The separated solid was filtered and crystallised from
benzene/petroleum ether (40–60°).
3-[(1,3-Dioxo-2,3-dihydro-1H-isoindo-2-yl)aminocarbonyl-
methyl] quinoxalin-2(1H)-one (4): To a solution of acid hydrazide 1
(1.09 g, 0.005 mol) in glacial acetic acid (10 mL), the appropriate
Yield: 72%; m.p. 223–225°C; IR: 3463 (NH), 1733, 1669 (2C=O),

576 JOURNAL OF CHEMICAL RESEARCH 2009
H
N
O
O
H
N
C6H5NCO
6h
N
H
N
O
N
H
10
O
H
N
N
RNCO, 24h
1
R
5
N
11a, R= C6H5
11a,b
N
HN
11b, R= 4-Cl-C6H
O
H
N
O
C6H5NCS
6h
H
N
H
N
N
12
O
N
H
S
ClCH2COOH
H2SO4
NaOH
H
H
N
H
N
N
O
O
O
N
N
N
O
NH
N
N
N
S
N
N
HN
S
N
NH
S 15
O
13
R-X
14
H
N
O
N
N
N
N
SR
16a,b
16a, R= C2H5
16b, R= CH2C6H5
Scheme 2
acid anhydride (0.005 mol) was added and the mixture was heated
under reflux for 4 h. After cooling, the reaction mixture was poured
onto crushed ice (30 g). The solid separated was filtered, washed with
water and crystallised from glacial acetic acid. Yield: 35%; m.p. 311–
313°C; IR: 3445–3130 (NH), 1720, 1680, 1640 (3C=O), 1601 (C=N);
1H NMR (DMSO-d6): 3.93 (s, 2H, CH2); 5.83 (s, 1H, vinylic =CH);
6.96–7.96 (m, 8H, ArH); 10.62, 10.91 (2 s, 1H, NH, OH tautomers of
–CONH, D2O exchangeable); 11.41 (s, 1H, N4H, D2O exchangeable)
and 11.69, 12.46 (2 s, 1H, N1H, OH, tautomers of quinoxaline, D2O
exchangeable). Anal. Calcd for C18H12N4O4: C, 62.06; H, 3.47; N,
16.08. Found: C, 61.89; H, 3.37; N, 15.94%.
3-[(5-Benzylsulfanyl-1,3,4-oxadiazol-2-yl)methyl]quinoxalin-
2(1H)-one (6): An equimolar amount of 5 (2.60 g, 0.01 mol) and
benzyl chloride (1.26 g, 0.01 mol) in ethanolic potassium hydroxide
(0.08 g KOH in 20 mL ethanol) was heated under reflux for 3 h.
On cooling, the reaction mixture was poured onto crushed ice; the
solid separated was filtered and crystallised from dioxane. Yield:
67%; m.p. 277–279°C; IR: 3423 (NH), 1682 (C=O), 1637 (C=N);
1H NMR (DMSO-d6): 3.57 (s, 2H, CH2), 4.53 (s, 2H, SCH2), 6.05 (s,
1H, vinylic =CH), 7.04–7.49 (m, 9H, ArH), 10.38 (s, 1H, N4H, D2O
exchangeable), 11.72 (s, 1H, N1H, D2O exchangeable); MS: m/z 351
(M + 1, 12.30%), 350 (M+, 26.10%). Anal. Calcd for C18H14N4O2S:
C, 61.70; H, 4.02; N, 15.98. Found: C, 61.83; H, 4.14; N, 16.01%.
3-[(5-Carboxymethylsulfanyl-1,3,4-oxadiazol-2-yl)methyl]
quinoxalin-2(1H)-one (7): To a solution of 5 (2.60 g, 0.01 mole)
in ethanolic sodium hydroxide (0.4 g NaOH, 80 mL ethanol),
monochloroacetic acid (0.94 g, 0.01 mole) was added. The reaction
mixture was heated under reflux for 2 h, and diluted with water, then
acidified with acetic acid and crystallised from dioxane. Yield: 66%;
m.p. 242–244°C; IR: 3420–2714 (OH, NH), 1753, 1665 (2C=O),
1
1611 (C=N); H NMR (DMSO-d6): 4.13 (s, 2H, CH2), 4.31 (s, 2H,
SCH2), 5.88 (s, 1H, vinylic =CH), 7.00–7.79 (m, 4H, ArH), 11.65
(s, 1H, N4H, D2O exchangeable), 12.23, 12.57 (2 s, 1H, N1H, OH,
tautomers of quinoxaline, D2O exchangeable), 13.09 (s, 1H, COOH,

JOURNAL OF CHEMICAL RESEARCH 2009 577
D2O exchangeable); MS: m/z 320 (M + 2, 7.04%), 319 (M + 1,
10.23%), 318 (M+, 69.69%). Anal. Calcd for C13H10N4O4S: C, 49.05;
H, 3.16; N, 17.60. Found: C, 48.91; H, 3.27; N, 17.64%.
3-[2-(4-Oxo-3-phenyl-1,3-thiazolidin-2-ylidene)hydrazinecarbonyl
methyl]quinoxalin-2(1H)-one (13): A mixture of phenylthiosemi-
carbazide 12 (3.53 g, 0.01 mol) and monochloroacetic acid (0.94 g,
0.01 mol), in absolute ethanol (30 mL) was stirred at room
temperature for 1 h., anhydrous sodium acetate (0.82 g, 0.01 mol)
was then added and the reaction mixture was heated under reflux for
10 h. The solid separated was filtered and crystallised from ethanol.
Yield: 63%; m.p. 230–232°C; IR: 3448–3141 (NH), 1713, 1624
(2C=O), 1603 (C=N); 1H NMR (DMSO-d6): 4.16 (s, 2H, CH2),
4.42 (s, 2H, SCH2), 6.03 (s, 1H, vinylic =CH), 7.06–7.71 (m, 9H,
ArH), 10.37 (s, 1H, CONH, D2O exchangeable), 11.70 (s, 1H, N4H,
D2O exchangeable), 11.90, 12.55 (2 s, 1H, N1H, OH, tautomers of
quinoxaline, D2O exchangeable), MS: m/z 395 (M + 2, 3.56%), 393
(M+, 3.56%). Anal. Calcd for C19H15N5O3S: C, 58.00; H, 3.84; N,
17.80. Found: C, 58.02; H, 4.01; N, 18.01%.
3-[(5-Oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl]quinoxalin-2(1H)-
one (8): To a solution of 7 (3.18 g, 0.01 mol) in glacial acetic acid
(10 mL), H2O2 (5 mL) was added. The solution was left overnight
with stirring, the solvent was removed under vacuum and the solid
was crystallised from chloroform. Yield: 52%; m.p. 237–239°C;
IR: 3397–3107 (NH); 1709, 1677 (2C=O), 1604 (C=N); 1H NMR
(DMSO-d6): 4.17 (s, 2H, CH2), 6.02 (s, 1H, vinylic =CH), 6.96–7.72
(m, 4H, ArH), 10.36 (s, 1H, NH, D2O exchangeable), 11.70 (s, 1H,
N4H, D2O exchangeable), 12.56 (s, 1H, N1H, D2O exchangeable);
MS: m/z 245 (M + 1, 3.87%), 244 (M+, 14.78%). Anal. Calcd for
C11H8N4O3: C, 54.10; H, 3.30; N, 22.94. Found: C, 54.07; H, 3.36;
N, 23.11%.
3-[(5-Phenylamino-1,3,4-thiadiazol-2-yl)methyl]quinoxalin-2-
(1H)-one (14): A solution of phenylthiosemicarbazide 12 (3.53 g,
0.01 mol) in conc. sulfuric acid (10 mL) was kept at room temperature
for 4 h, while stirring at intervals. Thereafter, it was poured onto
crushed ice, and neutralised with 10% NaOH. The separated solid
was filtered and crystallised from ethanol. Yield: 70%; m.p. 282–
General procedure for the synthesis of compounds 9a,b
To a solution of 5 (2.60 g, 0.01 mol) in absolute ethanol (200 mL),
formaldehyde (10 mL, 40%) was added. The mixture was heated
to give a clear solution, then the corresponding secondary amine
(0.01 mol) was added and the reaction mixture was stirred at room
temperature. The solid separated was filtered and crystallised from
chloroform.
3-[(4-(Diethylamino)methyl)-5-sulfanylidene-4,5-dihydro-1,3,4-
oxadiazol-2-yl)methyl]quinoxalin-2(1H)-one (9a): Yield: 53%; m.p.
288–290°C; IR: 3449 (NH), 1671(C=O), 1611(C=N), 1224 (C=S);
1H NMR (DMSO-d6): 1.07–1.12 (t, 6H, J = 7.2 Hz, N(CH2CH3)2);
3.89–3.91 (q, 4H, J = 7.2 Hz, N(CH2CH3)2); 4.30 (s, 2H, CH2); 4.41
(s, 2H, NCH2N); 6.01 (s, 1H, vinylic =CH), 7.02–7.33 (m, 4H, ArH);
11.21 (s, 1H, N4H, D2O exchangeable), 11.47 (s, 1H, N1H, D2O
exchangeable); MS: m/z 347 (M + 2, 12.03%), 346 (M + 1, 30.96%),
345 (M+, 9.64%). Anal. Calcd for C16H19N5O2S: C, 55.63; H, 5.54;
N, 20.27. Found: C, 55.49; H, 5.30; N, 20.51%.
3-[(4-(Morpholin-4-yl)methyl)-5-sulfanylidene-4,5-dihydro-1,3,4-
oxadiazol-2-yl)methyl]quinoxalin-2(1H)-one (9b): Yield: 37%; m.p.
249–251°C; IR: 3446 (NH), 1669 (C=O), 1611 (C=N), 1225 (C=S);
1H NMR (DMSO-d6): 3.08–3.11 (m, 4H, CH2OCH2), 3.54–3.77 (m,
4H, CH2NCH2), 4.32 (s, 2H, CH2), 4.96 (s, 2H, NCH2N), 5.83 (s,
1H, vinylic =CH), 7.01–7.77 (m, 4H, ArH), 10.25 (s, 1H, N4H, D2O
exchangeable),11.41 (s, 1H, N1H, D2O exchangeable). Anal. Calcd
for C16H17N5O3S: C, 53.47; H, 4.76; N, 19.48. Found: C, 53.56; H,
4.73; N, 19.45%.
3-[2-(Phenylcarbamoyl)hydrazinecarbonylmethyl]quinoxalin-
2(1H)-one (10): Compound 1 (6.54 g, 0.03 mol) was heated under
reflux with phenyl isocyanate (0.03 mol) in absolute ethanol (60 mL)
for 6 h. On cooling, the solid separated was filtered and crystallised
from acetic acid/water. Yield: 90%; m.p. 260–262°C; IR: 3425–3270
(NH), 1681, 1637 (2C=O), 1613 (C=N); 1H NMR (DMSO-d6): 3.77
(s, 2H, CH2), 5.72 (s, 1H, vinylic =CH), 6.97–7.72 (m, 9H, ArH),
9.40, 9.84, 10.45(3 s, 3H, 3NH, D2O exchangeable), 11.56 (s, 1H,
N4H, D2O exchangeable),12.63 (s, 1H, N1H, D2O exchangeable);
MS: m/z 337 (M+, 1.63%). Anal. Calcd for C17H15N5O3: C, 60.52; H,
4.48; N, 20.76. Found: C, 60.52; H, 4.29; N, 20.55%.
1
284°C; IR: 3447–3283 (NH), 1675 (C=O), 1624 (C=N); H NMR
(DMSO-d6): 3.82 (s, 2H, CH2), 5.77 (s, 1H, vinylic =CH), 7.01–7.76
(m, 9H, ArH), 10.48 (s, 1H, NH, D2O exchangeable), 11.59 (s, 1H,
N4H, D2O exchangeable),12.66 (s, 1H, N1H, D2O exchangeable);
MS: m/z 337(M + 2, 3.85%), 336(M + 1, 5.84%), 335(M+, 24.19%).
Anal. Calcd for C17H13N5OS: C, 60.88; H, 3.90; N, 20.88. Found: C,
61.01; H, 4.00; N, 20.69%.
General procedure for the synthesis of compounds 16a,b
A mixture of equimolar amount of compound 15 (1.675 g, 0.005 mol)
and the appropriate alkyl or aryl halide (0.005 mol) in alcoholic
potassium hydroxide (0.28 g KOH in 20 mL ethanol) was heated
under reflux for 3 h. The reaction mixture was cooled, poured
onto crushed ice, the solid separated was filtered and crystallised
from acetone.
3-[(5-Ethylsulfanyl-4-phenyl-1,5-dihydro-1,2,4-triazol-3-yl)-
methyl]-quinoxalin-2(1H)-one (16a)
Yield: 60%; m.p. 266–268°C; IR: 3173 (NH), 1677(C=O),
1
1635 (C=N); H NMR (DMSO-d6): 1.29–1.36 (t, 3H, J = 7.2 Hz,
CH2CH3), 3.09–3.16 (q, 2H, J = 7.2 Hz, CH2CH3), 3.57 (s, 2H, CH2),
5.57 (s, 1H, vinyl =CH), 6.94–7.66 (m, 9H, ArH), 11.12 (s, 1H, N4H,
D2O exchangeable), 11.49 (s, 1H, N1H, D2O exchangeable). Anal.
Calcd for C19H17N5OS: C, 62.79; H, 4.71; N, 19.26. Found: C, 62.61;
H, 4.68; N, 19.18%.
3-[5-(Benzylsulfanyl-4-phenyl-1,5-dihydro-1,2,4-triazol-3-
yl)methyl]-quinoxalin-2(1H)-one (16b): Yield: 49%; m.p. 247–
249°C; IR: 3168 (NH), 1678 (C=O), 1631 (C=N); 1H NMR (DMSO-
d6): 3.56 (s, 2H, SCH2), 5.55 (s, 1H, vinylic =CH), 6.92–7.63 (m,
14H, ArH), 11.07 (s, 1H, N4H, D2O exchangeable), 11.45 (s, 1H,
N1H, D2O exchangeable); MS: m/z 427 (M + 2, 1.20%), 426 (M + 1,
4.92%), 425 (M+, 15.20%). Anal. Calcd for C24H19N5OS: C, 67.74;
H, 4.50; N, 16.45. Found: C, 67.69; H, 4.50; N, 16.61%.
Evaluation of anti-inflammatory activity
The minimal inhibitory concentrations (MIC) of 12 compounds
againstdifferentbacterialisolates(Staphylococcusaureus, Escherichia
coli, Pseudomonas aeruginosa and Bacillus subtilis) were determined
by the agar-dilution method according to the National Committee for
Clinical Laboratory Standards.14
General procedure for the synthesis of compounds 11a,b
A mixture of compound 1 (2.18 g, 0.01 mol) and the appropriate
isocyanate derivative (0.012 mol) was heated under reflux in absolute
ethanol (50 mL) for 24 h. The formed precipitate was filtered and
crystallised from ethanol.
Minimal inhibitory concentration (MIC) measurement
3-[(4-Phenyl-5-oxo-1,5-dihydro-1,2,4-triazol-3-yl)methyl]
quinoxalin-2(1H)-one (11a): Yield: 95%; m.p. 261–263°C; IR: 3448
(NH), 1772, 1684 (2C=O), 1609 (C=N); 1H NMR (DMSO-d6): 3.80
(s, 2H, CH2), 5.74 (s, 1H, vinylic =CH), 7.00–7.75 (m, 9H, ArH),
9.43, 9.60 (2 s, 1H, NH, OH, D2O exchangeable), 10.48 (s, 1H, N4H,
D2O exchangeable), 11.59, 12.66 (2 s, 1H, N1H, OH, tautomers of
quinoxaline, D2O exchangeable). Anal. Calcd for C17H13N5O2: C,
63.94; H, 4.10; N, 21.93. Found: C, 63.75; H, 4.24; N, 21.74%.
3-[(4-(4-Chlorophenyl)-5-oxo-1,5-dihydro-1,2,4-triazol-3-yl)
methyl]quinoxalin-2(1H)-one (11b): Yield: 97%; m.p. 233–235°C;
IR: 3425 (NH), 1773, 1683 (2C=O), 1613 (C=N); 1H NMR (DMSO-
d6): 3.71 (s, 2H, CH2), 5.64 (s, 1H, vinylic =CH); 6.98–7.81(m, 8H,
ArH), 9.19 (s, 1H, NH, D2O exchangeable); 11.46 (s, 1H, N4H,
D2O exchangeable),11.68, 12.16(s, brs, 1H, N1H, OH, tautomers of
quinoxaline, D2O exchangeable); MS: m/z 353 (M+, 0.51%). Anal.
Calcd for C17H12ClN5O2: C, 57.71; H, 3.41; N, 19.79. Found: C,
57.59; H, 3.60; N, 19.90%.
Mueller Hinton agar plates containing two- fold serial dilution of the
respective compounds were surface inoculated with about 104 CFU
of the test organism per spot and incubated at 37°C for 18 hours.
The plates were then observed for the presence or absence of
microbial growth. The lowest concentration showing no growth was
taken as the minimal inhibitory concentration (MIC).
Results of antimicrobial activity
The results of antimicrobial testing revealed that all compounds
showed weak antibacterial activity. On the other hand, compounds 14
and 16b were the most active against Pseudomonas aeruginosa.
The authors thank Dr Amal E. Saafan, Department of
Microbiology and Immunology, Faculty of Pharmacy, Beni-
Swief University for help in performing the anti-microbial
testing.

578 JOURNAL OF CHEMICAL RESEARCH 2009
7
L.M. Thomasco, R.C. Gadwood, E.A. Weaver, J.M. Ochoada, C.W. Ford,
G.E. Zurenko, J.C. Hamel, D. Stapert, J.K. Moerman, R.D. Schaadt and
B.H. Yagi, Bioorg. Med. Chem. Lett., 2003, 13, 4193.
G. Turan-Zitouni, Z.A. Kaplancikli, M.T. Yildiz, P. Chevallet and
D. Kaya, Eur. J. Med. Chem., 2005, 40, 607.
R.P. Tenorio, C.S. Carvalho, C.S. Pessanha,, J.G. de Lima, A.R. de Faria,
A.J. Alves, E.J.T. de Melo and A.J.S. Goes, Bioorg. Med. Chem. Lett.,
2005, 15, 2575.
Received 29 June 2009; accepted 17 August 2009
Paper 09/0659 doi: 10.3184/030823409X12510409044803
Published online: 8 September 2009
8
9
References
1
2
S.A. Khan, K. Saleem and Z. Khan, Eur. J. Med. Chem., 2007, 42, 103.
P. Corona, G. Vitale, M. Loriga, G. Paglietti, P. La Colla, G. Collu,
G.G. Sanna and R. Loddo, Eur. J. Med. Chem., 2006, 41, 1102.
V.K. Tandon, D.B. Yadav, H.K. Maurya, A.K. Chaturvedi and P.K. Shukla,
Bioorg. Med. Chem., 2006, 14, 6120.
G. Aguirre, H. Cerecetto, R. Di Mario, M. Gonzalez, E.M. Montoya
Al-Faro, A. Jaso, B. Zarranz, A.M. Ortega, I. Aldana and A. Monge-Vega,
Bioorg. Med. Chem. Lett., 2004, 14, 3835.
10 H.S. Gold and M.D. Moellering Jr, N. Engl. J. Med., 1996, 335, 1445.
11 Y. Kurasawa, Y. Moritaki, T. Ebukuro, and A. Takada, Chem. Pharm.
Bull., 1983, 31, 3897.
12 Y. Kurasawa, S. Nakamura, K. Moriyama, K. Suzuki and A. Takada,
Heterocycles, 1984, 22, 1189.
13 O.I. El-Sabbag, M.E. El-Sadek, S.M. Lashine, S.H. Yassin and
S.M. El-Nabtity, Med. Chem. Res., DOI 10.1007/s 00044-009-9203-y.
14 National Committee for Clinical Laboratory Standards (1997): Methods
for dilution antimicrobial susceptibility tests for bacterial standard.
Document M7-A4. Natl. Committee Clin. Lab.Stand., Wayne, PA, USA.
3
4
5
6
A. Burguete, E. Pontiki, D. Hadjipavlou-Litina, R. Villar, E. Vicente,
B. Solano, S. Ancizu, S. Perez-Silanes, I. Aldana and A. Monge, Bioorg.
Med. Chem. Lett., 2007, 17, 6439.
H.M. Refaat, A.A. Moneer and O.M. Khalil, Arch. Pharm. Res., 2004, 27,
1093.