Antimicrobial Evaluation of New Quinoxaline Derivatives Synthesized by Selective Coupling with Alkyl Halides and Amino Acids Esters

Article abstract of DOI:10.1002/jhet.2896

Alkylation of quinoxaline scaffold 1 in the presence of K₂CO₃ preferred N-alkylation than O-alkylation. Quinoxaline hydrazide 6 was successfully coupled with various amino acids, esters, and amines via azide-coupling method. New heterocyclic compounds containing quinoxaline linked to 1,3,4-oxadiazolethione or pyrazole were obtained from cyclization of 6 with CS₂ and acetylacetone, respectively. A series of hydrazide Schiff's bases were formed from hydrazide 6 by condensation with a set of aldehydes and ketones. NMR spectroscopy and mass spectrometry were used for structure elucidation of new compounds. The antimicrobial activity of the synthesized compounds was investigated toward two wild-type bacterial strains (Staphylococcus aureus and Escherichia coli) and two fungal species (Alternaria brassicicola and Fusarium oxysporum). Four compounds displayed a significant activity toward S.?aureus. The ester 4 showed higher activity than the standard drugs, which make it a promising lead compound.

Full text of DOI:10.1002/jhet.2896

Month 2017 Antimicrobial Evaluation of New Quinoxaline Derivatives Synthesized by
Selective Coupling with Alkyl Halides and Amino Acids Esters
*
Ahmed T. A. Boraei,
El Sayed H. El Tamany, Ibrahim A. I. Ali, and Sara M. Gebriel
Chemistry Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt
*
E-mail: ahmed_tawfeek83@yahoo.com
Additional Supporting Information may be found in the online version of this article.
Received November 28, 2016
DOI 10.1002/jhet.2896
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
Alkylation of quinoxaline scaffold 1 in the presence of K2CO3 preferred N-alkylation than
O-alkylation. Quinoxaline hydrazide 6 was successfully coupled with various amino acids, esters, and
amines via azide-coupling method. New heterocyclic compounds containing quinoxaline linked to
1,3,4-oxadiazolethione or pyrazole were obtained from cyclization of 6 with CS2 and acetylacetone,
respectively. A series of hydrazide Schiff’s bases were formed from hydrazide 6 by condensation with
a set of aldehydes and ketones. NMR spectroscopy and mass spectrometry were used for structure
elucidation of new compounds. The antimicrobial activity of the synthesized compounds was investigated
toward two wild-type bacterial strains (Staphylococcus aureus and Escherichia coli) and two fungal
species (Alternaria brassicicola and Fusarium oxysporum). Four compounds displayed a significant
activity toward S. aureus. The ester 4 showed higher activity than the standard drugs, which make it a
promising lead compound.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
RESULTS AND DISCUSSION
Quinoxaline derivatives are very important class of
nitrogen-containing heterocycles [1–3]. They show
anticancer, anticonvulsant, antimalarial, anti-inflammatory,
antiamoebic, antioxidant, antidepressant, antiprotozoal,
antibacterial, and anti-HIV activities [4–14]. Moreover,
they displayed potent antimycobacterial activity [15],
anti-infectives [16], and topoisomerase inhibition
activity [17]. Quinoxaline derivatives were also reported
as NMDA receptor antagonists and DNA cleaving
agents [18,19].
Consequently, synthesis of new functionalized
quinoxaline compounds contain quinoxaline linked to
amino acids, other heterocycle or benzylidene moiety is
necessary and expected to show significant biologically
activity. Herein, among the new synthesized compounds,
4, 6, 11c, and 12c displayed strong to moderate activity
toward Staphylococcus aureus.
Chemistry. Synthesis and Alkylation of 1. Heating of
isatin with acetic anhydride for 6 h afforded N-acetylisatin,
which was stirred with o-phenylenediamine in DMF at
room temperature to give the quinoxaline precursor 1
in good yield. Quinoxaline 1 was refluxed with acetic
anhydride to give N-acetyl derivative 2. Alkylation of
quinoxaline
1
with benzyl bromide and ethyl
chloroacetate to give the N-alkylated quinoxalinones 3
and 4 was performed in the presence of K2CO3 and
acetone. The ester
corresponding acid 5 when stirred for 3 h in methanol-
containing aq. KOH. Hydrazinolysis of was
4
was hydrolyzed to the
4
performed by heating with hydrazine hydrate in
methanol to afford the hydrazide 6, which was
acylated with acetyl chloride in benzene-containing
pyridine to yield the corresponding acetyl derivative 7
(Scheme 1).
© 2017 Wiley Periodicals, Inc.

A. T. A. Boraei, E. S. H. El Tamany, I. A. I. Ali, and S. M. Gebriel
Vol 000
Scheme 1. Alkylation of quinoxaline 1 and hydrazinolysis of the ester 4.
Coupling of hydrazide 6 with amino acids esters and amines
using the azide-coupling method. Reaction of hydrazide 6
with NaNO2/HCl at low temperatures afforded the azide
8, which was directly coupled with a series of amino
acids esters (glycine, L-serine, L-leucine, and β-alanine) in
the presence of triethyl amine to give respective coupled
products 9a–d. The quinoxalinone amino acid esters
9a–d were heated with hydrazine hydrate in methanol for
40 min to yield the hydrazides 10a–d. Azide-coupling
method was successfully applied for coupling of azide 8
with N-propyl amine and benzyl amine to produce the
amides 11a,b (Scheme 2).
Scheme 2. Coupling of amino acid esters and amines to quinoxalinone azide 8.
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Month 2017
Antimicrobial Evaluation of New Quinoxaline Derivatives Synthesized by
Selective Coupling with Alkyl Halides and Amino Acids Esters
Condensation of hydrazide 6 with some aldehydes and
protons, and the respective methylene carbon appeared at
45.6 ppm. The NMR of the ester 4 showed the ethoxy
protons (CH3CH2O) as triplet and quartet at 1.20 and
4.23 ppm while the corresponding ethoxy carbons
(CH3CH2O) were observed at 14.5 and 61.8 ppm. The
NCH2 protons of 4 appeared as singlet at 5.18 ppm, and
NCH2 carbon was observed at 44.5 ppm. The presence of
methylene carbon signal (NCH2) at 45.6 ppm in 3 and
44.5 ppm in 4 strongly supports the N-alkylation.
The 1H NMR of the acid 5 showed a signal at 5.05 ppm
for NCH2 and a broad signal at 13.19 ppm for the COOH.
The hydrazide 6 revealed the disappearance of the ethoxy
signals and observation of two new singlet signals at 4.92
and 9.26 ppm for the hydrazino group (NHNH2). The
acetylated hydrazide 7 showed two singlet signals at 1.91
and 2.00 ppm for the two CH3 and the three NH signals
at 9.61, 9.89 and 10.12 ppm.
ketones.
Quinoxalinone-1,3,4-oxadiazolethione 12 was
obtained from reaction of hydrazide 6 with carbon
disulfide in ethanol-containing aq. KOH then acidification
with HCl. Whereas, refluxing of 6 with acetyl acetone in
methanol-containing acetic acid afforded quinoxalinone-
pyrazole derivative 13. In addition, hydrazide 6 was
condensed with some aldehydes and ketones (namely,
benzaldehyde,
3-chlorobenzaldehyde,
4-methoxy
benzaldehyde, acetophenone, and isatin) in methanol-
containing acetic acid to give the corresponding
hydrazones 14–18 (Scheme 3).
Compounds characterization.
The structure of 1 was
established from its 1H NMR and 13C NMR, which
showed the acetamide methy1 protons at 1.92 ppm and
the respective methyl carbon at 24.2 ppm. The aromatic
protons appeared between 7.17 and 7.85 ppm while the
aromatic carbons appeared between 115.8 and
The structures of the coupled amino acid esters (9a–d)
were elucidated from their 1H NMR spectra, which
displayed the methoxy protons (OCH3) as singlet around
3.66 ppm and NCH2 signal around 5.05 ppm along with
the amino acid characteristic signals, which appeared as
follows:
137.3
ppm,
whereas
the
remaining
carbons
(N═Cquinoxaline) and the two carbonyls (C═Oquinoxaline
+acetyl) were assigned at 155.2, 157.2, and 168.4 ppm.
The quinoxaline NH and the acetamide NH were
appeared at 9.79 and 12.48 ppm.
The structure 2 was deduced from the disappearance of
quinoxaline NH signal and the appearance of singlet
signal at 2.29 ppm equivalent to six protons of acetyl
groups (two COCH3). Benzylated quinoxaline 3 showed
singlet signal at 5.62 ppm for the benzyl methylene
Glycinated quinoxalinone 9a showed the glycine CH2 as
doublet at 4.80 ppm and glycine NH at 7.06 ppm.
Serinated quinoxalinone 9b showed serine OH at
3.32 ppm, CH2 at 3.69–3.74 ppm, CH at 4.39–4.41 ppm,
and NH at 8.77 ppm.
Scheme 3. Synthesis of linking 1,3,4-oxadiazolethione with quinoxalinone and condensation of hydrazide 6 with some aldehydes and ketones.
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A. T. A. Boraei, E. S. H. El Tamany, I. A. I. Ali, and S. M. Gebriel
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Table 1
Antimicrobial activity of quinoxaline derivatives.
Fungi
Gram-positive bacteria
Gram-negative bacteria
Compound
Staphylococcus aureus
Escherichia coli
Alternaria brassicicola
Fusarium oxysporum
2
4
9c
10c
Cefoperazone
Amoxycillin
Ampiclox
DMF
1.20
1.74
0.96
0.96
1.30
0.90
0.85
—
—
—
—
—
—
—
—
—
—
—
—
—
NT
NT
NT
—
NT
NT
NT
—
NT
NT
NT
—
Zone diameter of growth inhibition was measured in centimeters (cm).
(—), no antimicrobial activity.
NT, “not tested.”
Leucinated quinoxalinone 9c revealed leucine methyl
protons at 0.87 ppm, CH at 1.24–1.27 ppm, CH2 at 1.99–
2.03 ppm, CH at 4.60–4.61 ppm, and the NH at 7.23 ppm.
β-Alaninated quinoxalinone 9d showed the two methylene
groups of β-alanine as triplet at 2.52 ppm and multiplet at
3.48–3.50 ppm. The NH of β-alanine appeared at 6.93 ppm.
Hydrazinolysis of the esters 9a–d to the corresponding
widely disseminated and careless use of antimicrobials
[20–23]. Searching for new antimicrobials to overcome
the emergence of antibiotic resistance is necessary
nowadays. Several reports highlighted the reoccurrence
of previously controlled lethal diseases such as
tuberculosis and attributed this to the development of
drug resistant strains that are no longer controlled by the
existing drugs [24–27].
Accordingly, all synthesized compounds were
preliminary evaluated for their in vitro antibacterial
activity against two wild-type bacterial strains (S. aureus
as Gram-positive and Escherichia coli as Gram-negative)
and two fungal species (Alternaria brassicicola and
Fusarium oxysporum). Cefoperazone (CFP) 75 mg,
Amoxycillin (AMC) 30 mg, and Ampiclox (AX) 25 mg
1
hydrazides 10a–d was confirmed from their H NMR and
13C NMR. All spectra missed the methoxy signals, and
instead, NH2 signal was appeared around 4.00 ppm along
with three NH signals around 8.50, 9.00, and 9.60 ppm.
The structures of aminated quinoxalinones 11a,b were
1
assigned from H NMR and 13C NMR, which showed
the NH of the amine at 8.17–8.19 (11a) and 8.64–
8.66 ppm (11b); in addition, compound 11a showed the
propyl signals at 0.82 ppm (CH3), 1.40 ppm (CH2), and
3.02 ppm (CH2). 13C NMR of 11a displayed the propyl
signals at 11.8 (CH3), 22.7 (CH2), and 40.9 ppm (CH2).
Compound 11b showed doublet signal at 4.32 ppm for
CH2, and the respective carbon appeared at 42.7 ppm.
1H NMR, which of the oxadiazolethione 12, showed the
NCH2 at 5.63 ppm and NH of the oxadiazolethione at
were
used
as
antibacterial
standards,
and
dimethylformamide was used as a reference.
The results showed that four compounds have antibacterial
activity against S. aureus. Among the tested compounds, the
ester 4 showed the highest inhibition zone at 10-mg/mL
concentration followed by the acetylated quinoxaline 2.
Compounds 9c and 10c showed moderate activity.
Moreover, all compounds did not show any activity toward
E. coli, A. brassicicola, and F. oxysporum (Table 1).
1
14.59 ppm. H NMR of the pyrazole 13 was displayed
the three CH3 signals at 2.16, 2.33, and 2.52 ppm. The
NCH2 and pyrazole CH signal appeared at 5.93 and
6.08 ppm, respectively. Compounds 14–16 showed a
characteristic singlet signal for benzylidene CH
(─N═CH-Ph) at 8.11 (14), 8.26 (15), and 8.04 (16) ppm.
The 13C NMR spectra of 14 displayed a signal at
144.8 ppm characteristic benzylidene carbon (N═CH-Ph).
Compound 17 showed two singlet signals at 1.93 and
2.34 ppm for two CH3, whereas the two NHs appeared at
9.75 and 11.10 ppm. The 13C NMR of 17 showed the
two CH3 carbons at 14.1 and 24.2 ppm. Compound 18
revealed the three NH signals (isatin and two acetamides)
at 9.66, 10.72, and 11.50 ppm (Supporting Information).
CONCLUSION
In conclusion, new N-substituted quioxalinones were
synthesized by reaction of quinoxaline
1
with
different alkyl halides. Azide-coupling method was
used for coupling of hydrazide 6 with a series of
amino acid methyl esters to give the coupled products
9a–d, which then reacted with hydrazide hydrate to
afford the hydrazides 10a–d. The hydrazide 6 was
used as a key intermediate for the synthesis of new
quinoxaline derivatives via the reaction with carbon
disulfide and some aldehydes and ketones. The ester
Biological activity.
The antimicrobial resistance is a
serious threat to global public health, because of the
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Month 2017
Antimicrobial Evaluation of New Quinoxaline Derivatives Synthesized by
Selective Coupling with Alkyl Halides and Amino Acids Esters
4 and acetylated quinoxaline 2 showed the highest
antibacterial activity toward S. aureus and expected to
be promising leads.
N-(2-(40-benzyl-30-oxo-30,40-dihydroquinoxaline-20-yl)phenyl)
1
acetamide (3).
White solid, mp 206–208°C. H NMR
(300 MHz, CDCl3): δ 2.12 (s, 3H, CH3), 5.62 (s, 2H,
CH2), 7.24–7.94 (m, 13H, Ar─H), 10.42 (s, 1H,
─NH─COCH3). 13C NMR (75 MHz, DMSO-d6): δ 24.0
(CH3CO), 45.6 (NCH2), 115.4, 1234.0, 127.4, 127.7,
129.1, 130.0, 130.1, 130.8, 131.2, 133.2, 136.4 (18
Cquionoxalin+2phenyl), 154.4, 156.7 (C═O, C═Nquinoxaline),
168.3 (CH3CO). LR-MS (EI) Calc. for C23H19N3O2:
369.15, found 369.0.
EXPERIMENTAL
Chemistry.
Melting points were determined on a
Temp-melt II melting-point apparatus, and the values are
uncorrected. TLC was carried out on silica gel 60 F254
Aluminum plates (E. Merck, layer thickness 0.2 mm),
Ethyl 2-(30-(2″-acetamidophenyl)-20-oxoquinoxaline-10(2H)-
1
yl)acetate (4).
Yellow solid, mp 160–162°C. H NMR
1
and purity detection was performed using UV lamp. H
(300 MHz, CDCl3): δ 1.20 (t, 3H, J 6.9 Hz, CH3), 2.22
(s, 3H, CH3), 4.23 (q, 2H, CH2), 5.18 (s, 2H, NCH2),
7.17–8.30 (m, 8H, Ar─H), 10.43 (s, 1H, ─NH─COCH3).
13C NMR (75 MHz, DMSO-d6): δ 14.5 (CH3), 24.0
(CH3CO), 44.5 (NCH2), 61.8 (OCH2CH3), 115.0, 123.7,
124.0, 124.3, 129.0, 130.1, 130.2, 131.1, 132.9, 133.3,
137.3 (12 Cquinoxaline+phenyl), 154.1, 155.8 (C═O, C═N
NMR and 13C NMR spectra were recorded on a Varian
German 200 M11Z operating at 300 and 75 MHz,
respectively. Chemical shifts were reported in parts per
million (ppm) values relative to TMS as internal
reference. Mass spectra were measured on a GC-MSQP
1000EX 2010.
Synthesis of N-(2-(30-oxo-30,40-dihydroquinoxaline-20-yl)
C
quinoxaline), 168.0 (CH3CO), 168.4 (COester). LR-MS (EI)
phenyl)acetamide (1).
A mixture of isatin (1.0 mmol)
Calc. for C20H19N3O4: 365.14, found 365.0.
2-(30-(2″-Acetamidophenyl)-20-oxoquinoxaline-10(2H)-yl)ace
ticacid (5). To ester 4 (1.0 mmol) in methanol (10 mL),
and acetic anhydride (5.0 mL) was refluxed for 6 h,
cooled, and poured to cold water, and the ppt was
collected by filtration to give N-acetylisatin in 90% yield.
KOH (4.0 mmol/1.0 mL H2O) was added and stirred for
3 h, cooled, then acidified with drops of concentrated
HCl, filtered, dried, and crystallized from methanol to
Without
further
purification,
o-phenylenediamine
(1.0 mmol) was added to N-acetylisatin (1.0 mmol) in
DMF, and stirring was continued for 12 h and poured to
cold water. The crude product was washed with water,
dried, and recrystallized from ethanol to give 1 in 70%
yield as yellow powder, mp 280–282°C [Lit. [28] 285–
1
give 5 in 60% yield as brown solid, mp 260–262°C. H
NMR (300 MHz, DMSO-d6): δ 1.90 (s, 3H, CH3), 3.18
(br., 1H, OH), 5.05 (s, 2H, NCH2), 7.20–8.06 (m, 8H,
Ar─H), 9.68 (s, 1H, ─NH─COCH3), 13.19 (br, 1H,
COOH). LR-MS (EI) Calc. C18H15N3O4: 337.11, found
1
286°C]. H NMR (300 MHz, DMSO-d6): δ 1.92 (s, 3H,
CH3), 7.17–7.85 (m, 8H, Ar─H), 9.79 (s, 1H,
NHquinoxaline), 12.48 (s, 1H, NHacetamide). 13C NMR
(75 MHz, DMSO-d6): δ 24.2 (CH3), 115.8, 123.4, 123.6,
129.0, 130.0, 130.6, 131.3, 132.5, 133.1, 137.4 (12
Cquinoxaline+phenyl), 155.2, 157.2 (C═O, C═Nquinoxaline),
168.4 (CH3C═O). LR-MS (EI) Calc. for C16H13N3O2:
337.0.
2-(30-(2″-Acetamidophenyl)-20-oxoquinoxaline-10(2H)-yl)ace
tohydrazide (6).
To ester 4 (1.0 mmol) in methanol,
hydrazine hydrate (3.0 mmol) was added, and the
mixture was heated under reflux for 4 h, cooled,
filtered, and dried. It was recrystalizated from methanol
to give 6 in 50% yield as white gray powder, mp 242–
279.1, found 279.0.
1
Synthesis of N-(2-(40-acetyl-30-oxo-30,40-dihydroquioxaline-
2-yl)phenyl)acetamide (2). Quinoxaline 1 (1.0 mmol) was
244°C. H NMR (300 MHz, DMSO-d6): δ 1.91 (s, 3H,
CH3), 4.30 (s, 2H, ─NH─NH2), 4.92 (s, 2H, CH2),
7.19–7.90 (m, 8H, Ar─H), 9.26 (s, 1H, ꢀNH─NH2),
9.58 (s, 1H, ─NH─COCH3); 13C NMR (75 MHz,
DMSO-d6): δ 24.2 (CH3CO), 44.6 (NCH2), 115.0,
124.1, 130.0, 130.1, 131.0, 131.1, 133.6, 137.4 (12
added to acetic anhydride (5 mL), and the mixture was
heated under reflux for 4 h. The mixture was poured to
ice water, filtered, took the ppt, and dried. The product
was recrystallized from MeOH to give 2 in 80% yield as
dark brown powder, mp 186–188°C. 1H NMR
(300 MHz, CDCl3): δ 2.29 (s, 6H, 2 CH3); 7.27–8.13 (m,
8H, Ar─H), 12.49 (s, 1H, ─NH─COCH3); LR-MS (EI)
Calc. for C18H15N3O3: 321.1, found 322.0.
Cquinoxaline+phenyl),
Cquinoxaline), 166.0 (2 CO). LR-MS (EI) Calc. for
154.3,
156.1
(C═O,
C═N
C18H17N5O: 351.13, found 351.0.
2-(30-(2″-Acetamidophenyl)-20-oxoquinoxaline-10(2H)-yl)ace
tamidehydrazide (7). A mixture of hydrazide 6 (1.0 mmol)
General procedure for the alkylation.
A mixture of
and acetyl chloride (1.0 mmol) in benzene (30.0 mL) and
pyridine (2.0 mL) was stirred overnight; the solid product
that formed was washed with methanol to give 7 in 70%
yield as white solid, mp 272–274°C. 1H NMR
(300 MHz, DMSO-d6): δ 1.91 (s, 3H, CH3), 2.00 (s, 3H,
CH3), 5.03 (s, 2H, NCH2), 7.20–7.90 (m, 8H, Ar─H),
quinoxaline 1 (1.0 mmol) and K2CO3 (1.2 mmol) in
acetone (10 mL) containing drops of DMF were stirred
for 1 h, then the appropriate alkylhalide (1.1 mmol) was
added, and the mixture was heated under reflux for 5 h.
Solvent was removed, and products were crystalized from
MeOH to give 3 in 70% yield and 6 in 60% yield.
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A. T. A. Boraei, E. S. H. El Tamany, I. A. I. Ali, and S. M. Gebriel
Vol 000
9.61 (s, 1H, NH), 9.89 (s, 1H, NH), 10.12 (s, 1H, NH). LR-
MS (EI) Calc. for C20H19N5O4: 393.14, found 393.0.
General procedure for coupling of hydrazide 6 with amino
CDCl3): δ 2.12 (s, 3H, COCH3), 2.52 (t, 2H, J 6.0 Hz,
CH2β-ala), 3.48–3.50 (m, 2H, CH2β-ala), 3.58 (s, 3H,
OCH3), 4.97 (s, 2H, NCH2), 6.93 (s, 1H, NHβ-ala), 7.21–
8.22 (m, 8H, Ar─H), 10.30 (s, 1H, ─NHCOCH3). LR-
MS (EI) Calc. for C22H22N4O5: 422.16, found 422.0.
General procedure for hydrazinolysis of quinoxaline amino
acid esters. To the appropriate amino acid derivatives 9a–
d (1.0 mmol) in MeOH (10 mL), add hydrazine hydrate
(3.0 mmol), and the mixture was heated under reflux for
40 min, cooled, and filter, and then purify the products by
acid esters and amines.
To a cold solution (ꢀ5°C) of
hydrazide 6 (1.0 mmol) in acetic acid (2 mL), hydrochloric
acid (5 N, 4 mL), and water (20 mL) was added portion
wise under stirring a cold solution (0°C) of sodium nitrite
(1.1 mmol) in water (20 mL). After stirring at the same
temperature for 30 min, the azide 8 was extracted with cold
ethyl acetate and washed successively with cold water, 5%
Na2CO3, and water. After drying over anhydrous sodium
sulfate, the azide was used without further purification in
the next step. A mixture of amino acid ester hydrochlorides
or amines (1.0 mmol), triethylamine (1.1 mmol) in ethyl
acetate (30 ml), was stirred at 0°C for 20 min, and the
formed triethylamine hydrochloride was filtered off. The
previously prepared azide 8 solution (cold) was added to
the cold amino acid ester or amine solution in ethyl acetate.
The mixture was kept 24 h in the refrigerator and then at
room temperature for an additional 24 h. Then, it was
washed with 0.1 N HCl, water, 5% Na2CO3, water, and
then dried over anhydrous sodium sulfate. The solvent was
evaporated in vacuum, and the residue was crystallized
from ethyl acetate-petroleum ether to give the respective
recrystallization from methanol.
2-(20-(30-(2″-Acetamidophenyl)-20-oxoquinoxaline-10(2H)-yl)
acetamido)acetohydrazide (10a). Yellowish white powder
in 40% yield, mp 232–234°C. 1H NMR (300 MHz,
DMSO-d6): δ 1.90 (s, 3H, CO─CH3), 3.71 (d, 2H, J
5.7 Hz, ─NHNH2), 4.23 (s, 2H, CH2Gly), 5.01 (s, 2H,
NCH2), 7.19–7.89 (m, 8H, Ar─H), 8.48–8.52 (m, 1H,
─NHNH2), 9.05 (s, 1H, ─CONHGly), 9.61 (s, 1H,
─NHCOCH3).
2-(20-(30-(2″-Acetamidophenyl)-20-oxoquinoxaline-10(2H)-yl)
acetamido)-30-hydrohy propanehydrazide (10b).
Yellowish
white solid in 40% yield, mp 252–254°C. 1H NMR
(300 MHz, DMSO-d6): δ 1.97 (s, 3H, ─COCH3), 3.10
(br, 1H, OHSer), 3.63–3.81 (m, 2H, CH2Ser), 4.42–4.45
(m, 1H, CHSer), 4.95–5.16 (m, 4H, NCH2, ─NHNH2),
7.11–7.91 (m, 9H, Ar─H, NH), 8.34 (d, 1H, J 8.1 Hz,
coupled products.
Methyl 2-(20-(30-(2″-acetamidophenyl)-20-oxoquinoxaline-10
─NHNH2), 9.92 (s, 1H, ─NHCOCH3).
(2H)-yl)acetamidoacetate (9a).
Light yellow powder in
2-(20-(30-(2″-Acetamidophenyl)-20-oxoquinoxaline-1(2H)-yl)
acetamido)-40-methyl pentanehydrazide (10c). Light white
1
40% yield, mp 156–158°C. H NMR (300 MHz, CDCl3):
δ 2.11 (s, 3H, COCH3), 3.71 (s, 3H, OCH3), 4.02 (d, 2H,
J 4.8 Hz, NCH2Gly), 5.05 (s, 2H, NCH2), 7.06 (br, 1H,
─NHGly), 7.20–8.21 (m, 8H, Ar─H), 10.30 (s, 1H,
─NH─COCH3). LR-MS (EI) Calc. for C21H20N4O5:
powder in 30% yield, mp 260–262°C. 1H NMR
(300 MHz, DMSO-d6): δ 0.83, 0.88 (2d, 6H, J 6.6 Hz, 2
CH3Leu), 1.45–1.61 (m, 3H, CHLeu, CH2Leu), 1.91 (s, 3H,
COCH3), 4.25–4.36 (m, 3H, CHLeu, ─NHNH2), 4.93–
5.09 (2d, 2H, Jgem 18 Hz, NCH2), 7.20–7.88 (m, 8H,
Ar─H), 8.44 (d, 1H, J 8.4 Hz, ─NHNH2), 9.21 (s, 1H,
408.14, found 408.0.
Methyl 2-(20-(30-(2″-acetamidophenyl)-20-oxoquinoxaline-10
(2H)-yl)acetamido)-30-hydroxypropanoate
(9b).
Dark
1
NH), 9.64 (s, 1H, ─NHCOCH3).
yellow powder in 40% yield, mp 131–133°C. H NMR
(300 MHz, DMSO-d6): δ 1.91 (s, 3H, COCH3), 3.32 (br,
1H, OHSer), 3.67 (s, 3H, OCH3), 3.69–3.74 (m, 2H,
CH2Ser), 4.39–4.41 (m, 1H, CHSer), 5.06 (s, 2H, NCH2),
7.20–7.89 (m, 8H, Ar─H), 8.77 (d, 1H, J 9.0 Hz, NHSer),
9.65 (s, 1H, ─NHCOCH3). LR-MS (EI) Calc. for
3-(20-(30-(2″-Acetamidophenyl)-20-oxoquinoxaline-10(2H)-yl)
acetamido)propane hydrazide (10d). White powder in 40%
1
yield, mp 244–246°C. H NMR (300 MHz, DMSO-d6): δ
1.90 (s, 3H, COCH3), 2.18 (t, 2H, J 6.9 Hz, CH2β-ala),
3.25–3.30 (m, 2H, CH2β-ala), 4.13 (br, 2H, ─NHNH2),
4.90 (s, 2H, NCH2), 7.20–7.89 (m, 8H, Ar─H), 8.22 (br,
1H, ─NHNH2), 9.01 (s, 1H, NHβ-ala), 9.60 (s, 1H,
NHCOCH3). 13C NMR (75 MHz, DMSO-d6): δ 23.7
(CH3), 33.9 (CH2β-ala), 35.9 (CH2β-ala), 45.0 (NCH2),
115.0, 124.1, 130.2, 131.2, 133.7, 135.0, 138.0, (12
Cquinoxaline+phenyl), 154.5, 155.8 (C═O, C═Nquinoxaline),
166.1, 168.8, 170.4 (3 CO), LR-MS (EI) Calc.
C21H22N6O4: 422.17, found 422.0.
C22H22N4O6: 438.15, found 438.0.
Methyl 2-(20-(30-(2″-acetamidophenyl)-20-oxoquinoxaline-10
(2H)-yl)acetamido)-40-methylpropanoate
(9c).
Yellow
powder in 30% yield, mp 140–142°C. 1H NMR
(300 MHz, CDCl3): δ 0.87 (d, 6H, J 6.0 Hz, 2 CH3),
1.24–1.27 (m, 1H, CHLeu), 1.99–2.03 (m, 2H, CH2Leu),
2.11 (s, 3H, COCH3), 3.66 (s, 3H, OCH3), 4.60–4.61 (m,
1H, CHLeu), 5.03–5.12 (m, 2H, NCH2), 7.23 (br, 1H,
NHLeu), 7.27–7.94 (m, 8H, Ar─H), 10.32 (s, 1H,
─NHCOCH3). LR-MS (EI) Calc. for C25H28N4O5:
N-(2-(30-oxo-40-(2″-oxo-2″-(piperidin-1-yl)ethyl)-30,40-
dihydroquinoxaline-20-yl)phenyl)acetamide (11a).
White
powder in 70% yield, mp 238–240°C. 1H NMR
(300 MHz, DMSO-d6): δ 0.82 (t, 3H, J 6.9 Hz, CH3),
1.40 (q, 2H, CH2), 1.90 (s, 3H, COCH3), 3.02–3.08 (m,
2H, CH2), 4.921 (s, 2H, NCH2), 7.22–7.89 (m, 8H,
464.21, found 464.0.
Methyl 3-(20-(30-(2″-acetamidophenyl)-20-oxoquinoxaline-10
(2H)-yl)acetamido) propanoate (9d). Light white powder
in 40% yield, mp 196–198°C. 1H NMR (300 MHz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Antimicrobial Evaluation of New Quinoxaline Derivatives Synthesized by
Selective Coupling with Alkyl Halides and Amino Acids Esters
Ar─H), 8.17–8.19 (m, 1H, NH), 9.67 (s, 1H, NHCOCH3).
13C NMR (75 MHz, DMSO-d6): δ 11.8 (CH3), 22.7
(CH3CO), 24.1 (CH2), 40.9 (CH2), 45.6 (NCH2), 114.9,
123.6, 123.8, 124.1, 130.0, 130.1, 131.0, 131.2, 132.9,
133.67, 137.3 (12 Cquinoxaline+phenyl), 154.3, 156.0 (C═O,
156.0 C═N Cquinoxaline), 166.3, 168.45 (2 CO). LR-MS
(EI) Calc. for C21H22N4O3: 378.17, found 378.0.
C═Nquinoxaline), 167.9, 168.4 (2 CO). LR-MS (EI) Calc. for
C25H21N5O3: 439.16, found 439.0.
N0-(4-chlorobenzylidene)-20-(30-(2″-acetamidophenyl)-20-
oxoquinoxaline-10(2H)-yl)acetohydrazide (15).
White
powder in 70% yield, mp 292–294°C .1H NMR
(300 MHz, DMSO-d6): δ 1.93 (s, 3H, CH3), 5.54 (s, 2H,
NCH2), 7.20–8.09 (m, 12H, Ar─H), 8.26 (s, 1H,
─N═CH-Ph), 9.70 (br, 1H, NHCOCH3), 11.91 (br, 1H,
CONHN═C). LR-MS (EI) Calc. for C25H20N5O3Cl:
2-(30-(2″-Acetamidophenyl)-20-oxoquinoxaline-10(2H)-yl)-
N0-(20-phenyl propylidene)acetohydrazide (11b).
White
powder in 40% yield, mp 250–252°C. 1H NMR
(300 MHz, DMSO-d6): δ 1.86 (s, 3H, COCH3), 4.32
(d, 2H, J 5.7 Hz, CH2), 5.01 (s, 2H, NCH2), 7.23–7.90
(m, 13H, Ar─H), 8.64–8.66 (m, 1H, NH), 9.59 (s, 1H,
NHCOCH3). 13C NMR (75 MHz, DMSO-d6): δ 24.0
(CH3), 42.7 (CH2), 45.8 (NCH2), 115.1, 124.1, 127.3,
127.6, 128.7, 130.2, 131.0, 131.2, 133.0, 133.6, 137.3,
139.5 (18 Cquinoxaline+2 phenyl), 154.3, 156.1 (C═O,
C═Nquinoxaline), 166.6 (CO). LR-MS (EI) Calc. for
473.13, found 473.0.
N0-(3-methoxybenzylidene)-2-(30-(2″-acetamidophenyl)-20-
oxoquinoxaline-10(2H)-yl)acetohydrazide
(16).
Dark
yellow powder in 80% yield, mp 286–288°C. 1H
NMR (300 MHz, DMSO-d6): δ 1.93 (s, 3H, CH3),
3.81 (s, 3H, OCH3), 5.50 (s, 2H, NCH2), 7.00–7.92
(m, 12H, Ar─H), 8.04 (s, 1H, ─N═CH-Ph), 9.70 (br,
1H, NHCOCH3), 11.71 (s, 1H, CONHN═C). 13C
NMR (75 MHz, DMSO-d6): δ 24.1 (CH3), 44.7
(NCH2), 55.8 (OCH3), 114.8, 115.0, 115.3, 124.0,
127.0, 129.1, 130.0, 130.2, 131.1, 133.8 (18
Cquinoxaline+2phenyl), 144.7 (N═CH-Ph), 154.3, 155.6
(C═O, C═Nquinoxaline), 161.3, 167.6 (2 CO). LR-MS
C25H22N4O3: 426.17, found 426.0.
N-(2-(30-oxo-40-((5″-thioxo-4″,5″-dihydro-1,3,4-oxodiazol-
2″-yl)methyl)-30,40-dihydroquioxaline-20-yl)phenyl)acetamide
(12). To a mixture of the hydrazide 6 (1.0 mmol) in
methanol (10 mL) containing KOH (4 N/0.5 mL
H2O), carbon disulfide (4.0 mmol) was added; the
mixture was heated under reflux for 4 h, cooled,
poured to ice water and acidified with drops of
conc. HCl, and then filtered to give 12 in 80% yield
as white gray powder, mp 238–240°C. 1H NMR
(300 MHz, DMSO-d6): δ 1.90 (s, 3H, CH3), 5.63 (s,
2H, NCH2), 7.19–7.91 (m, 8H, Ar─H), 9.61 (s, 1H,
NHCOCH3), 14.59 (s, 1H, NH).
(EI) Calc. for C26H23N5O4: 469.18, found 469.0.
2-(30-(2″-Acetamidophenyl)-20-oxoquinoxaline-10(2H)-yl)-
N0-benzylideneacetohydrazide (17).
White powder in
60% yield, mp 284–286°C. 1H NMR (300 MHz,
DMSO-d6): δ 1.93 (s, 3H, CH3), 2.34 (s, 3H, CH3),
5.55 (s, 2H, NCH2), 7.21–7.92 (m, 13H, Ar─H), 9.75
(br, 1H, NHCOCH3), 11.10 (s, 1H, CONHN═C). 13C
NMR (75 MHz, DMSO-d6): δ 14.1 (CH3acetophenone),
24.2 (CH3CO), 44.6 (NCH2), 115.0, 124.1, 126.7,
128.9, 130.0, 130.1, 131.1, 133.0, 133.6, 137.4, 138.6
(19 Cquinoxaline+2phenyl, N═C-Ph), 154.3, 156.1 (C═O,
C═Nquinoxaline), 165.9, 168.2 (2 CO). LR-MS (EI) Calc.
General procedures for the synthesis of 13–18.
To
hydrazide 6 (1.0 mmol) in methanol (10 mL) containing
acetic acid (0.5 mL), the appropriate aldehyde or ketone
(1.1 mmol) was added, and the mixture was heated under
reflux for 4 h, cooled, filtered, dried, and recrystallized
from methanol.
for C26H23N5O3: 453.18, found 453.0.
2-(30-(2″-Acetamidophenyl)-20-oxoquinoxaline-10(2H)-yl)-
N0-(3-oxoindolin-20-ylidene)acetohydrazide (18).
Yellow
powder in 50% yield as mp 314–316°C. 1H NMR
(300 MHz, DMSO-d6): δ 1.94 (s, 3H, CH3), 5.55 (s,
2H, NCH2), 6.92–8.18 (m, 12H, Ar─H), 9.66 (s, 1H,
NHCOCH3), 10.72, 11.50 (br, 2H, CONHN═C,
NHisatin). LR-MS (EI) Calc. for C26H20N6O4: 480.15,
found 480.0.
N-(2-(40-(20-(3″,5″-dimethyl-4″,5″-dihydropyrazol-1-yl)-20-
oxoethyl)-30-oxo-30,40-dihydroquioxaline-2-yl)
phenyl)
acetamide (13).
Brown powder in 60% yield, m.p.
222–224°C. 1H NMR (300 MHz, CDCl3): δ 2.16 (s,
3H, COCH3), 2.33 (s, 3H, CH3pyrazol), 2.52 (s, 3H,
CH3pyrazol), 5.93 (s, 2H, NCH2), 6.08 (s, 1H,
CHpyrazol), 7.19–8.28 (m, 8H, Ar─H), 10.38 (s, 1H,
NHCOCH3). LR-MS (EI) Calc. for C23H21N5O3:
415.16, found 415.0.
Antimicrobial activity. The synthesized compounds in
DMF were tested by the paper-disc agar-plate method
[29] using 10-mg/mL concentration per disc against two
wild-type bacterial strains (E. coli NCMB 11943;
S. aureus NCMB 6571), A. brassicicola, and
F. oxysporum. Nutrient agar was used for testing the
bacterial strains, and potato dextrose agar was used for
fungi. The experiments were performed in triplicate,
negative controls (DMF loaded discs), and positive
controls (three commercial antibiotic discs, Oxoid) were
included. Inhibitory activity was recorded by measuring
the clear zone diameter [in centimeters (cm)] after
2-(30-(2″-Acetamidophenyl)-20-oxoquinoxaline-10(2H)-yl)-
N0-(20-phenylpropylidene)acetohydrazide
(14).
Gray
powder in 70% yield, mp 252–254°C. 1H NMR (300 MHz,
DMSO-d6): δ 1.93 (s, 3H, CH3), 5.53 (s, 2H, N─CH2),
7.21–7.92 (m, 13H, Ar─H), 8.11 (s, 1H, ─N═CH-Ph), 9.73
(s, 1H, NHCOCH3), 11.84 (s, 1H, CONHN═C). 13C NMR
(75 MHz, DMSO-d6): δ 24.1 (CH3), 44.4 (NCH2), 115.3,
124.0, 127.5, 129.3, 130.2, 131.1, 132.8, 133.8, 134.4 (18
Cquinoxaline+2phenyl) 144.8 (N═CH-Ph), 154.3, 155.6 (C═O,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. T. A. Boraei, E. S. H. El Tamany, I. A. I. Ali, and S. M. Gebriel
Vol 000
[11] He, W.; Myers, M. R.; Hanney, B. Bioorg Med Chem Lett
2003, 13, 3097.
[12] Kim, Y. B.; Kim, Y. H.; Park, J. Y.; Kim, S. K. Bioorg Med
Chem Lett 2004, 14, 541.
incubation at 37°C for 24 h for bacteria and at 30°C for
5 days incubation for fungi.
[13] Mohammad, R. I.; Hassani, Z. Arkivoc 2008, xv, 280.
[14] Bendale, A. R.; Kotak, D.; Damahe, D. P.; Sushil, P. N.;
Jadhav, A. G.; Vidyasaga, G. D. ChemicaSinica 2011, 2, 20.
[15] Santivañez-Veliz, M.; Pérez-Silanes, S.; Torres, E.; Moreno-
Viguri, E. Bioorg Med Chem Lett 2016, 26, 2188.
[16] Jampilek, J. Curr Med Chem 2014, 21, 4347.
[17] Palluotto, F.; Sosic, A.; Pinato, O.; Zoidis, G.; Catto, M.; Sissi,
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Acknowledgments. The authors would like also to thank Dr.
Metwaly Ramadan from the microbiology department, Faculty
of Science, Suez Canal University, Ismailia41522, Egypt for
doing the antimicrobial activity.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet