Exploration of quinoxaline derivatives as antimicrobial and anticancer agents

Received: 28 May 2019

DOI: 10.1002/jhet.3716

Revised: 21 July 2019

Accepted: 16 August 2019

A R T I C L E

Exploration of quinoxaline derivatives as antimicrobial and

anticancer agents

1

2

Ashraf H. Bayoumi | Adel H. Ghiaty | Shimaa M. Abd El‐Gilil |

2

Ebtehal M. Husseiny | Maha A. Ebrahim

1

Pharmaceutical Organic Chemistry

Abstract

Department Faculty of Pharmacy (Boys),

Al‐Azhar University, Cairo, Egypt

Novel 2 and 3‐substituted quinoxaline derivatives were synthesized through var-

ious synthetic pathways, among which cyanoacetamide and cyanoaceto-

hydrazide quinoxaline derivatives 4a‐c and 11a‐c, respectively, were

synthesized. Furthermore, methoxy quinoxaline derivatives 3c and quinoxaline

derivatives bearing substituted pyridines 6a,b, 12a,b, and 13a,b were designed to

be synthesized. However, we have synthesized acrylohydrazide 5a,b and 7/

acrylamide derivatives, Schiff base analogues 14a‐f, pyrazole derivatives 15a‐e,

amide derivatives 16a‐f, guanidine derivatives 16 g,h as well as, quinoxalin‐2‐

methylallyl propionate derivative 14g. All the synthesized compounds were con-

firmed via spectral data and elemental analyses. Moreover, the newly synthe-

sized compounds were evaluated for their antimicrobial activity (Gm +ve, Gm

2

Pharmaceutical Organic Chemistry

Department Faculty of Pharmacy (Girls),

Al‐Azhar University, Cairo, Egypt

Correspondence

Maha A. Ebrahim, Pharmaceutical

Organic Chemistry Department, Faculty

of Pharmacy (Girls), Al‐Azhar University,

Cairo, Egypt.

Email: maha.ahmed@azhar.edu.eg

−

ve in comparison to Gentamycin a standard) and fungi (in comparison to Keto-

conazole as a standard). Thus, compound 16b showed promising antimicrobial

activity against B. subtilis, P. vulgaris, and S. mutants with values ranging from

2

0 to 27‐mm zone of inhibition. While compounds 5a, 14e,f, and 16a,c,d,g,h

showed potent antimicrobial activity. Moreover, the National Cancer Institute

NCI) selected 20 compounds that were submitted for anticancer screening

against 60 types of cancer cell lines. The most active compounds are 5b and

2a where compound 5b containing 2,4‐dichlorophenyl moiety at

(

1

cyanoacetamide linkage of hydrazine quinoxaline backbone exerted significant

growth inhibition activity against Leukemia MOLT‐4, Renal cancer UO‐31,

and Breast cancer MCF‐7. In addition, compound 12a having 4,6‐

diaminopyridinone side chain at position‐3 of quinoxaline nucleus exhibited

remarkable anticancer activity against renal cancer UO‐31.

[

4]

[5]

[5,6]

1

| INTRODUCTION

antiviral antioxidant, antithrombotic,

vulsant

and anticon-

[

6]

activities. Considering the significant

In medicinal chemistry, there has been a lot of interest in

quinoxaline as an important class of nitrogen containing

heterocyclic compounds. Quinoxaline is a bioactive

precursor regarding its diverse biological activities such

applications in the field of medicinal chemistry, it was

intended to synthesize different derivatives of quinoxaline

attached to different substituents and heterocyclic struc-

tures at position two in which 3‐hydrazinyl and 3‐amino

quinoxaline derivatives were good scaffolds for these

[1]

[1,2]

[3]

as: antiinflammatory,

antimicrobial,

antitumor,

J Heterocyclic Chem. 2019;1–21.

wileyonlinelibrary.com/journal/jhet

1

2

BAYOUMI ET AL.

syntheses. So, it was aimed to synthesize new different

quinoxaline derivatives with antimicrobial and anticancer

activities. It was reported that 2,3‐dichloroquinoxaline 2

and (3‐chloro‐quinoxalin‐2‐yl)‐hydrazine 3b have signifi-

cant antibacterial activity against Staphylococcus aureus

4a‐c illustrated singlet at δ 3.16 to 4.10 ppm assigned for

the methylene protons beside deuterium oxide exchange-

able singlet at δ 9.47 to 11.00 ppm corresponding to the

amidic NH proton.

[

12,15]

Furthermore, the Knovenagal condensation

of the

[7]

ATCC 25923. Moreover, 2,3‐disubstituted quinoxaline

cyanoacetohydrazinyl derivatives 4a and 4c with substi-

tuted benzaldehyde afforded compounds 5a and 7 showed

arylidene CH at δ 8.51 to 8.98 ppm as singlet signals.

Moreover, cyclocondensation of cyanoacetamide deriv-

[7]

derivatives as compound I and II showed significant

antibacterial activity against Escherichia coli and antifun-

gal activity against Candida albicans, respectively.

Quinoxalines being containing nitrogen atom also

reported as a highly selective ATP competitive or mixed

competitive for substrate so it is considered an excellent

tyrosine kinase inhibitors for different cancer types as

[14]

atives with β‐diketones was previously discussed.

So

reaction of acetohydrazide derivative 4a with β‐diketones

namely, acetyl acetone, and ethylacetoacetate under reflux

using a catalytic amount of piperidine afforded the corre-

sponding pyridinone derivatives 6a,b, respectively.

[8]

chronic myelogenous leukemia. Moreover, compound

1

III exhibited excellent anticancer activity against HT‐29

The H NMR spectra of compounds 6a,b lacked singlet

[9]

and MCF‐7 cell lines.

corresponding to methylene protons and amidic NH pro-

tons of both compounds and exhibited singlet at δ 5.80 to

6

.01 ppm assigned for protons of pyrine C proton.

5

13

Also, the C NMR spectrum of compound 6a showed

two peaks at δ = 15.55 and 18.99 ppm due to two CH . In

addition, the C NMR spectrum of compound 6b

3

13

revealed peaks at δ = 11.75 and 19.10 ppm corresponding

to two CH (Scheme 1).

3

[

16]

3

‐Chloroquinoxalin‐2(1H)‐one

8,

3‐

[

14]

aminoquinoxalin‐ 2(1H)‐one 9,

3‐chloroquinoxalin‐2‐

[

17]

[18]

amine 10a,

and quinoxaline‐2,3‐diamine 10b

were

2

| RESULTS AND DISCUSSION

.1 | Chemistry

prepared as reported. Furthermore, solvent free reaction

of compounds 10a,b with ethylcyanoacetate produced

the corresponding cyanoacetamide derivatives 11a,b. The

1

H NMR spectra of compounds 11a‐c revealed singlet sig-

[5,7,10]

1

,4‐Dihydroquinoxaline‐2,3‐dione 1,

2,3‐dichloroqu-

nals at δ 4.00 ppm due to CH protons and another deute-

2

[11]

[7]

inoxaline 2,

and 2‐chloro‐3‐hydrazinylquinoxaline 3b

3‐hydrazinylquinoxalin‐2(1H)‐one 3a,

rium oxide exchangeable singlet signals at δ 11.9 ppm due

[7]

13

were pre-

to two amidic NH protons. The C NMR spectrum of com-

pared as reported.

pound 11b showed two peaks at δ 24.18 and 115.58 ppm

The alkyl/aryl ether derivative of quinoxaline was pre-

pared from reaction of chloro derivative with methanol in

the presence of sodium metal via elimination of HCl mol-

due to CH and C≡N carbons, respectively. In addition, a

2

peak at δ 167.36 ppm is assigned for amidic carbonyl car-

bon. 6‐Amino‐2‐oxopyridine‐3‐carbonitrile derivatives

12a,b and 6‐hydroxy‐2‐oxopyridine‐3‐carbonitrile deriva-

tives 13a,b were obtained from reaction of cyclization of

[12]

ecule.

So, 2‐hydrazinyl‐3‐methoxy quinoxaline 3c was

synthesized from heating 2‐chloro‐3‐hydrazinyl quino-

xaline 3b in sodium methoxide solution under reflux.

the cyanaoacetamide derivatives 12a,b with active methy-

1

[19]

The H NMR spectrum of compound 3c exhibited a sin-

lene containing compounds

namely, malononitrile,

glet signal at δ 3.095 ppm due to methoxy protons. While,

cyanoacetamide derivatives were prepared through reac-

tion of amino containing compounds with ethylcyanoa-

and ethyl cyanoacetate, respectively, under reflux in diox-

ane containing catalytic amount of piperidine.

The H NMR spectra of compounds 12a,b exhibited

D O exchangeable singlets at δ 1.54 to 2.00 ppm corre-

2

1

[13,14]

cetate via elimination of ethanol molecule.

Thus,

compounds 4a‐c were synthesized from the reaction of

hydrazinyl quinoxaline derivatives 3a‐c with ethylcyano-

acetate. The structure of compounds 4a‐c were evidenced

by spectral and elemental data. The IR spectrum of these

compounds exhibited absorption bands at 2273 to 2240

sponding to two NH protons as well as a singlet at δ

2

4.50‐4.90 ppm assigned for pyridine CH proton. Also, the

13

C NMR spectrum of compound 13a showed peaks at δ

163.53, 175.44, and 177.91 ppm corresponding to C═O of

pyridine, C―OH and C―NH , respectively. While, the

2

−

1

cm corresponding to cyano function as well as absorp-

H NMR spectrum of compound 13b revealed two deute-

−

1

tion bands at 1670 to 1615 cm due to amidic carbonyl

rium oxide exchangeable singlet signals at δ 2.00 and 9.07

1

group. In addition, the H NMR spectra of compounds

ppm due to NH and OH protons, respectively (Scheme 2).

2

BAYOUMI ET AL.

3

SCHEME 1

SCHEME 2

4

BAYOUMI ET AL.

Furthermore, the reaction of hydrazinyl derivatives 3a,

compound 3b reacted with ethyl acetoacetate to yield

the corresponding 3‐methyl pyrazolone derivative 15e

whose structure was confirmed by the presence of a peak

at δ 170.23 ppm in C NMR characteristic for carbonyl

carbon. A survey in the literature revealed that amino

b with different aldehydes, such as 4‐hydroxy‐benzalde-

hyde, thiophene‐2‐carboxaldehyde, and 2‐carboxy‐benzal-

dehyde afforded the Schiff bases 14a‐f, respectively. The

13

1

H NMR spectra of compounds 14a‐f revealed singlet

signals at δ 7.06 to 9.67 ppm corresponding to N═CH

containing compounds reacted with chloroacetyl chloride

13

[25]

protons. While, C NMR of compounds 14a‐c showed

signals assigned for N═C carbons at δ 138.17 to 146.52

ppm. It has been noted that 2‐benzylidene hydrazinyl‐

quinoxaline carboxylate derivatives 14e,f were obtained

from the reaction of 2‐carboxybenzaldehyde with the

hydrazinyl derivatives in methanol where the reaction

unexpectedly occurred at aldehydic and not the carboxylic

with elimination of HCl molecule.

In this investiga-

tion, quinoxaline‐2‐hydrazide derivatives 3a,b reacted

with chloroacetyl chloride at room temperature in the

presence of DMF to afford the corresponding

1

acetohydrazides 16a,b. The H NMR spectra of com-

pounds 16a,b exhibited singlet signals at δ 5.57 and 5.56

ppm, respectively, corresponding CH₂protons. While,

[20]

13

group adopting the reported method.

On the other hand, condensation of hydrazide deriva-

the C NMR spectrum of compound 16b showed signal

at δ 156.75 ppm due to carbonyl carbon. Phenylethanone

derivatives were obtained from reaction of phenacyl bro-

mide with the hydrazides 3a,b. So compounds 3a,b

reacted with phenacyl bromide to yield the corresponding

phenylethanone derivatives 16c,d. The structure of com-

pounds 16c,d was evidenced by the presence of singlets

at δ 4.52 and 4.46 ppm, respectively, characteristic for

[

21]

tives with ethyl acetoacetate was previously reported.

Thus, hydrazinylidene butanoate derivative 14g was pre-

pared from the reaction of compound 3b with ethyl

acetoacetate. The structure of compound 14g was con-

1

firmed via the presence of triplet and quartet in the H

NMR spectrum at δ 1.65 and 4.06 ppm characteristic

for the ester methyl and the methylene protons. Also,

CH protons. However, nucleophilic addition of hydra-

2

1

3

the C NMR of compound 14g revealed signal at δ

59.99 ppm corresponding to N═C carbon. It is well

zide containing compounds with phthalic anhydride has

[

26–28]

1

been reported.

In this work, compounds 3a,b

established in the literature that, 3‐amino‐5‐oxopyrazol

derivatives were synthesized via reaction of different

reacted with phthalic anhydride in glacial acetic acid to

give the corresponding hydrazine carbonyl benzoic acid

derivatives 16e,f and not the isoindoline‐1,3‐dione deriva-

tives. The C NMR spectra of compounds 16e,f revealed

two peaks at δ 165.96 to 166.03 ppm and δ 169.16 to

169.43 ppm assigned for ketonic carbonyl and carboxylic

carbonyl functions, respectively.

[

21,22]

hydrazide derivatives with ethyl cyanoacetate.

Con-

13

sequently, reacting the hydrazides 3a,b with ethyl

cyanoacetate in sodium methoxide solution afforded

the corresponding 3‐amino‐5‐oxo‐pyrazole derivatives

1

5a,b. The reaction was assumed to occur through

nucleophilic addition of NH on cyano function followed

by cyclization with removal of ethanol moiety. The H

NMR spectra of compounds 15a,b showed singlets at δ

On the other hand, amino containing compounds

reacted with cyanamide to give the corresponding

1

[

29]

carboximidamide derivatives.

Thus, the target com-

2

.66 and 2.99 ppm, respectively, characteristic for

pound 16g was obtained through reaction of hydrazinyl

derivative 3a with cyanamide in acidic medium. The

C NMR of compound 16g exhibited signal at δ 163.05

pyrazole CH₂protons. While, 3,5‐dimethylpyrazole

derivatives were reported to be synthesized from the

reaction of acid hydrazide derivatives with acetyl ace-

13

ppm due to C (NH)NH carbon (Scheme 3).

2

[

21,23]

tone.

Therefore, refluxing hydrazinyl derivatives

3

a,b with acetyl acetone yielded the corresponding

dimethyl pyrazolyl derivatives 15c,d. The structure of

1

13

such compounds was supported by H NMR and

C

2.2 | Biological evaluation

1

NMR. In the H NMR spectra of compounds 15c,d, there

are singlets at δ 2.19 and 2.04 ppm, respectively, due to

pyrazolyl‐C ‐CH protons in addition to another singlet

2.2.1 | Antimicrobial screening

3

at δ 2.30 ppm corresponding to pyrazolyl‐C ‐CH pro-

tons. Also, the C NMR spectra for these compounds

showed signals at δ 11.89 to 12.01 ppm and δ 13.73 to

Thirty six of the newly synthesized compounds were

screened for their antimicrobial activity using the agar

diffusion technique. The tested organisms were S. aureus,

B. subtilis (NRRL B‐543), and Streptococcus mutants

(ATCC 25175) as representatives of Gram +ve bacteria,

E. coli (ATCC 25955), and Proteus vulgaris (ATCC

13315) as representatives of Gram −ve bacteria and C.

albicans (ATCC 10231) as representative of fungi.

5

3

1

3

1

3.81 ppm assigned for pyrazolyl‐C ‐CH₃and

3

pyrazolyl‐C ‐CH carbons, respectively.

5

3

The synthesis of 3‐methyl‐5‐oxo pyrazole derivatives

from cyclocondensation of hydrazide derivatives with

[21,24]

ethyl acetoacetate has been reported.

Therefore,

BAYOUMI ET AL.

5

SCHEME 3 [Color figure can be viewed at wileyonlinelibrary.com] [Color figure can be viewed at wileyonlinelibrary.com]

Agar well diffusion method:

activity. Furthermore, compounds bearing benzylidine

Antimicrobial tests were carried out using the agar well

diffusion method on a sterile Petri dish containing

Mueller Hinton Agar (MHA) for bacteria and Sabouraud

Dextrose Agar (SDA) for fungi; 100 μL of the tested com-

pound solution was prepared by dissolving 1 mg of the

chemical compound in 1‐mL dimethyl sulfoxide (DMSO).

The inoculated plates were then incubated for 24 hours at

hydrazinyl carboxylic moiety 14e,f possess significant

antimicrobial activity. Finally, compounds having

phenylethanone hydrazinyl and guanidine hydrazinyl

moieties 16c,d,g,h, respectively, exerted significant anti-

microbial activity. All tested compounds have no activity

against fungi. In addition, the most active compounds

were further evaluated by determining their minimum

inhibitory concentration (MIC), and the data were repre-

sented in Table 2 and Figure 2.

3

7°C for bacteria and 48 hours at 28°C for fungi. Negative

controls were prepared using DMSO employed for dis-

solving the tested compound. Gentamycin (4 μg/mL) for

Gram +ve and Gram −ve bacteria while Ketoconazole

(

100 μg/mL) as antifungal were used as standards. After

2

.2.2 | The minimum inhibitory concentra-

incubation, antimicrobial activity was evaluated by mea-

suring the zone of inhibition against tested microorgan-

isms. Antimicrobial activity was expressed as inhibition

diameter zones in millimeters (mm).

zones (I.Z.) in mm diameter for the newly synthesized

compounds were represented in Table 1 and Figure 1.

tion (MIC)

MIC is the lowest concentration of a compound required

to inhibit the visible growth of a microorganism being

investigated after approximately 24 hours of incubation

in the appropriate growth medium. The MIC of active

compounds was studied against three strains of Gm +ve

bacteria (namely: S. aureus, B. subtilis, and S. mutants)

and two strains of Gm −ve bacteria (namely: E. coli, P.

vulgaris) in addition to fungi (namely: C. albicans). The

results obtained explained that 3‐oxo substituted

quinoxaline with cyanoacetohydrazide side chain 4a

exhibited moderate inhibition activity against S. aureus,

B. subtilis, and P. vulgaris, but it exerted no activity

against E. coli. While, 3‐hydroxyquinoxaline containing

[30–34]

Inhibition

Conclusion

Among the tested compounds, the following 10 com-

pounds 4a, 14d,e,f, 16a,b,c,d,g,h were found to be the

most active. Among the different functions which exerted

potent antimicrobial activity, the cyanoacetohydrazinyl

derivative 4a as well as acetohydrazinyl derivatives 16a,

b. Also, compounds containing thiophene methylene

hydrazinyl moiety 14d showed remarkable antimicrobial

6

BAYOUMI ET AL.

TABLE 1 Inhibition zones (I.Z.) in mm diameter for the newly synthesized compounds

Gram −Ve

Gram +Ve Bacteria

Bacteria

Fungi

Comp.

No

S.

aureus

B.

S.

E.

coli

P.

C.

subtilis

NA

11

mutants

vulgaris

albicans

3

c

11

NA

9

NA

10

13

NA

12

4

5

6

7

1

a

b

c

a

b

a

b

14

12

NA

8

10

NA

10

NA

12

14

13

NA

10

NA

11

NA

12

NA

11

NA

10

1a

1b

1c

2a

2b

3a

3b

4a

4b

4c

4d

4e

4f

NA

9

NA

10

NA

9

NA

10

NA

11

NA

10

14

12

NA

12

9

11

12

NA

11

NA

11

NA

10

NA

10

NA

16

11

13

11

NA

15

14

12

NA

10

15

10

12

18

4 g

5a

5b

5c

5d

5e

6a

6b

6c

6d

6e

6f

13

NA

18

8

12

NA

9

NA

10

NA

9

11

8

NA

10

NA

20

NA

14

10

17

15

27

20

14

26

9

15

14

9

16

NA

12

17

15

NA

12

16

NA

18

NA

13

NA

22

6 g

6 h

NA

15

14

16

15

Gentamycin

Ketoco‐nazole

Standard

24

26

20

30

25

20

Bold entries denote the types and names of microorganisms and compounds number.

BAYOUMI ET AL.

7

FIGURE 1 Inhibition zones (I.Z.) in mm diameter for the newly synthesized compounds [Color figure can be viewed at wileyonlinelibrary.

com]

TABLE 2 Minimum inhibitory concentration (MIC) of the active compounds in μg/mL

Minimum inhibitory concentration in μg/mL

Test Organisms

Comp.

No.

Gram +Ve

S. aureus

Gram −Ve

E. coli

Fungi

C. albicans

B. subtilis

625

S. mutants

1250

P. vulgaris

625

4

a

312.5

NA

1

4d

4e

4f

625

1250

NA

312.5

5000

10 000

NA

5000

2500

1125

312.5

625

312.5

2500

625

156.25

625

6a

6b

6c

6d

6g

6h

1250

312.5

1250

NA

1250

19.53

312.5

156.25

2500

156.25

625

312.5

625

19.53

312.5

625

NA

1250

NA

1250

2500

39.06

2500

625

10 000

acetohydrazide side chain 16a,b showed mild inhibition

against all tested organisms. Furthermore, hydrazine‐1‐

carboximidamide derivative 16g showed great antibacte-

rial activity against P. vulgaris and mild inhibition activity

against: B. subtilis and E. coli. Moreover, attachment of

hydrazinylidene benzoic acid 14e at position two of

quinoxaline backbone diminished the growth inhibition

toward all organisms.

replacement of 2‐phenylethanone with carboximidamide

side chain 16h highly decreased the growth inhibition

of all organisms.

It is to be noted that 3‐chloroquinoxaline derivatives

having hydrazinylidene linkage at position two 14d and

16f showed moderate inhibition toward all organisms.

On the other hand, 3‐hydrazino substituted quino-

xaline derivatives exhibited moderate to promising inhi-

bition especially against P. vulgaris. So, compounds

containing 2‐phenylethanone at hydrazide side chain

2

.2.3 | Microplate assay

The highly active compound 16b (MIC50 = 4.19 and 4.6

μg/mL for both Gm +ve B. subtilis and Gm −ve P.

vulgaris, respectively) was further submitted to micro-

1

6d exerted moderate inhibition toward all organisms.

[

35,36]

While, replacement of phenylethanone with chloro-

acetyl analogue 16b greatly increases inhibition mainly

toward B. subtilis and P. vulgaris. In addition,

plate assay

in comparison to Ciprofloxacin as a

reference drug. The experimental results cleared that

compound 16b possesses complete growth inhibition

8

BAYOUMI ET AL.

FIGURE 2 Minimum inhibitory concentration (MIC) of the

active compounds in μ g/mL [Color figure can be viewed at

wileyonlinelibrary.com]

FIGURE 3 Microplate growth inhibition assay of compound 16b

[

Color figure can be viewed at wileyonlinelibrary.com]

activity with concentration range 100 to 25 μg/mL, while

excellent growth inhibition at concentration 12.5 μg/mL

for both strains (Table 3 and Figure 3).

Twenty compounds were evaluated using screening

methodology of NCI

[

37]

(Table 4).

The one dose screen results revealed that compound

3c

possessing hydrazinyl moiety at position‐3 of

quinoxaline backbone illustrated moderate anticancer

activity against some cancer cell lines especially CNS can-

cer SNB‐75. While replacement of amino group of hydra-

zinyl moiety at position‐3 and methoxy group at position

two with cyanoacetamide function as well as either

hydroxyl or chloro group in compounds 4a,b, respec-

tively, resulted in a slight increase in the growth inhibi-

tion activity toward many cancer cell lines for example,

2

.2.4 | Anticancer screening

National Cancer Institute (NCI), Bethesda, Maryland,

USA has adopted an in vitro model consisting of 60

human tumor cell lines for primary anticancer screening.

Screening utilizes 60 different human tumor cell lines

representing leukemia, melanoma, and cancers of the

lung, colon, brain, ovary, breast, prostate, and kidney.

TABLE 3 Microplate growth inhibition assay of compound 16b

Mean of Growth Inhibitory%

B. subtilis

P. vulgaris

Conc. μg/mL

16b

100

91.32

76.35

36.37

18.47

6.19

0

Ciprofloxacin

16b

100

86.35

71.35

31.25

13.25

5.09

0

Ciprofloxacin

1

5

2

1

6

3

1

0

00

0

100

78.97

58.70

22.26

0

100

82.45

63.10

0

5

2.5

.25

.13

.56

.78

.39

0

MIC50

4.19

0.68

4.6

0.29

BAYOUMI ET AL.

9

TABLE 4 Anticancer screening results of selected compounds by NCI

Subpanel Cell Lines

Comp. No.

NSC‐No.

813143

813147

813142

Mean Growth %

Delta

36.86

25.80

26.23

Panel

(Growth Inhibition %)

3c

4a

4b

26.81

98.80

96.69

CNS cancer

Renal cancer

SNB‐75(26.63).

UO‐31 (27).

CNS cancer

Renal cancer

SNB‐75(22.05).

A498 (29.54),

UO‐31(25.06).

5

a

b

813152

813153

98.70

89.87

21.41

29.47

Leukemia

Breast cancer

MOLT‐4 (21.83).

MCF‐7 (22.71).

5

Leukemia

MOLT‐4 (35.60).

Colon cancer

EKVX (22.02), NCI‐H322M

(

20.24), NCI‐H522 (20.13).

SF‐268 (24.27), SNB‐75 (20.09).

OVCAR‐4 (26.98).

CNS cancer

Ovarian cancer

Renal cancer

Breast cancer

CAKI‐1 (27.29), UO31(35.49).

MCF‐7 (39.60), MDA‐

MB‐231/ATCC (24.40).

6

a

b

813148

95.41

19.23

Non–small cell

lung cancer

CNS cancer

Renal cancer

HOP‐92 (23.82).

SNB‐75 (20.54).

UO‐31 (21.18).

T‐47D (12.63).

SNB‐75 (22.19).

UO‐31 (23.89).

SR (23.61).

6

7

1

813141

813146

813145

813144

813156

813158

813155

813157

813154

813139

813150

813149

104.52

99.36

17.15

21.55

20.76

21.77

20.29

27.62

21.43

16.99

21.10

23.34

22.43

18.73

Breast cancer

CNS cancer

Renal cancer

Leukemia

1a

1b

1c

2a

2b

3a

3b

4a

5a

5c

96.87

98.16

102.46

97.18

Renal cancer

CNS cancer

Renal cancer

CNS Cancer

Renal cancer

UO‐31 (17.83).

UO‐31 (30.44).

SNB‐75 (15.23).

UO‐31 (12.86).

SNB‐75 (16.86).

UO‐31 (18.82).

UO‐31 (20.30).

HOP‐92 (16.34).

106.20

104.13

104.24

104.52

102.13

98.84

Non–small

cell lung cancer

1

5e

6e

813151

813140

104.13

94.06

25.03

22.85

CNS cancer

Leukemia

SNB‐75 (20.90).

CCRF‐CEM

1

(

22.10), SR (28.79).

NCI‐H522 (23.64).

Non–small

U251(23.40).

cell lung cancer

CNS cancer

OVCAR‐4(24.71).

Ovarian cancer

Breast cancer

MDA‐MB‐231 (20.72).

renal cancer UO‐31 in compound 4a as well as CNS can-

cer SNB‐75 together with renal cancer A498 and UO‐31

in compound 4b.

Furthermore, compounds 5a,b having chlorophenyl

moiety at acetamide linkage exhibited potent anticancer

activity against many cancer cell lines. Thus, compound

10

BAYOUMI ET AL.

5

a containing 4‐chlorophenyl nucleus showed good

anticancer activity against most cancer cell lines except

non–small cell lung cancer HOP‐92 and CNS cancer

SNB‐75 for compound 6a. Additionally, replacement of

oxo function at position two in compound 5b by methoxy

group in compound 7 decreased growth inhibition activ-

ity toward many cancer cell lines.

Screening results showed that compounds 11a‐c con-

taining cyanoacetamide moiety at position‐3 of

quinoxaline nucleus displayed significant growth inhibi-

tion activity against some cancer cell lines. Thus,

growth inhibition activity toward leukemia HL‐60 (TB)

and MOLT‐4 in addition to breast cancer MCF‐7. How-

ever, replacement of hydrogen atom at position‐2 of phe-

nyl moiety in compound 5a by chlorine atom in

compound 5b increased antitumor activity against most

cancer cell lines especially leukemia MOLT‐4, renal can-

cer UO‐31, and breast cancer MCF‐7.

On the other hand, attachment of pyridine ring at

hydrazinyl function as in compounds 5a,b decreased the

TABLE 5 Physicochemical properties based on Lipiniski′s rule of five, TPSA, %ABS, and number of rotatable bonds

Lipiniski′s Parameters

No of

H‐bond

donors

H‐bond

acceptors

Lipiniski

violation

Rotatable

Bonds

Compounds

MWt

MLOGP

0.08

2.58

0.42

2.35

1.85

2.42

0.95

1.58

1.64

2.23

0.37

1.01

TPSA

110.67

143.58

78.41

107.44

87.47

86.88

66.91

86.88

66.91

119.68

99.71

%ABS

70.82

59.46

81.95

71.93

78.82

79.03

85.92

79.03

85.92

67.71

74.60

4

5

1

a

243.22

400.22

294.27

288.76

308.29

328.74

252.66

271.10

294.31

312.75

218.22

236.66

3

1

3

2

3

2

3

2

5

4

3

5

3

4

3

0

4

5

1

3

4

5

3

b

2a

4d

4e

4f

6a

6b

6c

6d

6g

6h

TABLE 6 Pharmacokinetic properties and medicinal chemistry parameters

GI

BBB

P‐gp

Bioavailability

Log K

p

(Skin

Synthetic

Compound Absorption Permeant Substrate Score

CYP1A2 CYP2D6 Permeation), cm/s Accessibility

4

5

1

a

High

Low

No

Yes

No

Yes

No

0.55

0.56

0.55

No

Yes

No

−7.45

−6.01

−7.95

−5.13

−6.99

−6.09

−6.11

−5.22

−7.56

−6.67

2.87

3.38

3.08

2.89

2.91

2.89

2.78

2.97

2.80

3.14

3.05

b

Yes

No

2a

4d

4e

4f

High

Yes

No

6a

6b

6c

6d

6g

6h

Yes

BAYOUMI ET AL.

11

compound 11a having hydroxyl group at position two

showed a reasonable anticancer activity against renal can-

cer UO‐31. However, in compound 11a, replacement of

hydroxyl group by chlorine atom in compound 11b

resulted in a slight decrease in antitumor activity toward

most cancer cell lines except for leukemia SR.

Moreover, compound 12a having 6‐aminopyridinone

ring at position‐3 and hydroxyl group at position‐2 of

quinoxaline ring showed potent antitumor activity

against some cancer cell lines, namely renal cancer UO‐

Lipinski's parameters; this indicates that all of them have

promising drug‐like characters (Table 5).

In silico pharmacokinetic analysis of the most active

compounds

Pharmacokinetic properties determine the human thera-

peutic use of the drugs which include: absorption, distri-

[39]

bution, metabolism, excretion, and toxicity (ADMET).

So, in silico pharmacokinetic analysis is very important

to decrease the percentage drug failure in the step of

clinical trials (Table 6).

3

1. Although, replacement of hydroxyl group in com-

pounds 12a by chlorine atom in compound 12b decreased

anticancer activity against most cancer cell lines. Also,

substitution of 6‐amino pyridinone ring in compounds

4

| MATERIALS AND METHODS

.1 | Chemistry

1

2a,b by 6‐hydroxy pyridinone ring in compounds 13a,b

4

strongly decreased the anticancer activity toward many

cancer cell lines.

General: Melting points were determined on a Thomas‐

Hoover capillary apparatus and are uncorrected. Infrared

As indicated from the anticancer results, attachment

of o‐carbonylcarboxylic acid to hydrazinyl group in com-

pound 16e increased the antitumor activity against most

cancer cell lines for example, leukemia CCRF‐CEM. It

also exerted remarkable anticancer activity toward

non‐small cell lung cancer NCI‐H522, CNS cancer

U251, ovarian cancer OVCAR‐4, and breast cancer

MDA‐MB‐231/ATCC.

(

IR) spectra were recorded as films on KBr plates using a

1

Nicolet 550 Series II Magna FT‐IR spectrometer. H NMR

13

and C NMR spectra were measured on a Bruker 400‐

MHz and Mercury 100‐MHz NMR spectrometers, Faculty

of Pharmacy in Cairo, Bani‐Swif, and Mansoura Universi-

ties, Egypt in CDCl or DMSO‐d with TMS as the inter-

3

6

nal standard, where J (coupling constant) values are

estimated in Hertz (Hz). Mass spectra (MS) were recorded

on a Water's Micromass ZQ 4000 mass spectrometer

using the electro‐spray (ES) ionization mode. Microanaly-

ses were performed for C, H, and N and were carried out

on Perkin‐Elmer 2400 analyzer (Perkin‐Elmer, Norwalk,

CT, USA) at the Center of Mycology and Biotechnology,

Al‐Azhar University, Egypt. Progress of the reactions

was monitored by using TLC sheets precoated with UV

fluorescent silica gel Merck 60 F254 plates and were visu-

alized using UV lamp at 254 nm. Solvent for TLC:dichlo-

romethane:methanol in ratio 9:1 and 8:2.

3

| CONCLUSION

It was concluded that, most of compounds exhibited

potent anticancer activity against renal cancer UO‐31

and CNS cancer SNB‐75 cell lines. The most active

compounds are 5b and 12a where compound 5b con-

taining 2, 4‐dichlorophenyl moiety at cyanoacetohy-

drazide linkage of quinoxaline backbone exerted

significant growth inhibition activity against leukemia

MOLT‐4, renal cancer UO‐31, and breast cancer MCF‐

7

. In addition, compound 12a having 4,6‐diaminopyr-

idinone side chain at position‐3 of quinoxaline nucleus

showed remarkable anticancer activity against renal

cancer UO‐31.

4

.1.1 | 2‐Hydrazineyl‐3‐

methoxyquinoxaline 3c

A mixture of chloroquinoxaline 3b (0.2 g, 1 mmol) and

sodium metal (0.23 g, 1.5 mmol) was refluxed in metha-

nol (20 mL) for 12 hours. The reaction mixture was then

concentrated, dried, and washed with benzene to give the

methoxy derivative 3c. Gray powder, yield 90%, m.p.:

In silico studies

The most active antimicrobial and anticancer derivatives

were submitted to further in silico studies.

−

1

>

300°C. IR (KBr, cm ): 3414 (NH, NH ); 2988 (CH‐ali-

2

1

Lipinski's parameters

phatic); 1460 (C═C); 1145 (C―O―C). H NMR (DMSO‐

d , δ ppm): 2.04 (s, 2H, NH , D O exchangeable); 3.10

The most active derivatives were submitted for computa-

tional studies of Lipinski's parameters and topological

polar surface area (TPSA) were predicted. Lipinski's rule

of five is applied to the molecule to predict if it can be

6

2

(s, 3H, CH ); 3.9 (s, 1H, NH, D O exchangeable); 7.71 to

3

2

8.10 (m, 4H, quinoxaline‐C₅_,₆_,₇_,₈‐H). MS m/z (relative

+.

intensity %): 190.17 (M , 0.79); 136 (9.6); 105 (89.87); 77

[38]

used orally or not.

All compounds agree with

(100). Anal. form: C H N O (190.09). Calcd. (%): C,

9

10 4

12

BAYOUMI ET AL.

5

2

6.83; H, 5.30; N, 29.46. Found (%): C, 57.11; H, 5.43; N,

9.73.

117 (90),73 (100). Anal. form: C H ClN O (261.04).

11

8

5

Calcd. (%): C: 50.49, H: 3.08, N: 26.76. Found (%): C,

0.32; H, 3.17; N, 26.94.

5

4

.1.2 | 2‐Cyano‐N′‐(3‐substituted

quinoxaline‐2‐yl)acetohydrazide 4a‐c

4

2

.1.5 | 2‐Cyano‐N′‐(3‐methoxyquinoxalin‐

‐yl) acetohydrazide 4c

An equimolar mixture of the hydrazinyl derivatives 3a‐c

and ethyl cyanoacetate (0.11 g, 0.11 mL, 1 mmol) was

heated under reflux in absolute ethanol (15 mL) for 12

hours. The reaction mixture was then concentrated and

cooled to room temperature, and the obtained precipitate

was collected by suction filtration, dried, and crystallized

from dioxane to afford compound 4a,b and from ethanol

to afford 4c, respectively.

Yellow powder, yield: (69%), m.p. >300°C. (Highly

−

1

hygroscopic powder). IR (KBr, cm ): 3219 (2NH),

976 (CH‐aliphatic), 2260 (C≡N), 1615 (C═O); 1264

2

1

(

C―O). H NMR (DMSO‐d ) δ: 3.10 (s, 3H, CH ), 3.16

6

3

(

s, 2H, CH ), 3.95 (s, 1H, NH, D O exchangeable),

2 2

7.714 to 8.106 (m, 4H, quinoxaline C₅_,₆_,₇_,₈‐H), 9.47

(

s, 1H, amidic NH, D O exchangeable). MS m/z (relative

2

+

.

intensity %): 257 (M , 8), 199 (100), 127 (50), 87 (55.5),

7

5

2

3 (94). Anal. form: C H N O (257.09). Calcd. (%): C,

12 11 5 2

6.03; H, 4.31; N, 27.22. Found (%): C, 56.12; H, 4.39; N,

7.49.

4

.1.3 | 2‐Cyano‐N′‐(3‐oxo‐3,4‐

dihydroquinoxalin‐2‐yl)substituted

acetohydrazide 4a

Yellow powder, yield: (85%), m.p. >300°C. IR (KBr,

cm ): 3437 (OH); 3247 (NH); 3050 (CH‐aromatic);

−

1

4.1.6 | 3‐(4‐Substituted phenyl)‐2‐cyano‐N

′

‐(3‐oxo‐3,4‐dihydroquinoxalin‐2‐yl)

2

901, 2847 (CH‐aliphatic); 2273 (C≡N); 1670 (C═O);

1

acrylohydrazide 5a,b

1

635 (C═N). H NMR (DMSO‐d ) δ: 3.08 (s, 1H,

6

NH―NH―CO, D O exchangeable); 3.84 (s, 2H, CH );

2

An equimolar mixture of the acetohydrazide 4a (0.24 g,

7

.07 to 7.35 (m, 4H, quinoxaline C₅_,₆_,₇_,₈‐H); 8.75 (s,

H, NH―NH―CO); 12.063 (s, 1H, quinoxaline NH).

C NMR (DMSO‐d ) δ: 25.10 (CH ); 114.54 (CN);

1

mmol) and substituted benzaldehyde was heated

1

13

under reflux in dioxane (10 mL) containing few drops

of piperidine for 24 hours. The reaction mixture was

then concentrated, cooled to afford a precipitate which

was collected, dried, and crystallized from ethanol to

yield the acrylohydrazide 5a, b.

6

2

1

23.46, 124.66, 125.43, 128.65, 129.90, 141.66

(

quinoxaline C , C , C , C , C , C ; respectively);

5 8 6 7 8a 4a

1

%

61.68 (quinoxaline C ); 164.25 (quinoxaline C═O);

2

69.95 (C═O side chain). MS m/z (relative intensity

+.

): 243 (M , 10.5); 187 (31); 133 (100); 118 (4); 78

(

5

87). . Anal. form: C H N O (243.08). Calcd. (%): C,

11 9 5 2

4.32; H, 3.73; N, 28.79. Found (%): C, 54.60; H, 3.81;

4

.1.7 | 3‐(4‐Chlorophenyl)‐2‐cyano‐N′‐(3‐

oxo‐3,4‐dihydro‐quinoxalin‐2‐yl)

acrylohydrazide 5a

N, 29.01.

4

.1.4 | N′‐(3‐chloroquinoxalin‐2‐yl)‐2‐

Reddish yellow powder, yield: (52%), m.p. 185°C to

−

1

cyanoacetohydrazide 4b

186°C. IR (KBr, cm ): 3440 (OH‐tautomer, ―NH);

136 (CH‐aromatic); 2278 (C≡N); br. 1664 (2C═O),

1616 (C═N); 813 (1, 4‐di‐substituted phenyl); 738

3

Dark brown powder, yield: (85%), m.p. 200°C to 201°C.

−

1

IR (KBr, cm ): 3290, 3170 (NH), 3051 (CH‐aromatic),

924, 2850 (CH‐aliphatic), 2240 (C≡N), 1635 (amidic

(C―Cl).

H

NMR (DMSO‐d₆) δ: 2.51(s, 1H,

2

NH―NH―CO, under DMSO, D O exchangeable); 7.20

2

1

C═O), 1597 (C═C), 1558 (C═N), 748 (C―Cl). H NMR

to 7.22 (m, 4H, quinoxaline C₅_,₆_,₇_,₈‐H); 7.52 (d, 2H,

(

DMSO‐d ) δ: 4.1 (s, 2H, CH ), 3.98 (s, 1H, NH, D O

J = 8 Hz, 4‐chlorophenyl C ‐H); 7.54 (d, 2H, J = 8

6

2

2,6

exchangeable), 6.99 to 7.38 (m, 4H, quinoxaline C₅

Hz, 4‐chlorophenyl C ‐H); 8.57 (s, 1H, ―C═CH);

, 6, 7,

3,5

1

3

₈‐

H),11.00 (s, 1H, amidic NH, D O exchangeable).

C

11.30 (s, NH―NH―CO, D O exchangeable); 12.23 (s,

2

NMR (DMSO‐d ) δ: 27.13 (CH ); 115.65 (CN); 121.57,

1H, quinoxaline‐NH, D O exchangeable). MS m/z (rela-

6

2

+.

1

24.36, 127.26, 129.48, 134.04, 143.23 (quinoxaline C₅,

tive intensity %): 367 (M + 2, 12); 366 (M + 1, 17);

363 (26); 319 (100); 204 (45); 125 (61). Anal. form:

C H ClN O (365.07). Calcd. (%): C, 59.11; H, 3.31;

C , C , C , C , C ; respectively); 144.70 (C―Cl); 163.83

8

6

7

8a

4a

(

quinoxaline C ); 170.20 (C═O side chain). MS m/z (rela-

3

18 12

5 2

+

.

+.

tive intensity %): 263 (M + 2, 7), 261 (M , 10), 146 (53),

N, 19.15. Found (%) C, 58.89; H, 3.47; N, 19.43.

BAYOUMI ET AL.

13

4

.1.8 | 2‐Cyano‐3‐(2,4‐dichlorophenyl)‐N′‐

152.68 (pyridine C

dine C═O); 161.16 (quinoxaline‐ C

C═O). MS m/z (relative intensity %): 307 (M , 4); 228

63); 161 (100); 89 (80); 84 (88). Anal. form: C H N O

6

); 154.56 (pyridine C

4

); 159.97 (pyri-

(

3‐oxo‐3,4‐dihydroquinoxalin‐2‐yl)‐

); 163.88 (quinoxaline

3

+.

acrylohydrazide 5b

(

16

13 5 2

Reddish yellow powder, yield: (48%), m.p. 184°C to

(307.11). Calcd. (%): C, 62.53; H, 4.26; N, 22.79. Found

(%): C, 62.84; H, 4.38; N, 23.05.

−

1

85°C. IR (KBr, cm ): 3445 (OH‐tautomer); 3298

(

―NH); 3045 (CH‐aromatic); 2929 (CH‐aliphatic); 2277

C≡N); br. 1684 (2C═O); 845 (1, 2, 4‐trisubstituted phe-

1

4.1.11 | 6‐Ethoxy‐4‐methyl‐2‐oxo‐1‐((3‐oxo‐

nyl); 757 (C―Cl). H NMR (DMSO‐d ) δ: 2.50 (s, 1H, ,

NH―NH―CO, D O exchangeable); 7.19 to 7.25 (m, 4H,

quinoxaline C₅_,₆_,₇_,₈‐H); 7.52 (d, 1H, J = 8 Hz, 2, 4‐

6

3

,4‐dihydroquinoxalin‐2‐yl)amino)‐1,2‐

2

dihydropyridine‐3‐carbonitrile 6b

dichloro phenyl‐C ‐H); 7.68 (s, 1H, 2, 4‐dichloro phenyl‐

6

Yellow powder, yield: (32%), m.p. 185°C to 186°C. IR

C H); 8.08 (d, 1H, 2, 4‐dichloro phenyl‐C H); 8.98 (s,

3

5

−1

(

KBr, cm ): 3442 (OH‐tautomer, ―NH); 3198 (CH‐aro-

1

H, ―C═C H); 11.64 (s, 1H, , NH―NH―CO, D O

2

matic); 2990 (CH‐aliphatic); 2280 (C≡N); 1680 (C═O);

exchangeable); 12.44 (s, 1H, quinoxaline NH, D O

2

1

608 (C═N); 848 (1, 2, 3, 4‐tetra substituted phenyl). H‐

+.

exchangeable). MS m/z (relative intensity %): 403 (M

NMR (DMSO‐d , δ ppm): 1.61 (t, 3H, ―OCH CH ); 2.35

+.

6

2

3

+

4, 2); 401 (M + 2, 2); 399 (M , 1.5); 331 (66); 296

(

s, 3H, pyridine C ‐CH ); 2.47 (s, 1H, hydrazinyl NH,

4

3

(

2

35); 74 (100). Anal. form: C H Cl N O (399.03). Calcd.

%): C, 54.02; H, 2.77; N, 17.50. Found (%): C, 54.23; H,

.94; N, 17.69.

18

11

2 5 2

under DMSO, D O exchangeable); 3.84 (m, 2H,

2

―

OCH ); 5.80 (s, 1H, pyridine C ‐H); 7.09 to 7.36 (m,

2

5

4

H, quinoxaline C₅_,₆_,₇_,₈‐H); 12.95 (s, 1H, quinoxaline

13

NH, D O exchangeable). C NMR (DMSO‐d ): δ: 11.75,

2

6

4

.1.9 | 4,6‐Dimethyl‐2‐oxo‐1‐((3‐oxo‐3,4‐

19.10 (2 CH

3

); 47.67 (CH

2

); 100.91 (pyridine‐ C ); 114.67

5

dihydroquinoxalin‐2‐yl)amino)‐1,2‐

(CN); 123.46, 124.66, 125.34, 129.65, 133.00, 137.29

(quinoxaline C , C , C , C , C8a, C4a; respectively);

151.68 (pyridine C ); 152.56 (pyridine C ); 159.46 (pyri-

dine C═O); 161.68 (quinoxaline‐C ); 164.25 (quinoxaline

C═O). MS m/z (relative intensity %): 337 (M , 14); 314

36); 215 (83); 187 (39); 105 (67), 50 (100). Anal. form:

C H N O (337.12). Calcd. (%): C, 60.53; H, 4.48; N,

dihydropyridine‐3‐carbonitrile 6a and

5

8

6

7

6

‐Ethoxy‐4‐methyl‐2‐oxo‐1‐((3‐oxo‐3,4‐

6

4

dihydroquinoxalin‐2‐yl)amino)‐1,2‐

dihydropyridine‐3‐carbonitrile 6b

3

+.

(

An equimolar mixture of the acetohydrazide 4a (0.24 g, 1

mmol) and acetylacetone/ethyl acetoacetate (1 mmol)

was refluxed in ethanol/DMF mixture (5:2, 15 mL) con-

taining piperidine (0.5 mL) for 18 hours. The reaction

mixture was then concentrated and cooled at room tem-

perature, and the formed precipitate was collected, dried,

and crystallized from DMF to give compounds 6a,b.

17

15 5 3

20.76. Found (%): C, 60.81; H, 4.59; N, 21.02.

4

.1.12 | 2‐Cyano‐3‐(2,4‐dichlorophenyl)‐N′‐

(3‐methoxyquinoxalin‐2‐yl)acrylohydrazide

7

An equimolar mixture of compound 4c (0.26 g, 1 mmol)

and 2,4‐dichlorobenzaldehyde (0.174 g, 1 mmol) was

heated under reflux in dioxane (10 mL) containing piper-

idine (few drops) for 6 hours. The reaction mixture was

then concentrated, cooled, dried, and crystallized from

ethanol to produce compound 7. Yellowish white powder,

4

.1.10 | 4,6‐Dimethyl‐2‐oxo‐1‐((3‐oxo‐3,4‐

dihydroquinoxalin‐2‐yl)amino)‐1,2‐

dihydropyridine‐3‐carbonitrile 6a

Yellow powder, yield: (32%), m.p. 190°C to 191°C. IR

−

1

−1

(

KBr, cm ): 3435 (OH‐tautomer); 3170 (NH); 3019

CH‐aromatic); 2850 (CH‐aliphatic); 2282 (C≡N); 1671

C═O), 1616 (C═N); 838 (1, 2, 3, 4‐tetra substituted phe-

yield: (47%), m.p. >300°C. IR (KBr, cm ): 3471 (2NH);

2265 (C≡N); 1633 (C═O); 1464 (C═C); 847 (1, 2, 4‐ trisub-

1

stituted phenyl). H NMR (DMSO‐d ) δ: 3.34 (s, 1H,

6

1

nyl). H NMR (DMSO‐d ) δ: 1.61 (s, 6H, 2CH ); 2.50 (s,

NH―NH‐CO, D O exchangeable); 3.85 (s, 3H, OCH );

6

3

2

3

1

H, hydrazinyl quinoxalinyl‐NH, D O exchangeable);

7.58 to 7.78 (m, 4H, quinoxaline C₅_,₆_,₇_,₈‐H); 7.98 (d, 2H,

2

6

.01 (s, 1H, pyridine‐ C ‐H); 7.11 to 7.37 (m, 4H,

J = 8 Hz, 2,4‐dichlorophenyl C ‐H); 8.06 (s, 1H, 2,4‐

5

5,6

quinoxaline C₅_,₆_,₇_,₈‐H); 12.04 (s, 1H, quinoxaline NH,

dichlorophenyl C ‐H); 8.51 (s, 1H, ═CH―); 9.85 (s, 1H,

3

13

D O exchangeable). C NMR (DMSO‐d ) δ: 15.55, 18.99

NH―NH―CO, D O exchangeable). MS m/z (relative

2

6

2

+.

(

2 CH ); 108.99 (pyridine‐C ); 115.82 (pyridine‐C );

intensity %): 417 (M + 4, 16); 415 (58, M + 2); 414

(100, M + 1); 413 (39, M); 348 (94); 231 (77); 119 (83) .

Anal. form: C H Cl N O (413.04). Calcd. (%): C,

3

5

3

1

17.67 (CN); 123.29, 124.65, 125.46, 129.95, 132.55,

1

36.29 (quinoxaline C , C , C , C , C , C ; respectively);

5

8

6

7

8a

4a

19 13

2 5 2

14

BAYOUMI ET AL.

5

1

5.09; H, 3.16; N, 16.91. Found (%): C, 55.23; H, 3.40; N,

6.73.

246 (M, 9); 185 (11); 64 (100). Anal. form: C H ClN O

11

7

4

(246.03). Calcd. (%): C, 53.56; H, 2.86; N, 22.71. Found

%): C, 53.73; H, 3.12; N, 22.87.

(

4

.1.13 | 2‐Cyano‐N‐(3‐oxo‐3,4‐

dihydroquinoxalin‐2‐yl)acetamide 11a, N‐

3‐chloroquinoxalin‐2‐yl)‐2‐cyanoacetamide

1b and N,N′‐(quinoxaline‐2,3‐diyl)bis(2‐

cyanoacetamide) 11c

(

1

4.2 | N,N′‐(quinoxaline‐2,3‐diyl)bis(2‐

cyanoacetamide) 11c

−

1

Black powder, Yield 71%, m.p. >300°C. IR (KBr, cm ):

3

‐Aminoquinoxalin‐2(1H)‐one 9, 2‐amino‐3‐chloroquino-

3435 (NH); 3033 (CH‐aromatic); 2800 (CH‐aliphatic);

2240 (C≡N); 1668 (C═O); 1612 (C═N); 1408 (C═C). H

1

xaline 10a, and 2, 3‐diaminoquinoxaline 10b (1 mmol)

were fused with excess ethyl cyanoacetate (0.34 g, 0.33

mL, 3 mmol) at 210°C for 30, 1, and 10 hours, respec-

tively. The reaction mixture was then triturated

with ethanol, left to evaporate to afford black powder

that was washed with diethyl ether on hot to

afford cyanoacetamide derivative 11a, crystallized from

methylene chloride/methanol mixture (9.5: 0.5) to afford

NMR (DMSO‐d ) δ: 4.00 (s, 4H, 2‐CH ); 6.95‐7.33 (m,

6

2

4H, quinoxaline C₅_,₆_,₇_,₈‐H); 11.90 (s, 2H, 2‐NH, D O

2

+

.

exchangeable). MS m/z (relative intensity %): 295 (M

+.

+1, 32); 294 (M , 41); 249 (43); 175 (57); 121 (82); 65

(100). Anal. form: C H N O (294.09). Calcd. (%): C,

14

10 6 2

57.14; H, 3.43; N, 28.56. Found (%): C, 57.38; H, 3.67; N,

28.79.

1

1b and crystallized from DMF to afford 11c,

respectively.

4

.3 | 4,6‐Diamino‐2‐oxo‐1‐(3‐oxo‐3,4‐

4

.1.14 | 2‐Cyano‐N‐(3‐oxo‐3,4‐

dihydroquinoxalin‐2‐yl)‐1,2‐

dihydroquinoxalin‐2‐yl)acetamide 11a

dihydropyridine‐3‐carbonitrile 12a and

4

,6‐Diamino‐1‐(3‐chloroquinoxalin‐2‐yl)‐2‐

Brown powder, yield: (37%), m.p. >300°C. IR (KBr,

cm ): 3402 (OH‐tautomer); 3046 (CH‐aromatic); 2962,

oxo‐1,2‐dihydropyridine‐3‐carbonitrile 12b

−

1

2

869 (CH‐aliphatic); 2203 (C≡N); 1630 (C═O). H NMR

An equimolar mixture of the cyanoacetamide 11a,b (1

mmol) and malononitrile (0.066 g, 0.1 mL, 1 mmol)

was heated under reflux in dioxane (10 mL) containing

piperidine (0.5 mL) for 7 to 9 hours. The reaction mix-

ture was then concentrated and cooled, and the precip-

itate formed was collected, dried, and crystallized from

DMF and ethanol to produce compound 12a,b,

respectively.

(DMSO‐d ) δ: 4.00 (s, 2H, CH ); 7.07 to 7.14 (m,4H, C ‐

6

2

5

C ‐quinoxaline); 11.9 (s, 2H, 2‐NH, D O exchangeable).

8

2

13

C NMR (DMSO‐d ) δ: 22.98 (CH ); 115.58 (CN);

6

2

1

21.46, 124.25, 127.07, 129.44, 132.04, 151.23 (quinoxaline

C , C , C , C , C , C ; respectively); 164.08 (quinoxaline

C ); 166.15 (quinoxaline C═O); 175.93 (amidic C═O).MS

5

8

6

7

8a

4a

3

+

.

m/z (relative intensity %): 228 (M , 28); 220 (35); 134

33); 106 (62); 79 (100). Anal. form: C H N O (228.06).

(

11

8 4 2

Calcd. (%): C, 57.89; H, 3.53; N, 24.55. Found (%): C,

8.04; H, 3.79; N, 24.13.

5

4

.4 | 4,6‐Diamino‐2‐oxo‐1‐(3‐oxo‐3,4‐

dihydroquinoxalin‐2‐yl)‐1,2‐

dihydropyridine‐3‐carbonitrile 12a

4

.1.15 | N‐(3‐chloroquinoxalin‐2‐yl)‐2‐

cyanoacetamide 11b

Dark brown powder, yield: (42%), m.p. >300°C. IR (KBr,

cm ): 3470 (OH‐tautomer); 3300, 3250 (NH, NH ); 3027

(CH‐aromatic); 2277 (C≡N); 1670 (C═O); 1600 (C═N);

1434 (C═C). H NMR (DMSO‐d ) δ: 2.00 (s, 4H, 2 NH ,

−

1

−1

White powder, yield: (81%), m.p. >300°C. IR (KBr, cm ):

434 (OH‐tautomer); 3048 (CH‐aromatic); 2962, 2876

CH‐aliphatic); 2273 (C≡N);1684 (C═O); 760 (C―Cl).

2

3

(

1

6

2

1

H NMR (DMSO‐d ) δ: 4.00 (s, 2H, CH ); 7.07 to 7.35

D O exchangeable); 4.90 (s, 1H, pyridine C ‐H); 7.07 to

6

2

5

(

m, 4H, quinoxaline C

‐H); 11.92 (s, 1H, NH, D O

7.14 (m, 4H, quinoxaline, C₅_,₆_,₇_,₈‐H); 11.90 (s, 1H,

5

,6,7,8

2

13

exchangeable). C NMR (DMSO‐d ) δ: 24.18 (CH );

quinoxaline NH, D O exchangeable). MS m/z (relative

6

2

+.

1

15.58 (CN); 122.34, 123.44, 126.04, 128.37, 132.23,

intensity %): 295 (M +1, 4); 294 (M , 13); 161 (46);

106 (100). Anal. form: C H N O (294.09). Calcd. (%):

40.46 (quinoxaline C , C , C , C , C , C ; respectively);

5

8

6

7

8a

4a

14 10 6 2

45.07 (C―Cl); 162.20 (quinoxaline C ); 167.36 (amidic

C, 57.14; H, 3.43; N, 28.56. Found (%): C, 57.42; H, 3.60;

N, 28.42.

3

+

.

C═O). MS m/z (relative intensity %): 248 (M +2, 1.23);

BAYOUMI ET AL.

15

4

.5 | 4,6‐Diamino‐1‐(3‐chloroquinoxalin‐2‐

yl)‐2‐oxo‐1,2‐dihydropyridine‐3‐carbonitrile

2b

4.8 | 4‐Amino‐1‐(3‐chloroquinoxalin‐2‐yl)‐

6‐hydroxy‐2‐oxo‐1,2‐dihydropyridine‐3‐

1

carbonitrile 13b

−

1

White powder, yield: (55%), m.p. >300°C. IR (KBr,

cm ): 3375 (NH₂); 3075 (CH‐aromatic); 2153

White powder, yield: (57%), m.p. >300°C. IR (KBr, cm ):

−

1

3394 (OH, NH ); 3050 (CH‐aromatic); 2151 (C≡N); 1658

(C═O); 1592 (C═N); 1454 (C═C); 770 (C―Cl). H NMR

(DMSO‐d ) δ: 2.00 (s, 2H, NH , D O exchangeable); 6.00

2

1

(

C≡N);1666 (C═O); 1593 (C═N); 1455 (C═C); 775

1

C―Cl). H NMR (DMSO‐d ) δ: 1.54 (s, 2H, pyridine

6

2

C ‐NH , D O exchangeable); 1.70 (s, 2H, pyridine C ‐

(s, 1H, pyridine C H); 7.36 to 7.47 (m, 4H, quinoxalin

6

2

4

5

NH , D O exchangeable); 4.50 (s, 1H, pyridine C ‐H);

C₅_,₆_,₇_,₈‐ H); 9.07 (s, 1H, OH, D O exchangeable). MS m/

z (relative intensity %): 315 (M +2, 11); 313 (M , 13);

2

3

2

+

.

+.

7

.06 to 7.15 (m, 4H, quinoxaline C

‐H). MS m/z (rel-

5,6,7,8

+

.

+.

ative intensity %): 314 (M +2, 2); 312 (M , 4); 77 (9);

229 (40); 139 (7); 119 (100). Anal. form: C H ClN O

5 2

14

8

7

0 (100); 54 (49). Anal. form: C H ClN O (312.05).

(313.04). Calcd. (%): C, 53.60; H, 2.57; N, 22.33. Found

(%): C, 53.83; H, 2.69; N, 22.60.

14

9

6

Calcd. (%): C, 53.77; H, 2.90; N, 26.87. Found (%): C,

3.89; H, 3.04; N, 27.12.

5

4

.9 | 3‐(2‐(4‐Hydroxybenzylidene)

hydrazineyl)quinoxalin‐2(1H)‐one 14a, 4‐

(2‐(3‐chloroquinoxalin‐2‐yl)

hydrazineylidene)methyl)phenol 14b, 3‐(2‐

thiophen‐2‐ylmethylene)hydrazineyl)

quinoxalin‐2(1H)‐one 14c and 2‐chloro‐3‐(2‐

(

4

.6 | 4‐Amino‐6‐hydroxy‐2‐oxo‐1‐(3‐

substituted‐quinoxalin‐2‐yl)‐1,2‐

dihydropyridine‐3‐carbonitrile 13a,b

(

(thiophen‐2‐ylmethylene)hydrazinyl)

An equimolar mixture of the cyanoacetamide 11a,b (1

mmol), ethyl cyanoacetate (0.11 g, 0.11 mL, 1 mmol)

was heated under reflux in dioxane (10 mL) containing

piperidine (0.5 mL) for 7 and 24 hours, respectively. The

reaction mixture was then concentrated, cooled to afford

precipitate that was collected, dried, and crystallized

from DMF and methanol to yield compound 13a,b,

respectively.

quinoxaline 14d

To a suspension of the hydrazinyl derivative 3a,b (1

mmol) in methanol (10 mL) containing glacial acetic

acid (4 mL) and dioxane (2 mL), 4‐hydroxy

benzaldehyde/thiophen‐2‐carboxaldehyde (1 mmol)

were added. The reaction mixture was then heated

under reflux for 9 hours, concentrated, allowed to cool

to form a precipitate that was crystallized from dioxane

to afford the derivatives 14a,c and from ethanol to

afford 14b,d.

4

3

.7 | 4‐Amino‐6‐hydroxy‐2‐oxo‐1‐(3‐oxo‐

,4‐dihydroquinoxalin‐2‐yl)‐1,2‐

dihydropyridine‐3‐carbonitrile 13a

4.10 | 3‐(2‐(4‐Hydroxybenzylidene)

hydrazineyl)quinoxalin‐2(1H)‐one 14a

Black powder, yield: (46%), m.p. >300°C. IR (KBr,

cm ): 3438, 3342 (OH‐tautomer, NH, NH ); 3049

−

1

Yellow crystals, yield: (85%), m.p. 251°C to 252°C. IR

2

−

1

(

CH‐aromatic); 2215 (C≡N); 1685 (C═O); 1476 (C═C).

H NMR (DMSO‐d ) δ: 2.48 (s, 2H, NH , D O exchange-

(KBr, cm ): 3463 (OH); 3122 (NH); 3012 (CH‐aromatic);

1

2909, 2847 (CH‐aliphatic); 1675 (C═O); 1589 (C═N); 829

6

2

1

able); 3.975 (s, 1H, CH‐pyridine); 7.043 to 7.115 (m, 4H,

quinoxaline C₅‐H); 11.88 (s, 2H, NH and OH, D O

exchangeable). C NMR (DMSO‐d ) δ: 70.15 (pyridine‐

(1, 4‐disubstituted phenyl). H NMR (DMSO‐d ) δ: 2.17

6

(s, 1H, NH, D O exchangeable); 6.82 to 6.8 (m, 4H,

,6,7,8

2

13

quinoxaline C₅_,₆_,₇_,₈‐H); 7.56 (d, 2H, J = 6 Hz, 4‐OH‐phe-

6

C ); 75.80 (pyridine‐C ); 115.58 (CN); 123.46, 126.06,

nyl‐C ‐ H); 7.69 (d, 2H, J = 6 Hz, 4‐OH‐phenyl‐C

‐

3

5

2,6

3,5

1

28.15, 129.88, 143.22, 155.63 (quinoxaline C , C , C ,

H); 8.29 (s, 1H, ―N═CH); 10.01 (s, 1H, quinoxaline

5

8

6

C , C , C ; respectively); 160.83 (quinoxaline C═O);

NH, D O exchangeable); 11.00 (s, 1H, phenyl OH, D O

7

8a

4a

2

13

1

62.67 (quinoxaline‐C₃); 163.53 (pyridine C═O);

exchangeable). C NMR (DMSO‐d ) δ: 111.16, 111.42

6

1

75.44 (C―OH); 177.91 (C―NH ). MS m/z (relative

(phenyl C , C ); 123.46, 123.95, 124.78, 125.74, 126.21,

145.20 (quinoxaline C , C , C , C , C , C ; respectively);

5 8 6 7 8a 4a

2

3

5

+

.

intensity %): 295 (M , 16); 217 (18); 162 (45); 106

(

100). Anal. form: C H N O (295.07). Calcd. (%): C,

129.14, 130.58, 131.00 (phenyl C , C , C ); 146.52

1 2 6

14

9

5

3

5

6.95; H, 3.07; N, 23.72. Found (%): C, 56.87; H, 3.29;

(CH=N); 160.17 (phenyl C ); 160.99 (C ‐quinoxaline);

4

3

N, 23.88.

165.72 (C═O). MS m/z (relative intensity %): 280

16

BAYOUMI ET AL.

+

.

(

M ,77); 200 (85); 129 (97); 105 (74); 42 (100). Anal. form:

4.13 | 2‐Chloro‐3‐(2‐(thiophen‐2‐

ylmethylene)hydrazinyl) quinoxaline 14d

C H N O (280.1). Calcd. (%): C, 64.28; H, 4.32; N,

1

5

12 4 2

1

9.99. Found (%): C, 64.45; H, 4.51; N, 20.08.

Reddish brown crystals, yield: (98%), m.p. 229°C to

−

1

2

30°C. IR (KBr, cm ): 3414, 3267 (NH); 3167, 3072

(

CH‐aromatic); 2969 (CH‐aliphatic); 1605, 1553 (C═N);

1

4

.11 | 4‐((2‐(3‐Chloroquinoxalin‐2‐yl)

1420 (C═C); 1031 (C―S―C). H NMR (DMSO‐d

7.18 to 7.27 (m, 3H, thiophen C3,4,5‐H); 7.63 to 8.03 (m,

H, quinoxaline C₅_,₆_,₇_,₈‐H); 9.64 (S, 1H, ―N═CH); 12.38

(s, 1H, ―NH, D O exchangeable). MS m/z (relative inten-

6

) δ:

hydrazineylidene)methyl) phenol 14b

4

Red crystals, yield: (95%), m.p. 150°C to 151°C. IR (KBr,

2

+.

−

1

+.

cm ): 3396 (br., OH); 3273 (NH); 3050 (CH‐aromatic);

606 (C═N);1435 (C═C); 827 (1,4‐disubstituted‐phenyl).

sity %): 290 (M +2, 6); 288 (M , 11); 267 (69); 119 (30);

1

70 (100). Anal. form: C13 ClN S (288.02). Calcd. (%): C,

54.07; H, 3.14; N, 19.40; S, 11.10. Found (%): C, 54.23; H,

3.40; N, 19.28; S, 11.23.

H

9

4

1

H NMR (DMSO‐d ) δ: 3.42 (s, 1H, NH, D O exchange-

6

2

able); 6.93 (d, 2H, J = 8HZ, 4‐hydroxy phenyl C ₂_,₆H);

.12 (t, 1H, J = 8 Hz, quinoxaline‐C ‐H); 7.20 (t, 1H, J

7

6

=

8 Hz, quinoxaline C ‐H); 7.64 (d, 2H, J = 8 Hz, 4‐

7

4

.14 | 2‐((2‐(3‐Substituted quinoxalin‐2‐yl)

hydroxy phenyl C ‐H); 7.79 (d, 2H, J = 8 Hz,

quinoxaline C ‐H); 9.11 (s, 1H, ―N═CH); 10.20 (s, 1H,

phenyl OH, D O exchangeable). C NMR (DMSO‐d₆)

3

hydrazinylidene) methyl)benzoic acid 14e,f

8

13

2

An equimolar mixture of the hydrazinyl derivative 3a,b (1

mmol) and 2‐carboxy benzaldehyde (0.15 g, 1 mmol) was

heated under reflux in methanol for 10 hours. The reac-

tion mixture was then concentrated, cooled, triturated

with ethanol to form a precipitate that was collected,

dried, and crystallized from ethanol to yield compound

14e and from DMF to afford compound 14f, respectively.

δ: 115.37, 116.34 (phenyl C , C ); 122.82, 123.03,

3

5

1

25.30, 125.70, 126.64, 128.52 (quinoxaline C , C , C ,

5 8 6

C , C , C ; respectively); 129.04, 130.20, (phenyl C ,

7

8a

4a

2

C ); 138.17 (CH=N side chain); 145.01 (C―Cl); 160.71

6

(

C1‐phenyl); 162.84 (phenyl C ); 163.90 (quinoxaline

4

+

.

C ). MS m/z (relative intensity %): 300 (M +2, 9);

2

3

+.

98 (M , 15); 276 (100); 219 (48); 115 (86). . Anal. form:

C H ClN O (298.06). Calcd. (%): C, 60.31; H, 3.71; N,

15

11

4

1

8.76. Found (%): C, 60.49; H, 3.83; N, 19.02.

4

.15 | 2‐((2‐(3‐Chloroquinoxalin‐2‐yl)

hydrazinylidene)methyl) benzoic acid 14e

Yellow crystals, yield: (59%), m.p. >300°C. IR (KBr,

4

.12 | 3‐(2‐(Thiophen‐2‐ylmethylene)

−1

cm ): 3412 (br, COOH); 3215 (NH); 3072 (CH‐aromatic);

hydrazineyl)quinoxalin‐2(1H)‐one 14c

1

2

906, 2847 (CH‐aliphatic); 1678 (C═O). H NMR (DMSO‐

d ) δ: 3.1 (s, 1H, NH, D O exchangeable); 7.06 to 7.20 (m,

6

2

Black crystals, yield: (85%), m.p. 110°C to 111°C. IR

5H, quinoxaline C₅_,₆_,₇_,₈and ‐N═CH); 7.34 (d, 1H, J = 6

−

1

(

1

KBr, cm ): 3456 (OH tautomer and NH); 3198, 3086

Hz, benzoic acid C ‐H); 7.52 (t, 1H, J = 6 Hz, benzoic acid

6

CH‐aromatic); 2910, 2846 (CH‐aliphatic); 1679 (C═O);

C ‐H); 7.66 (t, 1H, J = 6 Hz, benzoic acid C ‐H); 7.89 (d,

5

4

1

589 (C═N), 1037 (C―S―C). H NMR (DMSO‐d ) δ:

6

1

H, J = 6 Hz, benzoic acid, C ‐H); 12.00 (s, 1H, COOH,

3

7

.13 to 7.22 (m, 4H, quinoxaline C₅_,₆_,₇_,₈‐ H); 7.380

D O exchangeable); 12.38 (s, 1H, quinoxaline NH, D O

2

(

d, 1H, J = 6 Hz, thiophene C ‐H); 7.52 (d, 1H, J = 6

+.

3

exchangeable). MS m/z (relative intensity %): 308 (M ,

7.5); 289 (56.8); 160 (5); 104 (100); 76 (50). Anal. form:

C H N O (308.29). Calcd. (%): C, 62.33; H, 3.92; N,

Hz, thiophene C ‐H); 7.647 (t, 1H, J = 6 Hz,

5

1

thiophene‐C ‐H); 8.79 (s, 1H, N═CH); 11.23 (s, 1H,

4

16

12 4 3

quinoxaline C ‐NH, D O exchangeable); 12.39 (s, 1H,

3

2

18.17. Found (%): C, 62.51; H, 4.08; N, 18.29.

13

quinoxaline‐NH, D O exchangeable).

C

NMR

2

(

DMSO‐d ) δ: 123.08, 123.98, 125.12, 125.95, 126.07,

6

1

28.34, 128.77, 128.85, 129.12, 140.04 (quinoxaline C₅,

4.16 | 2‐((2‐(3‐Chloroquinoxalin‐2‐yl)

C , C , C , C , C and thiophene C₂_,₃_,₄_,₅‐H); 142.24

hydrazinylidene)methyl) benzoic acid 14f

8

6

7

8a

4a

(CH=N); 161.27 (quinoxaline C ); 162.95 (quinoxaline

3

+.

C═O). MS m/z (relative intensity %): 270 (M , 13);

68 (100); 206 (33); 104 (68.5); 77 (74). Anal. form:

C H N OS (270.31). Calcd. (%): C, 57.76; H, 3.73; N,

Yellowish red powder, yield: (80%), m.p. >300°C. IR

−

1

2

(KBr, cm ): 3400, 3163 (OH, NH); 3020 (CH‐aromatic);

2938 (CH‐aliphatic); 1675 (C═O); 1500 (C═N); 1471

13

10 4

1

2

0.73; S, 11.86. Found (%): C, 58.02; H, 3.84; N, 20.97;

(C═C). H NMR (DMSO‐d ) δ: 3.35 (s, 1H, NH, D O

6

2

S, 12.02.

exchangeable); 7.12 (t, 1H, J = 8 Hz, quinoxalin C ‐H);

6

BAYOUMI ET AL.

17

7

8

.13 (d, 1H, J = 8 Hz, quinoxaline C ‐H); 7.40 (d, 1H, J =

4.19 | 3‐(3‐Amino‐5‐oxo‐4,5‐dihydro‐1H‐

pyrazol‐1‐yl)quinoxalin‐2(1H)‐one 15a

5

Hz, quinoxaline C ‐H); 7.55 (t, 1H, J = 8 Hz,

8

quinoxaline C ‐H); 7.57 (t, 1H, J = 8 Hz, benzoic acid

7

C ‐H); 7.69 (t, 1H, J = 8 Hz, benzoic acid C ‐H); 7.91 (d,

Brown crystals, yield: (89%), m.p.: 149°C to 150°C. IR

5

4

−

1

H, J = 8 Hz, benzoic acid C ‐H); 8.36 (s, 1H, ‐N═CH);

(KBr, cm ): 3407 (OH‐tautomer, ―NH ) 3174 (―NH);

6

2

1

9

.22 (d, 1H, J = 8 Hz, benzoic acid C ‐H); 11.15 (s, 1H, ‐

1745, 1676 (two C═O); 1608 (C═N). H NMR (DMSO‐

3

COOH, D O exchangeable). MS m/z (relative intensity

d ) δ: 2.07 (s, 2H, ―NH , D O exchangeable); 2.66 (s,

2

6

2

+.

%): 328 (M +2, 6); 326 (M , 14); 272 (100); 257 (39);

2H, tautomeric CH ); 7.02 to 7.14 (m, 4H, quinoxaline

2

7

5 (65). Anal. form: C H ClN O (326.06). Calcd. (%):

C5,6,7,8‐H); 12.07 (s, 1H, quinoxaline tautomeric NH,

16

11

4 2

C, 58.82; H, 3.39; N, 17.15. Found (%): C, 59.11; H, 3.48;

N, 17.37.

D O exchangeable). MS m/z (relative intensity %): 244

2

+.

(M +1, 24); 243 (M , 26); 159 (100); 111 (85); 80 (87).

Anal. form: C H N O (243.08). Calcd. (%): C, 54.32; H,

11

9 5 2

3.73; N, 28.79. Found (%): C, 54.61; H, 3.84; N, 29.04.

4

.17 | Ethyl‐3‐(2‐(3‐Chloroquinoxalin‐2‐yl)

hydrazineylidene)‐butanoate 14g

4

.20 | 5‐Amino‐2‐(3‐chloroquinoxalin‐2‐

To a suspension of the hydrazinyl derivative 3b (0.19 g, 1

mmol) in absolute ethanol (15 mL), ethyl acetoacetate

yl)‐2,4‐dihydro‐3H‐pyrazol‐3‐one 15b

(

0.13 g, 0.13 mL, 1 mmol) was added. The reaction mix-

Black crystalline powder, yield: (69%), m.p. >300°C. IR

−

1

ture was then heated under reflux for 24 hours, concen-

trated, allowed to cool to form a precipitate that was

crystallized from ethanol to produce 2‐methylallyl propi-

onate derivative 14g. Brown powder, yield: (85%), m.p.

(

KBr, cm ): 3437 (NH ); 3109, 3041 (CH‐aromatic);

2

1

643 (C═O); 1551 (C═N); 1483, 1406 (C═C); 764

1

(

C―Cl). H NMR (DMSO‐d ) δ: 2.01 (s, 2H, NH , D O

6

2

exchangeable); 2.99 (s, 2H, tautomeric CH ); 7.409 (t,

2

−

1

>

300°C. IR (KBr, cm ): 3305 (NH); 3151, 3060 (CH‐aro-

1

H, J = 8 Hz, quinoxaline C ‐H); 7.42 (t, 1H, J = 8 Hz,

6

matic); 2992, 2933 (CH‐aliphatic); 1725 (C═O); 1602

quinoxaline C ‐H); 7.57 (d, 1H, J = 8 Hz, quinoxaline

7

1

(C═N). H NMR (DMSO‐d ) δ: 1.165 (t, 3H, J = 8 Hz,

6

C ‐H); 7.83 (d, 1H, J = 8 Hz, quinoxaline C ‐H). MS m/

5

8

+.

CH CH ); 1.190 (s, 3H, N═C―CH ); 2.271 (s, 2H,

2

3

z (relative intensity %): 263 (M +2, 33); 261 (M , 69);

N═C―CH ); 4.061 (q, 2H, J = 8 Hz, CH CH ); 5.80 (s,

2

3

222 (100); 180 (87); 100 (84). Anal. form: C H ClN O

11

8

5

NH, D2O exchangeable); 7.036 to 7.199 (m, 4H,

(

261.04). Calcd. (%): C, 50.49; H, 3.08; N, 26.76. Found

13

^q^uⁱⁿ^o^x^a^lⁱⁿ^e^C5,6,7,8^‐^H⁾^.

C NMR (DMSO‐d ) δ: 16.21

6

(%): C, 50.76; H, 3.17; N, 26.59.

(

N═C―CH ); 17.71 (CH CH ); 44.47 (N═C―CH );

3

2

3

2

6

1.51 (CH ―CH ); 125.91, 126.53, 126.65, 129.19,

2

3

1

33.21, 143.34 (quinoxaline C , C , C , C , C , C ;

4.21 | 3‐(3,5‐Dimethyl‐1H‐pyrazol‐1‐yl)

quinoxalin‐2(1H)‐one 15c and2‐Chloro‐3‐

(3,5‐dimethyl‐1H‐pyrazol‐1‐yl)quinoxaline

15d

5

8

6

7

8a

4a

respectively); 143.52 (C―Cl); 159.99 (N═C―CH₃);

61.16 (quinoxaline C ); 169.35 (COO). MS m/z (relative

1

3

+

.

+.

intensity %): 308 (M + 2, 8.65); 306 (M , 24.04); 259

79); 221 (68); 197 (80); 42 (100). Anal. form:

C H ClN O (306.09). Calcd. (%): C, 54.82; H, 4.93; N,

(

An equimolar mixture of the hydrazinyl derivative 3a,b (1

mmol) and acetylacetone (0.10 g, 0.10 mL, 1 mmol) was

heated under reflux in ethanol for 22 to 25 hours. The

reaction mixture was then concentrated and cooled at

room temperature, and the precipitate formed was col-

lected, dried, and crystallized from ethanol to produce

the pyrazole derivatives 15c,d.

14

15

4 2

1

8.26. Found (%): C, 55.14; H, 5.19; N, 17.97.

4

.18 | 3‐(3‐Amino‐5‐oxo‐4,5‐dihydro‐1H‐

pyrazol‐1‐yl)quinoxalin‐2(1H)‐one 15a and

5

dihydro‐3H‐pyrazol‐3‐one 15b

‐Amino‐2‐(3‐chloroquinoxalin‐2‐yl)‐2,4‐

To a suspension of the hydrazinyl derivative 3a and 3b (1

mmol) in methanol (15 mL), ethyl cyanoacetate (0.11 g,

4.22 | 3‐(3,5‐Dimethyl‐1H‐pyrazol‐1‐yl)

quinoxalin‐2(1H)‐one 15c

0

.11 mL, 1 mmol) and Na metal (0.02 g, 1 mmol) were

added. The reaction mixture was then heated under

reflux for 12 hours, concentrated, allowed to cool to form

a precipitate that was recrystallized from ethanol to

afford the oxopyrazole derivative 15a and from DMF to

afford 15b; respectively.

Brick red powder yield: (75%), m.p. 79°C to 80°C. IR

−

1

(KBr, cm ): 3568, 3450 (OH‐tautomer); 3182, 3031

(CH‐aromatic); 2969, 2914 (CH‐aliphatic); 1677 (C═O).

1

H NMR (DMSO‐d ) δ: 2.19 (s, 3H, C ‐pyrazole CH );

6

3

2.30 (s, 3H, C ‐pyrazole‐CH ); 6.09 (s, 1H, pyrazole C ‐

5

3

4

1

8

BAYOUMI ET AL.

+.

H); 7.35 to 7.4 (m, 2H, quinoxaline C₇_,₈H); 7.62 (t, 1H, J

6 Hz, quinoxaline C ‐H); 7.78 (d, 1H, J = 6 Hz,

m/z (relative intensity %): 262 (M +2, 14); 260 (M ,

=

20); 195 (24); 167 (33); 54 (100). Anal. form: C H ClN O

6

12

9

4

quinoxaline C ‐H); 12.87 (s, 1H, quinoxaline‐NH, D O

(260.68). Calcd. (%):C, 55.29; H, 3.48; N, 21.49. Found (%):

C, 55.53; H, 3.62; N, 21.75.

5

2

13

exchangeable). C NMR (DMSO‐d ) δ: 12.01, 13.81

6

(

2CH ); 107.70 (pyrazole C ); 123.47, 124.26, 128.79,

3 4

1

29.05. 130.78, 142.21 (quinoxaline C , C , C , C , C ,

5 8 6 7 8a

4

.25 | 2‐Chloro‐N′‐(3‐substituted‐

C ; respectively); 147.30 (pyrazole C ); 149.46 (pyrazole

C ); 161.27 (quinoxaline‐C ); 164.11 (quinoxaline C═O).

MS m/z (relative intensity %): 240 (M , 14); 211 (39);

4a

5

quinoxalin‐2‐yl)acetohydrazide 16a,b

3

+

.

To a well‐stirred solution of the hydrazinyl derivative 3a,

b (1 mmol) in dimethylformamide (5 mL), chloroacetyl

chloride (0.11 g, 0.08 mL, 1 mmol) was added dropwise

while stirring. The reaction mixture was then left to be

stirred overnight at room temperature, the obtained pre-

cipitate was filtered, washed with ethanol, dried, and

crystallized from DMF to yield the acetohydrazide deriv-

atives 16a,b.

1

98 (47); 121 (41.7); 44 (100). Anal. form: C H N O

13

12 4

(

240.1). Calcd. (%): C, 64.99; H, 5.03; N, 23.32. Found

%): C, 64.78; H, 5.24; N, 23.50.

4

.23 | 2‐Chloro‐3‐(3,5‐dimethyl‐1H‐

pyrazol‐1‐yl)quinoxaline 15d

Brick red powder yield: (57%), m.p. 115°C to 116°C. IR

−

1

(KBr, cm ): 3125, 3054 (CH‐aromatic); 2930 (CH‐ali-

1

phatic); 1568 (C═N); 1485, 1421 (C═C). H NMR

4.26 | 2‐Chloro‐N′‐(3‐oxo‐3,4‐

dihydroquinoxalin‐2‐yl)acetohydrazide 16a

(DMSO‐d ) δ: 2.04 (s, 3H, pyrazole C ‐CH ); 2.30 (s, 3H,

6

3

pyrazole C ‐CH ); 6.05 (s, 1H, pyrazole C ‐H); 7.99 (t,

5

3

4

Yellow powder, yield: (61%), m.p. 249°C to 250°C. IR

2

H, J = 8 HZ, quinoxaline C₆_,₇H); 8.17 (d, 1H, J =

−

1

(

2

(

KBr, cm ): 3437 (OH tautomer); 3039 (CH‐aromatic);

904 (CH‐aliphatic); 1680 (C═O); 1616 (C═C); 758

8

HZ, quinoxaline C ‐H); 8.18 (d, 1H, J = 8HZ,

5

13

quinoxaline C ‐H). C NMR (DMSO‐d ) δ: 11.89, 13.73

8

6

1

C―Cl). H NMR (DMSO‐d ) δ: 2.73 (s, 1H, NH―NH‐

(2CH ); 107.56 (pyrazole C ); 122.71, 123.93, 127.85,

6

3

4

CO, D O exchangeable); 5.57 (s, 2H, CH ); 7.36 to 7.53

1

28.95, 129.93, 140.71 (quinoxaline C , C , C , C , C ,

2

5

8

6

7

8a

(

m, 4H, quinoxaline C

‐H); 12.19 (s, 2H, OH and

C₄_aof; respectively); 141.93 (pyrazole C ‐); 142.85

5,6,7,8

13

5

NH, D O exchangeable). C NMR (DMSO‐d ) δ: 37.11

(

pyrazole C ); 149.59 (C―Cl); 155.19 (quinoxaline‐ C ).

2

6

3

+

.

CH ); 123.16, 123.83, 127.90, 128.62, 129.88, 145.71

MS m/z (relative intensity %): 260 (M +2, 26); 258

2

+.

quinoxaline C , C , C , C , C , C , respectively);

5 8 6 7 8a 4a

(M , 7); 207 (67); 129 (75); 89 (100). Anal. form:

1

60.02 (quinoxaline C ); 162.78 (quinoxaline C═O);

C H ClN (258.07). Calcd. (%): C, 55.29; H, 3.48; N,

3

13

11

4

65.75 (amidic C═O). MS m/z (relative intensity %): 254

2

1.49. Found (%): C, 55.58; H, 4.37; N, 21.89.

+.

(

M

+2, 8); 252 (M , 10.6); 157 (20); 105 (46.9); 44

(

4

2

100). Anal. form: C H ClN O (252.04). Calcd. (%): C,

7.54; H, 3.59; N, 22.18. Found (%): C, 47.78; H, 3.71; N,

2.45.

10

9

4

.24 | 2‐(3‐Chloroquinoxalin‐2‐yl)‐5‐

methyl‐2,4‐dihydro‐3H‐pyrazol‐3‐one 15e

To a suspension of the hydrazinyl derivative 3b (0.19 g, 1

mmol) in methanol (15 mL), ethyl acetoacetate (0.13 g,

4.27 | 2‐Chloro‐N′‐(3‐chloroquinoxalin‐2‐

yl)acetohydrazide; 16b

0

.13 mL, 1 mmol) and Na metal (0.02 g, 1 mmol) were

added. The reaction mixture was then heated under

reflux for 12 hours, concentrated, allowed to cool, tritu-

rated with ethanol to form a precipitate that was recrys-

tallized from DMF to afford the oxopyrazole derivative

Yellow crystals, yield: (76%), m.p. >300°C. IR (KBr,

cm ): 3416 (OH‐tautomer, NH); 3050 (CH‐aromatic);

−

1

2995, 2834 (CH‐aliphatic); 1628 (C═O); 1484 (C═C); 756

1

>

5e. White crystalline powder, yield: (71%), m.p.

(C―Cl). H NMR (DMSO‐d ) δ: 3.34 (s, 1H, NH―NH‐

6

−

1

300°C. IR (KBr, cm ): 3063 (CH‐aromatic); 2990,

CO, D O exchangeable); 5.66 (s, 2H, CH ); 7.75 to 7.84

2

1

2

912, 2855 (CH‐aliphatic); 1708 (C═O); 1619 (C═N). H

(m, 2H, quinoxaline C ‐ H); 8.33 (d, 1H, J = 8 Hz,

6,7

NMR (DMSO‐d ) δ: 1.243 (s, 3H, CH ); 1.579 (s, 2H,

quinoxaline C ‐H); 8.37 (d, 1H, J = 8 Hz, quinoxaline

6

3

8

13

CH ); 7.115 to 7.298 (m, 4H, quinoxaline C₅_,₆_,₇_,₈‐H).

C

C ‐H); 10.05 (s, 1H, amidic NH, D O exchangeable).

2

5

2

+

.

+.

NMR (DMSO‐d ) δ: 24.04 (CH ); 47.17 (CH ); 125.99,

MS m/z (relative intensity %): 274 (M +4, 2); 272 (M

+2, 24); 270 (M , 66); 101 (53); 89 (88); 75 (100). Anal.

form: C H Cl N O (270.01). Calcd. (%): C, 44.30; H,

6

3

2

+

.

1

26.57, 126.60, 129.09, 133.13, 143.34 (quinoxaline C₅,

C , C , C , C , C ; respectively); 143.92 (C―Cl); 159.78

8

6

7

8a

4a

10

8

2 4

(

C―CH ); 161.01 (quinoxaline C ); 170.23 (C═O). MS

2.97; N, 20.67. Found (%): C, 44.53; H, 3.14; N, 20.89.

3

BAYOUMI ET AL.

19

4

.28 | 3‐(2‐(2‐Oxo‐2‐phenylethyl)

heated under reflux in glacial acetic acid (20 mL) for 14

hours. The reaction mixture was then concentrated and

cooled to room temperature, and the precipitate formed

was collected, dried, and crystallized from ethanol to give

compound 16c and from DMF to give compound 16f,

respectively.

hydrazineyl)quinoxalin‐2(1H)‐one 16c and

2

1

‐(2‐(3‐chloroquinoxalin‐2‐yl)hydrazineyl)‐

‐phenylethan‐1‐one 16d

To a well‐stirred solution of the hydrazinyl derivatives 3a

and 3b (1 mmol) in dioxane (15 mL), phenacyl bromide

(0.2 g, 1 mmol) was added while stirring. The reaction

mixture was then left to be stirred for 2 hours at room

temperature, then refluxed for 12 hours, concentrated,

allowed to cool to form a precipitate that was washed

with ether and crystallized from dioxan to give compound

4.32 | 2‐(2‐(3‐Oxo‐3,4‐dihydroquinoxalin‐2‐

yl)hydrazine‐1‐carbonyl)benzoic acid 16e

1

6c and from ethanol to afford compound 16d,

Yellow powder, yield: (89%), m.p. >300°C. IR (KBr,

cm ): 3385 (br, OH and NH); 1733, 1677 (2 C═O). H

−

1

respectively.

NMR (DMSO‐d ) δ: 2.5 (1H, NH, D O exchangeable);

6

2

7

.20 to 7.46 (m, 4H, quinoxaline‐C₅_,₆_,₇_,₈‐H); 7.69 to 8.05

4

.29 | 3‐(2‐(2‐Oxo‐2‐phenylethyl)

(

m, 4H, benzoic acid C₃_,₄_,₅_,₆‐H); 11.99 (s, 1H, OH, D O

2

hydrazineyl)quinoxalin‐2(1H)‐one 16c

exchangeable); 12.59 (s, 2H, OH and NH, D O exchange-

able). C NMR (DMSO‐d ) δ: 123.60, 124.02, 124.32,

2

13

6

Yellow crystals, yield: (56%), m.p. 189°C to 190°C. IR

126.04, 126.18, 127.95, 129.51, 129.60, 129.89, 131.81,

−

1

(

KBr, cm ): 3405 (NH); 3100 (CH‐aromatic); 2984, 2913

CH‐aliphatic); 1693 (C═O). H NMR (DMSO‐d ) δ: 2.50

s, 2H, ―NH―NH―, D O exchangeable); 4.52 (s, 2H,

135.87, 144.71 (quinoxaline C , C , C , C , C , C and

5

8

6

7

8a

4a

1

6

phenyl ring); 161.99 (quinoxaline C₃); 162.99

2

(

quinoxaline C═O); 165.96 (amidic C═O); 169.19

CH ); 7.47 to 7.52 (m, 4H, quinoxaline C₅_,₆_,₇_,₈‐H);7.58 to

+.

2

(

COOH). MS m/z (relative intensity %): 324 (M , 12.7);

7

.68 (m, 3H, phenyl C₃_,₄_,₅‐H);8.08 (d, 1H, J = 8 Hz, phe-

289 (32); 239 (58.7); 197 (28.6); 104 (100). Anal. form:

nyl C ‐H); 8.14 (d, 1H, J = 8 Hz, phenyl C ‐H); 13.27 (s,

1

6

C H N O (324.29). Calcd. (%): C, 59.26; H, 3.73; N,

1

16

10 4 3

1

H, amidic NH, D O exchangeable). MS m/z (relative

2

7.28. Found (%): C, 59.60; H, 3.85; N, 17.45.

+

.

intensity %): 294 (M , 19); 276 (100); 205 (24); 164 (78);

05 (75). Anal. form: C H N O (294.11). Calcd. (%):

1

16

14 4 2

C, 65.30; H, 4.79; N, 19.04. Found (%): C, 65.49; H, 4.85;

N, 19.21.

4

.33 | 2‐(2‐(3‐Chloroquinoxalin‐2‐yl)

hydrazine‐1‐carbonyl)‐benzoic acid 16f

4

.30 | 2‐(2‐(3‐chloroquinoxalin‐2‐yl)

Brown powder, yield: (79%), m.p. >300°C. IR (KBr,

hydrazineyl)‐1‐phenylethan‐1‐one 16d

−

1

cm ): 3433 (br. OH, NH); 3130 (CH‐aromatic); 1715,

1

635 (2C═O); 1488, 1407 (C═C). H NMR (DMSO‐d ) δ:

6

Yellow crystals, yield: (63%), m.p. 194°C to 195°C. IR

−

1

3.34 (s, 1H, NH, D O exchangeable); 7.47 (d, 1H, J = 8

2

(

KBr, cm ): 3413 (NH); 3144 (CH‐aromatic); 1679

C═O); 1607, 1545 (C═N); 1482, 1402 (C═C); 753

C―Cl). H NMR (DMSO‐d ) δ: 2.51 (s, 1H, ―NH―CH ,

HZ, phenyl C ‐H); 7.57 (t, 1H, J = 8 Hz, phenyl C ‐H);

6

5

1

7.68 (t, 1H, J = 8 Hz, quinoxaline C ‐H); 7.87 (t, 2H, J

6

2

=

8 Hz, phenyl C ‐H and quinoxaline C ‐H); 8.05 (d,

4

7

D O exchangeable); 3.49 (s, 1H, NH―NH―CH , D O

exchangeable); 4.46 (s, 2H, CH ); 7.15 to 7.51 (m, 9H,

phenyl C₂_,₃_,₄_,₅_,₆‐H, quinoxaline C

tive intensity %): 314 (M +2, 2); 312 (M , 7); 272 (12);

2

1

H, J = 8 Hz, quinoxaline C ‐H); 8.20 (d, 1H, J = 8 Hz,

5

2

quinoxaline C ‐H); 8.32 (d, 1H, J = 8 Hz, phenyl C ‐H);

8

3

‐H). MS m/z (rela-

5,6,7,8

+

.

+.

11.00 (s, 1H, amidic‐NH, D O exchangeable); 11.59 (s,

2

13

1

H, ‐COOH, D O exchangeable). C NMR (DMSO‐d₆)

2

1

02 (26); 76 (100). Anal. form: C H ClN O (312.08).

16

13

4

δ: 124.41, 125.01, 125.59, 125.86, 127.70, 127.91

Calcd. (%): C, 61.44; H, 4.19; N, 17.91. Found (%): C,

1.72; H, 4.28; N, 18.04.

(

quinoxaline‐ C , C , C , C , C , C ; respectively);

5

8

6

7

8a

4a

6

1

29.88, 131.02, 133.04, 135.94 (phenyl ‐C₁_,₂_,₃_,₄_,₅_,₆);

38.00 (C‐CONH); 144.72 (C―COOH); 148.89 (C―Cl);

4

.31 | 2‐(2‐(3‐Substituted‐2‐yl)hydrazine‐1‐

162.31 (quinoxaline C

3

); 166.03 (C═O); 169.43 (COOH).

+.

carbonyl)benzoic acid 16e and 16f

MS m/z (relative intensity %): 344 (M + 2, 100); 342

+.

(

M , 5); 299 (70); 102 (24). Anal. form: C H ClN O

16 11 4 3

An equimolar mixture of the hydrazinyl derivative 3a,b (1

mmol) and phthalic anhydride (0.15 g, 1 mmol) was

(342.05). Calcd. (%): C, 56.07; H, 3.23; N, 16.35. Found

(%) C, 56.38; H, 3.49; N, 16.46.

20

BAYOUMI ET AL.

4

.34 | 2‐(Substituted‐2‐yl)hydrazine‐1‐

REFERENCES AND NOTES

carboximidamide 16 g,h

[1] U. Natarajan, I. Kaliappan, N. K. Singh, Der Pharma Chemica

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A mixture of the hydrazinyl derivatives 3a,b (1 mmol)

and cyanamide (0.08 g, 2 mmol) was heated under

reflux in absolute ethanol (15 mL) acidified with conc.

HCl (5 drops) for 12 h. The reaction mixture was then

concentrated, allowed to attain room temperature, and

the precipitate formed was collected, dried, and crystal-

lized from DMF to produce the guanidine derivative 16g

and from ethanol to afford the compound 16h,

respectively.

[

2] N. Umarani, K. Ilango, Int J Pharm Sci Rev Res 2010, 2, 24.

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5] V. Kotra, K. Pradeep, R. Vasanthi, Der Pharma Chemica 2013,

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[

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6] E. Elkaeed, A. Ghiaty, A. El‐Morsy, K. El‐Gamal, H. Sakr,

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8] R. Padma, S. Guhanathan, Pelagia Research Library‐Der

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4.35 | 2‐(3‐Oxo‐3,4‐dihydroquinoxalin‐2‐yl)

hydrazine‐1‐carboximidamide 16g

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Brick red powder yield: (37%), m.p. >300°C. Found (%):

C, 49.35; H, 4.80; N, 38.79. IR (KBr, cm ): 3429 (OH‐

[

10] P. K. Dubey, V. S. H. Krishnan, K. S. Chowdary, Indian J Chem

−

1

2000, 39B, 329.

tautomer); 3318 to 3370 (―NH , 3‐NH); 3115, 3042

[11] D. R. Romer, J Heterocyclic Chem 2009, 46, 317.

2

1

(CH‐aromatic); 1666 (C═O); 1615 (C═N). H NMR

DMSO‐d ) δ: 2.50 (s, 4H, ―NH and NH―NH, D O

[12] C. Chen, J. Chen, H. Gu, N. Bao, H. Dai, Molecules 2017, 22,

(

1126, 1.

6

2

exchangeable); 6.22 (s, 1H, ―C═NH, D O exchange-

[13] A. A. Fadda, S. Bondock, R. Rabie, H. A. Etman, Turk J Chem

2008, 32, 259.

2

able); 7.02 to 7.17 (m, 4H, quinoxaline C₅_,₆_,₇_,₈‐H);

13

1

1.96 (s, 1H, quinoxaline NH, D O exchangeable).

C

[14] A. A. Farag, Der Pharma Chemica 2015, 7, 130.

2

NMR (DMSO‐d ) δ: 123.43, 124.66, 125.16, 129.29,

[15] E. S. Darwish, K. A. Atia, A. M. Farag, Heterocycles 2014, 89,

6

1

30.88, 148.95 (quinoxaline C , C , C , C , C , C ,

1393.

5

8

6

7

8a

4a

respectively); 161.45 (quinoxaline C ); 163.05 (C (NH)

[16] S. A. Galal, A. S. Abdelsamie, H. Tokuda, N. Suzuki, A. Lida,

M. M. El‐Hefnawi, R. A. Ramadan, M. H. E. Atta, H. I. El

Diwani, Eur J Med Chem 2011, 46, 327.

3

NH ); 163.93 (quinoxaline C═O). MS m/z (relative

2

+

.

+.

intensity %): 219 (M +1, 13); 218 (M , 23); 134 (71);

06 (100); 76 (99). Anal. form: C H N O (218.09).

[

17] S. Parraa, F. Laurentb, G. Subraa, C. D. Masquefaa, V.

Benezecha, J. R. Fabreguettesa, J. P. Vidalc, T. Pocockd, K.

Elliottd, R. Smalld, R. Escalea, A. Michelb, J. P. Chapata, P.

A. Bonneta, Eur J Med Chem 2001, 36, 255.

1

9

10 6

Calcd. (%): C, 49.54; H, 4.62; N, 38.51.

[

18] H. Saikachi, S. Tagami, Chem Pharm Bull 1961, 9, 941.

4

1

.36 | (3‐Chloroquinoxalin‐2‐yl)hydrazine‐

‐carboximidamide 16h

19] X. K. Liu, L. X. Ma, Z. Y. Wei, X. Cui, S. Zhan, X. M. Yin, H. R.

Piao, Molecules 2017, 22, 273, 1.

[

20] A. H. R. Betrow, K. M. Hamza, R. M. Tarhoun, Univ Bulletin

Red powder yield: (51%), m.p. 159°C to 160°C. Anal.

form: C H ClN (236.06). Calcd. (%): C, 45.68; H, 3.83;

2013, 15.

9

6

[

21] F. A. Yassin, J Microbiol Antimicrob 2010, 2, 93.

N, 35.51. Found (%): C, 46.01; H, 3.97; N, 35.80. IR

−

1

[22] Z. M. Nofal, H. H. Fahmy, E. S. Zarea, W. El‐Eraky, Acta Pol

Pharm 2011, 68, 507.

(

1

KBr, cm ): 3369 (NH, NH ); 3152 (CH‐aromatic);

2

1

625, 1565 (C═N); 1474 (C═C); 749 (C―Cl). H NMR

[

23] L. J. Hu, Z. J. Zhan, M. Lei, L. H. Hu, Arkivoc 2013, 189.

(

DMSO‐d ) δ: 1.04 (s, 1H, NH―C═NH, D O exchange-

6

2

[

24] M. H. Ashokbhai, P. J. Merambhai, P. K. Narbherambhai, K. K.

able); 1.55 (s, 2H, NH , D O exchangeable); 4.72 (s, 1H,

2

Kapuriya, P. K. Patel, Arch Appl Sci 2014, 6, 74.

NH―NH‐C (NH), D O exchangeable); 5.30 (s, 1H,

2

[25] T. Singh, S. Sharma, V. K. Srivastava, Indian J Chem B 2006, 45,

―

C═NH, D O exchangeable); 7.02 to 7.69 (m, 4H,

2

1557.

quinoxaline C

‐H). MS m/z (relative intensity %):

5,6,7,8

+.

[26] S. M. Mosaad, K. I. Mohammed, M. A. Ahmed, S. G. Abdel‐

Hamide, J Biol Sci 2004, 4, 504.

2

38 (M +2, 1.5); 236 (M , 40); 186 (38); 171 (100); 62

(60).

[

27] W. A. Bayoumi, A. M. Barghash, M. M. Gineinah, M. A.

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How to cite this article: Bayoumi AH, Ghiaty

AH, Abd El‐Gilil SM, Husseiny EM, Ebrahim MA.

Exploration of quinoxaline derivatives as

antimicrobial and anticancer agents. J Heterocyclic

Chem. 2019;1–21. https://doi.org/10.1002/jhet.3716

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Exploration of quinoxaline derivatives as antimicrobial and anticancer agents

DOI: 10.1002/jhet.3716

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