Synthesis and characterization of N′-(11H-indeno[1,2-b]quinoxalin-11-ylidene)benzohydrazonamides as potential antimicrobial agents

Article abstract of DOI:10.1080/00397911.2020.1786122

A series of new N′-(11H-indeno[1,2-b]quinoxalin-11-ylidene)benzohydrazonamides 3a–3j was synthesized in excellent yields from the reaction of N³-substituted benzohydrazonamides 1 and 2-(11H-indeno[1,2-b]quinoxalin-11-ylidene)malononitrile 2 in

Full text of DOI:10.1080/00397911.2020.1786122

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Synthesis and characterization of
N′-(11H-indeno[1,2-b]quinoxalin-11-
ylidene)benzohydrazonamides as potential
antimicrobial agents
Mohsen A.-M. Gomaa, Momein H. El-Katatny & Huda A. Ali
To cite this article: Mohsen A.-M. Gomaa, Momein H. El-Katatny & Huda A. Ali (2020): Synthesis
and characterization of N′-(11H-indeno[1,2-b]quinoxalin-11-ylidene)benzohydrazonamides as
potential antimicrobial agents, Synthetic Communications
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https://doi.org/10.1080/00397911.2020.1786122
Synthesis and characterization of N0-(11H-indeno[1,2-
b]quinoxalin-11-ylidene)benzohydrazonamides as potential
antimicrobial agents
Mohsen A.-M. Gomaaa , Momein H. El-Katatnyb, and Huda A. Alia
b
aFaculty of Science, Department of Chemistry, Minia University, El-Minia, Egypt; Faculty of Science,
Department of Botany, Minia University, El-Minia, Egypt
ABSTRACT
ARTICLE HISTORY
Received 19 March 2020
A series of new N0-(11H-indeno[1,2-b]quinoxalin-11-ylidene)benzohydra-
zonamides 3a–3j was synthesized in excellent yields from the reaction
of N3-substituted benzohydrazonamides 1 and 2-(11H-indeno[1,2-b]qui-
KEYWORDS
noxalin-11-ylidene)malononitrile
2
in dichloromethane or with
Antimicrobial activity; 11H-
indeno[1,2-b]quinoxalin-11-
one; 2-(11H-indeno[1,2-
b]quinoxalin-11-ylidene)ma-
lononitrile; N0-(11H-
indeno[1,2-b]quinoxalin-11-
ylidene)benzohy-
11H-indeno[1,2-b]quinoxalin-11-one 4 in ethyl acetate at ambient tem-
perature. The new compounds have been characterized and screened
for biological activity. Some of them showed significant antibacterial
and antifungal activities. In particular, compounds 3c and 3e showed
interesting activities as antibacterial agents while compounds 3a 3c, 3e,
3g, and 3i showed high antifungal activities.
drazonamide
GRAPHICAL ABSTRACT
Introduction
Quinoxalines are an important class of benzoheterocycles which has received much atten-
tion in recent years owing to their both biological properties and pharmaceutical applica-
tions. These derivatives are particularly interesting since some of them showed anti-HIV
activity,[1,2] antimicrobial,[3–11] anticancer,[12–26] antimalarial,[27–32] anti-inflamma-
tory,[33,34] antinociceptive,[35–37] antitubercular,[38–40] anthelmintic,[41,42] antidiabetic,[43]
and they constitute useful intermediates in organic synthesis.
Besides this, indenoquinoxaline derivatives are important classes of nitrogen-contain-
ing heterocycles and have attracted attention because of their applications in the synthe-
sis of organic semiconductors.[44,45]
CONTACT Mohsen A.-M. Gomaa
magomaa@mu.edu.eg
Department of Chemistry, Minia University, El-Minia
61519, Egypt.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

2
M. A.-M. GOMAA ET AL.
11-Indeno[1,2-b]quinoxalin-2-one is widely used for the preparation of diverse
derivatives exhibiting a wide range of biological activity. Its oxime is a noncytotoxic
inhibitor of inflammatory cytokine and the production of nitrogen monoxide.[46] Schiff
bases obtained from the 11-indeno[1,2-b]quinoxalin-2-one are highly cytotoxic and
possess antiviral activity.[47] Also, benzohydrazides of 11-indeno[1,2-b]quinoxalin-2-
one were reported as a-glucosidase inhibitors.[48]
N-Phenylhydrazonamides (N-phenylamidrazones) provide a highly variable source for
the synthesis of nitrogen-containing heterocycles.[49] Moreover, they exhibit a great variety
of biological activities, among which are corticotrophin-releasing factor receptor antagonists,
insecticides, or sphingosine-1-phosphate receptor 3 (S1P3) antagonists as well.[50–52]
Recently we reported a very simple practical method for the synthesis of new (isatin-3-ylide-
ne)benzohydrazonamide derivatives in eco-friendly procedures. The antibacterial screening
results of these products showed that the tested compounds have apparent broad-spectrum
antibacterial activities against the Gram-positive and Gram-negative bacteria.[53]
Figure 1. Design of N0-(11H-indeno[1,2-b]quinoxalin-11-ylidene)benzohydrazonamides.

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3
In light of these findings, we proposed that combination of the pharmacophoric ele-
ments 11H-indeno[1,2-b]quinoxaline derivatives and benzohydrazonamides in a simple
chemical framework as N0-(11H-indeno[1,2-b]quinoxalin-11-ylidene)benzohydrazonamide
derivatives (Fig. 1) and investigation of their antimicrobial activity will be worthwhile.
Hence, the present study aims to synthesize a series of N0-(11H-indeno[1,2-b]quinoxalin-
11 ylidene)benzohydrazonamides and evaluate their potential as antimicrobial agents.
Results and discussion
Chemistry
As a part of our ongoing research programs in the area of heterocyclic compounds con-
taining nitrogen, definitely benzohydrazonamides (amidrazones)[53–56] herein, we report
novel procedures for the synthesis of new indenoquinoxaline benzohydrazonamide
derivatives and evaluation of their antimicrobial activity. As a result of this research
program, and for the purpose of obtaining new and more potent antibiotic compounds
that can improve the current chemotherapeutic treatments, we have synthesized and
evaluated 10 new N0-(11H-indeno[1,2-b]quinoxalin-11-ylidene)benzohydrazonamides.
Thus when we reacted benzohydrazonamide 1a–1j with 2-(11H-indeno[1,2-b]quinoxa-
lin-11-ylidene)malononitrile (2) in dichloromethane (DCM), we have obtained a deep yel-
low precipitate of hydrazonamides 3a–3j with excellent yield (88–95%) (Scheme 1 and
Table 1).
The release of the malononitrile molecule from the above reaction prompted us to
synthesize the target product 3 directly from the reaction of benzohydrazonamide 1
Scheme 1. Reagents and conditions: (i) DMSO, 300 W microwave irradiation (125–130 ꢀC), 1–3 min.
(ii) DCM, reflux, 2–3 h.
Table 1. N0-(11H-indeno[1,2-b]quinoxalin-11-ylidene)benzohydrazonamides 3 produced via Scheme 1.
S no.
R
1a–1j
3a–3j
Yield of 3 (%)
1
2
3
4
5
6
7
8
9
H
1a
1b
1c
1d
1e
1f
1g
1h
1i
3a
3b
3c
3d
3e
3f
3g
3h
3i
90
91
85
84
89
89
86
90
86
91
4-CH3
4-CH3O
4-Br
4-NO2
4-Cl
2-CH3
2-Cl
3-CH3
3-Cl
10
1j
3j

4
M. A.-M. GOMAA ET AL.
Scheme 2. Reagents and conditions: (i) ethanol, reflux, 5 h. (ii) ethyl acetate, 2 h.
Table 2. N0-(11H-indeno[1,2-b]quinoxalin-11-ylidene)benzohydrazonamides 3 produced via Scheme 2.
S no.
R
1a–1j
3a–3j
Yield of 3 (%)
1
2
3
4
5
6
7
8
9
H
1a
1b
1c
1d
1e
1f
1g
1h
1i
3a
3b
3c
3d
3e
3f
3g
3h
3i
94
95
88
84
92
93
89
92
89
90
4-CH3
4-CH3O
4-Br
4-NO2
4-Cl
2-CH3
2-Cl
3-CH3
3-Cl
10
1j
3j
Scheme 3. Rationale for the synthesis of N0-(11H-indeno[1,2-b]quinoxalin-11-ylidene)benzohydrazona-
mide 3 from 1 and 2.

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SYNTHETIC COMMUNICATIONSV
5
with 4. Accordingly, we reacted 11H-indeno[1,2-b]quinoxalin-11-one 4 with the candi-
date benzohydrazonamide 1a–1j in ethyl acetate at room temperature to obtain the cor-
responding hydrazonamides3a–3j with excellent yield (85–92%) via a condensation
reaction, see Scheme 2 and Table 2.
Comparison of the spectral data of both of products obtained from the reaction of
1a–1j with 3, or 4, proved unambiguously the agreement of the results of identification
of both of them, that is, the product 3, (obtained from two different pathways) see
Schemes 1 and 2.
The structures of obtained N0-(11H-indeno[1,2-b]quinoxalin-11-ylidene)benzo-hydra-
zonamide derivatives 3a–3j were established on the basis of IR, high-resolution mass
1
spectra (HRMS), H and 13C NMR spectroscopy.
Scheme 4. Rationale for the synthesis of N0-(11H-indeno[1,2-b]quinoxalin-11-ylidene)benzohydrazona-
mide 3 from 1 and 4.

6
M. A.-M. GOMAA ET AL.
Thus the structural assignment of 3a–3j is based on the following data: In their 13C
NMR spectra, products 3a–3j showed low-intensity signals at the low field between
1
d ¼ 153.73–161.90 ppm, which were assigned to the imine (C ¼ N) groups. In their H
NMR spectra, characteristic signals at d ¼ 8.16–9.96 ppm were assigned to the secondary
amino group proton. IR absorption peaks for NH groups at ꢀmax ¼ 3296–3251 cmꢁ1
along with bands at ꢀmax ¼ 1585–1602 cmꢁ1 corresponding to the imine (C ¼ N) were
assigned. The mass spectra of compounds 3a–3j showed the molecular ion peaks as the
base peaks. For example, the HRMS spectra of 3a confirmed the molecular formula as
m/z calculated for C28H19N5 [M]þ 425.1640; found: 425.1631; for more details see
Experimental section. Thus these results support the structure of compounds 3a–3j.
The formation of compounds 3a–3j can be rationalized on the basis of extrusion of a
dicyanomethylene molecule from the adduct 5 (Scheme 3),[53,55] or via a direct conden-
sation of 1a–1j and 4 with liberation a molecule of water affording the hydrazonamide
3 as depicted in (Scheme 4).
In vitro antimicrobial activity
All of the prepared compounds were screened for their in vitro antimicrobial activity by
using agar disk diffusion assay. The microorganisms used for the antimicrobial study
included two phytopathogenic fungi for tomato (Aspergillus flavus and Fusarium oxyspo-
rum), that reported previously[57,58] and four human pathogenic bacteria (Bacillus cereus,
Staphylococcus aureus, Serratia marcescens, and Pseudomonas aeruginosa). The pathogenic
bacteria were reported as food-borne diseases[59] and were known as important human
pathogens for ventilator-associated pneumonia.[60] The antimicrobial activities of the com-
pounds were assessed by measuring the diameter of the inhibition clear zone, as shown in
Table 3. Among the synthesized compounds, 3c and 3e were found to be the most
Table 3. Antimicrobial activity of N0-(11H-indeno[1,2-b]quinoxalin-11-ylidene)benzo-hydrazonamide 3a–3j.
Antimicrobial activity by measuring inhibition clear zone size (mm)
Gram positive bacteria
Grame negative bacteria
Fungi
Fusarium
Staphylococcus
Pseudomonas
aeruginosa
Serratia
marcescens
Aspergillus
flavus
Compound Name
Bacillus cereus
aureus
oxysporum
3a
3b
3c
3d
3e
3f
3g
3h
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
þ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
þ
þþþ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
þþ
ꢁ
þþþ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
þþþþ
ꢁ
ꢁ
ꢁ
ꢁ
3i
3j
ꢁ
ꢁ
ꢁ
þ
ꢁ
ꢁ
ꢁ
ꢁ
Standard1 (Amikin)
Standard2
(Augmentin)
Standard 3
(Fluconazole)
DCM
þþþ
ꢁ
þþþþ
þþþ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
þþþþ
ꢁ
þþþþ
ꢁ
Key to symbols: inactive ¼ ꢁ (inhibition zone <2 mm); slightly active ¼ þ (inhibition zone 3–5 mm); moderately active ¼
þþ (inhibition zone 6–10mm); highly active ¼ þþþ (inhibition zone 11–18 mm); severe ¼ þþþþ (inhibition >18).

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SYNTHETIC COMMUNICATIONSV
7
promising candidates against (Serratia marcescens) antibacterial agents compared with anti-
biotics like Amikin and Augmentin. Most of the tested compounds have apparent broad-
spectrum antifungal activities against the tested fungi (Fusarium oxysporum) compared with
antifungal like Fluconazole. The solvent control did not show any antibacterial activity.
Conclusion
Novel N0-(11H-indeno[1,2-b]quinoxalin-11-ylidene)benzohydrazonamides 3a–3j were syn-
thesized by canonical methods using easily available starting materials. The synthesized
compounds were evaluated for their antimicrobial activity. Among the compounds tested,
3c and 3e were found to be the most promising candidates against (Serratia marcescens)
as antibacterial agents. Most of the tested compounds have apparent broad-spectrum
antifungal activities against the tested fungi (Fusarium oxysporum).
Experimental
Chemistry
General
Uncorrected melting points (mps) were determined on a Griffin & George apparatus.
Infrared (IR) spectra (KBr) were recorded on a Bruker Vector 22 FTIR instrument. The
1
400 MHz H NMR and 100 MHz 13C NMR spectra were observed on a Bruker Avance
MA 400 spectrometer. Mass spectra (70 eV, electron-impact mode) were recorded by
(fast atom bombardment-mass spectrometry (FAB-MS) on a Finnigan MAT 95.
High-resolution mass spectroscopy (HRMS) spectra were obtained with a Waters
Q-TOF Premier (ESI) spectrometer.
The original spectra are provided as Supporting Information.
Starting materials
N3-substituted benzamidrazones[61] 1a–1j, 2-(11H-indeno[1,2-b]quinoxalin-11-ylidene)-
malononitrile[62] (2) and 11H-indeno[1,2-b]quinoxalin-11-one[63] (4) were prepared
according to the literature procedures. Ninhydrin and o-phenylenediamine were
obtained from Sigma-Aldrich and used as received. Ethyl acetate was purified according
to the literature.[64]
Synthesis of N0-(11H-indeno[1,2-b]quinoxalin-11-ylidene)benzohydrazonamide
Method A: An appropriate amounts of ninhydrin (1 mmol), phenylenediamine
(1 mmol) and malononitrile (1.2 mmol) were wetted with 2–3 drops of DMSO, mixed
thoroughly, put in an open vessel and exposed to 300 W microwave irradiation for
3 min in a three-step mode with interval (1 min–30s–1min). Then the reaction mixture
was allowed to cool down, 20 mL water was added, and the resulting solid 2 was filtered
off, washed with 20 mL warm water, and recrystallized from ethanol/
chloroform.[62]Thus a solution of 2-(11H-indeno[1,2-b]quinoxalin-11-ylidene)malononi-
trile (2) (0.25 mmole) (5.0 mL) was added to a solution of benzohydrazonamide (1a–1j)

8
M. A.-M. GOMAA ET AL.
(0.25 mmole) in methylene chloride (5.0 mL). Refluxing for 1–2 h at 38 ꢀC the color con-
verted from yellow into a deep yellow a precipitate (3a–3j) was formed after cooling,
dried, and recrystallized from ethyl acetate.
Method B: A solution containing 1,2-phenylenediamines (1.0 mmol) and ninhydrine
(1.0 equiv.) in ethanol (10 mL) was stirred at 70 ꢀC for 5 h. After the reaction was com-
pleted, the solution was diluted with ethanol (10 mL) and stirred in an ice bath for
30 min. The resultant solid 4 was filtrated, washed with cold ethanol (10 mL), and
recrystallized from ethanol to give pure 11H-indeno[1,2-b]quinoxalin-11-one (4).[63]
Thus 11H-indeno[1,2-b]quinoxalin-11-one (4) (0.25 mmole) was dissolved in ethyl acet-
ate (3.0 mL) then added to a solution of benzohydrazonamide (1a–1j) (0.25 mmole) in
ethyl acetate (3.0 mL), after addition with stirring the color converted into yellow.
Finally, a deep yellow precipitate (3a–3j) is formed after 2 h which is filtered off, dried,
and recrystallized from ethyl acetate.
N0-(11H-Indeno[1,2-b]quinoxalin-11-ylidene)-N-phenylbenzohydrazonamide (3a)
Yellow powder; yield 96 mg (90%)a, 101 mg (94%)b; mp 229–232 ꢀC; IR (KBr) (ꢀmax
1
cmꢁ1): 3220 (NH), 1625 (C ¼ N), 1592 (C ¼ C); H NMR (400 MHz, CDCl3): d ¼ 6.86
(s, 2H, Ar-H), 6.86 (s, 1H, Ar-H), 7.11 (m, 2H, Ar-H), 7.34 (m, 5H, Ar-H), 7.64 (m,
4H, Ar-H), 8.05 (d, 1H, J ¼ 6.1 Hz, Ar-H), 8.12 (m, 2H, Ar-H), 8.84 (m, 1H, Ar-H),
9.11 (br, 1H, NH); 13C NMR (100 MHz, CDCl3): d ¼ 121.92, 123.84, 124.45, 127.82,
128.37, 128.42, 128.83, 129.26, 129.41, 128.63, 129.69, 130.04, 130.19, 130.29, 130.52,
131.54, 131.85, 133.03, 135.18, 137.30, 139.51, 142.10, 142.64, 151.72, 152.17, 154.32,
160.76. HRMS (ESI) m/z calcd. for C28H19N5 [M]þ: 425.1631; found: 425.1640.
a. Yield via method A
b. Yield via method B
Antimicrobial activity
In vitro antimicrobial activity-screening tests of the products 3a–3j
In this experiment, the antibacterial and antifungal activity of 10 compounds that were
designated as 3a–3j were investigated. The microorganisms used for the antimicrobial
study included two pathogenic fungi to tomato (Aspergillus flavus and Fusarium oxyspo-
rum), and four human pathogenic bacteria, two Gram-positive bacteria (Bacillus cereus
and Staphylococcus aureus), and two Gram-negative bacteria (Pseudomonas aeruginosa
and Serratia marcescens). The pathogenic bacteria were tested as food-borne disease,
and as an important human pathogen. All microorganisms were obtained from the cul-
ture collection of Microbial Repository of Botany and Microbiology MRBM,
Department of Botany and Microbiology, Faculty of Science, Minia University, El-
Minia, Egypt. In the same test, 40 lg from the powder of each compound were dis-
solved in 40.0 lL methylene chloride. The disk diffusion method was used to assay the
antimicrobial activity.[65] Disks with 5.0 mm diameter were prepared from Whatman’s
No. 3 filter paper and they were sterilized by autoclaving. The disk that was assigned to
each compound was immersed in the filter-sterilized (filter 0.22 lL) solutions of tested
compounds individually. Each of the bacterial and fungal strains was then inoculated on

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SYNTHETIC COMMUNICATIONSV
9
nutrient agar and PDA plates, respectively, and spread by a sterile glass rod. Plates were
left for about 5.0 min for the agar medium to absorb extra moisture. Assigned disks
were then placed carefully over the agar medium in the center for each microbe and
incubation was done at 37 ꢀC for 24 h for bacteria and at 30 ꢀC for 72 h for fungi. The
antimicrobial activity was measured by determining the size of the inhibition clear zone
(ICZ) in mm. Amikine, Augmentin and Fluconazole as well as methylene chloride were
used as controls.
Full experimental details and spectral data of the synthesized compounds can be
accessed on the publisher’s website.
Acknowledgments
Prof. Mohsen A.-M. Gomaa is deeply indebted to the Deutsche Forschungsgemeinschaft (DFG)
for awarding DFG fellowship. Thanks are also due to Prof. Dr. Georg Manolikakes at
Fachbereich Organische Chemie, TU Kaiserslautern, Kaiserslautern, for measuring NMR and
HRMS spectra.
ORCID
Mohsen A.-M. Gomaa
http://orcid.org/0000-0002-2603-1759
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