Design, synthesis, and antimicrobial evaluation of some nifuroxazide analogs against nosocomial infection

Article abstract of DOI:10.1002/jhet.3891

A series of 10 p-substitutedbenzoylmethylene hydrazide derivatives 4a-j were synthesized by protecting carboxylic group of 4-hydroxybenzoic acid using methanol and sulfuric acid than reacting it with hydrazide to form 4-hydroxybenzohydrazide followed by reacting with a variety of aldehydes and evaluated for their activity against nosocomial infection. All the synthesized compounds were characterized by Fourier-transform infrared (FT-IR), ¹H nuclear magnetic resonance (NMR), and mass spectral data. The in vitro antimicrobial potential of synthesized compounds was estimated against prominent strains of nosocomial pathogens (Staphylococcus aureus, Escherichia coli, and Aspergillus niger). The antimicrobial evaluation revealed compounds 4b, 4c, 4d, 4e, 4f, and 4j to be the most active compounds of the series with IC₅₀ value for antibacterial in the range 0.39 to 0.75 μM/mL. Furthermore, the in vitro cytotoxic potential of the compounds was appraised by hemolytic assay. The results showed that some of the synthesized compounds exhibited marked activity.

Full text of DOI:10.1002/jhet.3891

Received: 20 May 2019
DOI: 10.1002/jhet.3891
Revised: 17 December 2019
Accepted: 22 December 2019
A R T I C L E
Design, synthesis, and antimicrobial evaluation of some
nifuroxazide analogs against nosocomial infection
Deepak K. Dwivedi1,2
Ram Kishore Agrawal1
| Adarsh Sahu1 | Sachin J. Dighade2
|
1Department of Pharmaceutical Sciences,
Dr. Harisingh Gour Central University,
Sagar, India
Abstract
A series of 10 p-substitutedbenzoylmethylene hydrazide derivatives 4a-j were
synthesized by protecting carboxylic group of 4-hydroxybenzoic acid using
methanol and sulfuric acid than reacting it with hydrazide to form
4-hydroxybenzohydrazide followed by reacting with a variety of aldehydes and
evaluated for their activity against nosocomial infection. All the synthesized
compounds were characterized by Fourier-transform infrared (FT-IR), 1H
nuclear magnetic resonance (NMR), and mass spectral data. The in vitro anti-
microbial potential of synthesized compounds was estimated against promi-
nent strains of nosocomial pathogens (Staphylococcus aureus, Escherichia coli,
and Aspergillus niger). The antimicrobial evaluation revealed compounds 4b,
4c, 4d, 4e, 4f, and 4j to be the most active compounds of the series with IC50
value for antibacterial in the range 0.39 to 0.75 μM/mL. Furthermore, the
in vitro cytotoxic potential of the compounds was appraised by hemolytic
assay. The results showed that some of the synthesized compounds exhibited
marked activity.
2Department of Pharmaceutical
Chemistry, Institute of Pharmaceutical
Education and Research, Wardha, India
Correspondence
Deepak K. Dwivedi, Department of
Pharmaceutical Sciences, Dr. Harisingh
Gour Central University, Sagar, India.
Email: dk.dwivedi95@gmail.com
1 | INTRODUCTION
Nifuroxazide is an oral nitro-furan antibiotic drug. It
has excellent characteristics such as wide spectrum of
Nosocomial infections (NIs) are hospital-acquired infections
(HAIs).[1] As per World Health Organization (WHO), the
classical definition of the term encompasses any infection
occurring in a patient in a hospital or any other healthcare
facility in which the infection was not present or incubating
at the time of admission. Consequences of NIs range from
mild nausea, vomiting, to fatal meningitis.[2] Currently, NIs
has become a common occurrence in both developed and
developing countries, accounting for approximately 1.4 mil-
lion incidences worldwide.[3] The pathogens predominantly
implicated include resistant bacterial strains of Staphylococ-
cus aureus and Escherichia coli; fungal strains of Candida
and Aspergillus have also been incriminated in the certain
manifestations of NIs.[4] The strains being resistant to the
first line antimicrobial chemotherapy considerably limit the
therapeutic intervention of NIs.[5]
activity and better chances for structure manipulation for
better activity. Consequently, NF is advocated as an out-
standing lead compound (Figure 1). Scientific literature
reports modification of the NF moieties to yield structures,
which were successfully investigated as monoamine
oxidase inhibitors,[6] antifungal,[7] anticonvulsant,[8] anti-
inflammatory,[9] bactericidal,[10] and trypanocidal agents.[11]
The findings have emphasized the potential of these molec-
ular structures for the development of novel drugs. Herein,
we report the design, synthesis, and evaluation of the anti-
microbial activity of p-substitutedbenzoylmethylene hydra-
zide derivatives against NIs. The nifuroxazide hydrazone
was substituted with 10 different aldehydes elected
according to physiochemical properties such as electron
releasing, withdrawing, and electron distribution. Antimi-
crobial activity was evaluated against microorganisms
J Heterocyclic Chem. 2020;1–6.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals, Inc.
1

2
DWIVEDI ET AL.
FIGURE 1 (A) Chemical structure of nifuroxazide (NF) (B) General structure of substituted analogs
SCHEME 1 General scheme
for the synthesis of p-
substitutedbenzoylmethylene
hydrazide derivatives 4a-j
reported as popular pathogens (S. aureus, E. coli, and Asper-
gillus niger). The molecular characterization was investi-
gated by infrared (IR), nuclear magnetic resonance (NMR),
and mass spectroscopic analysis.
The structures 4a-j (Figure 2) of the synthesized com-
pounds was elucidated using Fourier-transform IR (FT-
1
IR), H NMR, and mass spectroscopic methods. The IR
spectra of synthesized compounds 4a-j showed hydrazine
N H bands in 3400 to 3200 cm−1, C O bands in 1620 to
1750 cm−1 and C N bands in 1600 to 1620 region. Cl
and NO2 bands were seen in IR (7231560-1523 to
1367-1350).1H NMR spectra of compounds (a-j) showed
two signals in the δ 5.435 ppm and δ 8.7 to 7.7 ppm,
which were attributed to the OH and N CH proton,
respectively.
The synthesized nifuroxazide analogs were evaluated
against prominent strains of nosocomial pathogens. Activ-
ity demonstrated by compounds 4b (m-OH), 4c (p-Cl), 4d
(m-NO2), 4e (p-dimethylamine), 4f (p-diethylamine),
and 4j (p-Br) were comparatively better than that
exhibited by the reference standard. The anti-no-
socomial activity of the synthesized nifuroxazide ana-
logs was evaluated against three prominent strains
(S. aureus, E. coli, and A. niger) of nosocomial patho-
gens by the cup-plate method.
The IC50 value obtained for each compound and that
obtained for the reference standards (nifuroxazide, cipro-
floxacin, and miconazole) are listed in Figure 3. It was
observed that in comparison with the reference standards
the compounds 4b, 4c, 4d, 4e, 4f, and 4j demonstrated
superior efficacy with respect to compounds 4a, 4g, 4h,
and 4i. The most potent compound of the series is com-
pound 4d (m-NO2) (IC50 value 0.39, 0.42, and 0.68 μg/mL).
The nifuroxazide hydrazones constitute an important
class of biologically active agents such as antimicrobial,
antiprotozoal, antichagasic, and anti-inflammatory
agents. An extensive literature search revealed that
nifuroxazide are demonstrated to be the noble bioactive
molecules. Hence, it is worth to synthesize some
nifuroxazide derivatives for better antimicrobial activity.
The essential of new antibacterial and antifungal agents
is justified since microorganisms are being resistant to
the existing drugs available in the market.[12,13]
2 | RESULT AND DISCUSSION
The benzhydrazide derivatives could also be synthesized
from p-substituted methyl benzoates. Thus, based on litera-
ture reports, the methyl esters were synthesized from the
corresponding p-hydroxy-benzoic acid using dried metha-
nol and sulfuric acid and refluxing it for 3 to 4 hours. Then
p-hydroxy methyl benzoate 2 was treated with hydrazine
hydrate under reflux condition for 5 to 6 hours to furnish p-
hydroxy benzhydrazide 3, a mixture of equimolar propor-
tion of p-hydroxybenzhydrazides with substituted aromatic
aldehydes p-substitutedbenzoylmethylene hydrazide deriva-
tives (Scheme 1).[14]

DWIVEDI ET AL.
3
FIGURE 2 Structure of p-substitutedbenzoylmethylene hydrazide derivatives 4a-j
FIGURE 3 In vitro
antibacterial, antifungal, and
hemolytic activity (human
erthyrocytes) of the 4a-j antibacterial
strain, Staphylococcus aureus (SA);
Escherichia coli (EC); Antifungal
strain, Aspergillus niger
In the context of cytotoxic, HD50 was used. HD50 stands
for median hemolytic dose. It is the dose at which 50%
hemolysis of human erythrocytes takes place. Nifuroxazide,
ciprofloxacin, and miconazole were used as the reference
drugs for the study. HD50 value of the compounds ranged
between 0.6 and 2.5 μg/mL. All the synthesized compounds
exhibited mild to moderate cytotoxic propensity. The least
cytotoxic compound of the series was found to be com-
pound 4i while maximum cytotoxicity was observed for
compound 4c with HD50 value 2.15 μg/mL. It can be stated
that the presence of non-substituted pyrrole may be respon-
sible for the increased cytotoxicity of the compound.

4
DWIVEDI ET AL.
2.1 | IC50—the half maximal inhibitory
concentration, HD50—median
hemolytic dose
NMR (DMSO), δ ppm: 10.86 (1H, s, NH); 10.11 (1H, s,
OH), 7.86 (1H, s, NH), 7.41-7.39 (2H, Ar H), 7.23-7.22
(2H, d, J 8 Hz); 5.59 (1H, t, J 8 Hz), 2.86-2.82 (2H, m).
LC/MS- m/z calculated for C12H10N2O3: 230.06, found
230.16 (M+).
From the results obtained, it can be deduced that substi-
tution at the p- position of aromatic ring with an electron
releasing group 4e p-((dimethyl amino) benzylidene), 4f
p-(diethyl amino) benzylidene), and m- position in the
aromatic ring with electron withdrawing group 4d (m-
nitrobenzylidene), 4g (m-chloro-benzylidene), and 4b (m-
hydroxy-benzylidene) may be responsible for the increase
in activity of parent nucleus. The substitution at m-
position in the aromatic ring with NO2 group yielded the
superior compound of the series. Furthermore, the pres-
ence of non-substituted pyrrole may have resulted in a
decreased bioactivity as observed in the case of com-
pound 4h. This was recognized as the least active com-
pound of the series.
3.2.2 | 4b. N0-(2-hydroxybenzylidene)-
4-hydroxybenzhydrazide
Yield 60%; light brown color; m.p. 130-135ꢀC,
λmax = 343.60; IR (KBr) 3500-3200 cm−1 (OH) (Broad),
(N C), 3400-3200 cm−1 (N H), 1637.24 cm−1 (C O),
1610.59 cm−1,1H NMR (MeOD), 11.68 (1H, s, NH); 11.01
(1H, s, OH); 9.69 (1H, s, OH); 8.79 (1H, s, HC N), 8.11
(2H, s, Ar H); 7.62-7.58 (2H, m, Ar H), 6.97-6.93 (4H,
m, Ar H); LC/MS- m/z calculated for C14H12N2O3:
256.08, found 256.12 (M+).
3 | EXPERIMENTAL SECTION
3.2.3 | 4c. N0-(4-chlorobenzylidene)-
4-hydroxybenzhydrazide
Reagents and solvents were procured from LOBA
Chemie and Himedia Lab. Reaction progress was moni-
tored by thin-layer chromatography (TLC) on silica gel
precoated F254 and melting point. The spectra of com-
pounds were recorded using FT-IR - 8400S (Shimadzu),
1H NMR (Bruker, 400 MHz FT NMR), and mass spectra
(Q-Tof Micro mass spectrometer).
Yield 79%; yellow color; m.p. 200-202ꢀC, λmax = 382.40;
IR (KBr) 3500-3200 cm−1 (OH) (Broad), 3400-3200 cm−1
(N H), 1637.24 cm−1 (C O), 1610.59 cm−1 (N C),
1
723 cm−1 (Cl), H NMR (DMSO), δ ppm: 10.86 (1H, s,
NH); 10.11 (1H, s, OH); 7.86 (1H, s, N CH); 7.41-7.30
(4H, m, Ar H); 7.03-6.99 (2H, m, Ar H); 5.60 (2H, d,
J 8 Hz). LC/MS- m/z calculated for C14H11N2O2Cl:
273, found 273.21(M+).
3.1 | General procedure for the synthesis
of p-substitutedbenzoylmethylene
hydrazide derivatives 4a-j
3.2.4 | 4d. N0-(3-nitrobenzylidene)-
4-hydroxybenzhydrazide
A mixture of equimolar proportion of p-hydroxy-
benzhydrazides (2 g, 0.0025 mol) and substituted aro-
matic aldehydes (2 mL, 0.0025 mol), in a solution of
ethanol/acetic acid/sulfuric acid/water (20:8:7:8), and
three drops of glacial acetic acid was added; mixture was
refluxed. The insoluble product was filtered off and puri-
fied by recrystallization in N,N-dimethyl formamide.
Yield 78%; faint yellow crystal; m.p. 250-255ꢀC,
λmax = 313.20; IR (KBr) 3500-3200 cm−1 (OH) (Broad),
1637.24 cm−1 (C O), 1610.59 cm−1 (N C), 1560-1523,
1
1367-1350 cm−1 (NO2), 3400-3200 cm−1 (N H), H NMR
(DMSO), δ ppm: 11.59 (1H, s, NH); 9.73 (1H, s, OH); 8.44
(1H, s); 8.12 (1H, d, J 4 Hz); 7.89-7.86 (2H, d, J 12 Hz), 7.75
(3H, t, J 8 Hz); 7.08 (1H, d, J 8 Hz, Ar H); 6.88 (2H, d,
J 8 Hz, Ar H); LC/MS- m/z calculated for C14H11N3O4:
285, found 285.31(M+).
3.2 | Spectral data of the final
compounds 4a-j
3.2.1 | 4a. N0-((4H-furan-2-yl)
methylene)-4-hydroxybenzhydrazide
3.2.5 | 4e. N0-(4-(dimethylamino)
benzylidene)-4 hydroxybenzhydrazide
Yield 71%; black color; m.p. 270-273ꢀC, λmax = 371.40;
IR (KBr) 3500-3200 cm−1 (OH) (Broad), 3400-3200 cm−1
(N H), 1745.24 cm−1 (C O), 1606.59 cm−1 (N C), 1H
Yield 65%; red crystal; m.p. 170-175ꢀC, λmax = 391.50.;
IR (KBr) 3500-3200 cm−1 (OH) (Broad), 1637.24 cm−1
(C O), 1610.59 cm−1 (N C), 1068 cm−1 (N C); 1H NMR

DWIVEDI ET AL.
5
(DMSO), δ ppm: 11.66 (1H, s, NH); 9.76 (1H, s, OH); 8.31
(2H, s, N CH); 7.64-7.62 (2H, m, Ar H); 6.98-6.96 (2H,
m, Ar H), 6.54-6.48 (4H,m, Ar H); LC/MS- m/z calcu-
lated for C16H17N3O2: 283, found 283.41(M+).
(C O), 1640.59 cm−1 (N C), 1068 cm−1 (N C);1H NMR
(DMSO), δ ppm: 11.69 (1H, s, NH); 9.72 (1H, s, OH); 8.82
(1H, s, N CH); 7.97-7.93 (2H, m, Ar H); 7.78-7.75 (2H,
m, ArH); 7.58 (2H, d, J 8 Hz); 6.87 (1H, t, J 4 Hz, Ar H).
LC/MS- m/z calculated for C14H12N2O2: 240.08, found
240.05 (M++ 1).
3.2.6 | 4f. (N0-(4-(diethylamino)
benzylidene)-4-hydroxybenzhydrazide
3.2.10 | 4j. (N0-(4-bromobenzylidene)-
Yield 71%; Yellow crystal; m.p. 180-185ꢀC, λmax = 491.50;
IR (KBr) 3500-3200 cm−1 (OH) (Broad), 1637.24 cm−1
(C O), 1610.59 cm−1 (N C), 1068 cm−1 (N C); 1H NMR
(DMSO), δ ppm: 11.58 (1H, s, NH); 10.11 (1H, s, OH);
8.39 (1H, s, N CH); 7.86 (2H, s, Ar H); 7.71-7.69 (2H,
d, J 8 Hz); 7.30 (2H, d, J 4 Hz); 6.62 (2H, d, J 8 Hz,
Ar H), 3.62 (4H,d, (CH2)2); 1.52 (6H, d, J 8 Hz,
(CH2CH3)2). LC/MS- m/z calculated for C18H21N3O2:
311.1634, found 311.41(M+).
4-hydroxybenzhydrazide)
Yield 82%; Buff color crystal; m.p. 175-179ꢀC,
λmax = 450.00.; IR (KBr) 3400-3200 cm−1 (OH) (Broad),
1648.74 cm−1 (C O), 1640.59 cm−1 (N C), 1068 cm−1
(N C); 1H NMR (DMSO), δ ppm: 11.65 (1H, s, NH); 9.72
(1H, s, OH); 8.37 (1H, s, N CH); 7.83 (2H, d, J 8 Hz,
Ar H); 7.64-7.57 (4H, m, ArH); 6.88-6.86 (1H, m, Ar H).
LC/MS- m/z calculated for C14H11BrN2O2:318.00, found
318.56 (M++ 1), 319.76 (M + 2).
3.2.7 | 4g. (N0-(3-chlorobenzylidene)-
4-hydroxybenzhydrazide)
3.3 | Procedure of antimicrobial assay
Yield 59%; Orange crystal; m.p. 150-155ꢀC, λmax = 483.00;
IR (KBr) 3500-3200 cm−1 (OH) (Broad), 1647.24 cm−1
(C O), 1620.59 cm−1 (N C), 1066 cm−1 (N C); 1H NMR
(DMSO), δ ppm: 11.69 (1H, s, NH); 10.02 (1H, s, OH);
8.61 (1H, s, N CH); 7.39-7.35 (4H, m, Ar H); 7.30-7.29
(2H, m, ArH); 6.97 (2H, d, J 8 Hz); 6.86 (1H, t, J 8 Hz,
Ar H). LC/MS- m/z calculated for C14H11ClN2O2:
274.05, found 275.05(M++ 1).
The synthesized targeted compounds 4a-j were screened
by the cup-plate method. For antibacterial activity, G (+)
bacteria S. aureus (ATCC 25923), G (−) E. coli (ATCC
8739), and for antifungal activity, G (+) A. niger (ATCC
16404) have been used. The strains were collects from a
microbiological laboratory, IPER College, Wardha, Nag-
pur. The culture was grown in nutrient agar medium
(antibacterial) and Sabouraud's agar medium (antifun-
gal), and nifuroxazide, ciprofloxacin, and miconazole
were used as reference standards.[15] IC50 was calculated
by graph pad prism.
3.2.8 | 4h. (N0-((1H-pyrrole-2-yl)]
methylene)-4-hydroxybenzohydrazide)
Yield 85%; Orange crystal; m.p. 150-155ꢀC,
λmax = 440.00.; IR (KBr) 3400-3200 cm−1 (OH) (Broad),
1648.74 cm−1 (C O), 1640.59 cm−1 (N C), 1068 cm−1
(N C);1H NMR (DMSO), δ ppm: 11.35 (1H, s, NH);
10.90 (1H, s, NH); 9.89 (1H, s, OH); 7.97 (1H, s,
N CH); 7.78-7.77 (4H, m, Ar H); 7.35-7.29 (2H, m,
ArH); 6.96 (2H, d, J 8 Hz); 6.87 (1H, t, J 4 Hz, Ar H),
6.20-6.17 (1H,m, Pyrolle H). LC/MS- m/z calculated for
C12H11N3O2: 229.08, found 230.05 (M++ 1).
3.4 | Procedure of cytotoxic study
(hemolytic assay)
Erythrocyte suspension was prepared by centrifuging
10 mL of whole human blood with isotonic buffer for
10 minutes at 3000 rpm. The supernatant was separated,
and packed cells were suspended with an equal volume
of normal saline and re-centrifuged. The process was
repeated until a clear supernatant was obtained. From
the resultant, 10% erythrocyte suspension was prepared.
To 2 mL of saline solution, 1 mL of PBS and 1 mL sample
solution, and 0.5 mL were added and incubated at 37ꢀC
for 30 minutes. After incubation, the reaction vessel was
allowed to cool, and absorbance was measured spectro-
photometrically at 560 nm. Percentage hemolysis and
HD50 of the compound under study were calculated.[16]
3.2.9 | 4i. (N0-benzylidene-
4-hydroxybenzhydrazide)
Yield 72%; Orange crystal; m.p. 165-169ꢀC, λmax = 420.00.;
IR (KBr) 3400-3200 cm−1 (OH) (Broad), 1648.74 cm−1

6
DWIVEDI ET AL.
[6] E. Maccioni, S. Alcaro, R. Cirilli, S. Vigo, M. C. Cardia,
M. L. Sanna, P. Matyus, J. Med. Chem. 2011, 54(18), 6394.
[7] N. K. Fuloria, V. Singh, M. Shaharyar, M. Ali, Molecules 2009,
14, 1898.
4 | CONCLUSION
The present work led to the synthesis and development of
10 antimicrobial molecules of p-substituted benzoylmethylene
hydrazide derivatives that have shown significant activity with
good yield. The derivatives were synthesized by reacting p-
substituted benzhydrazide with a variety of aldehydes. The
compounds were characterized by using ultraviolet (UV),
IR, 1H NMR, and mass spectroscopy. The synthesized
targeted compounds 4a-j were screened against nosocomial
infection using cup-plate method. Thus, preliminary in vitro
antimicrobial activity of compounds 4b, 4c, 4d, 4e, 4f, and 4j
demonstrated superior efficacy with respect to compounds
4a, 4b, 4c, and 4d against tested organism. The substitution
at m-position in the aromatic ring with NO2 group yielded
the superior compound of the series. The compounds 4a-j
was also evaluated for in vitro cytotoxicity assay in human
erythrocytes, which confirms the low cytotoxicity thereby
helping in the design of novel potent compounds.
[8] H. N. Dogan, S. Rollas, H. Erdeniz, Il Farmaco 1998, 53, 462.
ꢀ
ꢀ
[9] B. Koçyigit-Kaymakçıoglu, E. E. Oruç-Emre, S. Ünsalan,
N. Tabanca, S. I. Khan, D. E. Wedge, S. Rollas, Med. Chem.
Res. 2012, 21, 3499.
[10] M. Ishii, S. D. Jorge, A. A. de Oliveira, F. Palace-Berl,
I. Y. Sonehara, K. F. M. Pasqualoto, L. C. Tavares, Bioorg. Med.
Chem. 2011, 19, 6292.
[11] S. U. Tekale, Synthesis of Some Bioactive Heterocyclic Com-
pounds Using Reusable Heterogeneous Catalysts, 2015.
[12] H. G. Petering, H. H. Buskirk, J. A. Crim, Cancer Res. 1967, 27,
1115.
[13] J. Gollub, C. A. Ball, G. Binkley, J. Demeter, D. B. Finkelstein,
J. M. Hebert, M. Schroeder, Nucleic Acids Res. 2003, 31, 94.
[14] A. Masunari, L. C. Tavares, Bioorg. Med. Chem. 2007, 15, 4229.
[15] Indian Pharmacopoeia-Volume II, I, Noida, New Delhi 2010,
p. 1681.
[16] C. Botta, T. Langerholc, A. Cencicˇ, L. Cocolin, PLoS One 2014,
9(4), 94457.
ORCID
Deepak K. Dwivedi https://orcid.org/0000-0003-1164-
5181
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
REFERENCES
[1] G. Ducel, J. J. Haxhe, F. Tanner, M. Zumofen, Guide pratique
pour la lutte contre l'infection hospitalière. WHO/[2] 1979.
[2] Chin, J. Control of Communicable Diseases Manual. Washington:
American Public Health Association 2000.
How to cite this article: Dwivedi DK, Sahu A,
Dighade SJ, Agrawal RK. Design, synthesis, and
antimicrobial evaluation of some nifuroxazide
analogs against nosocomial infection. J Heterocyclic
Chem. 2020;1–6. https://doi.org/10.1002/jhet.3891
[3] E. Tikhomirov, Chemioterapia 1987, 6(3), 148.
[4] G. M. L. Consoli, G. Granata, R. Picciotto, A. R. Blanco,
C. Geraci, A. Marino, A. Nostro, MedChemComm 2018, 9(1), 160.
[5] M. F. El Shehry, S. Y. Abbas, A. M. Farrag, S. I. Eissa,
S. A. Fouad, Y. A. Ammar, Med. Chem. Res. 2018, 27(10), 2287.