Synthesis and antibacterial activity of Schiff bases of 5-substituted isatins

Article abstract of DOI:10.1016/j.cclet.2015.10.027

Based on the existing reports on the bioactive isatin derivatives, a number of Schiff bases were synthesized by reacting 5-substituted isatins with bioactive amines/hydrazides and their structures were confirmed using spectroscopic methods such as NMR, IR

Full text of DOI:10.1016/j.cclet.2015.10.027

Accepted Manuscript
Title: Synthesis and antibacterial activity of schiff bases of
5-substituted isatins
Author: Kamaleddin Haj Mohammad Ebrahim Tehrani
Maryam Hashemi Maryam Hassan Farzad Kobarfard Shohreh
Mohebbi
PII:
S1001-8417(15)00421-0
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.cclet.2015.10.027
CCLET 3477
To appear in:
Chinese Chemical Letters
Received date:
Revised date:
Accepted date:
7-4-2015
4-8-2015
10-10-2015
Please cite this article as: K.H.M.E. Tehrani, M. Hashemi, M. Hassan, F. Kobarfard,
S. Mohebbi, Synthesis and antibacterial activity of schiff bases of 5-substituted isatins,
Chinese Chemical Letters (2015), http://dx.doi.org/10.1016/j.cclet.2015.10.027
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Graphical Abstract
Synthesis and antibacterial activity of schiff bases of 5-substituted isatins
Kamaleddin Haj Mohammad Ebrahim Tehrania, Maryam Hashemia, Maryam Hassanb, Farzad Kobarfardc,d, Shohreh
Mohebbia,*
a Department of Medicinal Chemistry, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran.
b
Department of Pharmaceutical Biotechnology, School of Pharmacy, Zanjan University of Medical Sciences,
Zanjan, Iran.
c
Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences,
Tehran, Iran.
d Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
R
N
X
O
X = H, F, Cl, Me
N
H
O
O
S
O
O
O
~
~
~
~
~
R:
~
N
NH2
N
NH2
N
N
N
N
NH
O
H
H
H
H
H
N
OH
A series of Schiff bases of 5-substituted isatins were synthesized and tested for their antibacterial activity. Among the tested
derivatives, compounds 2d, 3b, 5c and 6a showed promising activity against P. aeruginosa.
Page 1 of 10

Original article
Synthesis and antibacterial activity of schiff bases of 5-substituted isatins
Kamaleddin Haj Mohammad Ebrahim Tehrania, Maryam Hashemia, Maryam Hassanb, Farzad
Kobarfardc,d, Shohreh Mohebbia,
a Department of Medicinal Chemistry, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran.
b Department of Pharmaceutical Biotechnology, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran.
c Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
d Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
ARTICLE INFO
ABSTRACT
Based on the existing reports on the bioactive isatin derivatives, a number of Schiff
bases were synthesized by reacting 5-substituted isatins with bioactive
amines/hydrazides and their structures were confirmed using spectroscopic methods
such as NMR, IR and mass spectrometry. Furthermore, N-benzylation of isatin
followed by the Schiff base formation furnished a new series of compounds (11a-
13c) which allowed the analysis of the effect of isatin N-substitution on the
bioactivity of the resulting compounds. The antibacterial activity of the synthesized
derivatives was evaluated using a microtiter plate method on a series of gram positive
and gram negative bacterial strains. Compounds 2d, 3b, 5c and 6a were among the
most potent derivatives against P. aeruginosa (MIC = 6.25 µg/ml). Analysis of the
structure-activity relationship showed that the incorporation of (thio)urea-based
Schiff bases lead to more potent derivatives with a broader spectrum of antibacterial
activity. In addition, highly lipophilic compounds such as 11a-12c did not show any
measurable antibacterial activity, which implies that an optimal lipophilicity might be
an important requirement for the antibacterial activity of the studied isatins. Finally,
the finding that hydantoin derivatives of N-benzylisatins (13a-13c) still exhibit some
antibacterial activity prompted us to consider exploring the bioactivity of more
diverse derivatives of isatin-aminohydantoin Schiff bases (compounds 1a-1d) in our
future studies.
Article history:
Received 7 April 2015
Received in revised form 4 August 2015
Accepted 10 October 2015
Available online
Keywords:
Synthesis
Isatin
Schiff base
Hydantoin
Antibacterial
1. Introduction
Compounds derived from isatin (1H-indole-2,3-dione) have long been known to possess versatile biological activities.
Like indole-based derivatives, isatins have been studied for their potential antimicrobial [1], antiviral [2-4] and
antiproliferative [5-7] activities. Isatin is also a part of many heterocyclic natural products of biological interest [8, 9].
Thiosemicarbazone derivatives of N-methylisatin (Methisazone) have long been used as antiviral agents against active
variola and vaccinia viruses [10].
Corresponding author.
E-mail address: shmohebbi@zums.ac.ir
Page 2 of 10

In several studies aimed at developing antibacterial agents, isatin has been considered as the core fragment. By different
chemical modifications including Schiff base formation, N-alkylation/acylation [1,11], Mannich base synthesis [12,13] and
metal complexation [14,15], research groups have reported a variety of chemical entities, many of which showed
promising activity in antibacterial screenings. Some examples of isatin derivatives with reported antimicrobial activity
have been disclosed in Fig. 1.
On the other hand, hydrazone derivatives have been among the most interesting class of compounds especially in
antimicrobial drug research. In a series of focused studies on (thio)semicarbazones of aromatic aldehydes/ketones, we have
found some potent antimycobacterial, antifungal and anticancer compounds among hydrazones derived from substituted
indole-3-carboxaldehydes and benzaldehydes [16-20]. Our results on indole-based derivatives encouraged us to extend our
studies to isatin derivatives, which could be considered as a close analog of their indole counterparts.
Based on the above considerations and using the molecular hybridization strategy, in the present study a series of
compounds containing isatin and hydrazone fragments were designed (Fig. 2). The final compounds were prepared starting
from 5-substituted isatins and appropriate hydrazide derivatives. In addition to (thio)semicarbazide, the other starting
amines/hydrazides were in turn selected based on the previous reports indicating their antibacterial activity. Evaluation of
the existing reports shows that small molecules derived from hydantoin [21,22], 4-hydroxybenzohydrazide [23] and
isoniazid [24] have demonstrated promising antibacterial activity.
S
S
NH2
NH2
N
NH
O
O
NH
O
N
N
N
X
R2
H2N
O
N
N
N
R
A
B
C
R
N
R1
Fig. 1. Bioactive isatin derivatives. A. Methisazone [2]; B. Modified methisazone derivatives as antiviral protease inhibitors [3]; C. Mannich
bases of isatin as anticancer agents, X = NH, S [5]; D. Isatinhydrazones with activity against multidrug resistant cells, X = O, S, Ar: substituted
phenyl [6]
R
O
N
X
O
O
N
N
H
R1
A
B
Fig. 2. A. Isatin; B. General structure of the synthesized derivatives
Page 3 of 10

We found it interesting to assess whether molecular hybrids containing isatin and bioactive amines/hydrazides
could demonstrate promising activity against pathogenic bacteria. To this end, 34 Schiff base derivatives of 5-
substituted isatins were prepared and evaluated against 6 clinically important bacterial strains of both gram-positive
and gram-negative class.
2. Experimental
Melting points were measured using an Electrothermal 9200 apparatus and were uncorrected. The proton nuclear
magnetic resonance (1H NMR) spectra were measured on a 400 MHz Bruker Avance DRX spectrometer.
Compounds were dissolved in d6-DMSO or CDCl3 and TMS was used as an internal standard. The 13C NMR spectra
were also recorded on the same spectrometer and the compounds were dissolved in d6-DMSO. The infrared spectra
were obtained using a Bruker Tensor 27 FT-IR spectrophotometer and KBr was used as a diluent. ESI-MS spectra
were obtained using Agilent 6410 Triple Quad LC/MS. The derivatives were analyzed for C, H, N, S by a Costech
model 4010 and the obtained values were in agreement with the proposed structures within ±0.4% of the theoretical
values. The spectral characterization data of the synthesized intermediates and final compounds has been provided in
the Supporting information.
2.1.1. General procedure for the synthesis of Schiff bases
Equimolar amines and 5-substituted isatins (1 mmol of each) were added to 96% w/w ethanol (20 ml) containing
8 drops of glacial acetic acid. The mixture was heated under reflux for 5 h and then cooled to room temperature. The
resulting solid was collected by filtration, washed with cold ethanol and dried in open air. The derivatives thus
prepared had sufficient analytical purity. The synthesis and spectral characterizations of compounds 4b [25], 4c [26],
5c [25], 6a [27], 6b, 6c and 6d [28] have been previously reported in the literature.
2.1.2. General procedure for the synthesis of N-benzylisatins 8-10
To a flask containing acetonitrile (15 ml) were added isatin (294 mg, 2 mmol), K2CO3 (332 mg, 2.4 mmol) and KI
(66 mg, 0.4 mmol). Stirring was started and after 5 min, fluorobenzyl chlorides (433 mg, 3 mmol) were added
dropwise. After 3 h of reflux, the mixture was cooled to room temperature and filtered. The filtrate was concentrated
under reduced pressure and the resulting oil was solidified upon the addition of n-hexane. The solid was
recrystallized in water to afford the titled compounds.
2.2. Evaluation of antibacterial activity
Antimicrobial activity of the synthesized derivatives was evaluated using a microtiter plate method. The bacterial
strains included P. aeruginosa (ATCC 27853), E. coli (ATCC 25922), E. faecalis (ATCC 29212), S. aureus (ATCC
25923) and Methicillin resistant Staphylococcus aureus (MRSA, ATCC 43300). Amikacin was used as a standard
antibiotic. The detailed procedure has been described in our previous work [29].
3. Results and discussion
3.1. Chemistry
The final imine/hydrazone derivatives were prepared via reacting 5-substituted isatins with the selected amines
including 1-aminohydantoin, semicarbazide, thiosemicarbazide, benzohydrazide, 4-hydroxybenzohydrazide and
isoniazid (Scheme 1). The components were added to ethanol with a few drops of acetic acid as a catalyst. The
Schiff base products were thus prepared in good yields and acceptable purity. For compounds 11-13, an additional
step was required, which was the N-benzylation of isatin using fluorinated benzyl chlorides (Scheme 2). This
reaction was performed using potassium carbonate in acetonitrile. Compounds 8, 9 and 10 were then reacted with 3
different hydrazides following the above mentioned procedure. All the derivatives were analyzed using IR, NMR
1
and Mass spectrometry and also elemental analysis. In the H NMR spectra of the derivatives, isatin hydrogens
appeared as two sets of doublets (at ca. 6.93 and 7.59 ppm) and two sets of triplets (at ca. 7.10 and 7.36 ppm). In the
case of 5-substituted isatins, one singlet and two sets of doublets in the aromatic region were observed. This pattern
Page 4 of 10

was helpful to recognize the peaks corresponding to the hydrazide and N-fluorobenzyl fragments. In the IR spectra,
absorptions related to carbonyl functions of isatin and hydrazide moieties were the most intense ones appearing at
1680-1730 cm-1. The mass of the derivatives was also confirmed by ESI-MS, where values related to hydrogen
and/or sodium adducts of the intact molecule were observed.
R
O
N
X
X
RNH2
O
O
Ethanol, AcOH
N
H
N
H
X = H, F, Cl, Me
O
O
O
S
O
~
~
~
~
R:
~
N
NH2
N
H
NH2
N
H
N
N
NH
O
H
H
1a:
1b:
1c:
2a:
2b:
2c:
4a:
4b:
4c:
X = H
X = F
X = Cl
X = H
X = F
X = Cl
3a: X = H
3b: X = F
3c: X = Cl
3d: X = Me
X = H
X = F
X = Cl
5a: X = H
5b: X = F
5c: X = Cl
5d: X = Me
1d:
2d:
4d:
X = Me
X = Me
X = Me
Scheme 1. Synthetic route to Schiff bases of 5-substituted isatins
Scheme 2. Synthetic route to compound 7 and Schiff bases of N-arylmethylisatin 11a-13c. Reagents and conditions: a. phenylhydrazine, ethanol
96% (w/w), acetic acid; b. fluorinated benzyl chlorides, K2CO3, KI, acetonitrile; c. compounds 8-10, Ethanol 96% (w/w), acetic acid.
3.2. Antimicrobial activity
The in vitro antibacterial activity of the synthesized derivatives was evaluated against 6 clinically important
bacterial strains from both gram positive and gram negative groups (Table 1). Most interestingly, the tested
derivatives exhibited the highest activity on P. aeruginosa among which compounds 2d, 3b, 5c and 6a were the
Page 5 of 10

most potent ones (MIC = 6.25 µg/ml). This is an important finding since P. aeruginosa is a highly opportunistic
pathogen and compounds with activity against this pathogenic bacterium are of special value. Further research and
optimizations on these compounds may ultimately lead to the discovery of promising therapeutic agents.
As a general view, the (thio)urea-based hydrazone derivatives 1a-3d were more active than aroyl-based
derivatives 4a-6d. This observation should be considered in designing new isatin-hydrazones, especially when a
broad spectrum of antibacterial activity is desired. It is also worth mentioning that among the bacterial strains
evaluated, S. aureus and MRSA were the most resistant to the hydrazone derivatives.
Despite their moderate activity, hydantoin derivatives 1a-1d were active against all the tested strains. This implies
that introduction of hydantoin moiety provides the broader spectrum of antibacterial activity, though further
optimization efforts are needed to improve their potency. The other interesting finding is that among the derivatives
with a fluorobenzyl substitution at the isatin N-1 position (11a-13c), the new benzylic substituent has been tolerated
only in the hydantoin class (as in 13a-13c). As can be seen in Table 2, the N-1 benzylation of isatin did not lead to
any active compounds among benzoylhydrazones (11a-11c) and phenylhydrazones (12a-12c). This observation
provides a new opportunity to optimize the potency of hydantoin derivatives through further structural
manipulations including the introduction of new substituents at the isatin N-1 position. This is the topic of our
ongoing studies.
According to the Lipinski’s rule of five [30], a number of molecular properties play an important role in the
optimum oral bioavailability and “drug-likeness” of small molecules. These properties include: number of hydrogen
bond donors (should be less than 5); number of hydrogen bond acceptors (should be less than 10); lipophilicity
(clogP value should be smaller than 5); and molecular weight (should be less than 500). These properties for the
synthesized isatin derivatives were calculated and presented in Table 3. Among the various physicochemical
parameters, lipophilicity has been the most evaluated one in the studies on antibacterial isatins [1]. According to the
table, the ClogP values of the most potent isatins fall between 0.72–2.27. Therefore, with regard to compounds 11a-
12d, it could be hypothesized that in addition to steric hindrance, their highly lipophilic character might have a
contribution to their loss of activity. This however must be further evaluated in the future studies through the
introduction of substituents that lead to a wide range of ClogP values.
It is also important to note that the MW of the potent derivatives in this study is low enough to allow further
molecular expansions in the future studies, meaning that more complex derivatives could still have the MW below
500. Finally, in a general view, all the synthesized derivatives conform to the limitations of Lipinski's rule of five.
Table 1. Antibacterial activity of isatin Schiff bases 1a-6d
Code
MIC (µg/ml)
P. aeruginosa
12.5
25
E. coli
12.5
12.5
25
E. faecalis
12.5
>50
25
S. aureus
25
MRSAa
25
1a
1b
1c
1d
2a
2b
2c
2d
3a
3b
3c
3d
12.5
25
25
12.5
25
25
25
25
>50
25
>50
12.5
>50
25
25
12.5
>50
>50
>50
>50
50
>50
25
12.5
12.5
6.25
12.5
6.25
>50
>50
25
>50
25
>50
>50
25
>50
>50
25
25
50
>50
>50
>50
25
>50
>50
>50
>50
12.5
Page 6 of 10

4a
4b
>50
25
>50
12.5
>50
>50
>50
>50
>50
>50
>50
25
>50
25
>50
12.5
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
31
>50
12.5
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
31
4c
>50
>50
>50
>50
6.25
>50
6.25
>50
25
>50
>50
>50
>50
12.5
>50
50
4d
5a
5b
5c
5d
6a
6b
>50
25
6c
12.5
>50
16
6d
>50
>50
12.5
Amikacin
16
aMethicillin resistant Staphylococcus aureus
Table 2. Antibacterial activity of compounds 7 and N-fluorobenzylisatin derivatives 11a-13c
Code
MIC (µg/ml)
E. faecalis
P. aeruginosa
>50
E. coli
>50
>50
>50
>50
>50
>50
>50
6.25
12.5
6.25
16
S. aureus
>50
MRSA
>50
>50
>50
>50
>50
>50
>50
6.25
6.25
6.25
31
7
11a
>50
>50
>50
>50
>50
>50
>50
12.5
12.5
12.5
12.5
>50
>50
11b
>50
>50
11c
>50
>50
12a
>50
>50
12b
>50
>50
12c
>50
>50
13a
12.5
12.5
12.5
16
6.25
6.25
6.25
31
13b
13c
Amikacin
Table 3. Calculated molecular properties related to the Lipinski’s rule of five
Code
ClogP
0.379
0.522
1.092
0.878
0.826
0.969
1.539
HBDa
HBAb
MWc
2
2
2
2
4
4
4
7
8
7
7
6
7
6
244.21
262.20
278.65
258.23
204.19
222.18
238.63
1a
1b
1c
1d
2a
2b
2c
Page 7 of 10

1.325
1.255
1.398
1.968
1.754
2.221
2.364
2.934
2.720
1.554
1.697
2.267
2.053
0.724
0.867
1.437
1.223
2.466
5.008
5.008
5.008
5.253
5.253
5.253
3.166
3.166
3.166
4
4
4
4
4
2
2
2
2
3
3
3
3
2
2
2
2
2
1
1
1
1
1
1
1
1
1
6
5
6
5
5
5
6
5
5
6
7
6
6
6
7
6
6
4
6
6
6
5
5
5
8
8
8
218.21
220.25
238.24
254.70
234.28
265.27
283.26
299.71
279.29
281.27
299.26
315.71
295.29
266.25
284.25
300.70
280.28
237.26
373.38
373.38
373.38
345.37
345.37
345.37
352.32
352.32
352.32
2d
3a
3b
3c
3d
4a
4b
4c
4d
5a
5b
5c
5d
6a
6b
6c
6d
7
11a
11b
11c
12a
12b
12c
13a
13b
13c
a Number of hydrogen-bond donors; b Number of hydrogen-bond acceptors; c Molecular weight
4. Conclusion
In summary, we evaluated the antibacterial activity of isatin-based hydrazone derivatives, which provided
valuable clues for the further lead optimization studies. The most interesting observation was the promising activity
of the tested hydrazones against P. aeruginosa as a clinically important strain. However, the derivatives did not
exhibit a pronounced activity against MRSA. Incorporation of (thio)urea fragments as amine components (which
include semicarbazide, thiosemicarbazide and 1-aminohydantoin) led to an improved and broader spectrum of
antibacterial activity. Among them, 1-aminohydantoin imines 1a-1d were interesting not only because of their broad
spectrum of activity, but also because their N-1 benzyl analogs were still active. The latter is an important finding
since it provides the opportunity to conduct new lead optimization studies and design new isatin-hydantoin
derivatives with improved potency and spectrum of activity.
Acknowledgement
The authors would like to express their appreciation to the research deputy of Zanjan University of Medical
Sciences and Zanjan Institute for Advanced Studies in Basic Sciences for granting access to the NMR facility.
Page 8 of 10

References
[1] P. Pakravan, S. Kashanian, M.M. Khodaei, F.J. Harding, Biochemical and pharmacological characterization of isatin and its derivatives: from
structure to activity, Pharmacol. Rep. 65 (2013) 313-335.
[2] M.C. Pirrung, S.V. Pansare, K.D. Sarma, K.A. Keith, E.R. Kern, Combinatorial optimization of isatin-β-thiosemicarbazones as anti-poxvirus
agents, J. Med. Chem. 48 (2005) 3045-3050.
[3] L. Zhou, Y. Liu, W.L. Zhang, et al., Isatin compounds as noncovalent SARS coronavirus 3C-like protease inhibitors, J. Med. Chem. 49 (2006)
3440-3443.
[4] S.T. Xue, L.L. Ma, R.M. Gao, Y.H. Li, Z.R. Li, Synthesis and antiviral activity of some novel indole-2-carboxylate derivatives, Acta Pharm.
Sin. B 4 (2014) 313-321.
[5] A.T. Taher, N.A. Khalil, E.M. Ahmed, Synthesis of novel isatin-thiazoline and isatin-benzimidazole conjugates as anti-breast cancer agents,
Arch. Pharmacal. Res. 34 (2011) 1615-1621.
[6] M.D. Hall, N.K. Salam, J.L. Hellawell, et al., Synthesis, activity, and pharmacophore development for isatin-β-thiosemicarbazones with
selective activity toward multidrug-resistant cells, J. Med. Chem. 52 (2009) 3191-3204.
[7] Z.L. Song, M.N. Wang, A. Zhang, Alectinib: a novel second generation anaplastic lymphoma kinase (ALK) inhibitor for overcoming
clinically-acquired resistance. Acta Pharm. Sin. B 5 (2015) 34-37.
[8] P. Zhang, X.M. Li, J.N. Wang, X. Li, B.G. Wang, Prenylated indole alkaloids from the marine-derived fungus Paecilomyces variotii, Chin.
Chem. Lett. 26 (2015) 313-316.
[9] Z.G. Li, G.Q. Dong, S.Z. Wang, et al., Optical evodiamine derivatives: Asymmetric synthesis and antitumor activity, Chin. Chem. Lett. 26
(2015) 267-271.
[10] M. Bray, Pathogenesis and potential antiviral therapy of complications of smallpox vaccination, Antiviral Res. 58 (2003) 101–114.
[11] Y. Wang, F.Y. Chan, N. Sun, et al., Structure-based design, synthesis, and biological evaluation of isatin derivatives as potential
glycosyltransferase inhibitors, Chem. Biol. Drug Des. 84 (2014) 685-696.
[12] Y.L.N. Murthy, B. Govindh, B.S. Diwakar, K. Nagalakshmi, K.V.R. Rao, Synthesis and bioevaluation of Schiff and Mannich bases of isatin
derivatives with 4-amino-5-benzyl-2, 4-dihydro-3H-1, 2, 4-triazole-3-thione, Med. Chem. Res. 21 (2012) 3104-3110.
[13] S.N. Pandey, D. Sriram, G. Nath, E. DeClercq, Synthesis, antibacterial, antifungal and anti-HIV activities of Schiff and Mannich bases
derived from isatin derivatives and N-[4-(4’-chlorophenyl)thiazol-2-yl] thiosemicarbazide, Eur. J. Pharm. Sci. 9 (1999) 25-31.
[14] A.D. Kulkarni, S.A. Patil, P.S. Badami, SNO donor Schiff bases and their Co(II), Ni(II) and Cu(II) complexes: synthesis, characterization,
electrochemical and antimicrobial studies, J. Sulfur Chem. 30 (2009) 145-159.
[15] M.C. Rodríguez-Argüelles, R. Cao, A.M. García-Deibe, et al., Antibacterial and antifungal activity of metal(II) complexes of acylhydrazones
of 3-isatin and 3-(N-methyl)isatin, Polyhedron 28 (2009) 2187-2195.
[16] K. Haj Mohammad Ebrahim Tehrani, F. Kobarfard, P. Azerang, et al., Synthesis and antimycobacterial activity of symmetric
thiocarbohydrazone derivatives against Mycobacterium bovis BCG, Iran. J. Pharm. Res. 12 (2013) 331-346.
[17] K. Haj Mohammad Ebrahim Tehrani, S. Sardari, V. Mashayekhi, et al., One pot synthesis and biological activity evaluation of novel Schiff
bases derived from 2-hydrazinyl-1, 3, 4-thiadiazole, Chem. Pharm. Bull. 61 (2013) 160-166.
[18] V. Mashayekhi, K. Haj Mohammad Ebrahim Tehrani, S. Amidi, F. Kobarfard, Synthesis of novel indole hydrazone derivatives and
evaluation of their antiplatelet aggregation activity, Chem. Pharm. Bull. 61 (2013) 144-150.
[19] V. Mashayekhi, K. Haj Mohammad Ebrahim Tehrani, P. Azerang, S. Sardari, F. Kobarfard, Synthesis, antimycobacterial and anticancer
activity of novel indole-based thiosemicarbazones, Arch. Pharm. Res. 2013, doi: 10.1007/s12272-013-0242-z.
[20] K. Haj Mohammad Ebrahim Tehrani, V. Mashayekhi, P. Azerang, et al., Synthesis and antimycobacterial activity of novel
thiadiazolylhydrazones of 1-substituted indole-3-carboxaldehydes, Chem. Biol. Drug. Des. 83 (2014) 224-236.
[21] J. Handzlik, E. Szymańska, J. Chevalier, et al., Amine–alkyl derivatives of hydantoin: New tool to combat resistant bacteria, Eur. J. Med.
Chem. 46 (2011) 5807-5816.
[22] E. Szymańska, K. Kieć-Kononowicz, Antimycobacterial activity of 5-arylidene aromatic derivatives of hydantoin, Il Farmaco 57 (2002) 355-
362.
[23] R.P. Bhole, K.P. Bhusari, Synthesis and 3D-QSAR of p-hydroxybenzohydrazide derivatives with antimicrobial activity against multidrug-
resistant Staphylococcus aureus, J. Korean Chem. Soc. 54 (2010) 77-87.
[24] K.N. Myangar, J.P. Raval, Design, synthesis, and in vitro antimicrobial activities of novel azetidinyl-3-quinazolin-4-one hybrids,
Med. Chem. Res. 21 (2012) 2762-2771.
Page 9 of 10

[25] Z.J. Liang, D.Y. Zhang, J. Ai, et al., Identification and synthesis of N′-(2-oxoindolin-3-ylidene)hydrazide derivatives against c-Met kinase,
Bioorg. Med. Chem. Lett. 21 (2011) 3749-3754.
[26] K. Debnath, S. Pathak, A. Pramanik, Facile synthesis of ninhydrin and isatin based hydrazones in water using PEG-OSO3H as a highly
efficient and homogeneous polymeric acid-surfactant combined catalyst, Tetrahedron Lett. 54 (2013) 4110-4115.
[27] L. Tripathi, R. Singh, J.P. Stables, Design & synthesis of N′-[substituted] pyridine-4-carbohydrazides as potential anticonvulsant agents, Eur.
J. Med. Chem. 46 (2011) 509-518.
[28] T. Aboul-Fadl, H.A. Abdel-Aziz, M.K. Abdel-Hamid, et al., Schiff bases of indoline-2, 3-dione: potential novel inhibitors of mycobacterium
tuberculosis (Mtb) DNA gyrase, Molecules 16 (2011) 7864-7879.
[29] M. Hassan, Y. Javadzadeh, F. Lotfipour, R. Badomchi, Determination of comparative minimum inhibitory concentration (MIC) of
bacteriocins produced by enterococci for selected isolates of multi-antibiotic resistant Enterococcus spp, Adv. Pharm. Bull. 1 (2011) 75-79.
[30] C.A. Lipinski, F. Lombardo, B.W. Dominy, P.J. Feeney, Experimental and computational approaches to estimate solubility and permeability
in drug discovery and development settings, Adv. Drug Deliv. Rev. 46 (2001) 3-26.
Page 10 of 10