Design, synthesis, and antibacterial evaluation of some novel 3′-(phenylamino)-1′ h-spiro[indoline-3,2′-quinazoline]-2, 4′(3′ h)-dione derivatives

Article abstract of DOI:10.1080/00397911.2013.796992

A combinatorial synthesis and evaluation of antibacterial activity against clinically isolated resistant strains of Gram-positive and Gram-negative bacteria of 3′-(phenylamino)-1′H-spiro[indoline-3,2′- quinazoline]-2,4′(3′H)-dione derivatives is described

Full text of DOI:10.1080/00397911.2013.796992

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Design, Synthesis and Antibacterial Evaluation of
Same Novel 3'-(Phenylamino)-1'H-spiro[Indoline-3,2'-
quinazoline] -2,4'(3'H)-dione Derivatives
Ali A. Mohammadi a , Saber Askari a , Hamed Rohi b & Ali Abolhasani Soorki c
a Chemistry and Chemical Engineering Research Center of Iran (CCERCI) , Tehran , I.R. , Iran
b Department of Chemistry , Faculty of Sciences, Shahid Beheshti University, G.C., Evin ,
Tehran , I.R. , Iran
c Research institute of applied sciences, Academic center for education, culture and
research , Tehran , Iran
Accepted author version posted online: 27 Aug 2013.
To cite this article: Synthetic Communications (2013): Design, Synthesis and Antibacterial Evaluation of Same Novel 3'-
(Phenylamino)-1'H-spiro[Indoline-3,2'-quinazoline] -2,4'(3'H)-dione Derivatives, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2013.796992
To link to this article: http://dx.doi.org/10.1080/00397911.2013.796992
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Design, synthesis and antibacterial evaluation of same novel 3'-(phenylamino)-1'H-
spiro[indoline-3,2'-quinazoline] -2,4'(3'H)-dione derivatives
Ali A. Mohammadi1, Saber Askari1, Hamed Rohi2, Ali Abolhasani Soorki3
1Chemistry and Chemical Engineering Research Center of Iran (CCERCI), Tehran, I.R. ,
Iran, 2Department of Chemistry, Faculty of Sciences, Shahid Beheshti University, G.C.,
Evin, Tehran, I.R., Iran, 3Research institute of applied sciences, Academic center for
education, culture and research, Tehran, Iran
Corresponding author. Tel.: +98-21-44580798; Fax: +98-21-44580777; E-mail:
aliamohammadi@ccerci.ac.ir
Abstract
A combinatorial synthesis and evaluated antibacterial activity against clinically
isolated resistant strains of Gram-positive and Gram-negative bacteria of 3'-
(phenylamino)-1'H-spiro[indoline-3,2'-quinazoline]-2,4'(3'H)-dione derivatives is
described.
KEYWORDS: Isatoic anhydride, Spirooxindole , Quinazoline, Alum, Antibacterial
activity
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INTRODUCTION
Multicomponent1-5 and domino reactions6-9 are powerful tools in the creation of several
bonds in a single operation as well as in modern drug discovery process in terms of lead
finding and lead optimization.
2,3-Dihydroquinazoline-4(3H)-ones and spirooxindole derivatives are important in
biologically active and heterocyclic compounds.
Quinazolinones derivatives are an important class of molecules with biological and
pharmaceutical utility revealing antiinflammatory,10 antihypertensive,11 anticancer,12
antiviral,13 and antibacterial activity.14 In addition, these compounds are present in
several bioactive natural products.15,16
Spirooxindole are useful as antibacterial, antiinflammatory, anticancer and iaxatives.17,18
Furthermore, this ring structures were recently isolated from plant and fungi; for example
pteropodine or uncarine C (PT) was specifically isolated from cat's claw,19
spirotryprostatin B, a natural alkaloid has been isolated from the fermentation broth of
aspergillusfumigatus and identified as a novel inhibitor of microtubule assembly.20,21
Also, horsfiline was isolated from the malaysian medicinal plant horsfildea superba
warb,22 whereas spiro[pyrrolidine-3,30-oxindole] alkaloid elacomine was derived from E.
commutate (Figure 1).23
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There are several methods reported in the literature for the preparation of spirooxindoles
derivatives.24-27
RESULTS AND DISCUSSION
We have concentrated most of our recent studies on the synthesis of heterocycles
compounds,28 alum,29,30 and MCRs31,32 for the synthesis of 2,3-dihydroquinazolin-4(3H)-
one,33 spiro[indoline-3,2-quinazoline]-2,4(3H)-dione,34 oxindole,35 and spirooxindole.36
In the course of our investigations, we envisioned the one-pot three-component synthesis
of 3'-(phenylamino)-1'H-spiro[indoline-3,2'-quinazoline]-2,4'(3'H)-dione 4a-m from
isatoic anhydride 1, isatins 2 and phenyl hydrazine 3 in the presence of alum as a non-
toxic, easily available and heterogeneous catalyst.(Scheme 1)
The results of optimization experiments for the preparation of 3'-(phenylamino)-1'H-
spiro[indoline-3,2'-quinazoline]-2,4'(3'H)-dione by a straightforward one-pot three-
component condensation involving isatoic anhydrides 1, isatins 2, and phenyl hydrazine 3
in ethanol was stirred and refluxed with alum as catalysts are presented in Table 1.
It is noticeable that when the isatoic anhydride 1a-b, isatin 2a–m, and phenyl hydrazine 3
in the presence of alum were stirred at reflux for within 1 h, in all cases the reaction led to
the formation of the intermediates 8 that could be isolated and characterized by
spectroscopic methods. Furthermore, the continuation of reaction for 3 h led to a mixture
of 4a–m and intermediates 8 (monitored by TLC and spectroscopic methods), meanwhile
after the times indicated in Table 1, just 4a–m were obtained and the intermediates 8 was
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not detected in the final mixture.
According to the results, the reaction can be mechanistically considered to proceed via
the initial formation of the intermediates 8 by the nucleophilic addition of phenyl
hydrazine to isatoic anhydride as a key intermediate. Then, the isatin attacks N-atom from
8 to form an intermediate 9, leaving a water to afford 10, which then transforms the final
product via nucleophilic attack taking place by the nitrogen group. (Scheme 2)
The newly synthesized compounds were screened in vitro for their antibacterial activities
against of bacteria Escherichia coli ATCC 25922, Pseudomonas aeruginusa ATCC
85327, Klebsiella pneumonia, ATCC 29655 (Gram-negative bacteria), Enterococcus
faecalis ATCC 29737, Bacillus subtilis ATCC 465, Bacillus pumilus PTCC 1114,
Micrococcus luteus PTCC 1110, Staphylococcus aureus ATCC 25923, Staphylococcus
epidermidis ATCC 12228, Sterptococcus mutans PTCC 1601 (Gram-positive bacteria) by
the disk diffusion method (IZ),37 and subsequently the minimum inhibitory concentration
method (MIC).38
Activities of each compound were compared with Tetracycline and Gentamicin as
standards. MIC and IZ results for bacterial strains are shown in Table 2.
The screening results indicate that some of the tested compounds exhibit significant
antibacterial activities when compared with the reference drugs. It was observed that the
compounds containing R1=H and R3=Cl substituted groups show better activity than the
other test compounds and the reference, Tetracycline and Gentamicin, drugs.
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Meanwhile, 3'-(phenylamino)-1'H-spiro[indoline-3,2'-quinazoline]-2,4'(3'H)-dione
compounds 4e, 4j, 4k, 4l exhibited good activity, while the remaining compounds
generally showed inferior activities against all the tested strains.
CONCLUSION
In summary, we have developed a new strategy that provides an efficient entry in to 1'H-
spiro[isoindoline-1,2'-quinazoline]-3,4'(3'H)-dione derivatives via a one-pot three
component reaction from isatoic anhydride, isatine, and phenyl hydrazine. Our designed
process requires mild reaction conditions, have high yields of products, uses very simple
accessible starting materials and solvents, as well as an inexpensive, non-toxic, and easily
available heterogeneous catalyst, and easy experimental workup procedure.
EXERIMENTAL
General
Melting points were obtained in open capillary tubes and were measured on an electro-
thermal 9200 apparatus. Mass spectra were recorded on a Shimadzu QP 1100 BX mass
spectrometer. The IR spectra were recorded on KBr pellets on a Shimadzu IR-470
spectrophotometer. 1H and 13C NMR spectra were determined on a Bruker 300 DRX
Avance instrument at 300 and 75 MHz. Elemental analysis for C, H and N were
performed using a Heraus CHN rapid analyzer.
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General Procedure For Preparation Of 3'-(Phenylamino)-1'H- Spiro[Indoline-3,2'-
Quinazoline]-2,4'(3'H)-Dione (3a-M)
A mixture of isatoic anhydride 1 (1 mmol), isatin 2 (1 mmol), phenyl hydrazine 3 (1
mmol), 0.3 g (0.6 mmol) alum, and 10 ml EtOH in a 50 ml flask was stirred at reflux for
time period as indicated in Table 1. After completion of the reaction (monitored by TLC,
ethylacetate/n-hexane, 1:1), 25 ml EtOH was added to the reaction mixture, and
recrystallized from ethanol to afford pure product.
3'-(Phenylamino)-1'H-Spiro[Indoline-3,2'-Quinazoline]-2,4'(3'H)-Dione (4a)
yellow powder (92%); mp: 174 -176 ºC. IR (KBr): vmax = 3296, 3067, 1736, 1656, 1613
1
cm-1; H NMR (CDCl3) δ= 6.67-7.92 (15H, m, H-Ar, 2NH), 10.45 (1H, s, NH) ppm; 13C
NMR (CDCl3) δ= 78.7, 110.5, 110.8, 113.5, 113.9, 114.4, 117.9, 119.7, 122.2, 125.6,
127.7, 127.9, 128.7, 131.1, 134.4, 143.3, 146.7, 148.9, 165.6, 175.8 ppm; MS: m/z (%)=
356(M+). Anal. Calcd for C21H16N4O2: C, 70.77; H, 4.53; N, 15.72%. Found: C, 70.71; H,
4.48; N, 15.64%.
SUPPLEMENTARY INFORMATION
General experimenl procedures, IR, 1H and 13C NMR, and MS data, and experimental
analysis for compounds 4a-m are available online.
ACKNOWLEDGMENTS
We gratefully acknowledge financial support from the Research Council of Iran National
Science Foundation: INSF.
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Table 1. The synthesis of 2-Aryl-3-(phenylamino)- 1'H-spiro[indoline-3,2'-quinazoline]-
2,4'(3'H)-dione 4a–m
Entry R1
R2
H
R3 Product 4
H
Yielda (%) Time(h)
A
H
92
5.5
B
H
Br
H
H
H
97
5
C
D
CH3
Bz
90
83
5
6
H
H
H
E
H
NO2
95
4
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F
CH3 Br
H
85
5
G
H
Et
Br
H
H
93
90
5
4
Me NO2
I
Et
H
H
H
60
87
7
6
J
Br
Cl
K
H
H
Cl
90
6
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L
H
NO2 Cl
94
88
5
6
M
Me
H
Cl
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Table 2. Antibiotic activity of the synthesized compounds and standard antibiotics against some gram positive and gram negative
bacteria, as determined by disc diffusion test (IZ) and Minimum Inhibitory Concentration (MIC) methods.
Tetracycline (30
(ig/disc)
Gentamicin
(10 iig/disc)
4a
4b
4c
4d
4e
4f
Microorganisms
IZa
MICb
IZ
MIC
NTc
IZ MIC IZ MIC IZ MIC IZ MIC IZ MIC IZ MIC
Bacillus subtilis (ATCC
465)
21
4
0
0
0
0
0
14 128 13 256
0
0
0
0
0
NT
NT
NT
NT
NT
0
0
0
0
0
NT 16
NT 18
NT 16
NT 18
NT 16
4
4
8
4
4
12 512
Bacilluspumilus (PTCC
1114)
17
19
20
34
8
4
NT
NT
NT
NT
18
14
16
14
16 14 128
64 12 256
32 14 256
32 15 256
0
0
NT
NT
Micrococcus luteus
(PTCC 1110)
Staphylococcus aureus
(ATCC 25923)
Staphylococcus
epidermidis (ATCC
4
14 128
<2
8
512

12228)
Sterptococcus mutans
(PTCC 1601)
24
0
2
0
23
0
NT
4
16
14
8
32 16 64
0
0
0
0
0
NT
NT
NT
NT
NT
0
0
0
0
0
NT 18 <2 15 32
Escherichia coli (ATCC
25922)
NT
8
64
0
0
0
0
NT
NT
NT
NT
NT 16
4
14 32
Enterococcus faecalis
(ATCC 29737)
9
NT
8
256
NT 14 16
NT 15 32
0
0
NT
NT
Pseudomonas aeruginosa
(ATCC 85327)
0
NT
16
12
0
10 256
10 256
Klebsiella pneumonia
(ATCC 29655)
8
NT
NT 14
8
13 256
Microorganisms
4g
IZ
14
4h
4i
4j
MIC IZ
NT 20
4k
MIC IZ
16
41
MIC IZ
23
4m
0
MIC
64
IZ
0
MIC IZ
NT
MIC IZ
MIC
NT
Bacillus subtilis
(ATCC 465)
0
4
8
<2

Bacillus pumilus
(PTCC 1114)
13
0
128
NT
512
0
0
0
NT
NT
NT
0
0
0
NT 22
NT 18
NT 25
<2
4
19
16
18
4
8
2
28
20
20
<2
2
0
0
0
NT
NT
NT
Micrococcus luteus
(PTCC 1110)
Staphylococcus
aureus (ATCC
25923)
12
2
2
Staphylococcus
epidermidis (ATCC
12228)
0
NT
0
NT
0
NT 23
2
15
4
19
2
0
NT
Sterptococcus
mutans (PTCC 1601)
Escherichia coli
(ATCC 25922)
Enterococcus
0
0
0
NT
NT
NT
0
0
0
NT
NT
NT
0
0
0
NT 28
NT 22
NT 19
<2
<2
<2
17
14
10
8
16
19
8
0
0
0
NT
NT
NT
32
<2
8
128 16
faecalis (ATCC

29737)
Pseudomonas
aeruginosa (ATCC
85327)
0
0
NT
NT
0
0
NT
NT
0
0
NT 17
NT 15
8
4
0
0
NT 15
NT 12
16
16
0
0
NT
NT
Klebsiella
pneumonia (ATCC
29655)
aInhibition Zone (mm)
bMinimum Inhibitory Concentration (ng/ml)
cNot Tested

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Scheme 1. synthesis of pyrroles 3a-h
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16

ACCEPTED MANUSCRIPT
Scheme 2.
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ACCEPTED MANUSCRIPT
Figure 1.
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18