Synthesis and in vitro antimicrobial evaluation of piperazine substituted quinazoline-based thiourea/thiazolidinone/chalcone hybrids

Article abstract of DOI:10.1134/S1068162015020132

In frames of the search for new biological entities to fight against recent drug-resistant microbial strains, we report a library of quinazoline-based thiourea/4-thiazolidinone/chalcone hybrids. The newly synthesized compounds were studied for efficacy against several bacteria (Staphylococcus aureus, Bacillus cereus, Pseudomonas aeruginosa, and Klebsiella pneumoniae) and fungi (Candida albicans and Aspergillus clavatus) using the broth dilution technique. From the biological evaluation, (E)-3-(3,4-dimethoxyphenyl)-1-(4-((4-(4-ethylpiperazin-1-yl)quinazolin-2-yl)amino)phenyl)prop-2-en-1-one was found to be the most active analogue (microbial inhibition concentration 3.12 μg/mL) to inhibit the bacterial growth. The rest of the compounds showed equipotent efficacy (3.12-12.5 μg/mL) as compared to the standard. Final compounds were characterized by FT-IR, ¹H NMR, ¹³C NMR, mass spectroscopy, and elemental analysis.

Full text of DOI:10.1134/S1068162015020132

ISSN 1068ꢀ1620, Russian Journal of Bioorganic Chemistry, 2015, Vol. 41, No. 2, pp. 209–222. © Pleiades Publishing, Ltd., 2015.
Synthesis and In Vitro Antimicrobial Evaluation
of Piperazine Substituted QuinazolineꢀBased
Thiourea/Thiazolidinone/Chalcone Hybrids1
D. R. Shah, H. P. Lakum, and K. H. Chikhalia2
Department of Chemistry, School of Sciences, Gujarat University, Ahmedabed, Gujarat, 380009 India
Received June 11, 2014; in final form, July 23, 2014
Abstract—In frames of the search for new biological entities to fight against recent drugꢀresistant microbial
strains, we report a library of quinazolineꢀbased thiourea/4ꢀthiazolidinone/chalcone hybrids. The newly synꢀ
thesized compounds were studied for efficacy against several bacteria (Staphylococcus aureus, Bacillus cereus,
Pseudomonas aeruginosa, and Klebsiella pneumoniae) and fungi (Candida albicans and Aspergillus clavatus
)
using the broth dilution technique. From the biological evaluation, (E)ꢀ3ꢀ(3,4ꢀdimethoxyphenyl)ꢀ1ꢀ(4ꢀ((4ꢀ
(4ꢀethylpiperazinꢀ1ꢀyl)quinazolinꢀ2ꢀyl)amino)phenyl)propꢀ2ꢀenꢀ1ꢀone was found to be the most active anaꢀ
logue (microbial inhibition concentration 3.12 μg/mL) to inhibit the bacterial growth. The rest of the compounds
showed equipotent efficacy (3.12–12.5 g/mL) as compared to the standard. Final compounds were characterized
µ
by FTꢀIR, 1H NMR, 13C NMR, mass spectroscopy, and elemental analysis.
Keywords: 4ꢀthiazolidinone, antibacterial activity, antifungal activity, chalcone, quinazoline, thiourea
DOI: 10.1134/S1068162015020132
2 1
INTRODUCTION
antiꢀtubercular [11], antiꢀmalarial [12], and antiꢀ
diuretic [13] activities. Quinazoline linked thiourea
hybrid derivatives have been identified as impressive
antimicrobial agents [14]. Furthermore, the presence
of piperazine substituents at Cꢀ4 position of quinazoꢀ
line core has proved to be the active key in various bioꢀ
logical effects [15]. Moreover, quinazoline and their
condensed products with thiazolidinone derivatives
have been reported to possess interesting antimicrobial
activity [16, 17].
Encouraged by our previous successful research
efforts [10, 18,19] in this regard, we decided to further
extend the above methodology to identify more
quinazolinyl hybrids. In view of the aboveꢀmentioned
knowledge of different pharmacophores and in conꢀ
tinuation of our research program, we have designed
(figure) and synthesized quinazolineꢀthiourea/thiazoꢀ
lidinone/chalcone hybrids and incorporated piperaꢀ
zine and electronic environment to get single bioactive
molecule framework. Compounds were subjected to
evaluation of their antibacterial and antifungal
potency against various bacterial strains. As a result,
some of the derivatives showed excellent activity in the
range of 3.12–12.5 μg/mL of MIC.
During the past few decades, the growing populaꢀ
tion is affected with significant increase in the freꢀ
quency of severe infectious diseases because of the
increasing number of multiꢀdrugꢀresistant (MDR)
microbial pathogens. Increasing number of MDR
strains developed by the microbes makes currently
used antimicrobial drugs ineffective. Over the past
years, alleviation of opportunistic microbial infections
became an imperative and challenging problem due to
the inactiveness of susceptible microorganism. Rapid
multiplication of drug resistant strains poses a severe
threat in recent years [1–3]. Such infection readily
affects debilitated and immune compromised patients.
Hence, there is an urgent need to alleviate drug resisꢀ
tance by providing more effective potential therapeuꢀ
tic agents [4, 5].
The search for novel bioactive agents with higher
selectivity and lower toxicity continues to be an area of
intensive investigation in synthetic medicinal chemisꢀ
try. On the path of identifying various chemical subꢀ
stances that may serve as leads for designing novel bioꢀ
active agents, nitrogenꢀcontaining heterocycles are of
particular interest. Quinazoline scaffold has been
extensively studied for its many pharmacological
properties [6], which include antiꢀcancer [7], antiꢀ
inflammatory [8], antiꢀbacterial [9], antiviral [10],
RESULTS
Chemistry
1
The scheme outlines the synthetic pathway used to
The article is published in the original.
Corresponding author: phone: +91ꢀ79ꢀ26300969/9427155529;
fax: +91ꢀ79ꢀ26308545; eꢀmail: chikhalia_kh@yahoo.com.
2
obtain compounds (Va –e, VIIIa–e, Xa–e, and XIIIa–e).
The first step comprises formation of quinazolineꢀ
209

210
SHAH et al.
2,4(1H,3H)ꢀdione (1) in very good yield by the reacꢀ piperazine in isopropyl alcohol to form 2ꢀchloroꢀ4ꢀ(4ꢀ
tion of anthranilic acid and urea [20]. Cyclization of
intermediate ( ) with POCl3 forms the 2,4ꢀdichloroꢀ
phenylpiperazinꢀ1ꢀyl)quinazoline(III). Compound (III
was then reacted to ammonium thiocyanate and variꢀ
)
I
quinazoline (II). This was further reacted to
Nꢀphenyl ous amines to give final thiourea derivatives (Va – e ).
O
O
N
Cl
Urea
160°C
NH
OH
TEA, POCl
3
N
N
O
NH2
H
Cl
(
I
)
(II)
S
N=C=S
N
N
Cl
N
N
NH NH
N
N
Nꢀphenyl piperazine
IPA, RT
N
NH SCN
4
Cu, Toluene
Substituted amine,
Acetone, 40–45°C
N
N
N
N
N
R
(
Va–e)
(
III
)
(
IV)
(II)
S
N=C=S
N
N
Cl
N
N
NH
R
N
Nꢀethyl piperazine
IPA, RT
NH SCN
4
Cu, Toluene
Substituted piperazine
Acetone, 40–45°C
N
N
N
N
N
N
N
(VI)
(
VII
)
(VIIIa–e)
COCH3
COCH
N
N
NH
N
N
NH
4ꢀamino acetophenone
IPA, Reflux
Substituted aldehyde
MeOH, NaOH
N
R
N
N
N
(IX
)
(Xa–e)
S
O
S
(VI)
N
R
NHN
N
NHNH
N
N
N
NHNH2
N
H
N
N
N
Cyclization
ClCH COOC H
2 5
NAOAc, EtOH, Reflux
ArꢀNCS
EtOH, Reflux
Hydrazine hydrate
IPA, Reflux
2
R
N
N
N
N
N
(
XI
)
(
XIIa–e
)
(XIIIa–e)
Scheme. Synthetic route for the synthesis of quinazolineꢀbased final hybrid
Va VIIIa Xa , and XIIIa ) derivatives.
(
–e
,
–e
,
–e
–e
Intermediated (II) was then further reacted to
yl piperazinefꢀorming 2ꢀchloroꢀ4ꢀ(4ꢀethylpiperazinꢀ1ꢀ yl)quinazolinꢀ2ꢀyl)amino)phenyl)ethanone
yl)quinazoline (VI) further reacted with ammonium and 4ꢀ(4ꢀethylpiperazinꢀ1ꢀyl)ꢀ2ꢀhydrazinylquinazoꢀ
thiocyanate and piperazine to give final (VIIIa ) comꢀ line (XI), respectively. Out of them, (IX) was then conꢀ
pounds. Intermediate 2ꢀchloroꢀ4ꢀ(4ꢀethylpiperazinꢀ densed to various aldehydes to form chalcone (Xa
1ꢀyl)quinazoline (VI) was refluxed to replace 2ꢀCl analogues, whereas intermediate (XI) was reacted with
position with 4ꢀamino acetophenone and hydrazine various phenyl isothiocyanate and further cyclized
N
ꢀethꢀ hydrate that gives 1ꢀ(4ꢀ((4ꢀ(4ꢀethylpiperazinꢀ1ꢀ
(
IX
)
–e
–e)
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SYNTHESIS AND IN VITRO ANTIMICROBIAL EVALUATION
211
N
N
N
N
R
N
N
NH
N
N
Cl
Quinazolineꢀchalcone hybrid
N
N
N
R
N
R
N
N
NHN
N
N
R
Design of the title quinazolineꢀbased hybrids.
with chloroethylacetate and sodium acetate to form whereas Ketoconazole was used as standard control
drug for antifungal activity.
desired thiazolidinone (XIIIa–e) derivatives. The acꢀ
curacy of the synthesis of final compounds was conꢀ
firmed on the basis of 1H NMR, 13C NMR, and mass
spectra and the purity was ascertained by elemental
analysis. Physical and analytical data of title comꢀ
pounds are elaborated in Table 1.
In vitro antibacterial activity. Table 2 shows that all
the newly synthesized quinoline scaffolds were found
to exhibit good to moderate activity against the specifꢀ
ic microbial strain. Bioassay results of the series of
(Va – e ) compounds revealed that final analogue (Ve),
bearing electron donating methyl group at para posiꢀ
tion of phenyl ring, was found to be the most active
compound that inhibits the gramꢀpositive S. aureus
bacterial growth at the lowest minimum inhibitory
Biological Evaluation
All newly synthesized quinazoline derivatives (Va
–e,
concentration (MIC) value of 3.12
pound (Vc) with chloro group showed lower effectiveꢀ
ness with 12.5 g/mL MIC against the same bacteria.
The presence of an electron snatching substituent, like
nitro group (Vb), proved to be intrinsic to conduce
noteworthy activity at 12.5 g/mL of MIC against the
B. cereus strain. Compound (Vd) containing chloro
group at para position of the phenyl ring showed halfꢀ
fold (6.25 g/mL MIC) inhibitory activity against
μg/mL. Comꢀ
VIIIa Xa , and XIIIa ) were examined for anꢀ
–e,
–e
–e
timicrobial activity against two gramꢀpositive bacterial
strains (Staphylococcus aureus MTCC 96, Bacillus
cereus MTCC 430), two gramꢀnegative bacterial strains
μ
(
Pseudomonas aeruginosa MTCC 741, Klebsiella pneuꢀ
μ
moniae MTCC 109), and two fungal strains (Aspergillus
clavatus MTCC 1323, Candida albicans MTCC 183)
using agar dilution method [21]. Ciprofloxacin was
μ
used as standard control drug for antibacterial activity, gramꢀnegative P. aeruginosa strain as compared to
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212
SHAH et al.
Table 1. Physical and analytical data of final synthesized quinazolinyl derivatives (Va
–
e
,
VIIIa
Elemental analysis
calcd. found
%C %H %N %C %H %N
440.56 72 129–133 68.16 5.49 19.08 68.32 5.47 19.03
–e, Xa–e, and XIIIa–e)
Mol. Yield,
Entry
R
Mol. formula
mp (°C)
weight
%
(Va )
H
C25H24N6S
(
Vb
)
)
2ꢀNO2
3ꢀCl
C25H23N7O2S 485.56 67 162–164 61.84 4.77 20.19 61.67 4.76 20.13
C25H23ClN6S 475.01 65 163–165 63.21 4.88 17.69 63.03 4.87 17.65
C25H23ClN6S 475.01 65 130–131 63.21 4.88 17.69 63.31 4.89 17.64
(
Vc
(
Vd
)
)
4ꢀCl
(
Ve
4ꢀCH3
C26H26N6S
454.59 67 213–215 68.69 5.76 18.49 68.76 5.77 18.44
N
N
C29H39N7O3S
(
VIIIa
)
)
565.73 66 139–141 61.57 6.95 17.33 61.39 6.96 17.29
O
O
O
O
N
C22H31N7O2S
(
VIIIb
457.59 65 162–164 57.74 6.83 21.43 57.86 6.81 21.39
O
N
N
C20H29N7S
C21H31N7S
(
VIIIc
)
)
399.56 64 201–203 60.12 7.32 24.54 59.95 7.31 24.48
413.58 67 110–112 60.99 7.55 23.71 61.09 7.53 23.64
N
N
(VIIId
N
C26H33N7S
(
VIIIe
)
475.65 67 221–223 65.65 6.99 20.61 65.49 6.97 20.55
N
N
C29H29N5O
(
Xa
)
)
463.57 66 221–221 75.14 6.31 15.11 74.92 6.32 15.07
479.57 67 112–114 72.63 6.10 14.60 72.46 6.12 14.59
O
OH
C29H29N5O2
(
Xb
O
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SYNTHESIS AND IN VITRO ANTIMICROBIAL EVALUATION
213
Table 1. (Contd.)
Elemental analysis
Mol. Yield,
Entry
R
Mol. formula
mp (
°C)
calcd.
found
weight
%
%C %H %N %C %H %N
O
C27H27N5O2
(
Xc
)
)
453.54 65 164–166 71.50 6.00 15.44 71.40 6.01 15.48
523.63 69 207–209 71.11 6.35 13.37 70.91 6.34 13.34
O
O
O
C31H33N5O3
(
Xd
O
O
HO
C31H33N5O2
(Xe
)
507.63 67 154–157 73.35 6.55 13.80 73.47 6.54 13.76
(
(
(
(
(
XIIIa
XIIIb
XIIIc
XIIId
XIIIe
)
)
)
)
)
H
C23H25N7OS 447.56 74 152–154 61.72 5.63 21.91 61.66 5.64 21.86
C24H27N7OS 461.58 66 142–144 62.45 5.90 21.24 62.31 5.88 21.29
C23H24ClN7OS 482.00 55 154–158 57.31 5.02 20.34 57.21 5.01 20.31
C23H24ClN7OS 482.00 61 122–124 57.31 5.02 20.34 57.16 5.01 20.30
C23H24FN7OS 465.55 56 197–200 59.34 5.20 21.06 59.51 5.19 21.00
2ꢀCH3
2ꢀCl
2ꢀCl
2ꢀF
standard ciprofloxacin drug (3.12
spectively. Analogue (Va )manifested excellent inhibiꢀ exhibited good inhibitory profile at MIC 3.12 and
tion of gramꢀnegative K. pneumoniae strain at 12.5 g/mL against gramꢀnegative K. pneumoniae and
12.5 g/mL of MIC. P. aeruginosa bacteria, respectively.
For the series (VIIIa
μg/mL MIC), reꢀ most active analogue in the series. Compound (VIIIb)
μ
μ
–e) derivatives, compound (VIIId)
In the series of (Xa ) derivatives, compound (Xa)
–
e
bearing ꢀethyl piperazine ring showed the strong inꢀ
with unsubstituted phenyl ring showed excellent
hibitory action at 3.12 g/mL of MIC against gramꢀ
growth inhibition of gramꢀpositive S. aureus bacteria
positive S. aureus strain. Analogues (VI IIb) with
at 3.12 g/mL of MIC. Two derivatives with 3,4ꢀ
ꢀethoxy carbonyl piperazine showed slightly reꢀ
dimethoxy (Xd) and 3,5ꢀdimethoxy,4ꢀhydroxy (Xe
duced activity of 6.25 g/mL MIC against the same
substituents on phenyl ring appeared with slightly diꢀ
bacteria. Compound (VIIIc) bearing ꢀmethyl pipꢀ
minished activity (MIC 12.5 g/mL) against the same
erazine moiety appeared with halfꢀfold growth inhiꢀ
bacteria.
bition (6.25 g/mL MIC) of gramꢀpositive B. cereus
N
μ
–
μ
N
)
μ
N
μ
μ
bacteria as compared to reference ciprofloxacin drug From the bioassay of (XIIIa
(3.125 g/mL MIC). Excellent inhibition with unsubstituted phenyl ring displayed remarkable
(3.12 g/mL of MIC) against gramꢀnegative activity (12.5 g/mL MIC) against S. aureus bacteria.
P. aeruginosa strain was noted for trimethoxy phenyl atꢀ The inhibition of B. cereus strain’s growth at
–e), compound (VIIIa)
μ
μ
μ
tached piperazine compound (VIIIa), which was the 3.12 g/mL of MIC was greatly achieved by methyl
μ
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214
Table 2. In vitro antibacterial and antifungal activity in MIC* (
Gramꢀpositive bacteria Gramꢀnegative bacteria
SHAH et al.
µ
g/mL) of compounds (Va
–e,
VIIIa–e,
Xa
–e, and XIIIa–e)
Fungal strains
Entry
R
S. aureus B. cereus P. aeruginosa K. pneumoniae A. clavatus C. albicans
MTCC 96 MTCC 430 MTCC 741 MTCC 109 MTCC 1323 MTCC 183
(
Va
)
H
25
400
12.5
100
25
6.25
100
400
6.25
3.12
400
3.12
50
25
6.25
12.5
400
(Vb
)
2ꢀNO2
3ꢀCl
400
(
Vc
Vd
)
12.5
100
3.12
25
100
50
400
200
25
(
)
)
4ꢀCl
3.12
25
3.12
(
Ve
4ꢀCH3
200
100
50
100
100
(
VIIIa
)
)
50
N
N
O
O
O
(
VIIIb
6.25
25
12.5
25
3.12
200
100
25
O
N
O
N
(
(
(
VIIIc
VIIId
VIIIe
)
)
)
100
6.25
400
100
25
3.12
N
N
3.12
200
100
400
200
6.25
N
N
200
50
3.12
400
N
O
N
(
Xa
)
)
3.12
100
200
12.5
200
400
50
100
200
(
Xb
50
100
3.12
OH
O
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SYNTHESIS AND IN VITRO ANTIMICROBIAL EVALUATION
215
Table 2. (Contd.)
Gramꢀpositive bacteria Gramꢀnegative bacteria
R
Fungal strains
Entry
S. aureus B. cereus P. aeruginosa K. pneumoniae A. clavatus C. albicans
MTCC 96 MTCC 430 MTCC 741 MTCC 109 MTCC 1323 MTCC 183
(
Xc
)
)
50
12.5
3.12
400
25
25
3.12
O
O
(Xd
12.5
100
200
3.12
100
O
O
O
O
(
Xe)
12.5
200
100
100
6.25
200
50
12.5
HO
(
(
(
(
(
XIIIa
XIIIb
XIIIc
XIIId
)
)
)
)
H
12.5
3.12
400
100
100
12.5
200
2ꢀCH3
2ꢀCl
3ꢀCl
2ꢀF
400
3.12
200
50
12.5
3.12
200
25
25
25
100
100
50
3.12
100
3.125
200
25
400
XIIIe
)
100
3.125
–
6.25
3.12
Ciprofloxacin†
Ketoconazole†
3.125
–
3.125
–
–
–
3.125
–
–
–
3.125
–
DMSO (control)
–
–
–
* MIC, minimum inhibitory concentration. † Standard.
containing substituent at ortho position of phenyl ring derivatives demonstrated equipotent and halfꢀfold anꢀ
XIIIb) whereas (XIIIe) analogue bearing fluoro group tigrowth activity as compared to the control drug ketoꢀ
showed halfꢀfold inhibitory action (6.25 g/mL MIC) conazole (MIC 3.125 g/mL). Analogue (Va ) exhibꢀ
as compared to standard ciprofloxacin drug ited superior activity against C. albicans fungi with
(3.12 g/mL MIC). Compound (XIIIa) was found the lowest MIC value, i.e. 3.12 g/mL. Moreover,
potentially active against gramꢀnegative P. aeruginosa compounds (Vd) exerted potential inhibitory effiꢀ
bacterial strain with MIC 3.12 g/mL. Compound ciency (6.25 g/mL) against the same strain. With
XIIId) containing orthochloro phenyl ring appeared 12.5 g/mL MIC, compound (Ve) also appeared with
with significant inhibition of K. pneumoniae at lowest good inhibition of C. albicans fungal strain’s growth.
MIC value of 3.12 g/mL. All the remaining anaꢀ
logues were observed with good to promising inhibitoꢀ
ry effects at MIC level ranging from 25–400 g/mL.
(
μ
μ
μ
μ
μ
μ
(
μ
μ
For (VIIIa
containing ꢀmethyl and
zine ring, respectively, showed equipotent antigrowth
activities (3.12 g/mL MIC) against A. clavatus fungi
compared to control drug ketoconazole (3.125 g/mL
MIC). Derivative (VIIId) appeared with halfꢀfold
(6.25 g/mL) inhibitory action against C. albicans
–
e
) derivatives, (VIIIc) and (VIIIe
)
N
Nꢀmethylꢀ3ꢀphenyl piperaꢀ
μ
μ
In vitro antifungal activity. Antifungal activity data
(Table 2) showed that among the (Va ) analogues,
Vc ) bearing meta chloro substituted phenyl ring disꢀ
played excellent antigrowth activity at 3.12 g/mL
MIC, whereas (Vb) with nitro substituent at ortho poꢀ
sition of phenyl ring also showed good activity at
6.25
μ
–e
(
μ
μ
fungal strain.
From bioassay data of (Xa–e), compound (Xd) was
μ
g/mL MIC against A. clavatus fungi. These two found more active analogue for the inhibition of
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216
SHAH et al.
A. clavatus fungi at 3.12
μ
g/mL MIC. Compound (Xc
)
bearing chalcone bases. Compound (Xd) showed the
displayed strong inhibitory action against C. albicans equipotent efficacy towards the bacteria. Most of the
fungi at 3.12 g/mL MIC. Moreover, analogue (Xe) exꢀ compounds appeared with superior and remarkable
hibited remarkable antifungal action with 12.5
MIC against the same fungi.
In the series of (XIIIa
XIIIc) showed equal potency (3.12
the inhibition of A. clavatus fungal strain. Moreover,
analogue (XIIIb) was found remarkably lower active,
with 12.5 g/mL MIC against the same strain. Derivꢀ
ative (XIIIe) bearing fluoro substituent appeared with
superior antigrowth activity towards C. albicans fungi
at 3.12 g/mL MIC. Compound (XIIIa) showed diꢀ
minished inhibitory action at 12.5 g/mL MIC
μ
μg/mL activity. Therefore, it is concluded that there exists
ample scope for further study in this class of comꢀ
pounds in order to discover various biological profiles
such as anticancer activity or antiꢀHIV activity. The
study is currently ongoing and the results will be pubꢀ
lished in due course.
–e
) derivatives, compound
(
μg/mL MIC) for
μ
EXPERIMENTAL
μ
Material and Methods
μ
All the chemicals and solvents used for the syntheꢀ
sis work acquired from commercial sources were of
analytical grade and were used without further purifiꢀ
cation. Anthranilic acid, urea, various amines, piperaꢀ
zine, and aldehydes were procured from Sigma Aldꢀ
rich Chemicals Pvt. Ltd., Mumbai, India. Hydrazine
hydrate was purchased from Spectrochem Pvt. Ltd.,
Mumbai, India. 4ꢀAmino acetophenone and TLC
plates were obtained from Merck, Germany. Evaporaꢀ
tion of solvents was carried out on a rotary evaporator
under reduced pressure or using a highꢀvacuum pump.
Melting points were determined by using open capilꢀ
lary tubes and are uncorrected. TLC was run on
EꢀMerck preꢀcoated 60 F254 plates and the spots were
rendered visible by exposing to UV light or iodine. IR
spectra (νmax, cm–1) were recorded on BRUKER
TENSOR series FTꢀIR and SHIMADZU HYPER IR
spectrometers using KBr pellets. NMR spectra were
recorded by 400 MHz BRUKER AVANCE instruꢀ
ment using TMS as internal standard (chemical shift
against the C. albicans fungal strain. The activity level
of many analogues was found to increase within the
scaffolds studied in the research work presented here,
whereas all other derivatives appeared with fungal acꢀ
tivity varying in the range from 25 to 400 g/mL MIC.
μ
DISCUSSION
The presented biological evaluation showed novel
and innovative results from medicinal point of view.
Among the compounds with halogen substituents,
mainly chloro substituent showed more remarkable
antibacterial and antifungal activity than fluoro group.
Methyl group, due to the electron donating tendency,
may give good efficacy whereas unsubstitution on pheꢀ
nyl ring lead promising results in antifungal assay. Hetꢀ
erocyclic aldehyde (furfuraldehyde) gave good anticiꢀ
pation in antibacterial and antifungal activity.
piperazine showed better antibacterial efficacy than
ꢀmethyl piperazine, therefore one may conclude
Nꢀethyl
N
in , ppm) and DMSOꢀd6 as a solvent. Spectra were
δ
that ethyl group may improve antibacterial action
faster than methyl group. However, for antifungal
1
taken with a resonant frequency of 400 MHz for H
and 100 MHz for 13C NMR. The splitting patterns are
designated as follows; s, singlet; d, doublet; dd, douꢀ
blet of doublets; and m, multiplet. Elemental analysis
was done on “Haraeus Rapid Analyser”. The mass
spectra were recorded on JEOL SXꢀ102 (EI) instruꢀ
ment with 60 eV ionizing energy.
assay, the conclusion is reverse for the
Nꢀethyl and
N
ꢀmethyl piperazine. Presumably, the steric hinꢀ
drance of hydroxyl group between two methyl groups
reduces the potential effect in (Xe) as compare to other
aldehydes.
Quinazolineꢀ2,4(1
acid (10 g, 0.07 mol) and urea (43.79 g, 0.73 mol) were
stirred at 160 C for 6 h. Reaction was monitored by
TLC in hexane–ethyl acetate (6 : 4). After completion
of the reaction, the mixture was cooled to 100 C and
water was added while stirring for 5 min. The precipiꢀ
tate formed was filtered off and washed with water to
yield a solid cake that was suspended in a solution of
0.5 N NaOH and heated to boil for 5–10 min. The mixꢀ
ture was cooled and pH adjusted to 2 with concentrated
HCl; the solid was filtered off. After washing with waꢀ
ter–methanol (1 : 1), the product was dried, giving
H,3H)ꢀdione (I). Anthranilic
CONCLUSION
°
In this article, we have presented the initial efforts
made toward the discovery of novel, potentially active
quinazolineꢀlinked thiourea/thiazolidinone/chalcone
hybrids. Owing to the presence of three pharmacologꢀ
ically active nuclei, viz., quinazoline, piperazines, and
thiourea/thiazolidinone/chalcone, in one single molꢀ
ecule, compounds executed potent antimicrobial
effect. From the bioassays it is clear that the introducꢀ
tion of appropriate substituent in the quinazoline
based ring leads to more active antimicrobial derivaꢀ
tives. It can be stated that the variation of antimicroꢀ
bial activity may be associated with the nature of tested
microorganisms and is due to the chemical structure
of the tested compounds. In the present study, higher
°
white solid of (
2,4ꢀDichloroquinazoline
2,4(1 ,3 )ꢀdione ( ) (5 g, 0.03 mol), triethylamine
(6.43 mL, 0.05 mol), and POCl3 (25 mL, 0.27 mol)
I). Yield 87%; mp 112–113°C [20].
(II). Quinazolineꢀ
H
H
I
potency has been observed with the final compounds were refluxed for 7 h (monitored by TLC in toluene–
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SYNTHESIS AND IN VITRO ANTIMICROBIAL EVALUATION
217
acetone (5 : 5). After the excess POCl3 was distilled off ondary), 3020 (C–H, aromatic), 2944 (C–H, aliphatꢀ
ic), 1667 (C=N), 1445 (ꢀNO2), 1315 (C–N), 1278
under vacuum, crushed ice was added to the residue.
Reaction mixture was then stirred for 1 h at 0–5 C.
The solid product was filtered, washed with water, and
dried to give yellow solid of 2,4ꢀdichoroꢀquinazoline (II).
Yield 67%; mp 116–117 C.
2ꢀChloroꢀ4ꢀ(4ꢀphenylpiperazinꢀ1ꢀyl)quinazoline (III).
To a solution of 2,4ꢀdichloroquinazoline (II) (5 g,
0.025 mol) and isopropyl alcohol (40 mL), 1ꢀphenyl
piperazine (5.29 g, 0.032 mol) was added and stirred at
room temperature for 8–12 h. Reaction progress was
observed by TLC in hexane–ethyl acetate (8 : 2).
Washing of the crude solid with IPA and drying gives
1
°
(C=S); H NMR: 9.14 (s, 1H), 8.19 (dd,
2H), 7.94 (dd, = 7.1, 1H), 7.78–7.52 (m, 5H), 7.40
(td, = 7.4 Hz, 1H), 7.09 (t, = 6.5 Hz, 2H), 6.67–
6.57 (m, 3H), 3.66–3.60 (m, 4H), 3.53 (t, = 4.8 Hz,
= 5.0 Hz, 2H); C NMR (100 MHz,
ppm): 182.24, 163.30, 155.77, 151.30,
150.96, 140.41, 134.99, 134.18, 131.22, 130.18, 129.35,
125.74, 125.26, 124.62, 123.32, 122.82, 120.31,
116.77, 111.60, 49.48, 47.89; ESIꢀMS ( + 1): 486.24.
J = 7.5 Hz,
J
J
J
°
J
13
2H), 3.43 (t,
DMSOꢀd6
J
,
δ
M
1ꢀ(3ꢀChlorophenyl)ꢀ3ꢀ(4ꢀ(4ꢀphenylpiperazinꢀ1ꢀyl)
quinazolinꢀ2ꢀyl)thiourea (Vc). IR: 3375 (N–H, secꢀ
ondary), 3045 (C–H, aromatic), 2924 (C–H, aliphatꢀ
ic), 1634 (C=N), 1342 (C–N), 1204 (C=S);
1H NMR: 8.75 (s, 1H), 8.05–7.77 (m, 3H), 7.51 (td,
pure solid of (III). Yield 69%; mp 124–126°C.
2ꢀIsothiocyanatoꢀ4ꢀ(4ꢀphenylpiperazinꢀ1ꢀyl)quinazoꢀ
line (IV). A solution of 2ꢀchloroꢀ4ꢀ(4ꢀphenylpiperꢀ
azinꢀ1ꢀyl)quinazoline (III) (2 g, 0.006 mol), ammoniꢀ
um thiocynate (0.93 g, 0.012 mol), and copper powder
(0.75 g, 0.012 mol) in anhydrous toluene was refluxed
J
J
= 7.2 Hz, 1H), 7.38 (t,
= 6.1 Hz, 1H), 7.12–7.01 (m, 4H), 6.65 (dd,
J
= 4.5 Hz, 1H), 7.11 (t,
= 6.2 Hz,
J = 4.9 Hz, 3H), 3.57–3.46 (m, 6H);
J
3H), 3.72 (dd,
at 90–120°C for 18 h. The completion of the reaction
13C NMR: 178.91, 164.24, 156.15, 150.57, 150.21,
144.35, 132.57, 130.18, 129.64, 128.24, 125.71,
125.01, 124.24, 123.46, 120.64, 120.27, 119.66,
was monitored by TLC in ethanol–acetone (1 : 1).
The reaction mixture was filtered and concentrated
under reduced pressure. The resulting residue was disꢀ
solved in dichloromethane and washed with brine,
and dried over Na2SO4. The dried solution was conꢀ
centrated under reduced pressure to obtain the comꢀ
116.34, 111.24, 49.87, 47.24; ESIꢀMS (
476.67.
M + 1):
1ꢀ(4ꢀChlorophenyl)ꢀ3ꢀ(4ꢀ(4ꢀphenylpiperazinꢀ1ꢀyl)
quinazolinꢀ2ꢀyl)thiourea (Vd). IR: 3435 (N–H, secꢀ
ondary), 3012 (C–H, aromatic), 2935 (C–H, aliphatꢀ
pound (IV). Yield 75%; mp 144–146
Synthesis of 1ꢀ ubstituted phenylꢀ3ꢀ(4ꢀ(4ꢀpheꢀ
nylpiperazinꢀ1ꢀyl)quinazolinꢀ2ꢀyl)thiourea Va – e ) .
°C.
s
1
ic), 1667 (C=N), 1335 (C–N), 1234 (C=S); H
(
A
NMR: 8.10 (dd,
7.77 (td, = 6.8, 1H), 7.53 (td,
= 6.2 Hz, 2H), 7.22 (d, = 7.1 Hz, 2H), 7.09 (dd,
= 6.3 Hz, 2H), 6.64 (dd, = 6.1Hz, 4H), 3.72–3.30
(m, 8H); C NMR: 178.91, 163.30, 155.77, 151.30,
150.96, 139.93, 130.18, 129.37, 129.35, 128.20,
125.74, 125.26, 123.32, 121.95, 120.31, 116.77,
111.57, 48.54, 45.67; ESIꢀMS (
1ꢀ(4ꢀ(4ꢀPhenylpiperazinꢀ1ꢀyl)quinazolinꢀ2ꢀyl)ꢀ3ꢀ
ꢀtolyl)thiourea (Ve). IR: 3420 (N–H, secondary),
J
= 7.4 Hz, 1H), 9.02–7.84 (m, 2H),
solution of 2ꢀisothiocyanatoꢀ4ꢀ(4ꢀphenylpiperazinꢀ
1ꢀyl)quinazoline (IV) (0.01 mol) and substituted
amine (0.01 mol) in dry acetone was stirred at 40–
J
J
= 7.0, 1H), 7.35 (d,
J
J
J
J
45°C for 12–18 hrs. The completion of the reaction
13
was monitored by TLC in ethanol–acetone (1 : 1).
The reaction mixture was filtered and concentrated
under reduced pressure. The resulting residue was disꢀ
solved in dichloromethane, washed with brine, and
dried over anhydrous Na2SO4. The dried solution was
concentrated under reduced pressure to obtain the tiꢀ
M + 1): 476.04.
(p
3035 (C–H, aromatic), 2924 (C–H, aliphatic), 1615
(C=N), 1334 (C–N), 1220 (C=S); 1H NMR: 9.57 (s,
tle compounds (Va
–e).
1H), 8.45 (dd,
7.78 (td, = 7.3, 1H), 7.54 (t,
4H), 7.08 (t, = 7.3 Hz, 2H), 6.62 (dd,
3H), 3.66–3.62 (m, 3H), 3.53–3.47 (m, 4H), 3.47–
3.43 (m, 2H), 2.32 (s, 3H); 13C NMR: 179.71, 162.00,
155.77, 151.30, 150.96, 137.67, 132.71, 130.30,
130.18, 129.35, 125.74, 125.26, 123.32, 120.97,
120.31, 116.77, 111.60, 50.12, 45.42, 20.24; ESIꢀMS
J
= 7.2, 1H), 7.95 (dd,
= 6.7, 1H), 7.21 (s,
= 7.3 Hz,
J = 7.4, 1H),
Spectral Data of Compounds (Va
–e)
J
J
1ꢀPhenylꢀ3ꢀ(4ꢀ(4ꢀphenylpiperazinꢀ1ꢀyl)quinazolinꢀ
2ꢀyl)thiourea (Va). IR: 3234 (N–H, secondary), 3061
(C–H, aromatic), 2935 (C–H, aliphatic), 1666
(C=N), 1327 (C–N), 1234 (C=S); 1H NMR: 9.78 (s,
1H, ꢀNH linked to quinazoline ring), 8.20–7.99 (m,
2H, ArꢀH), 7.82 (s, 1H, ꢀNH linked to phenyl ring),
7.75–7.49 (m, 2H, ArꢀH), 7.36–7.15 (m, 5H, ArꢀH),
7.01–6.58 (m, 5H, ArꢀH), 3.59–3.48 (m, 4H,
ꢀCH2piperazine), 3.47–3.01 (m, 4H, –CH2piperaꢀ
J
J
(M
+ 1): 455.64.
2ꢀChloroꢀ4ꢀ(4ꢀethylpiperazinꢀ1ꢀyl)quinazoline (VI).
To a solution of 2,4ꢀdichloroquinazoline (II) (5 g,
0.025 mol) and isopropyl alcohol (40 mL), 1ꢀethyl
piperazine (3.7 g, 0.032 mol) was added and stirred at
room temperature for 8–12 h. Reaction progress was
observed by TLC in hexane–ethyl acetate (8 : 2).
zine); 13C NMR: 180.08, 169.11, 165.86, 156.23,
150.72, 138.56, 132.97, 130.65, 129.77, 128.92,
127.12, 126.89, 123.31, 122.58, 120.11, 115.46, 110.32,
49.85, 47.21; ESIꢀMS (M + 1): 441.66.
1ꢀ(2ꢀNitrophenyl)ꢀ3ꢀ(4ꢀ(4ꢀphenylpiperazinꢀ1ꢀyl) Washing of the crude solid with IPA and drying gives
quinazolinꢀ2ꢀyl)thiourea (Vb). IR: 3275 (N–H, secꢀ pure solid of (VI). Yield 57%; mp 134–135 C.
°
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 41
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2015

218
SHAH et al.
4ꢀ(4ꢀEthylpiperazinꢀ1ꢀyl)ꢀ2ꢀisothiocyanatoquinazoꢀ (q,
J
= 6.3 Hz, 3H); C NMR: 182.54, 164.01, 154.41,
= 6.3 Hz, 2H), 1.37 (t,
13
J
= 6.0 Hz, 3H), 1.07 (t,
line (VII). A solution of 2ꢀchloroꢀ4ꢀ(4ꢀethylpiperazinꢀ
1ꢀyl)quinazoline (VI) (2 g, 0.007 mol), ammonium
thiocynate (1.1 g, 0.014 mol), and copper powder
(0.91 g, 0.014 mol) in anhydrous toluene was refluxed
J
153.57, 150.57, 130.37, 126.64, 125.14, 123.24,
113.64, 62.54, 50.56, 49.11, 48.64, 48.04, 44.57,
14.70, 12.34; ESIꢀMS (
M + 1): 458.37.
at 90–120°C for 18 h. The completion of the reaction
Nꢀ(4ꢀ(4ꢀEthylpiperazinꢀ1ꢀyl)quinazolinꢀ2ꢀyl)ꢀ4ꢀmeꢀ
was monitored by TLC in ethanol–acetone (1 : 1).
The reaction mixture was filtered and concentrated
under reduced pressure. The resulting residue was disꢀ
solved in dichloromethane, washed with brine, and dried
over Na2SO4. The dried solution was concentrated under
reduced pressure to obtain the compound (VII). Yield
thylpiperazineꢀ1ꢀcarbothioamide (VIIIc). IR: 3336
(N–H, secondary), 3053 (C–H, aromatic), 2926 (C–
H, aliphatic), 1670 (C=N), 1406 (C–N), 1298 (C=S);
1H NMR: 9.57 (s, 1H, ꢀNH linked to quinazoline ring),
8.09–7.51 (m, 4H, ArꢀH), 3.98 (m, 4H, ꢀCH2 NꢀMe
piperazine), 3.34(m, 4H, ꢀCH2 NꢀEt piperazine), 2.98
(m, 4H, ꢀCH2 NꢀEt piperazine), 2.74 (m, 4H, ꢀCH2
NꢀMe piperazine), 2.40 (q, 2H, ꢀCH2), 2.19 (s, 3H,
ꢀCH3), 1.03 (t, 3H, CH3); 13C NMR: 180.31, 168.97,
163.12, 155.89, 132.58, 127.44, 126.21, 123.12,
110.63, 53.84, 52.31, 50.58, 49.06, 47.29, 46.12,
77%; mp 168–169
Synthesis of ꢀ(4ꢀ(4ꢀethylpiperazinꢀ1ꢀyl)quinazolinꢀ
2ꢀyl)substituted piperazineꢀ1ꢀcarbothioamide (VIIIa e).
°C.
N
–
A solution of 4ꢀ(4ꢀethylpiperazinꢀ1ꢀyl)ꢀ2ꢀisothiocyꢀ
anatoquinazoline (VII) (0.01 mol) and substituted
piperazine (0.01 mol) in dry acetone was stirred at 40–
45°C for 12–18 h. The completion of the reaction was
13.83; ESIꢀMS (
M + 1): 400.30.
monitored by TLC in ethanol–acetone (1 : 1). The reꢀ
action mixture was filtered and concentrated under reꢀ
duced pressure. The resulting residue was dissolved in
dichloromethane, washed with brine, and dried over
anhydrous Na2SO4. The dried solution was concenꢀ
trated under reduced pressure to obtain the titled comꢀ
4ꢀEthylꢀ ꢀ(4ꢀ(4ꢀethylpiperazinꢀ1ꢀyl)quinazolinꢀ2ꢀyl)
N
piperazineꢀ1ꢀcarbothioamide (VIIId). IR: 3367 (N–H,
secondary), 3015 (C–H, aromatic), 2938 (C–H, aliꢀ
phatic), 1615 (C=N), 1438 (C–N), 1211 (C=S);
1H NMR: 9.57 (s, 1H), 8.13 (dd,
(dd,
(td,
J
= 7.4, 1H), 7.93
= 7.1 Hz, 1H), 7.54
= 5.4 Hz, 2H), 3.65 (t,
= 6.0 Hz, 2H), 3.24 (t, = 6.0
= 5.5 Hz, 4H), 2.53 (dt, = 5.4 Hz,
= 6.3 Hz, 4H), 1.07 (td, = 6.4 Hz, 6H);
pounds (VIIIa–e).
J
J
= 7.5 Hz, 1H), 7.77 (td,
= 7.3 Hz, 1H), 4.04 (t,
J
J
J
= 5.1 Hz, 2H), 3.31 (t,
Hz, 2H), 2.75 (dt,
4H), 2.39 (dq,
J
J
J
J
Spectral Data of Compounds (VIIIa
–e)
J
J
N
ꢀ(4ꢀ(4ꢀEthylpiperazinꢀ1ꢀyl)quinazolinꢀ2ꢀyl)ꢀ4ꢀ
13C NMR: 183.56, 162.41, 154.24, 153.24, 132.18,
127.74, 126.26, 124.32, 110.82, 51.47, 51.04, 50.11,
48.24, 47.68, 12.18; ESIꢀMS (
ꢀ(4ꢀ(4ꢀEthylpiperazinꢀ1ꢀyl)quinazolinꢀ2ꢀyl)ꢀ4ꢀmeꢀ
thylꢀ3ꢀphenylpiperazineꢀ1ꢀcarbothioamide (VIIIe) IR:
(2,3,4ꢀtrimethoxybenzyl)piperazineꢀ1ꢀcarbothioamꢀ
ide (VIIIa). IR: 3301 (N–H, secondary), 3042 (C–H,
aromatic), 2924 (C–H, aliphatic), 1634 (C=N), 1404
(C–N), 1267 (C=S); 1H NMR: 9.45 (s, 1H), 8.12–7.54
M + 1): 414.25.
N
.
(m, 4H), 6.92 (d,
J
J = 7.3 Hz, 1H), 6.62 (d, J = 6.2 Hz,
1H), 4.05 (t, = 5.4 Hz, 2H), 3.79 (s, 9H), 3.66 (dd,
3424 (N–H, secondary), 3038 (C–H, aromatic), 2924
(C–H, aliphatic), 1634 (C=N), 1426 (C–N), 1228
J
J
J
J
= 4.9 Hz, 4H), 3.38 (t,
= 5.5 Hz, 2H), 2.78 (q,
= 5.5 Hz, 2H), 2.68 (t,
= 5.2 Hz, 4H), 1.07 (t,
180.56, 163.41, 155.24, 154.01, 152.24, 151.72,
140.72, 130.18, 125.78, 125.74, 125.26, 123.84,
123.32, 111.82, 108.12, 60.65, 60.58, 56.79, 51.70,
51.15, 50.06, 48.04, 47.51, 12.34; ESIꢀMS (
566.24.
J
J
= 5.1 Hz, 2H), 3.33 (t,
= 6.2 Hz, 2H), 2.73 (t, (C=S); 1H NMR: 9.50 (s, 1H), 8.12 (dd,
J
= 7.51H),
= 7.1 Hz, 1H), 7.57
= 7.0, 1H), 7.34–7.01 (m, 5H), 4.51 (dd, = 6.9 Hz,
1H), 4.02 (dt, = 4.9 Hz, 1H), 3.71–3.57 (m, 2H),
3.52 (dt, = 5.1 Hz, 1H), 3.39 (t, = 5.7 Hz, 2H),
3.30 (t, = 4.9 Hz, 2H), 2.88–2.76 (m, 5H), 2.66–
2.54 (m, 3H), 2.29 (s, 3H), 1.09 (t, = 6.3 Hz, 3H);
13C NMR: 184.12, 166.40, 155.24, 152.24, 141.20,
130.18, 129.63, 128.43, 125.74, 125.51, 125.26,
123.32, 111.82, 66.78, 51.12, 50.89, 50.75, 50.24,
J
J
= 5.0 Hz, 2H), 2.59 (dd, 7.96 (dd,
= 6.4 Hz, 3H); 13C NMR:
(d,
J = 7.2 Hz, 1H), 7.80 (td, J
J
J
J
J
J
J
J
M + 1):
Ethyl 4ꢀ((4ꢀ(4ꢀethylpiperazinꢀ1ꢀyl)quinazolinꢀ2ꢀ
yl)carbamothioyl)piperazineꢀ1ꢀcarboxylate (VIIIb).
IR: 3467 (N–H, secondary), 3024 (C–H, aromatic),
2967 (C–H, aliphatic), 1614 (C=N), 1434 (C–N),
1232 (C=S); 1H NMR: 9.43 (s, 1H), 8.11 (dd,
Hz, 1H), 7.91 (dd, = 7.1 Hz, 1H), 7.77 (td,
1.5 Hz, 1H), 7.54 (td,
(m, 4H), 3.62 (dd,
2H), 3.34 (t,
2.75 (t,
48.10, 47.34, 44.14, 13.5\; ESIꢀMS (
1ꢀ(4ꢀ((4ꢀ(4ꢀEthylpiperazinꢀ1ꢀyl)quinazolinꢀ2ꢀyl)amiꢀ
= 7.5 no)phenyl)ethanone (IX). 2ꢀChloroꢀ4ꢀ(4ꢀethylpiperꢀ
= 7.0, azinꢀ1ꢀyl)quinazoline (VI) (2 g, 0.007 mol) was reꢀ
= 7.5, 1.6 Hz, 1H), 4.25–4.14 fluxed with 4ꢀamino acetophenone (1.05 g,
= 5.0 Hz, 4H), 3.39 (t, = 6.1 Hz, 0.00781 mol) in IPA (20 mL) for 7–8 h. Reaction was
= 5.3 Hz, 2H), 3.28 (t, = 4.9 Hz, 2H), monitored by TLC in hexane–ethyl acetate (3 : 2). Afꢀ
= 5.5 Hz, 2H), 2.50 (t, = 5.0 Hz, 2H), 2.38 ter completion, crude solid obtained was filtered and
M + 1): 476.14.
J
J
J
J
J
J
J
J
J
J
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SYNTHESIS AND IN VITRO ANTIMICROBIAL EVALUATION
219
13C NMR: 192.57, 163.84, 158.31, 156.75, 153.35,
141.56, 140.05, 131.63, 131.33, 130.18, 128.73,
128.71, 125.74, 125.26, 123.32, 121.83, 120.64,
117.76, 117.54, 108.34, 52.66, 51.05, 48.28, 12.10;
washed with IPA to give solid of desire compound (IX).
Yield 68%; mp 126–128 C; IR: 3465 (N–H, secondꢀ
ary), 3033 (C–H, aromatic), 2984 (C–H, aliphatic),
°
1645 (C=O), 1545(–CH=CH–); 1H NMR: 8.11 (dd,
ESIꢀMS (
(E)ꢀ1ꢀ(4ꢀ((4ꢀ(4ꢀEthylpiperazinꢀ1ꢀyl)quinazolinꢀ2ꢀ
yl)amino)phenyl)ꢀ3ꢀ(furanꢀ2ꢀyl)propꢀ2ꢀenꢀ1ꢀone (Xc)
M + 1): 480.12.
J
= 7.5, 1.4 Hz, 1H), 7.97 (dd,
7.84–7.75 (m, 3H), 7.55 (td,
7.11 (d,
24.0, 4.9 Hz, 4H), 2.82 (t,
4.9 Hz, 2H), 2.51 (s, 3H), 2.42 (q,
J
= 7.5, 1.4 Hz, 1H),
J
= 7.4, 1.5 Hz, 1H),
.
J
= 7.5 Hz, 2H), 5.95 (s, 1H), 3.36 (dt,
= 4.9 Hz, 2H), 2.65 (t,
J
J
=
=
IR: 3435 (N–H, secondary), 3057 (C–H, aromatic),
2934 (C–H, aliphatic), 1621 (C=O), 1611 (C=N),
J
J
= 6.3 Hz, 2H),
1
13
1527 (
−
CH=CH
−
); H NMR: 8.09 (dd,
J
= 7.5 Hz,
= 7.1 Hz, 1H),
= 7.2 Hz, 1H), 7.41 (d,
= 7.2 Hz, 2H), 6.99 (dd,
= 7.6 Hz, 1H), 3.42–3.36
(m, 2H), 3.32–3.26 (m, 2H), 2.81–2.74 (m, 2H),
2.56–2.50 (m, 2H), 2.40 (q, = 6.3 Hz, 2H), 1.06 (t,
= 6.3 Hz, 3H); C NMR: 193.26, 165.61, 155.82,
1.07 (t,
J = 6.3 Hz, 3H); C NMR: 194.25, 163.86,
1H), 7.99–7.89 (m, 2H), 7.85 (dd,
7.82–7.72 (m, 3H), 7.61 (d,
= 5.0 Hz, 1H), 7.05 (d,
= 7.1 Hz, 1H), 6.63 (t,
J
156.14, 155.32, 151.62, 143.93, 141.56, 131.63,
130.18, 129.82, 129.04, 128.73, 125.74, 125.26,
124.17, 123.32, 123.15, 117.54, 107.61, 52.82, 50.24,
J
J
J
J
J
47.35, 16.22, 13.78; ESIꢀMS (
1ꢀ(4ꢀ((4ꢀ(4ꢀEthylpiperazinꢀ1ꢀyl)quinazolinꢀ2ꢀyl)amiꢀ
no) phenyl)ꢀ3ꢀsubstituted phenylpropꢀ2ꢀenꢀ1ꢀone (Xa e).
M + 1): 376.83.
J
13
–
J
1ꢀ(4ꢀ((4ꢀ(4ꢀEthylpiperazinꢀ1ꢀyl)quinazolinꢀ2ꢀyl)amiꢀ
no)phenyl) ethanone (IX), 0.01 mol, and 0.013 mol of
a substituted aldehyde were slowly added in 60 mL of
MeOH. 10% 1 N NaOH was then added, and the reꢀ
action was stirred for 12–20 h at room temperature.
Progress of reaction was followed by TLC in MeOH–
acetone (3 : 2). After completion, the pH of the soluꢀ
tion was adjusted to 2 with HCl solution. The precipiꢀ
tate thus obtained was filtered off, washed with water,
and recrystallized from boiling EtOH to get respective
151.56, 149.16, 143.04, 141.56, 131.63, 130.18,
128.73, 125.75, 125.26, 123.32, 120.17, 117.54,
112.57, 112.46, 108.25, 52.64, 51.75, 47.51, 13.25;
ESIꢀMS (M + 1): 454.68.
(E)ꢀ3ꢀ(3,4ꢀDimethoxyphenyl)ꢀ1ꢀ(4ꢀ((4ꢀ(4ꢀethylpiꢀ
perazinꢀ1ꢀyl)quinazolinꢀ2ꢀyl)amino)phenyl)propꢀ2ꢀenꢀ
1ꢀone (Xd). IR: 3325 (N–H, secondary), 3055 (C–H,
aromatic), 2931 (C–H, aliphatic), 1674 (C=O), 1620
(C=N), 1599 (–CH=CH–), 1300 (C–O–C, aryl),
1041 (O–CH3); 1H NMR: 8.02 (d, 1H,
CH=CH–),
−
compounds (Xa–e).
7.89–7.75 (m, 4H, Ar–H), 7.65–7.48 (m, 2H, ArꢀH),
7.42 (d, 1H, –CH=CH–), 7.12–6.87 (m, 5H, ArꢀH),
5.19 (s, 1H, –NH), 3.86 (s, 6H, –OCH3), 3.37 (m,
4H, –CH2 piperazine), 2.65 (m, 4H, –CH2 piperaziꢀ
ne), 2.39 (q, 2H, –CH2), 1.11 (t, 3H, –CH3);
13C NMR: 190.21, 165.76, 162.80, 154.44, 152.32,
150.28, 143.78, 140.55, 135.12, 134.86, 133.64,
132.46, 128.74, 126.88, 125.11, 122.24, 120.68,
115.26, 114.27, 113.34, 112.54, 106.08, 39.99, 39.78,
Spectral Data of Compounds (Xa
–e)
(E)ꢀ1ꢀ(4ꢀ((4ꢀ(4ꢀEthylpiperazinꢀ1ꢀyl)quinazolinꢀ2ꢀ
yl)amino)phenyl)ꢀ3ꢀphenylpropꢀ2ꢀenꢀ1ꢀone (Xa). IR:
3464 (N–H, secondary), 3024 (C–H, aromatic),
2961 (C–H, aliphatic), 1663 (C=O), 1628 (C=N),
1534 (–CH=CH–); 1H NMR: 8.05 (dd,
7.94 (dd,
(td, = 7.4 Hz, 1H), 7.28–6.84 (m, 8H), 6.27 (d,
= 6.2 Hz, 1H), 3.28 (dt, = 5.1 Hz, 4H), 2.77 (q,
= 6.4 Hz, 2H), 2.67 (t, = 5.1 Hz, 2H), 2.58 (t,
= 5.0 Hz, 2H), 1.07 (t, = 6.4 Hz, 3H), 1.68 (s, 1H);
J
= 7.51H),
J
= 7.6 Hz, 1H), 7.79–7.66 (m, 3H), 7.56
39.16, 38.74, 13.56; ESIꢀMS (
(E)ꢀ1ꢀ(4ꢀ((4ꢀ(4ꢀEthylpiperazinꢀ1ꢀyl)quinazolinꢀ2ꢀ
yl)amino)phenyl)ꢀ3ꢀ(4ꢀhydroxyꢀ3,5ꢀdimethylphenyl)propꢀ
2ꢀenꢀ1ꢀone (Xe). IR: 3546 ( OH), 3425 (N–H, seconꢀ
dary), 3085 (C–H, aromatic), 2924 (C–H, aliphatic),
1638 (C=O), 1633 (C=N), 1529 (–CH=CH–);
1H NMR: 8.64 (s, 1H), 8.08 (dd,
= 7.4 Hz, 1H),
8.03–7.92 (m, 2H), 7.80–7.71 (m, 3H), 7.52 (td,
7.4 Hz, 1H), 7.38 (d, = 5.2 Hz, 1H), 7.15 (d, = 7.5 Hz,
2H), 6.99 (s, 2H), 5.74 (s, 1H), 3.37 (dt, = 5.1 Hz,
4H), 2.77 (t, = 5.8 Hz, 2H), 2.56–2.43 (m, 4H), 2.31
(s, 6H), 1.08 (t,
M + 1): 524.38.
J
J
J
J
J
J
−
J
13C NMR: 192.28, 163.34, 156.57, 152.84, 144.36,
141.56, 135.88, 131.63, 130.18, 129.46, 129.02,
128.73, 128.06, 125.74, 125.26, 123.32, 122.95,
117.54, 110.11, 51.44, 50.48, 48.21, 12.54; ESIꢀMS
J
J
=
J
J
(M
+ 1): 464.25.
J
(E)ꢀ1ꢀ(4ꢀ((4ꢀ(4ꢀEthylpiperazinꢀ1ꢀyl)quinazolinꢀ2ꢀyl)
J
amino)phenyl)ꢀ3ꢀ(2ꢀhydroxyphenyl)propꢀ2ꢀenꢀ1ꢀone
(Xb). IR: 3545 (ꢀOH), 3482 (N–H, secondary), 3022
(C–H, aromatic), 2915 (C–H, aliphatic), 1667
(C=O), 1625 (C=N), 1523 (–CH=CH–); 1H NMR:
13
J
= 6.3 Hz, 3H); C NMR: 194.25,
163.86, 156.14, 155.32, 151.62, 143.93, 141.56,
131.63, 130.18, 129.82, 129.04, 128.73, 125.74,
125.26, 124.17, 123.32, 123.15, 117.54, 107.61, 52.82,
8.61 (s, 1H), 8.03 (dd,
2H), 7.80–7.71 (m, 3H), 7.51 (d,
7.29 (d, = 5.2 Hz, 1H), 7.22–7.06 (m, 3H), 7.22–
5.54 (m, 7H), 6.73 (dd, = 7.4 Hz, 1H), 6.76–5.54 (XI). 2ꢀChloroꢀ4ꢀ(4ꢀethylpiperazinꢀ1ꢀyl)quinazoline
(m, 2H), 5.76 (s, 1H), 3.35 (d, = 5.0 Hz, 4H), VI) (2 g, 0.007 mol) was refluxed with hydrazine
2.73 (t, = 5.4 Hz, 2H), 2.50 (t, = 5.0 Hz, 2H), 2.20 hydrate (0.39 g, 0.00781 mol) in IPA (20 mL) for 7–
(q, = 6.3 Hz, 2H), 0.98 (t, = 6.3 Hz, 3H); 8 h. Reaction was monitored by TLC in hexane–ethyl
J
= 7.4 Hz, 1H), 7.92–7.82 (m,
50.24, 47.35, 16.22, 13.78; ESIꢀMS (M + 1): 508.83.
J
= 7.1 Hz, 1H),
J
4ꢀ(4ꢀEthylpiperazinꢀ1ꢀyl)ꢀ2ꢀhydrazinylquinazoline
J
J
(
J
J
J
J
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 41
No. 2
2015

220
SHAH et al.
acetate (3 : 2). After completion, crude solid obtained Yield 69%; mp 144–148°C; IR: 3354 (N–H, secondꢀ
was filtered and washed with IPA to give solid of desiꢀ ary), 3011 (C–H, aromatic), 2924 (C–H, aliphatic),
1
redcompound (XI). Yield 74%; mp 112–113
°C; IR:
1645 (C=N), 1125 (C=S); H NMR: 8.01 (dd,
= 7.5, 1.4 Hz, 1H), 7.93 (ddd, = 74.5, 7.5, 1.4 Hz,
(C–H, aliphatic), 1644 (C=N); H NMR: 8.03 (dd, 2H), 8.78–7.51 (m, 3H), 8.78–7.32 (m, 4H), 8.78–
= 7.5, 1.6 Hz, 1H), 7.91 (dd, = 7.4, 1.5 Hz, 1H), 7.24 (m, 6H), 8.78–7.06 (m, 7H), 7.02 (td, = 7.5,
7.76 (td, = 7.5, 1.4 Hz, 1H), 7.53 (td, = 7.5, 1.4 Hz, 1.5 Hz, 1H), 5.36 (s, 1H), 3.39 (t, = 5.1 Hz, 2H),
1H), 3.38 (t, = 5.1 Hz, 2H), 3.32 (t, = 5.0 Hz, 2H), 3.32 (t, = 5.1 Hz, 2H), 2.87 (s, 1H), 2.74 (t,
3.06 (s, 1H), 2.96 (s, 1H), 2.73 (t, = 5.1 Hz, 2H), 2.51 = 5.1 Hz, 2H), 2.50 (t, = 5.1 Hz, 2H), 2.37 (q,
(t, = 5.1 Hz, 2H), 2.45 (s, 1H), 2.36 (q, = 6.3 Hz,
3318 (N–H, secondary), 3012 (C–H, aromatic), 2929
J
J
1
J
J
J
J
J
J
J
J
J
J
J
J
J
= 6.3 Hz, 2H), 1.06 (t,
= 6.3 Hz, 3H); 13C NMR:
J
J
J
13
2H), 1.06 (t,
150.35, 144.47,
123.32, 114.17, 51.70, 51.70, 50.06, 48.04, 48.04, 125.09, 123.32, 113.98, 51.70, 51.70, 50.06, 48.04,
12.34; ESIꢀMS ( + 1): 273.35. 48.04, 12.34; ESIꢀMS ( + 1): 442.87.
J
= 6.3 Hz, 3H); C NMR: 163.04, 181.16, 163.81, 150.37, 149.15, 134.74, 130.18,
130.18, 125.74, 125.26, 129.75, 129.38, 127.75, 125.74, 125.44, 125.26,
M
M
N
ꢀ(3ꢀChlorophenyl)ꢀ2ꢀ(4ꢀ(4ꢀethylpiperazinꢀ1ꢀ
yl)quinazolinꢀ2ꢀyl)hydrazinecarbothioamide (XIId)
Yield 82%; mp 136–139 C; IR: 3312 (N–H, secondꢀ
.
Synthesis of 2ꢀ(4ꢀ(4ꢀEthylpiperazinꢀ1ꢀyl)quinazolinꢀ2ꢀ
yl)ꢀNꢀSubstituted Phenyl Hydrazine Carbothioamide
XIIa
°
ary), 3042 (C–H, aromatic), 2922 (C–H, aliphatic),
1678 (C=N), 1158 (C=S); H NMR: 9.28 (s, 1H),
(
–e)
1
A solution of 0.01 mol of 4ꢀ(4ꢀethylpiperazinꢀ1ꢀ
yl)ꢀ2ꢀhydrazinylquinazoline (XI) and equimolar
amount of substituted phenyl isothiocyanate in 60 mL
of EtOH was heated under reflux for 1–2 h. Reaction
was followed by TLC inhexane–ethyl acetate (3 : 2)
mobile phase. The precipitate obtained was filtered
off, washed with water, and recrystallized from ethanol
9.14 (s, 1H), 7.99 (dd,
J
= 7.5, 1.4 Hz, 1H), 7.86 (dd,
= 7.5, 1.4 Hz, 1H), 7.70 (td, = 7.5, 1.4 Hz, 1H),
= 7.5, 1.5 Hz, 1H), 7.27–7.20 (m, 2H),
= 7.3, 1.4 Hz, 1H), 7.10 (dt, = 7.3, 1.5 Hz,
= 26.4, 5.0 Hz, 4H), 2.76
= 5.1 Hz, 2H), 2.40 (q,
= 6.3 Hz, 3H); 13C NMR:
J
J
7.47 (td,
7.17 (dt,
J
J
J
1H), 5.49 (s, 1H), 3.37 (dt,
(t, = 5.1 Hz, 2H), 2.51 (t,
= 6.3 Hz, 2H), 1.06 (t,
J
J
J
J
J
to get desired compounds (XIIa
2ꢀ(4ꢀ(4ꢀEthylpiperazinꢀ1ꢀyl)quinazolinꢀ2ꢀyl)ꢀ
nylhydrazinecarbothioamide (XIIa). Yield 68%; mp
134–136 C; IR: 3456 (N–H, secondary), 3027 (C–H,
–e).
179.72, 163.81, 150.37, 149.15, 140.58, 133.11,
130.18, 128.83, 125.74, 125.26, 124.05, 123.32,
120.61, 119.66, 113.98, 51.70, 51.70, 50.06, 48.04,
Nꢀpheꢀ
°
48.04, 12.34; ESIꢀMS (M + 1): 442.45.
aromatic), 2935 (C–H, aliphatic), 1632 (C=N), 1142
1
2ꢀ(4ꢀ(4ꢀEthylpiperazinꢀ1ꢀyl)quinazolinꢀ2ꢀyl)ꢀ
Nꢀ(2ꢀ
(C=S); H NMR: 9.79 (s, 1H), 8.00 (s, 1H), 7.85 (s,
fluorophenyl)hydrazinecarbothioamide (XIIe). Yield
75%; mp 188–190 C; IR: 3524 (N–H, secondary),
3112 (C–H, aromatic), 2850 (C–H, aliphatic), 1645
1H), 7.81 (s, 1H), 7.71 (s, 1H), 7.48 (s, 1H), 7.36–
7.26 (m, 4H), 7.07 (s, 1H), 3.92 (s, 1H), 3.34–3.26
(m, 4H), 2.70–2.66 (m, 2H), 2.31–2.27 (m, 2H),
°
(C=N), 1164 (C=S); 1H NMR: 9.39 (s, 2H), 7.99 (dd,
13
2.16–2.04 (m, 2H), 1.08–1.04 (m, 3H); C NMR:
J
= 7.5, 1.4 Hz, 1H), 7.86 (dd,
7.71 (td, = 7.5, 1.4 Hz, 1H), 7.48 (td,
1H), 7.44–7.21 (m, 1H), 7.16–6.90 (m, 3H), 5.47 (s,
1H), 3.39 (t, = 5.1 Hz, 2H), 3.33 (t, = 5.1 Hz, 2H),
2.74 (t, = 5.0 Hz, 2H), 2.51 (t, = 5.1 Hz, 2H), 2.36
(q, = 6.3 Hz, 2H), 1.07 (t, = 6.3 Hz, 3H);
J
= 7.5, 1.4 Hz, 1H),
179.72, 163.81, 150.37, 149.15, 139.19, 130.18,
128.96, 128.96, 125.74, 125.26, 124.47, 123.32,
121.54, 121.54, 113.98, 51.70, 51.70, 50.06, 48.04,
J
J
= 7.4, 1.5 Hz,
J
J
48.04, 12.34; ESIꢀMS (
2ꢀ(4ꢀ(4ꢀEthylpiperazinꢀ1ꢀyl)quinazolinꢀ2ꢀyl)ꢀ
tolyl)hydrazinecarbothioamide (XIIb). Yield 77%; mp
126–128 C; IR: 3547 (N–H, secondary), 3021 (C–H,
aromatic), 2838 (C–H, aliphatic), 1621 (C=N), 1101
(C=S); 1H NMR: 8.02 (dd,
= 7.4, 1.5 Hz, 1H), 7.87
(dd, = 7.5, 1.4 Hz, 1H), 7.72 (td, = 7.5, 1.4 Hz,
1H), 7.49 (td, = 7.5, 1.4 Hz, 1H), 7.31–7.12 (m,
3H), 7.10–6.99 (m, 1H), 5.36 (s, 1H), 3.40 (t,
= 5.2 Hz, 2H), 3.33 (t, = 5.2 Hz, 2H), 2.85 (s,
1H), 2.73 (t, = 5.2 Hz, 2H), 2.48 (t, = 5.1 Hz, 2H),
2.34 (q, = 6.3 Hz, 2H), 2.24 (s, 3H), 1.06 (t, = 6.3 Hz,
M + 1): 408.56.
J
J
Nꢀ(oꢀ
J
J
13C NMR: 181.16, 163.81, 158.99, 150.37, 149.15,
130.18, 127.72, 125.74, 125.72, 125.26, 124.40,
123.94, 123.32, 117.15, 113.98, 51.70, 51.70, 50.06,
°
J
48.04, 48.04, 12.34; ESIꢀMS (M + 1): 426.02.
J
J
J
Synthesis of 2ꢀ(2ꢀ(4ꢀ(4ꢀEthylpiperazinꢀ1ꢀ
yl)quinazolinꢀ2ꢀyl)hydrazono)ꢀ3ꢀSubstituted
Phenylthiazolidinꢀ4ꢀone (XIIIa
J
J
J
J
–e)
J
J
3H); 13C NMR: 181.16, 163.81, 150.37, 149.15,
138.00, 132.78, 130.18, 129.94, 127.79, 125.74,
125.26, 124.65, 123.32, 123.10, 113.98, 51.70, 51.70,
An aliquot (0.01 mol) of appropriate thiosemicarꢀ
bazide (XIIa ) and 0.011 mol of chloroethyl acetate
–e
were refluxed in 30 mL of absolute EtOH in the presꢀ
ence of 0.04 mol of anhydrous NaOAc for 2 h. Reacꢀ
tion progress was observed by TLC in toluene–aceꢀ
tone (4 : 1). The mixture was then cooled, diluted with
50.06, 48.04, 48.04, 17.35, 12.34; ESIꢀMS (
422.34.
ꢀ(2ꢀChlorophenyl)ꢀ2ꢀ(4ꢀ(4ꢀethylpiperazinꢀ1ꢀ
M + 1):
N
yl)quinazolinꢀ2ꢀyl)hydrazinecarbothioamide (XIIc). water, and allowed to stand overnight. The solid precipꢀ
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 41
No. 2
2015

SYNTHESIS AND IN VITRO ANTIMICROBIAL EVALUATION
221
itated was washed with water, dried, and recrystallized 123.32, 116.83, 52.82, 51.67, 49.35, 32.47, 14.35;
from ethanol to afford final compounds (XIIIa ). ESIꢀMS ( + 1): 483.38.
–e
M
2ꢀ(2ꢀ(4ꢀ(4ꢀEthylpiperazinꢀ1ꢀyl)quinazolinꢀ2ꢀyl)hyꢀ
drazono)ꢀ3ꢀphenylthiazolidinꢀ4ꢀone (XIIIa). IR: 3298
(N–H, secondary), 3030 (C–H, aromatic), 2931 (C–H,
aliphatic), 1730 (C=O), 1672 (C=N), 1305 (C–N), 646
(C–S); 1H NMR: 11.26 (s, 1H, –NH), 7.95 (dd, 1H,
ArꢀCH),7.68 (d, 2H, ArꢀCH), 7.62 (d, 2H, ArꢀCH), 7.22
(d, 1H, –CH quinoline), 7.20 (d, 1H, ꢀCH quinoline),
6.99 (dd, 1H, –CH quinoline), 6.95 (d, 1H, ꢀCH
quinoline), 4.13 (s, 2H, –CH2 thiazolidinone), 3.52
2ꢀ(2ꢀ(4ꢀ(4ꢀEthylpiperazinꢀ1ꢀyl)quinazolinꢀ2ꢀyl)hyꢀ
drazono)ꢀ3ꢀ(2ꢀfluorophenyl)thiazolidinꢀ4ꢀone (XIIIe).
IR: 3354 (N–H, secondary), 3112 (C–H, aromatic),
2950 (C–H, aliphatic), 1710 (C=O), 1661(C=N), 1312
(C–N), 652 (C–S); 1H NMR: 8.14 (dd,
7.97 (dd, = 7.4 Hz, 1H), 7.71 (d,
(d, = 7.6 Hz, 1H), 7.2 (dd, = 7.5 Hz, 1H), 7.02 (dd,
= 7.4 Hz, 1H), 6.82 (d, = 6.3 Hz, 1H), 6.79 (d,
= 7.5, Hz, 1H), 3.75 (s, 2H), 3.42 (dd, = 5.2 Hz,
= 5.1 Hz, 2H), 2.17 (t, = 5.2 Hz, 2H),
= 6.3 Hz, 2H), 1.02 (t, = 6.3 Hz, 3H);
J
= 7.1 Hz, 1H),
J
J = 6.5 Hz, 1H), 7.25
J
J
J
J
J
J
(t, 4H, –CH2 piperazine), 3.48 (t, 4H, –CH2 piperaꢀ 4H), 2.22 (t,
J
J
2.11 (q,
J
J
zine), 1.94 (q, 2H, –CH2 ethyl), 1.22 (t, 3H, –CH3
13C NMR: 175.28, 161.76, 160.34, 156.28, 150.64,
137.35, 131.35, 130.13, 128.94, 126.81, 126.22,
125.74, 125.26, 123.32, 119.49, 111.83, 52.57, 51.38,
ethyl); 13C NMR: 172.13, 165.40, 162.82, 155.65,
150.30, 141.16, 140.81, 134.87, 128.92, 126.90,
122.26, 120.96, 116.75, 114.29, 40.01, 39.80, 39.38,
49.92, 30.34, 13.55; ESIꢀMS (M + 1): 466.28.
38.76, 12.98; ESIꢀMS (
2ꢀ(2ꢀ(4ꢀ(4ꢀEthylpiperazinꢀ1ꢀyl)quinazolinꢀ2ꢀyl)hyꢀ
drazono)ꢀ3ꢀ( ꢀtolyl)thiazolidinꢀ4ꢀone (XIIIb). IR: 3274
(N H, secondary), 3000 (C–H, aromatic), 2955 (C–H,
aliphatic), 1762 (C=O), 1671 (C=N), 1334 (C–N), 647
M + 1): 448.23.
o
Biological Screening
−
Antimicrobial assay. To determine the minimum
1
inhibitory concentration [21], a stock solution of the
(C–S); H NMR: 9.89 (s, 1H), 7.92 (td,
2H), 7.75 (d, = 7.4 Hz, 1H), 7.53 (d,
1H), 7.34–6.47 (m, 4H), 3.89 (s, 2H), 3.32 (t,
J = 7.7 Hz,
J = 7.1 Hz,
final synthesized compounds (100 g/mL) was preꢀ
µ
J
pared in dimethyl sulfoxide, and then test compounds
were incorporated in a specified quantity of molten
sterile agar, i.e., nutrient agar and dextrose agar for
antibacterial and for antifungal screening, respectively.
Such medium enclosing the test compound was
poured into a Petri dish at a depth of 4–5 mm and
allowed to solidify under aseptic conditions. A suspenꢀ
sion of the respective microorganism of 105 CFU/mL
was prepared and added to plates with serially diluted
compounds with concentrations in the range of 3.12–
J
J
J
= 5.2 Hz, 2H), 3.13 (t,
= 5.2 Hz, 2H), 2.55 (t,
J
J
= 5.1 Hz, 2H), 2.76 (t,
= 5.2 Hz, 2H), 2.43 (q,
= 6.3 Hz, 3H);
= 6.3 Hz, 2H), 2.20 (s, 3H), 1.07 (t,
J
13C NMR: 173.51, 164.21, 150.15, 149.81, 139.55,
136.33, 136.30, 130.96, 130.18, 129.38, 129.37,
128.87, 125.74, 125.26, 123.32, 114.83, 52.54, 50.11,
47.87, 31.04, 17.18, 13.11; ESIꢀMS (M + 1): 462.34.
3ꢀ(2ꢀChlorophenyl)ꢀ2ꢀ(2ꢀ(4ꢀ(4ꢀethylpiperazinꢀ1ꢀ
yl)quinazolinꢀ2ꢀyl)hydrazono)thiazolidinꢀ4ꢀone (XIIIc).
IR: 3290 (N–H, secondary), 3031 (C–H, aromatic),
2971 (C–H, aliphatic), 1733 (C=O), 1635 (C=N), 1368
100
(37 1)
µ
g/mL in dimethyl sulfoxide and incubated at
°C
temperature for 24 h (bacteria) or 48 h
(C–N), 640 (C–S); 1H NMR: 8.03 (dd,
7.95 (dd, = 7.4 Hz, 1H), 7.78 (d,
(d, = 7.6 Hz, 1H), 7.46 (dd, = 7.5 Hz, 1H), 7.39 (dd,
= 7.4 Hz, 1H), 7.22 (d, = 6.3 Hz, 1H), 7.09 (d,
= 7.5, Hz, 1H), 3.86 (s, 2H), 3.28 (dd, = 5.2 Hz,
4H), 2.75 (t, = 5.1 Hz, 2H), 2.50 (t, = 5.2 Hz, 2H),
2.38 (q, = 6.3 Hz, 2H), 1.07 (t, = 6.3 Hz, 3H);
J
= 7.1 Hz, 1H),
(fungi). Minimum concentration of the substance that
prevents the development of visible growth is considꢀ
ered to be the MIC value.
J
J = 6.5 Hz, 1H), 7.56
J
J
J
J
J
J
ACKNOWLEDGMENTS
J
J
J
J
Authors are very thankful to Prof. Nisha K. Shah,
13C NMR: 175.15, 168.64, 152.86, 147.3, 139.55, the Head of the Department of Chemistry, School of
136.39, 134.64, 131.26, 130.76, 130.18, 129.79,
129.27, 125.74, 125.26, 123.32, 112.83, 53.75, 50.06,
47.22, 33.57, 14.25; ESIꢀMS ( + 1): 483.28.
3ꢀ(3ꢀChlorophenyl)ꢀ2ꢀ(2ꢀ(4ꢀ(4ꢀethylpiperazinꢀ1ꢀyl)
Sciences, Gujarat University, Ahmedabad, India, for
her kind cooperation for providing support and
research facility. The authors wish to offer their deep
gratitude to TBꢀcare Laboratory, Ahmedabad, India,
M
quinazolinꢀ2ꢀyl)hydrazono)thiazolidinꢀ4ꢀone (XIIId). for carrying out the biological screenings. We are also
IR: 3254 (N–H, secondary), 3082 (C–H, aromatic), thankful to NFDDꢀRajkot, Gujarat, India, for carryꢀ
2905 (C–H, aliphatic), 1782 (C=O), 1667(C=N), 1373
ing out IR, H NMR, and 13C NMR analyses.
Mr. Dhruvin Shah would like to acknowledge UGC
New Delhi, for Junior Research Fellowship.
1
(C–N), 624 (C–S); 1H NMR: 8.11 (dd,
J
= 7.5 Hz, 1H),
= 6.5 Hz, 1H),
7.59–7.50 (m, 2H), 7.40–7.30 (m, 2H), 7.24–6.98
(m, 1H), 3.90 (s, 2H), 3.37 (d, = 5.1 Hz, 4H), 2.80
(q, = 6.4 Hz, 2H), 2.71 (t, = 5.1 Hz, 2H), 2.60 (t,
= 5.1 Hz, 2H), 1.07 (t, = 6.4 Hz, 3H); C NMR
(100 MHz, DMSOꢀd6 ppm): 174.54, 165.34,
155.27, 144.91, 141.37, 139.18, 132.09, 130.18,
129.29, 127.18, 126.64, 125.74, 125.26, 124.88,
7.98 (dd,
J = 7.4 Hz, 1H), 7.80 (td, J
J
REFERENCES
J
J
13
J
J
δ
1. Gootz, T.D., Crit. Rev. Immunol., 2010, vol. 30, pp. 79–
93.
,
2. Overbye, K.M. and Barrett, J.F., Drug Discov. Today
2005, vol. 10, pp. 45–52.
,
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 41
No. 2
2015

222
SHAH et al.
3. Niccolai, D., Tarsi, L., and Thomas, R.J., Chem. Comꢀ 13. Rahman, M.U., Rathore, A., Siddiqui, A.A., Parveen, G.,
mun., 1997, pp. 2333–2342.
4. Nathan, C., Nature, 2004, vol. 431, pp. 899–902.
and Yar, M.S., J. Enzyme. Inhib. Med. Chem., 2013.
DOI: 10.3109/14756366.2013.845820
14. Buha, V.M., Rana, D.N., Chhabria, M.T., Chikhaꢀ
lia, K.H., Mahajan, B.M., Brahmkshatriya, P.S., and
Shah, N.K., Med. Chem. Res., 2013, vol. 22, pp. 4096–
4109.
5. Raviglione, M.C., Tuberculosis, 2003, vol. 83, pp. 4–
14.
6. Khan, I., Ibrar, A., Abbas, N., and Saeed, A., Eur. J.
Med. Chem., 2014, vol. 76, pp. 193–244.
15. Zhang, Y., Huang, Y.ꢀJ., Xiang, H.ꢀM., Wang, P.ꢀY.,
Hu, D.ꢀY., Xue, W., Song, B.ꢀA., and Yang, S., Eur. J.
Med. Chem., 2014, vol. 78, pp. 23–34.
7. Marzaro, G., Guiotto, A., and Chilin, A., Exp. Opin.
Ther. Pat., 2012, vol. 22, pp. 223–252.
8. Alafeefy, A.M., Kadi, A.A., AlꢀDeeb, O.A.,
ElꢀTahir, K.E.H., and Alꢀjaber, N.A., Eur. J. Med.
Chem., 2010, vol. 45, pp. 4947–4952.
16. Desai, N.C. and Dodiya, A.M., Arab. J. Chem., 2011.
DOI: 10.1016/j.arabjc.2011.08.007
9. Parhi, A.K., Zhang, Y., Saionz, K.W., Pradhan, P.,
Kaul, M., Trivedi, K., Pilch, D.S., and LaVoie, E.J.,
Bioorg. Med. Chem. Lett., 2013, vol. 23, pp. 4968–4974.
10. Modh, R.P., De Clercq, E., Pannecouque, C., and
Chikhalia, K.H., J. Enz. Inhib. Med. Chem., 2013,
vol. 29, pp. 100–108.
11. Maurya, H.K., Verma, R., Alam, S., Pandey, S.,
Pathak, V., Sharma, S., Srivastava, K.K., Negi, A.S.,
and Gupta, A., Bioorg. Med. Chem. Lett., 2013, vol. 23,
pp. 5844–5849.
17. Desai, N.C., Dodiya, A., and Shihora, P., Med. Chem.
Res., 2012, vol. 21, pp. 1577–1586.
18. Modh, R.P., Patel, A.C., Mahajan, D.H., Pannecouꢀ
que, C., De Clercq, E., and Chikhalia, K.H., Arch.
Pharm., 2012, vol. 345, pp. 964–972.
19. Modh, R., P., Patel, A..C., and Chikhalia, K.H., Med.
Chem., 2012, vol. 8, pp. 182–192.
20. Paul, K., Sharma, A., and Luxami, V., Bioorg. Med.
Chem. Lett., 2014, vol. 24.
12. Mishra, M., Mishra, V., Senger, P., Pathak, A., and 21. Hawkey, P. and Lewis, D.A., Medical Bacteriology: A
Kashaw, S., Med. Chem. Res., 2014, vol. 23, pp. 1397– Practical Approach, Oxford: Oxford University Press,
1405. 2004.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 41
No. 2
2015