Synthesis and antimicrobial activity of N -[(2 Z)-3-(4,6- substitutedpyrimidin-2-yl)-4-phenyl-1,3-thiazol-2(3 H)-ylidene]-3, 5-dinitrobenzamide analogues

Article abstract of DOI:10.1002/jhet.964

In this study, we have synthesized 1-(4,6-disubstitutedpyrimidin-2-yl)-3- (3,5-dinitrobenzoyl)-thiourea derivatives (1a-1h) and N-[(2Z)-3-(4,6- disubstitutedpyrimidin-2-yl)-4-phenyl-1,3-thiazol-2(3H)-ylidene]-3, 5-dinitrobenzamide (2a-2h) analogues and ch

Full text of DOI:10.1002/jhet.964

March 2013
Synthesis and Antimicrobial Activity of N‐[(2Z)‐3‐(4,6‐
Substitutedpyrimidin‐2‐yl)‐4‐phenyl‐1,3‐thiazol‐2(3H)‐ylidene]‐
3, 5‐dinitrobenzamide Analogues
237
b
c
Sohail Saeed,a,b Rizwan Hussain, and Muhammad Ali
*
aDepartment of Chemistry, Research Complex, Allama Iqbal Open University, Islamabad 44000,
Pakistan
bNational Engineering and Scientific Commission, P.O. Box 2801, Islamabad, Pakistan
cDepartment of Pharmacy, University of the Punjab, Lahore‐54590, Pakistan
*
E-mail: sohail262001@yahoo.com
Additional Supporting Information may be found in the online version of this article.
Received March 3, 2011
DOI 10.1002/jhet.964
Published online 29 March 2013 in Wiley Online Library (wileyonlinelibrary.com).
In this study, we have synthesized 1‐(4,6‐disubstitutedpyrimidin‐2‐yl)‐3‐(3,5‐dinitrobenzoyl)‐thiourea
derivatives (1a‐1h) and N‐[(2Z)‐3‐(4,6‐disubstitutedpyrimidin‐2‐yl)‐4‐phenyl‐1,3‐thiazol‐2(3H)‐ylidene]‐3,
5‐dinitrobenzamide (2a‐2h) analogues and characterized by IR spectroscopy, NMR spectroscopy, elemental
analysis, and single crystal X‐ray diffraction data. The compounds (2a‐2h) were screened for antimicrobial
activity against Gram positive, Gram negative, and fungal species. The results of antimicrobial study indi-
cated that compounds showed most potential and appreciable antibacterial and antifungal activities.
J. Heterocyclic Chem., 50, 237 (2013).
INTRODUCTION
[14], analgesic, antibacterials, antirheumatic, antipyretic, and
antiHIV [15] activities. Some fused thiazolines find applica-
tions in the treatment of allergies, hypertension, inflammation,
schizophrenia, and bacterial and HIV infections [16]. 2‐Thiazo-
lylimino‐5‐arylidene‐4‐thiazolidinones show marked antimi-
crobial activity against bacteria, yeasts, and molds [17]. Some
cyclic chiral oligothiazolines, having a wheel‐like architecture
containing a linear array of thiazoline rings, are well known
supramolecules [18]. 2‐(Tetrahydronaphthalen‐1‐yl)iminothia-
zolidine exhibits pronounced antidepressant activity [19], and
β‐(hydrooxyethyl)thiazolidines are effective antihypertensives
[20]. 3‐Substituted 2‐(cyanoimino)thiazolidines can be used
in agriculture because of their neonicotinoid insecticidal activ-
ity [21]. 3‐Substituted thiazolidines show radioprotective prop-
erties against γ‐radiations [22]. 2‐Imino‐1,3‐thiazolines
derivatives have shown antifungal activity against the rice blast
fungus Pyricularia oryzae [23], and thus, can be used as fungi-
cides. 2‐Imino‐1,3‐thiazoline derivatives significantly inhibits
melanin production in a dose‐dependant manner, thus acting
as a skin whitening agent [24], and pifithrin‐α is a reversible in-
hibitor of p53‐mediated apoptosis and p53‐dependant gene
transcription [25].
In the family of heterocyclic compounds, nitrogen‐
containing heterocycles with a sulfur atom are the important
class of compounds in medicinal chemistry. Pyrimidine
moiety is an important class of N‐containing heterocycles
widely used as key building blocks for pharmaceutical agents
when attached with thiazole functional group. It exhibits a
wide spectrum of pharmacophore as it acts as bactericidal,
fungicidal [1], analgesic [2], antihypertensive [3], and antitu-
mor agents [4]. Among these, thiouracils are similarly used
as anti‐inflammatory and virucidal agents [5]. In addition,
preclinical data from literature survey indicate continuing
research in polysubstituted pyrimidine as potential antitumor
agents [6]. The biological and synthetic significance places
this scaffold at a prestigious position in medicinal chemistry
research.
Thiazole heterocycle is a commonly occurring substructure
in organic chemistry, found in a variety of structurally and
biologically interesting natural products, such as mirabazoles,
thiangazole, and tantazoles, which display selective cytotoxi-
city against murine solid tumors and are potent and selective
inhibitors of HIV‐1 [7, 8]. Synthetic thiazoline derivatives are
useful medicaments showing antifungal [9, 10], antitumor
[11], antiallergic [12], anti‐inflammatory [13], antihypertension
The importance of such work lies in the possibility that the
next generation thiazole derivatives bearing pyrimidine
nucleus might be more efficacious as antimicrobial agents.
© 2013 HeteroCorporation

238
S. Saeed, R. Hussain, and M. Ali
Vol 50
Scheme 1. Synthesis of N‐[(2Z)‐3‐(4,6‐substitutedpyrimidin‐2‐yl)‐4‐phenyl‐
1,3‐thiazol‐2(3H)‐ylidene]‐3,5‐dinitrobenzamide analogues.
nucleophiles, we have found the use of tetrabutylammonium
bromide (TBAB) as a phase transfer catalyst (PTC) can afford
aroyl isothiocyanates in good yield, as reported here (Scheme 1).
The compounds (1a‐1h) showed absorptions at 3351 and
3200 cm−1 for free and associated NH, at 1660–1685 for
carbonyl, and at 1230 cm−1 for thiocarbonyl groups in IR spectra
and singlets at δ 9.0–9.5 and 11.2–12.1 (ppm) for NH (1) and
NH (3) and peaks at 168–170 and 178–180 (ppm) for carbonyl
1
and thiocarbonyl were observed in H and 13C NMR spectra,
respectively.
The cyclocondensation of N‐[(4,6‐disubstitutedpyrimidin‐2‐
yl)carbamothioyl]‐3,5‐dinitrobenzamide (1a‐1h) with aceto-
phenone was achieved in the presence of bromine and base.
Thus, triethyl amine was added to a solution of N‐[(4,6‐
disubstitutedpyrimidin‐2‐yl) carbamothioyl]‐3,5‐dinitrobenza-
mide in anhydrous dichloromethane, followed by the treatment
with a mixture of acetophenone and bromine under an inert
atmosphere to afford heterocyclic N‐[(2Z)‐3‐(4,6‐substituted-
pyrimidin‐2‐yl)‐4‐phenyl‐1,3‐thiazol‐2(3H)‐ylidene]‐3,5‐
dinitrobenzamide derivatives (2a‐2h).
The absence of N-H peaks at 3200–3400 cm−1, slight shift-
ing of C═O absorptions to 1630–1675 cm−1, and appearance
of characteristic C═N at 1450–1495 cm−1 were observed in
the IR spectra. 1H NMR spectra showed the disappearance of
1
N-H peaks and emergence of a H characteristic singlet at δ
6.7–6.9 because of C═C-H of the thiazole ring.
In 13C NMR the characteristic peak for olefinic carbon at
δ107.5–107.8 (ppm) confirmed the formation of N‐[(2Z)‐3‐
(4,6‐substitutedpyrimidin‐2‐yl)‐4‐phenyl‐1,3‐thiazol‐2(3H)‐
ylidene]‐3,5‐dinitrobenzamide derivatives. Although the
same mesomeric anionic thiourea intermediate may
furnish either imino‐1,3‐thiazoles (S‐cyclization products)
or isomeric imidazole‐2‐thiones (N‐cyclization products), it has
already equally demonstrated [32] that under these conditions
the thermodynamically stable imino‐1,3‐thiazoles are the
However, a thorough investigation relating the structure and
the activity of the thiazole derivatives as well as their stability
under biological conditions is required. These detailed investi-
gations could be helpful in designing more potent antimicro-
bial agents. Since varying substituents is a common method
for drug design in medicinal chemistry and a useful medical
value of substituted thiazole derivatives containing pyrimidine
moiety, we aimed to synthesize new thiazole derivatives and
to investigate their antimicrobial activities. On the basis of
these reports, we herein report the synthesis, characterization,
and antimicrobial activity of a series of novel thiazole deriva-
tives bearing pyrimidine moiety.
exclusive products as reported in previous papers [33, 34].
Crystal structure study. The compound, 1‐(4,6‐
dimethylpyrimidin‐2‐yl)‐3‐(3,5‐dinitrobenzoyl)‐thiourea (1a),
crystallizes in a monoclinic primitive space group, P 21/n
(Table 1). The packing is three‐dimensional, but a
representative two‐dimensional view along the short
axis and a molecular diagram is provided in the
Supporting Information.
RESULTS AND DISCUSSION
Unlike its other analog, the molecule is almost planar. The ni-
tro groups are 5.05 (11)° and 9.40 (15)° from the phenyl ring
plane of C1‐C6. The thiourea group is almost coplanar with
the amido group. The 4, 6‐dimethyl‐pyrimidinyl ring plane,
C9‐C14/N5/N6, makes a dihedral angle of 1.31 (5) with the
the plane, C7/O5/N3/C8/S1/N4. There are intramolecular
N-H···O and N-H···N H‐bond interactions. The intermolecular
O-H···O H‐bond interactions link the molecules to form 2D net-
works in the crystal lattice (Table 2). There are also weak π···π
between neighboring benzene rings in the crystal lattice. There
is no residual solvent accessible void volume in the unit cell.
Synthesis and spectral properties. N‐[(4,6‐disubstituted-
pyrimidin‐2‐yl)carbamothioyl]‐3,5‐dinitrobenzamide (1a‐1h)
were prepared according to the published procedure
involving treatment of 3,5‐dinitrobenzoyl chloride with
ammonium thiocyanate in anhydrous acetone followed
by reaction with suitably substituted anilines [26–29].
The use of phase transfer catalysts as a method of agitating a
heterogeneous reaction system is gaining recognition
[30, 31]. In search of improved methods to prepare the
N‐[(4,6‐disubstitutedpyrimidin‐2‐yl) carbamothioyl]‐3,
5‐dinitrobenzamide by reacting isothiocyanates with
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2013
Synthesis and Antimicrobial Activity of N‐[(2Z)‐3‐(4,6‐substitutedpyrimidin‐2‐yl)‐
4‐phenyl‐1,3‐thiazol‐2(3H)‐ylidene]‐3,5‐dinitrobenzamide Analogues
239
Table 1
Table 2
Crystallographic data, data collection and structure refinement for 1‐(4,6‐
dimethylpyrimidin‐2‐yl)‐3‐(3,5‐dinitrobenzoyl)‐thiourea (1a).
Hydrogen bonds [Å and °] for compound 1a.
d (H…
A)
D (D…
A)
Empirical formula
Formula weight
Temperature
Wavelength
Crystal system
Space group
C14H14N6O6S
D‐H…A
d (D‐H)
<(DHA)
394.37
297 (2) K
N4─H4N···O6
N3─H3N···N6
0.88(2)
0.83(2)
1.97(2)
2.00(2)
2.32 (4)
2.44 (4)
2.62(4)
2.849(2)
2.705(2)
3.119 (3) 3.119 (3)
3.143 (3)
3.248(3)
171.9(19)
141.8(19)
1.54184 Å
Monoclinic
P21/n
a = 6.7892 (6) Å
b = 10.1823 (9) Å
O6─H6A···O3a 0.82 (4)
O6─H6B···O2b 0.73 (4)
164 (4)
146(4)
O6─H6B···O1b
0.73(4)
Unit cell dimensions
Symmetry codes:
c = 24.267 (2) Å
ax‐1/2, ‐y+1/2, z+1/2.
bx‐1/2, ‐y+3/2, z+1/2.
β= 92.901 (1)°
Volume
1675.4 (3) Å3
Z
4
Density (calculated)
Absorption coefficient
F(000)
1.563 g/cm3
the antibacterial studies, the efficacy against Gram‐positive is
higher than Gram‐negative bacteria. Two of eight compounds
showed good activity against S.epidermidis. In addition, 2e
and 2h showed high activity against Gram‐positive, Gram‐
negative bacteria, and fungi.
0.24 mm−1
816
Crystal size
0.40 × 0.16 × 0.14 mm3
Reflections collected
Independent reflections
Absorption correction
9067
2942
multI‐scan, SADABS (Sheldrick,
2004)
Max. and min.
transmission
Refinement method
(Δ/σ)max
Δρmax
Δρmin
0.909 and 0.967
CONCLUSIONS
Full‐matrix least‐squares on F2
The straightforward approach, simplicity and first one
step method make it an interesting approach for the synthe-
sis of thiazole‐pyrimidine core derivatives. An in vitro
screen led to the identification of compounds 2e and 2h
as potential antifungal candidates worthy of further struc-
tural modification and pharmacological evaluation. More-
over, the antimicrobial activity of this series suggests the
thiazole‐pyrimidine core offers a novel template for the de-
velopment of a new class of antimicrobial agents.
0.003
0.20 e Å−3
−0.23 e Å−3
CCDC
805048
Antimicrobial activities.
In the light of interesting
antimicrobial activities of thiazole derivatives were
screened for antibacterial and antifungal activity against
Staphylococcus aureus, Staphylococcus epidermidis,
Escherichia coli, Proteus valgaris, Candida albicans, and
Candida glabrata by the broth microdilution procedure.
The Gram‐positive antibacterial agent, amikacin, the
Gram‐negative antibacterial agent, gentamycin, and the an-
tifungal agent, nystatin, were used as controls. The in vitro
antimicrobial properties against a number of Gram‐nega-
tive, Gram‐positive bacteria, and yeasts are presented in
Table 3.
EXPERIMENTAL
Melting points were recorded on Electrothermal IA9000 series
digital melting point apparatus. The proton NMR and 13C spectra
Table 3
MIC values (μg/mL) of the synthesized thiazole derivatives against the
tested Gram‐positive, Gram‐negative bacteria and yeasts.
All the compounds inhibited the growth of bacteria with
MIC values ranging between 40 and 100 μg/mL and showed
antiyeast activity with MICs between 30 and 50 μg/mL.
Compounds which showed MIC of >100 μg/mL or above
have not been included for the discussion. According to the
antimicrobial studies, all the compounds showed such activity,
albeit lower than their antiyeast efficacy. This difference may
be due to the differences between the cell structure of bacteria
and yeast. The cell wall of fungi contain chitin, whereas the
cell wall of bacteria contains murein [35]. In addition, fungi
contain ergosterol in their cell membranes instead of the
cholesterol found in the cell membranes of animals [36].
When all the antiyeast MIC values are compared, two of eight
compounds showed good activity against C.albicans and
seven showed low activity against C.glabrata. According to
Compounds
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
2g
2h
100
100
100
100
50
>100
100
>100
100
80
100
80
50
100
50
50
50
80
>100
100
100
80
100
80
50
50
50
50
30
50
50
50
2c
50
50
50
50
30
50
50
30
1c
80
80
80
100
50
50
80
40
Ref. drugs
0.5a
2a
0.5b
2b
1: S.epidermidis (ATCC 12228), 2: S.aureus (ATCC 29213), 3: E.coli
(ATCC 25922), 4: P.vulgaris(ATCC 13315), 5: C.glabrata (ATCC
32554), 6: C.albicans (ATCC 90028)
aAmikacin.
bGentamycin.
cNystatin.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

240
S. Saeed, R. Hussain, and M. Ali
Vol 50
were recorded in DMSO‐d6 solvent on Bruker 300 MHz spectro-
photometer using tetramethylsilane as an internal reference,
respectively. The apparent resonance multiplicity is described as
s (singlet), br s (broad singlet), d (doublet), dd (doublet of doub-
lets), t (triplet), q (quartet), and m (multiplet). Infrared measure-
ments were recorded in the range 400–4000 cm−1 on spectrum
2000 by Perkin Elmer. Elemental analysis was carried out using
Perkin Elmer CHNS/O 2400. Obtained results were within 0.4
% of the theoretical values. Thin layer chromatography (TLC)
analysis were carried out on 5 × 20 cm plate coated with silica
gel GF254 type 60 (25–250 mesh) using an ethyl acetate‐dichlor-
omethane mixture (1:2) as solvent. Synthetic starting material,
reagents, and solvents were of analytical reagent grade or of the
highest quality commercially available and were purchased from
Aldrich Chemical Co., Merck Chemical Co. and were dried when
necessary. 4, 6‐disubstituted 2‐amino‐pyrimidines were prepared
by the literature method [37].
General procedure for preparation of compounds. 1‐(4,6‐
Disubstitutedpyrimidin‐2‐yl)‐3‐(3,5‐dinitrobenzoyl)‐thiourea
(1a‐1h). A solution of 3, 5‐dinitrobenzoyl chloride (26 mmol) in
anhydrous acetone (80 mL) and 3% tetrabutyl ammonium
bromide (TBAB) in acetone was added dropwise to a suspension
of ammonium thiocyanate in acetone (50 mL) and the reaction
mixture was refluxed for 45 min. After cooling to room
temperature, a solution of 4,6‐disubstituted‐2‐aminopyrimidines
of equimolar quantity in acetone (25 mL) was added and the
resulting mixture refluxed for 2.5 h. The reaction mixture was
poured into five times its volume of cold water, whereupon the
thiourea precipitated. The solid product was washed with water
and purified by recrystallization from ethyl acetate.
H), 3.19 (6H,s, pyrimidine‐OCH3); 13C NMR (300 MHz, DMSO‐
d6) in δ (ppm): 180.3, 168.2,164.5, 162.4, 153.5,140.2, 128.0,
123.4, 53.1.
1‐(4‐Ethyl‐6‐methylpyrimidin‐2‐yl)‐3‐(3,5‐dinitrobenzoyl)‐
thiourea (1c). Elemental analysis for C15H14N6O5S (MW = 390.3) in
wt % calc. C = 46.15, H = 3.61, N = 21.53, S = 8.21, found C =
46.18, H = 3.65, N = 21.50, S = 8.20. m.p. 161–162°C, yield 79
%. IR (KBr pellet) in cm−1: 3351 (free NH), 3205 (assoc. NH),
1
1684 (C═O), 1613 (C═N stretching), 1590 (aromatic C═C); H
NMR (300 MHz, DMSO‐d6) in δ (ppm): 12.77 (1H, s, broad,
NH), 11.64 (1H, s, broad, NH), 8.55–8.11 (3H, m, Ar CH), 6.55
(1H, s, pyrimidine‐5‐H), 1.79 (2H,m, pyrimidine‐CH2CH3); 1.28
(3H,t, pyrimidine‐CH2CH3); 1.21 (3H,s, pyrimidine‐CH3); 13C
NMR (300 MHz,DMSO‐d6) in δ(ppm):180.2, 168.0, 164.5, 162.4,
153.5, 140.2, 128.0, 123.4, 35.1, 24.3, 21.3.
1‐(4,6‐Diethylpyrimidin‐2‐yl)‐3‐(3,5‐dinitrobenzoyl)‐thiourea (1d).
Elemental analysis for C16H16N6O5S (MW = 404.4) in wt % calc.
C = 47.52, H = 3.99, N = 20.78, S = 7.93, found C = 47.56,
H = 3.99, N = 20.75, S = 7.92. m.p. 158–159°C, yield 86 %.
IR (KBr pellet) in cm−1: 3352 (free NH), 3207 (assoc. NH),
1686 (C═O), 1618 (C═N stretching), 1596 (aromatic C═C);
1H NMR (300 MHz, DMSO‐d6) in δ (ppm): 12.79 (1H, s,
broad, NH), 11.64 (1H, s, broad, NH), 8.50–8.17 (3H, m, Ar
CH), 6.54 (1H, s, pyrimidine‐5‐H),1.87 (4H,m, pyrimidine‐
CH2CH3); 1.28 (6H,t, pyrimidine‐CH2CH3); 13C NMR (300
MHz, DMSO‐d6) in δ (ppm): 180.0, 168.0, 164.5, 162.4,
153.5, 140.2, 128.0, 123.4, 34.6, 23.8.
1‐(4‐Ethoxy‐6‐methoxypyrimidin‐2‐yl)‐3‐(3,5‐dinitrobenzoyl)‐
thiourea (1e). Elemental analysis for C15H14N6O7S (MW = 422.3)
in wt % calc. C = 42.65, H = 3.34, N = 19.90, S = 7.59, found
C = 42.67, H = 3.39, N = 19.89, S = 7.59. m.p. 139–140°C,
yield 80 %. IR (KBr pellet) in cm−1: 3352 (free NH), 3201
(assoc. NH), 1688 (C═O), 1615 (C═N stretching), 1589
N‐[(2Z)‐3‐(4,6‐Disubstitutedpyrimidin‐2‐yl)‐4‐phenyl‐1,3‐
thiazol‐2(3H)‐ylidene]‐3,5‐dinitrobenzamide (2a‐2h).
Triethylamine (0.01 mol) was added to a stirred solution of 1‐(4,6‐
disubstitutedpyrimidin‐2‐yl)‐3‐(3,5‐dinitrobenzoyl)‐thioureas (0.01 mol)
in dry dichloromethane (30 mL), followed by drop‐wise
addition of a solution of bromine (0.01 mol) in acetophenone
(0.01 mol) under nitrogen. The reaction mixture was stirred for
1–2 h and progress of the reaction was monitored by thin layer
chromatography (hexane: ethyl acetate, 4:1). After the reaction
was complete, the mixture was filtered; the filtrate was
concentrated to afford thiazole derivatives, which were purified
by recrystallization from ethanol.
1
(aromatic C═C); H NMR (300 MHz, DMSO‐d6) in δ (ppm):
12.75 (1H, s, broad, NH), 11.66 (1H, s, broad, NH), 8.54–8.11 (3H,
m, Ar CH), 6.56(1H, s, pyrimidine‐5‐H),3.85 (2H,m, pyrimidine‐
OCH2CH3);2.15 (3H,t, pyrimidine‐OCH2CH3); 2.28 (3H,s,
pyrimidine‐OCH3); 13C NMR (300 MHz, DMSO‐d6) in δ (ppm):
180.2, 168.2,164.5, 162.4, 153.5,140.2, 128.0, 123.4, 56.4, 54.2,
28.5.
1‐(4‐Methoxy‐6‐methylpyrimidin‐2‐yl)‐3‐(3,5‐dinitrobenzoyl)‐
thiourea (1f). Elemental analysis for C14H12N6O6S (MW = 392.3)
in wt % calc. C = 42.86, H = 3.08, N = 21.42, S = 8.17, found
C = 42.84, H = 3.12, N = 21.41, S = 8.18. m.p. 153–154oC, yield
79 %. IR (KBr pellet) in cm−1: 3354 (free NH), 3206 (assoc.
NH), 1686 (C═O), 1614 (C═N stretching), 1596 (aromatic
C═C); 1H NMR (300 MHz, DMSO‐d6) in δ (ppm): 12.78 (1H, s,
broad, NH), 11.63 (1H, s, broad, NH), 8.53–8.09 (3H, m, Ar
CH), 6.59(1H, s, pyrimidine‐5‐H), 3.19 (3H,t, pyrimidine‐OCH3);
1.23 (3H,s, pyrimidine‐CH3); 13C NMR (300 MHz, DMSO‐d6) in
Spectroscopic data of representative compounds. 1‐(4,6‐
Dimethyl‐pyrimidin‐2‐yl)‐3‐(3,5‐dinitrobenzoyl)‐thiourea (1a).
Elemental analysis for C14H12N6O5S (MW = 376.3) in wt %
calc. C = 44.68, H = 3.21, N = 22.33, S = 8.52, found C =
44.71, H = 3.25, N = 22.30, S = 8.51. m.p. 155–156°C, yield
86 %. IR (KBr pellet) in cm−1: 3352 (free NH), 3208 (assoc.
NH), 1686 (C═O), 1615 (C═N stretching), 1592 (aromatic
1
C═C); H NMR (300 MHz, DMSO‐d6) in δ (ppm): 12.80 (1H,
s, broad, NH), 11.63 (1H, s, broad, NH), 8.54–8.14 (3H, m, Ar
CH), 6.56(1H, s, pyrimidine‐5‐H),1.21(6H,s, pyrimidine‐CH3);
δ
(ppm): 180.3,168.2,164.5,162.4,153.5,140.2, 128.0, 123.4,
56.3, 23.8.
1‐(4‐Ethoxy‐6‐ethylpyrimidin‐2‐yl)‐3‐(3,5‐dinitrobenzoyl)‐
13C NMR (300 MHz, DMSO‐d6) in
δ (ppm): 180.1,
168.4,164.5, 162.4,153.5,140.2, 128.0, 123.4, 25.4.
thiourea (1g). Elemental analysis for C16H16N6O6S (MW = 420.3) in
wt % calc. C = 45.71, H = 3.84, N = 19.99, S = 7.63, found C = 45.74,
H = 3.83, N = 19.96, S = 7.62. m.p. 136–138°C, yield 73 %. IR (KBr
pellet) in cm−1: 3351 (free NH), 3209 (assoc. NH), 1685 (C═O),
1613 (C═N stretching), 1590 (aromatic C═C); 1H NMR
(300 MHz, DMSO‐d6) in δ (ppm): 12.81 (1H, s, broad, NH),
11.60 (1H, s, broad, NH), 8.55–8.10 (3H, m, Ar CH), 6.52
(1H, s, pyrimidine‐5‐H),3.85(2H,m,pyrimidine‐OCH2CH3);2.45(3H,t,
pyrimidine‐OCH2CH3); 1.46 (2H,s, pyrimidine‐CH2CH3),1.24 (3H,s,
1‐(4,6‐Dimethoxypyrimidin‐2‐yl)‐3‐(3,5‐dinitrobenzoyl)‐thiourea
(1b). Elemental analysis for C14H12N6O7S (MW = 408.3) in wt %
calc. C = 41.18, H = 2.96, N = 20.58, S = 7.85, found C = 41.16, H
= 2.99, N = 20.57, S = 7.85. m.p 147–149°C, yield 82 %. IR (KBr
pellet) in cm−1: 3355 (free NH), 3207 (assoc. NH), 1682 (C═O),
1615 (C═N stretching), 1590 (aromatic C═C); 1H NMR (300
MHz, DMSO‐d6) in δ (ppm): 12.78 (1H, s, broad, NH), 11.60 (1H,
s, broad, NH), 8.51–8.11 (3H, m, Ar CH), 6.57(1H, s, pyrimidine‐5‐
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2013
Synthesis and Antimicrobial Activity of N‐[(2Z)‐3‐(4,6‐substitutedpyrimidin‐2‐yl)‐
4‐phenyl‐1,3‐thiazol‐2(3H)‐ylidene]‐3,5‐dinitrobenzamide Analogues
241
pyrimidine‐CH2CH3); 13C NMR (300 MHz, DMSO‐d6) in δ (ppm):
180.1,168.3,164.5,162.4,153.5,140.2, 128.0, 123.4, 56.7, 45.4,35.4,
22.1.
7.28 (5H, m, phenyl‐H), 6.76(1H, s, thiazole CH), 6.42 (1H, s,
pyrimidine‐5‐H), 1.85 (4H,m, pyrimidine‐CH2CH3),1.20 (6H,t,
pyrimidine‐CH2CH3); 13C NMR (300 MHz, DMSO‐d6) in δ
(ppm): 171.02, 168.31, 139.62, 138.04, 137.75, 136.25,
135.70, 134.30, 132.47, 130.10, 130.0, 129.56, 129.10, 128.64,
128.26, 126.81, 126.08,107.54, 46.12, 21.15.
1‐(4,6‐Diethoxypyrimidin‐2‐yl)‐3‐(3,5‐dinitrobenzoyl)‐thiourea
(1h). Elemental analysis for C16H16N6O7S (MW = 436.3) in wt %
calc. C = 44.04, H = 3.70, N = 19.26, S = 7.35, found C = 44.00,
H = 3.72, N =19.25, S = 7.38. m.p. 131–132°C, yield 81%. IR
(KBr pellet) in cm−1: 3350 (free NH), 3209 (assoc. NH), 1681
N‐[(2Z)‐3‐(4‐Ethoxy‐6‐methoxypyrimidin‐2‐yl)‐4‐phenyl‐1,3‐
thiazol‐2(3H)‐ylidene]‐3,5‐dinitrobenzamide (2e). Elemental
analysis for C23H18N6O7S (MW = 522.49) in wt % calc. C =
52.87, H = 3.47, N = 16.08, S = 6.14 and found to be C = 52.90,
H = 3.50, N = 16.05, S= 6.12. m.p. 236–238°C, yield 65 %.IR
(KBr pellet) in cm−1: 1672 (C═O), 1525 (Ar-C═C), 1495 (C═N
stretching), 1272 (C-S), 1153 (C-N). 1H NMR (300 MHz,
DMSO‐d6) in δ (ppm): 8.19–8.05 (3H, m, Ar CH), 7.65–7.28
(5H, m, phenyl‐H), 6.81(1H, s, thiazole CH), 6.56 (1H, s,
pyrimidine‐5‐H), 2.81 (2H,m, pyrimidine‐OCH2CH3); 2.75 (3H,s,
pyrimidine‐OCH3), 1.95 (3H,t, pyrimidine‐OCH2CH3); 13C NMR
(300 MHz, DMSO‐d6) in δ (ppm) : 171.02, 168.31, 139.62,
138.04, 137.75, 136.25, 135.70, 134.30, 132.47, 130.10, 130.0,
129.56, 129.10, 128.64, 128.26, 128.0, 126.81, 107.8, 56.7, 45.8,
29.31.
N‐[(2Z)‐3‐(4‐Methyl‐6‐methoxypyrimidin‐2‐yl)‐4‐phenyl‐1,3‐
thiazol‐2(3H)‐ylidene]‐3,5‐dinitrobenzamide (2f). Elemental
analysis for C22H16N6O6S (MW = 492.46) in wt % calc. C =
53.66, H = 3.27, N = 17.07, S = 6.51 and found to be C = 53.64,
H = 3.30, N = 17.10, S = 6.50. m.p. 241–242°C, yield 69 %.IR
(KBr pellet) in cm−1: 1674 (C═O), 1523 (Ar-C═C), 1490 (C═N
stretching), 1269 (C-S), 1151 (C-N). 1H NMR (300 MHz,
DMSO‐d6) in δ (ppm): 8.19–8.05 (3H, m, Ar CH), 7.65–7.28
(5H, m, phenyl‐H), 6.79(1H, s, thiazole CH), 6.51 (1H, s,
pyrimidine‐5‐H), 2.57 (3H,s, pyrimidine‐OCH3); 1.28 (3H,s,
pyrimidine‐CH3); 13C NMR (300 MHz, DMSO‐d6) in δ (ppm) :
171.02, 168.31, 139.62, 138.04, 137.75, 136.25, 135.70, 134.30,
132.47, 130.10, 130.0, 129.56, 129.10, 128.64, 128.26, 128.0,
126.81, 107.70, 54.25, 24.16.
N‐[(2Z)‐3‐(4‐Ethoxy‐6‐ethylpyrimidin‐2‐yl)‐4‐phenyl‐1,3‐thiazol‐
2(3H)‐ylidene]‐3,5‐dinitrobenzamide (2g). Elemental analysis for
C24H20N6O6S (MW = 520.51) in wt % calc. C = 55.38, H = 3.87, N
= 16.15, S = 6.16 and found to be C = 55.39, H = 3.90, N = 16.13,
S = 6.18. m.p. 251–253°C, yield 61 %.IR (KBr pellet) in cm−1:
1671 (C═O), 1528 (Ar-C═C), 1488 (C═N stretching), 1270 (C-S),
1151 (C-N). 1H NMR (300 MHz, DMSO‐d6) in δ (ppm): 8.19–8.05
(3H, m, Ar CH), 7.65–7.28 (5H, m, phenyl‐H), 6.80(1H, s,
thiazole CH), 6.48 (1H, s, pyrimidine‐5‐H), 2.74 (2H,m,
pyrimidine‐OCH2CH3);1.98 (3H,t, pyrimidine‐OCH2CH3),1.85
(2H,m, pyrimidine‐CH2CH3), 1.20 (3H,t, pyrimidine‐
CH2CH3); 13C NMR (300 MHz, DMSO‐d6) in δ (ppm) :
171.02, 168.31, 139.62, 138.04, 137.75, 136.25, 135.70,
134.30, 132.47, 130.10, 130.0, 129.56, 129.10, 128.64, 128.26,
128.0, 126.81, 107.52, 54.3, 46.34, 35.40, 21.31.
1
(C═O), 1613 (C═N stretching), 1596 (aromatic C═C); H NMR
(300 MHz, DMSO‐d6) in δ (ppm): 12.77 (1H, s, broad, NH),
11.61 (1H, s, broad, NH), 8.50–8.13 (3H, m, Ar CH), 6.56(1H, s,
pyrimidine‐5‐H),3.78(4H,m,pyrimidine‐OCH2CH3);2.41(6H,
t, pyrimidine‐OCH2CH3); 13C NMR (300 MHz, DMSO‐d6) in
δ (ppm): 180.0,168.2,164.5,162.4,153.5,140.2,128.0, 123.4,
56.1, 45.8.
N‐[(2Z)‐3‐(4,6‐Dimethylpyrimidin‐2‐yl)‐4‐phenyl‐1,3‐thiazol‐
2(3H)‐ylidene]‐3,5‐dinitrobenzamide (2a). Elemental analysis for
C22H16N6O5S (MW = 476.46) in wt % calc. C = 55.46, H = 3.38,
N = 17.64, S = 6.73 and found to be C = 55.11, H = 3.45, N =
17.65, S = 6.70. m.p.251°C, yield 65 %.IR (KBr pellet) in cm−1:
1670 (C═O), 1525 (Ar-C═C), 1456 (C═N stretching), 1275 (C-
S), 1155 (C-N). 1H NMR (300 MHz, DMSO‐d6) in δ (ppm):
8.50–8.13 (3H, m, Ar CH), 7.65–7.28 (5H, m, phenyl‐H), 6.73
(1H, s, thiazole CH), 6.45 (1H, s, pyrimidine‐5‐H), 1.23 (6H,s,
pyrimidine‐CH3); 13C NMR (300 MHz, DMSO‐d6) in δ (ppm) :
171.02, 168.31, 139.62, 138.04, 137.75, 136.25, 135.70, 134.30,
132.47, 130.10, 129.56, 129.10, 128.64, 128.26, 126.81,
126.08,107.68, 21.81,21.15.
N‐[(2Z)‐3‐(4,6‐Dimethoxypyrimidin‐2‐yl)‐4‐phenyl‐1,3‐thiazol‐2
(3H)‐ylidene]‐3,5‐dinitrobenzamide (2b). Elemental analysis for
C22H16N6O7S (MW = 358.39) in wt % calc. C = 51.97, H = 3.17,
N = 16.53, S = 6.31 and found to be C = 51.92, H = 3.22, N =
16.52, S = 6.35. m.p.245°C, yield 62 %.IR (KBr pellet) in cm−1:
1659 (C═O), 1528 (Ar-C═C), 1459 (C═N stretching), 1271 (C-S),
1152 (C-N). 1H NMR (300 MHz, DMSO‐d6) in δ (ppm): 8.25–8.05
(3H, m, Ar CH), 7.65–7.28 (5H, m, phenyl‐H), 6.78(1H, s, thiazole
CH), 6.54 (1H, s, pyrimidine‐5‐H), 3.21 (6H,s, pyrimidine‐OCH3);
13C NMR (300 MHz, DMSO‐d6) in δ (ppm) : 176.02, 169.50,
139.67, 138.62, 137.75, 136.05, 134.31, 132.49, 130.17, 130.1,
129.84, 129.10, 128.61, 128.08, 126.64, 126.08, 107.61,
55.10.31,53.13.
N‐[(2Z)‐3‐(4‐Ethyl‐6‐methylypyrimidin‐2‐yl)‐4‐phenyl‐1,3‐thiazol‐
2(3H)‐ylidene]‐3,5‐dinitrobenzamide (2c). Elemental analysis for
C23H18N6O5S (MW = 490.49) in wt % calc. C = 56.32, H = 3.70, N
= 17.13, S = 6.54 and found to be C = 56.36, H = 3.74, N = 17.11, S
= 6.53. m.p. 265–266°C, yield 59 %.IR (KBr pellet) in cm−1: 1668
(C═O), 1525 (Ar-C═C), 1456 (C═N stretching), 1275 (C-S), 1155
1
(C-N). H NMR (300 MHz, DMSO‐d6) in δ (ppm): 8.19–8.05 (3H,
m, Ar CH), 7.65–7.28 (5H, m, phenyl‐H), 6.77(1H, s, thiazole CH),
6.46 (1H, s, pyrimidine‐5‐H), 1.85 (2H,m, pyrimidine‐CH2CH3); 1.25
(3H,t, pyrimidine‐CH3); 1.21 (3H,s, pyrimidine‐CH3); 13C NMR (300
MHz, DMSO‐d6) in δ (ppm): 171.02, 168.31, 139.62, 138.04,
137.75, 136.25, 135.70, 134.30, 132.47, 130.10, 130.0, 129.56,
129.10, 128.64, 128.26, 126.81, 126.08, 107.8, 45.5,29.31,21.15.
N‐[(2Z)‐3‐(4,6‐Diethylpyrimidin‐2‐yl)‐4‐phenyl‐1,3‐thiazol‐
2(3H)‐ylidene]‐3,5‐dinitrobenzamide (2d). Elemental analysis
for C24H20N6O5S (MW = 504.51) in wt % calc. C = 57.14, H
= 4.00, N = 16.66, S = 6.36 and found to be C = 57.13,
H=4.25, N=16.65, S= 6.35. m.p. 248–249°C, yield 60 %.IR
(KBr pellet) in cm−1: 1672 (C═O), 1523 (Ar-C═C), 1481
(C═N stretching), 1268 (C-S), 1153 (C-N). 1H NMR (300
MHz, DMSO‐d6) in δ (ppm): 8.19–8.05 (3H, m, Ar CH), 7.65–
N‐[(2Z)‐3‐(4,6‐Diethoxypyrimidin‐2‐yl)‐4‐phenyl‐1,3‐thiazol‐
2(3H)‐ylidene]‐3,5‐dinitrobenzamide (2h). Elemental analysis for
C24H20N6O7S (MW = 536.51) in wt % calc. C = 53.73, H = 3.76,
N = 15.66, S = 5.98 and found to be C = 53.71, H = 3.81, N =
15.63, S = 5.98. m.p. 232–233°C, yield 65 %.IR (KBr pellet) in
cm−1: 1674 (C═O), 1522 (Ar-C═C), 1468 (C═N stretching),
1
1271 (C-S), 1158 (C-N). H NMR (300 MHz, DMSO‐d6) in δ
(ppm): 8.19–8.05 (3H, m, Ar CH), 7.65–7.28 (5H, m, phenyl‐H),
6.81(1H, s, thiazole CH), 6.50 (1H, s, pyrimidine‐5‐H), 2.81 (4H,
m, pyrimidine‐OCH2CH3);1.93 (6H,t, pyrimidine‐OCH2CH3);
13C NMR (300 MHz, DMSO‐d6) in δ (ppm): 171.02, 168.31,
139.62, 138.04, 137.75, 136.25, 135.70, 134.30, 132.47, 130.10,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

242
S. Saeed, R. Hussain, and M. Ali
Vol 50
130.0, 129.56, 129.10, 128.64, 128.26, 128.0, 126.81, 107.41,
56.41, 45.32.
these microbial suspensions. The stock solutions of the
synthesized compounds were prepared in dimethyl sulfoxide
(DMSO), which had no effect on the organisms in the
concentrations studied. The initial concentration was 200 mg/mL.
All of the dilutions were done with distillated water. The
concentrations of tested compounds were 100, 50, 25, 12.5, 6.25,
3.125 μg/mL. DMSO was used as negative control. Gentamycin,
amikacin, and nystatin were used as reference drugs for Gram‐
negative antibacterial activity, Gram‐positive antibacterial activity,
and anti‐fungal activity, respectively. All the inoculated plates were
incubated at 37°C and results were evaluated after 24 h for bacteria
and 48 h for fungi. The lowest concentration of the compounds that
prevented visible growth was considered minimal inhibitor
concentrations (MICs).
X‐ray data collection and structure refinement. 1a: A
yellow prism crystal of 1‐(4,6‐Dimethylpyrimidin‐2‐yl)‐3‐(3,5‐
dinitrobenzoyl)‐thiourea monohydrate, C14H12N6O5S1.H2O,
having approximate dimensions of 0.14 mm × 0.16 mm × 0.40
mm was mounted on glass fiber. All measurements were made
on
a Bruker SMART 1000 CCD detector with graphite
monochromated Mo‐Kα radiation. Indexing was performed
from 60 images that were exposed for 10 s for a preliminary
unit cell determination. Of which, 86 out of a total of 110
reflections were successfully indexed. The crystal‐to‐detector
distance was 50.00 mm. Crystal data: C14H12N6O5S1.H2O,
monoclinic, space group P21/n, a = 6.7892 (6) Å, b = 10.1823
(9) Å, c = 24.267 (2) Å, β = 92.901 (1)°, V = 1675.4 (3) Å3, T
= 297(2) K, Z = 4, F (000) = 816, Dx = 1.563 g cm−3, μ = 0.24
mm−1. The data were collected at a temperature of 24(1)°C to a
maximum 2θ value of 50.05°. A total of 1421 oscillation
images were collected in 4 runs. A sweep of data was done
using ω scans from 330.0 to 148.2° in −0.3° step, at χ = 54.7°
and φ = 0.0°. The exposure rate was 30.0 [sec./°]. The detector
swing angle was −30.00°. A second sweep was performed using
ω scans from 330.0 to 201.5° in −0.3° step, at χ = 54.7° and φ
= 90.0°. The detector swing angle was −30.00°. Another sweep
was performed using ω scans from 330.0 to 261° in −0.3° step,
at χ = 54.7° and φ = 180.0°. A final sweep was performed
using ω scans from 330.0 to 285° in −0.3° step, at χ = 54.7°
and φ = 270.0°. The crystal‐to‐detector distance was 50.00 mm.
Of the 11914 reflections that was collected, 2942 reflections
were unique. (Rint = 0.0200); equivalent reflections were
merged. The structure was solved by direct methods
(SHELXS97) and expanded using Fourier techniques. All non‐H
atoms were refined anisotropically. All of the C‐bound H atoms
are observable from difference Fourier map but are all placed at
geometrical positions with C-H = 0.93 and 0.96Å for phenyl
and methyl H‐atoms. All C‐bound H‐atoms are refined using
riding model with Uiso(H) = 1.2Ueq(Carrier). Both the N‐ and
O‐bound H‐atoms were located from difference Fourier map
and refined isotropically. CCDC 805048 contains the
supplementary crystallographic data for this article. [Copies of
this information may be obtained free of charge from the
Director, CCDC, 12 Union Road, Cambridge, CBZ IEZ, UK.
Facsimile (44) 01223 336 033, E‐mail: deposit@ccdc.cam.ac.uk
or http//www.ccdc.com.ac.uk/deposit].
Microbiology. Antibacterial and antifungal screening. For
the bacterial organisms, both Gram‐positive and Gram‐negative
bacteria were used. Gram‐positive and Gram‐negative bacteria
can be differentiated in the physical appearance of their cell
envelopes. The compounds were screened for their in vitro
antibacterial and antiyeast activities. Antimicrobial activities
were determined by the broth microdilution procedures and
principles of the Clinical and Laboratory Standards Institute
(CLSI) [38, 39]. Minimal inhibitory concentrations for each
compound were investigated against standard bacterial strains;
S.aureus (ATCC 29213), E.coli (ATCC 25922), S.epidermidis
(ATCC 12228), P.vulgaris (ATCC 13315) and yeast‐like fungi,
C.albicans (ATCC90028), C.glabrata (ATCC 32554). Bacterial
and fungal colonies of the test organisms were suspended
directly into a small volume of 0.9% saline and further diluted
until turbidity matched the Mc Farland Standard no: 0.5 Petri
dishes containing Mueller–Hinton agar for bacteria and
Sabouraud and Dextrose agar for fungi were impregnated with
Acknowledgments. Mr. Sohail Saeed is thankful to National
Engineering and Scientific Commission, Pakistan for providing the
facility of spectroscopic and microanalytical techniques free of
cost.
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Synthesis and Antimicrobial Activity of N‐[(2Z)‐3‐(4,6‐substitutedpyrimidin‐2‐yl)‐
4‐phenyl‐1,3‐thiazol‐2(3H)‐ylidene]‐3,5‐dinitrobenzamide Analogues
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet