Synthesis of phenyl thiazole hydrazones and their activity against glycation of proteins

Article abstract of DOI:10.1007/s00044-015-1349-1

Phenyl thiazole hydrazone derivatives 1-21 have been synthesized and screened for their in vitro antiglycation activity. Hydrazones 1-21 displayed assorted antiglycation activities having IC₅₀ values in the range of 187.61 ± 1.12-886.98 ± 5.29

Full text of DOI:10.1007/s00044-015-1349-1

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-015-1349-1
ORIGINAL RESEARCH
Synthesis of phenyl thiazole hydrazones and their activity against
glycation of proteins
•
Khalid Mohammed Khan Muhammad Irfan Mahwish Ashraf
•
•
•
•
•
Muhammad Taha Syed Muhammad Saad Shahnaz Perveen
M. Iqbal Choudhary
Received: 26 August 2014 / Accepted: 19 February 2015
Ó Springer Science+Business Media New York 2015
Abstract Phenyl thiazole hydrazone derivatives 1–21 have
been synthesized and screened for their in vitro antiglycation
activity. Hydrazones 1–21 displayed assorted antiglycation
activities having IC50 values in the range of 187.61 1.12–
and 16 exhibited weaker activities than standard. However,
compounds 19 and 20 showed no activity. When evaluated
for cytotoxicity against rat fibroblast cell line (3T3 cell line),
all compounds were found to be non-toxic in cellular model.
886.98 5.29 lM as compared to standard rutin (IC50
=
269.07 3.79 lM). Compounds 5 (IC50 = 187.61 1.12
lM), 3 (IC50 = 191.92 3.08 lM), 4 (IC50 = 193.77
Keywords Schiff bases ꢀ Phenyl thiazole hydrazones ꢀ
Antiglycation ꢀ AGEPs ꢀ Glycation of protein
3.06 lM),
6
(IC50 = 217.90 2.48 lM), 15 (IC50
= 221.98 2.34 lM), 2 (IC50 = 226.59 1.19 lM), 21
(IC50 = 229.67 1.95 lM), 18 (IC50 = 231.09 0.38 lM),
12 (IC50 = 242.94 2.05 lM), and 1 (IC50 = 264.22
5.60 lM), respectively, showed excellent antiglycation
activities superior to standard rutin. Compound 17
(IC50 = 269.94 1.11 lM) demonstrated a comparable
activity to the standard. Compounds 7, 8, 9, 10, 11, 13, 14,
Introduction
Hydrazones are heteroatomic compounds bearing azomethine
moiety (–C=N–) and also known as Schiff bases which are
generally prepared by condensation of active carbonyl groups
and primary amines. Schiff bases are recognized due to their
biological and pharmacological properties and showed potent
activities against bacteria, fungi, cancer, and viruses (Bharti
et al., 2010; Pandey et al., 2012). Hydrazones from aliphatic
aldehydes are comparatively unstable and are readily poly-
merized (Campbell et al., 1944). As far as aromatic aldehydes
are concerned, they have an effective conjugation system and
stability (Mohamed et al., 2011; Brewster, 1924; Munir et al.,
1985). Hydrazones have outstanding properties due to their
structural similarities with different naturally occurring
bioactive molecules. Simple and easy synthesis and the syn-
thetic flexibility are useful features of hydrazones to design
and synthesize new bioactive compounds (Mustapha et al.,
2011). Hydrazones have also been used as basic units of
certain dyes, and few of them are used as liquid crystals. In
addition, hydrazones have come into view to be a significant
intermediate in a number of enzymatic reactions involving
interaction of an enzyme with an amino or carbonyl group of
the hydrazones (Vennilaa et al., 2012; Amanullah et al., 2011;
Kadhum, 2011; AL-Garawi et al., 2012). At pH 5, hydrazone
undergoes rapid hydrolysis that increases its solubility in
K. M. Khan (&) ꢀ M. Irfan ꢀ M. Ashraf ꢀ
S. M. Saad ꢀ M. I. Choudhary
International Center for Chemical and Biological Sciences,
H. E. J. Research Institute of Chemistry, University of Karachi,
Karachi 75270, Pakistan
e-mail: khalid.khan@iccs.edu; hassaan2@super.net.pk
M. Taha
Atta-ur-Rahman Institute for Natural Product Discovery,
Universiti Teknologi MARA (UiTM), Puncak Alam Campus,
42300 Bandar Puncak Alam, Selangor D. E., Malaysia
M. Taha
Faculty of Applied Science, Universiti Teknologi MARA,
40450 Shah Alam, Malaysia
S. Perveen
PCSIR Laboratories Complex, Karachi, Shahrah-e-Dr.
Salimuzzaman Siddiqui, Karachi 75280, Pakistan
M. I. Choudhary
Department of Biochemistry, Faculty of Science, King
Abdulaziz University, Jeddah 22254, Saudi Arabia
123

Med Chem Res
water which also amplifies the antitumor activity of hydra-
zones toward ascetic tumor (Sidambaram et al., 2011; Patil
et al., 2011). In eukaryotic cells, hydrazones also play vital
role in transamination of transaminases which is found in
mitochondria and cytosol. All the transaminases posses the
prosthetic group, i.e., pyridoxal phosphate, which is non-co-
valently linked to enzyme protein (Mahmud et al., 2012).
Many industrial and biologically active compounds utilize
hydrazones as a substrate for cycloaddition, ring closure, and
replacement reaction (Musharraf et al., 2012). The benzoyl-
hydrazonesreportedfor antileishmanial (Tahaetal., 2013a, b)
and antioxidant activities (Anouar et al., 2013; Taha et al.,
2013a, b; Khan et al., 2012a, b). The chemical reaction be-
tween sugar aldehydes and proteins known as non-enzymatic
glycation is one of the key molecular basis of diabetic com-
plications due to hyperglycemia (Elhassan et al., 2012).
Hyperglycemia and hyperlipidemia are two important char-
acteristics of type 2 diabetes, an endocrine disorder-based
disease. In modern medicine, no satisfactory effective therapy
is still available to cure type 2 diabetes (Perez-Gutierrez et al.,
2010). Glycation is a non-enzymatic condensation reaction
between reducing sugars and amino groups of proteins that
rearranges to stable Amadori product (Monnier et al., 2008).
The ultimate effect of glycation is generation of high mole-
cular weight protein aggregates and other fluorescent entities,
referred to AGEs (advanced glycation end products). Some
AGEs such as carboxymethyllysine (CML) and pentosidine
have become highly useful biomarkers of glycoxidative
damages (Kazeem et al., 2012). It has been proposed that the
discovery of inhibitors of the glycation cascade should offer a
promising therapeutic approach for the prevention of diabetic
and its related pathogenic complications (Wu et al., 2009).
In recent past, we have reported several new classes of
synthetic and natural products as antiglycating agents (Khan
et al., 2009, 2011a, b, 2012a, b, 2013a, b; Taha et al., 2014).
Considering previous reports on the hypoglycemic activities
of benzothiazoles (Khan et al., 2011a, b), we envisaged that
due to structure similarities of phenyl thiazoles with ben-
zothiazoles might stimulate their hypoglycemic activities.
Therefore, a library of phenyl thiazoles 1–21 has been syn-
thesized and screened for antiglycation potential. The ob-
served results established that our initial hypothesis was
correct. We discovered the potent antiglycation compounds.
acetic acid in refluxing ethanol. After completion of re-
action, it was allowed to cool to room temperature, a
precipitate formation was occurred. Recrystallization
from methanol or ethanol afforded pure products in good
yields (Scheme 1). The structures of phenyl thiazoles
hydrazones (1–21) were deduced by NMR and EI MS
spectroscopic techniques. Elemental analysis results were
also found to be in good agreement with the calculated
values.
Antiglycation activity
Antiglycation compounds may serve as practical lead
compounds for the progress of new antidiabetic drugs that
will probably not only reduce the glycation process but also
help to eliminate glycation-induced oxidative stress (Taha
et al., 2014). As described earlier that the current study was
carried out due to close structural resemblance of phenyl
thiazole with benzothiazole which were found to be
antiglycating agents, we synthesized a library of phenyl
thiazole hydrazones (1–21) and evaluated their antiglyca-
tion potential. The experimental outcome indicates that our
initial supposition accurately drives the results (Table 1).
A careful look on the structures of the molecules used in
this study suggests that the antiglycation activity of com-
pounds 1–21 depends upon R1 substitution at the azome-
thine (C=N) residue or substitution at the phenyl ring
attached to it. Only those compounds were found to be
active where the R1 is a proton. Compounds 19 and 20 have
methyl group as R1 found to be completely inactive.
However, all other compounds having proton showed
strong to weak antiglycation potential.
Phenyl thiazole hydrazone derivatives 1–21 displayed
diversified antiglycation activities and showed IC50 values
between 187.61 1.12–886.98 5.29 lM, if compared
with standard rutin (IC50 = 269.07 3.79 lM). Com-
pounds 5 (IC50 = 187.61 1.12 lM), 3 (IC50 = 191.92
3.08 lM), 4 ((IC50 = 193.77 3.06 lM), 6 ((IC50
217.90 2.48 lM), 15 ((IC50 = 221.98 2.34 lM), 2
((IC50 = 226.59 1.19 lM), 21 (IC50 = 229.67
1.95 lM), 18 (IC50 = 231.09 0.38 lM), 12 (IC50
=
=
242.94 2.05 lM), and 1 (IC50 = 264.22 5.60 lM),
respectively, were found to be superior in activities as
compared to standard rutin. Compound 17 (IC50
=
269.94 1.11 lM) displayed a comparable activity to the
standard. Compounds 7, 8, 9, 10, 11, 13, 14, and 16 exhibited
weaker activities than standard. However, all compounds
were evaluated for cytotoxicity against rat fibroblast cell line
(3T3 cell line) and were found to be non-toxic in cellular
model.
Results and discussion
Chemistry
A library of phenyl thiazoles hydrazones (1–21) was
generated by the condensation of 4-hydrazino-4-phenyl
thiazole with varyingly substituted aromatic aldehydes
and acetophenone in the presence of catalytic amount of
Structure–activity relationship disclosed that the activity
of compounds 1–18 and 21 mainly depends upon the
substitution at the phenyl ring. Compound 5 (IC50
=
123

Med Chem Res
Scheme 1 Synthesis of phenyl
thiazole hydrazones (1–21)
187.61 1.12 lM) which has an ortho nitro residue is
found to be the active most compound among all tested
compounds. Compounds 6 (IC50 = 217.90 2.48 lM)
and 7 (IC50 = 437.81 5.37 lM) have meta and para
nitro group, respectively, and found to be weakly active as
compared to compound 5 due to slight change in position
of nitro group, suggesting that for a better antiglycation, the
nitro group must be at the ortho position of phenyl ring. If
we compare the activity of compounds 6 and 12
((IC50 = 242.9 2.05 lM), then it reveals that decrease
in activity of compound 12 may be due to the presence of a
chloro group at ortho position of phenyl ring.
Finnigan MAT-311A, Germany. Thin-layer chromatogra-
phy (TLC) was performed on pre-coated silica gel alu-
minum plates (Kieselgel 60, 254, E. Merck, Germany).
Chromatograms developed were visualized by UV at 254
and 365 nm.
Antiglycation assay
Bovine serum albumin-methylglyoxal glycation model
We performed the antiglycation assay according to the
following procedure described with some modification.
Reaction mixture contained 20 lL test sample, 50 lL BSA
(10 mg/mL), 50 lL MGO (14 mM), and 80 lL phosphate
buffer (100 mM; pH 7.4) containing NaN3 (3 mM) as a
antimicrobial agent. The reaction mixture was incubated
for 9 days at 37 °C. Each sample was run in triplicate.
Antiglycation effect of test sample was monitored by
measuring the specific fluorescence (excitation, 330 nm;
emission, 420 nm) against DMSO-treated control through a
microtitre plate spectrofluorometer (Spectra Max, Mole-
cular Devices, CA, USA). The IC50 values of compounds
were calculated by using the EZ-Fit Enzyme kinetics
software program (Perrella Scientific Inc. Amherst, MA,
Hydroxy-substituted phenyl ring containing compounds
3
(IC50 = 191.92 3.08 lM),
4
(IC50 = 193.77
3.06 lM), 15 (IC50 = 221.98 2.34 lM), and
2
(IC50 = 226.59 1.19 lM) demonstrated excellent ac-
tivity. The activity difference in this type of compounds is
also due to position of hydroxy group at phenyl ring.
Compound 3 displayed an equivalent activity to compound
4, suggesting that number of hydroxy does not influence
the activity; it is the position which affects the activity.
This fact is clearly proved by the comparable activities;
however, compound 15 contains an additional hydroxy
group. Compound 14 (IC50 = 321.13 1.84 lM) showed
a decreased activity due the obvious reason of positional
difference of hydroxy group.
USA). Rutin was used as
a
positive control
(IC50 = 269.07 3.79 lM).
The percentage inhibition of each test compound was
Compounds 1 (IC50 = 264.22 5.60 lM), 17 (IC50
=
269.94 1.11 lM), having hydroxy group as well as
methoxy and 18 (IC50 = 231.09 0.38 lM) having
dimethoxy, the activity pattern follows by positions of
hydroxy and methoxy suitable for interaction with sugar.
Same way ethoxy substitution at para position as in com-
pound 16 (IC50 = 488.19 2.11 lM), also follows the
same pattern.
determined by the formula given below:
% Inhibition ¼ ð1 ꢁ Fluorescence of test sample
=Fluorescence of the controlÞ ꢂ 100
Cytotoxicity evaluation on rat fibroblast 3T3 cell lines
In chloro-containing compounds, the positional isomer
follows the nitro and hydroxy residues pattern.
Rat fibroblast 3T3 cells were used in this assay. Briefly the
3T3-adherent cells (2 9 105 cells/mL) were cultured over-
night in CO2 environment in 96-well plate (at 37° C). Su-
pernatant was removed, and 50 lL of various concentration
of test compounds (100–12.5 lg/mL), 150 lL of DMEM
medium (supplemented with penicillin (100 units/mL), 5 %
(v/v) fetal bovine serum, and streptomycin (100 lg/mL)
were added to each well, and further incubation was carried
out for 72 h. After incubation, the culture medium was
aspirated and 50 lL (2 mg/mL in PBS) of MTT (3-[4,5-
dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide)
solution was added to each well. This reaction mixture was
Materials and methods
General experimental
NMR analyses were performed on Avance Bruker AM
300–500 MHz Instrument; CHN analysis was done with
Carlo Erba Strumentazion-Mod-1106, Italy. Electron im-
pact mass spectra (EI MS) were experimented on a
123

Med Chem Res
Table 1 In vitro antiglycation activity of phenyl thiazoles hydrazones 1–21
Comp.
IC50 SEMa
R1
R2
IC50 SEMa (µM) Comp. No. R1
R2
No
(µM)
242.94
2.05
H
H
H
H
1
12
13
14
264.22 5.6
226.59 1.19
191.92 3.08
886.98
5.29
H
H
2
3
321.13
1.84
221.98
2.34
H
H
4
193.77 3.06
15
488.19
2.11
H
H
H
16
17
18
H
H
H
5
6
7
187.61 1.12
217.90 2.48
437.81 5.37
269.94
1.11
231.09
0.38
NAb
NAb
8
9
H
H
19
20
CH3
CH3
327.99 5.91
493.26 1.51
229.67
1.95
H
H
H
-
10
11
21
278.42 2.17
321.47 3.87
269.07
3.79
Rutinb
-
a
SEM is the standard error of mean
b
Rutin is standard for antiglycation activity
123

Med Chem Res
12.91; O, 9.83; S, 9.85; Found; C, 62.73; H, 4.63; N, 12.89;
O, 9.85; S, 9.83.
then further incubated for 4 h. After 4 h, the MTT solution
was aspirated and cells were washed with phosphate-buf-
fered saline. Finally, DMSO (100 lL) was added to dissolve
the MTT-formazan adduct, formed by the action of mito-
chondrial dehydrogenase. The reaction plate was agitated at
room temperature for 15 min, and then, absorbance was
measured at 540 nm by using microplate reader (Spectra
Max Plus 384, Molecular Devices, CA, USA) (Dimas et al.,
1998). The percent viability was calculated as the relative
ratio of optical densities.
(E)-3-((2-(4-Phenylthiazol-2-yl)hydrazono)methyl)phenol
(2) Yield: (87 %); 1H-NMR (300 MHz, DMSO-d6): d
12.10 (s, 1H, H–NH), 9.57 (s, 1H, –OH), 7.92 (s, 1H,
CH=NAr), 7.84 (d, 2H, J = 7.2 Hz, H-20,60), 7.39 (t, 2H,
J = 7.8 Hz, H-30,50), 7.31–7.26 (m, 1H, H-5 and H-40),
7.21 (t, 1H, J = 7.8 Hz, H-500), 7.09 (s, 1H, H-200), 7.02 (d,
1H, J = 7.2 Hz, H-400), 6.76 (d, 1H, J = 8.1 Hz, H-600);
13C-NMR (DMSO-d6, 75 MHz): d 171.6 (C, C-2), 158.4
(C, C-300), 150.5 (C, C-4), 143.4 (C=N), 138.5 (CH, C-100),
133.3 (C, C-10), 129.8 (CH, C-500), 129.1 (CH, C-30, C-50),
128.4 (CH, C-40), 127.1 (CH, C-20, C-60), 121.2 (CH,
C-600), 118.8 (CH, C-400), 115.4 (CH, C-200), 105.4 (CH,
C-5); EI MS: m/z (rel. abund. %), 295 (M?, 100), 176
(100), 134 (100), 104 (47.1), 77 (43.9); 65 (39.3). Anal.
Calcd for C16H13N3OS; (295.36); C, 65.06; H, 4.44; N,
14.23; O, 5.42; S, 10.86; Found; C, 65.04; H, 4.46; N,
14.25; O, 5.44; S, 10.84.
Statistical analysis
All experiments were performed in microplate reader
(SpectraMax M2, Molecular Devices, CA, USA). Results
are presented as mean SEM from three experiments.
The obtained results were analyzed by SoftMaxPro 4.8, MS
Excel and GraphPad Prism-5.0, software package. IC50
values were determined by using EZ-FIT, Enzyme kinetics
software (Perrella Scientific, Inc., USA).
(E)-2-((2-(4-Phenylthiazol-2-yl)hydrazono)methyl)benzene-1,
1
4-diol (3) Yield: (87 %); H-NMR (300 MHz, DMSO-
d6): d 12.06 (s, 1H, NH), 9.35 (s, 1H, –OH), 8.90 (s, 1H,
–OH), 8.23 (s, 1H, CH = NAr), 7.84 (d, 2H, J = 7.5 Hz,
H-20,60), 7.39 (t, 2H, J = 7.5 Hz, H-30,50), 7.30–7.26 (m,
1H, H-40), 7.30 (s, 1H, H-5), 7.04 (d, 1H, J = 2.4 Hz,
H-600), 6.721–6.615 (m, 2H, H-300, H-400); 13C-NMR
(DMSO-d6, 75 MHz): d 171.2 (C, C-2), 154.2 (C, C-200),
152.1 (C, C-500), 150.1 (C, C-4), 143.8 (C = N), 132.9 (C,
C-10), 129.5 (CH, C-30, C-50), 128.1 (CH, C-40), 126.8 (CH,
C-20, C-60), 121.2 (C, C-100), 120.0 (CH, C-300), 118.8 (CH,
C-400), 116.2 (CH, C-600), 105.8 (CH, C-5); EI MS: m/z (rel.
abund. %), 311 (M?, 30.7), 294 (45.2), 176 (100), 134
(76.3). Anal. Calcd for C16H13N3O2S; (311.07); C, 61.72;
H, 4.21; N, 13.50; O, 10.28; S, 10.30; Found; C, 61.74; H,
4.23; N, 13.48; O, 10.30; S, 10.28.
General procedure for the synthesis of hydrazones 1–21
Commercially available 2-hydrazino-4-phenyl thiazole re-
acted with various aromatic aldehydes in absolute ethanol
or methanol in the presence of catalytic amount of acetic
acid which afforded compounds 1–21 in significant yields
(Scheme 1). In a typical reaction, 2-hydrazino-4-phenyl
thiazole (1 mmol) was reacted with different substituted
aromatic aldehydes (1 mmol) in ethanol under reflux for
3 h. The progress of reaction was monitored by TLC. After
completion of reaction, the mixture was allowed to cool to
room temperature. The solvent was evaporated by vacuum.
The crude product was recrystallized in ethanol which af-
forded pure thiazole hydrazones derivatives 1–21 in sig-
nificant yields.
(E)-2-((2-(4-Phenylthiazol-2-yl)hydrazono)methyl)benzene-
1,3,5-triol (4) Yield: (87 %); 1H-NMR (300 MHz,
DMSO-d6): d 10.41 (s, 1H, H-300,500), 9.76 (s, 1H, H–NH),
8.44 (s, 1H, CH=NAr), 7.83 (d, 2H, J = 7.2 Hz, H-20,60),
7.39 (t, 2H, J = 7.2 Hz, H-30,50), 7.31–7.27 (m, 2H, H-40,
H-5); 13C-NMR (DMSO-d6, 75 MHz): d 171.3 (C, C-2),
164.2 (C, C-200, C-600), 163.8 (C, C-400), 149.8 (C, C-4),
144.1 (C=N), 133.3 (C, C-10), 129.2 (CH, C-30, C-50), 128.3
(CH, C-40), 127.8 (CH, C-20, C-60), 106.5 (C, C-100), 104.8
(CH, C-5), 96.1 (CH, C-300, C-500); EI MS: m/z (rel. abund.
%), 327 (M?, 2.8), 309 (100), 161 (282.7), 134 (25.7).
Anal. Calcd for C16H13N3O3S; (327.07); C, 58.70; H, 4.00;
N, 12.84; O, 14.66; S, 9.80; Found; C, 58.68; H, 3.98; N,
12.86; O, 14.64; S, 8.98.
(E)-2-Methoxy-6-((2-(4-phenylthiazol-2-yl)hydrazono)methyl)
1
phenol (1) Yield: (81 %); H-NMR (300 MHz, DMSO-
d6): d 8.01 (s, 1H, H–NH), 7.84 (d, 2H, J = 7.2 Hz,
H-20,60), 7.68 (s, 1H, CH=NAr), 7.60 (d, 1H, J = 7.2 Hz,
H-600), 7.46 (d, 1H, J = 7.6 Hz, H-400), 7.45–7.38 (m, 2H,
H-40,H-500), 7.34 (s, 1H, H-5), 7.30 (t, 2H, J = 7.2 Hz,
H-30,50), 3.81 (s, 1H, H–OH), 3.30 (s, 3H, –OCH3); 13C-
NMR (DMSO-d6, 75 MHz): d 171.4 (C, C-2), 150.2 (C,
C-200), 150.0 (C, C-4), 149.2 (C, C-300), 143.1 (C=N), 133.1
(C, C-10), 129.20 (CH, C-30, C-50), 128.6 (CH, C-40), 127.4
(CH, C-20, C-6 ), 124.3 (CH, C-600), 119.2 (CH, C-100),
116.4 (CH, C-500), 115.20 (CH, C-400), 105.1 (CH, C-5),
56.4 (CH3, OCH3); EI MS: m/z (rel. abund. %), 325 (M?,
96.2), 308 (100), 176 (100), 134 (93.1), 104 (14.7). Anal.
Calcd for C17H15N3O2S; (325.09); C, 62.75; H, 4.65; N,
(E)-2-(2-(2-Nitrobenzylidene)hydrazinyl)-4-phenylthiazole
(5) Yield: (87 %); 1H-NMR (400 MHz, DMSO-d6): d
123

Med Chem Res
12.54 (s, 1H, H–NH), 8.41(s, 1H, CH=NAr), 8.04–8.02 (m,
2H, H-300, 600), 8.02 (d, 2H, J = 8 Hz, H-20,60), 7.65 (t, 1H,
J = 7.6 Hz, H-400), 7.48 (t, 2H, J = 7.2 Hz, H-500), 7.38 (t,
1H, J = 7.2 Hz, H-30,50), 7.39 (s, 1H, H-5); 13C-NMR
(DMSO-d6, 75 MHz): d 172.1 (C, C-2), 150.9 (C, C-4),
148.2 (C, C-200), 142.8 (C=N), 136.1 (C, C-500), 133.4 (C,
C-10), 132.3 (CH, C-400), 130.8 (CH, C-600), 130.4 (CH,
C-30, C-50), 129.4 (CH, C-40), 129.2 (C, C-100), 128.2 (CH,
C-20, C-60), 123.2 (CH, C-300), 105.7 (CH, C-5); EI MS: m/z
(rel. abund. %), 324 (M?, 58.5), 176 (100), 134 (100), 102
(36), 77 (21); 65 (8.4). Anal. Calcd for C16H12N4O2S;
(324.36); C, 59.25; H, 3.73; N, 17.27; O, 9.87; S, 9.89;
Found; C, 59.27; H, 3.75; N, 17.25; O, 9.85; S, 9.91.
J = 7.6 Hz, H-40); 13C-NMR (DMSO-d6, 75 MHz): d
171.8 (C, C-2), 150.1 (C, C-4), 143.4 (C=N), 134.2 (C,
C-300), 133.1 (C, C-10), 131.4 (CH, C-400), 130.2 (CH, C-30,
C-50), 130.1 (CH, C-500), 128.9 (CH, C-40), 127.5 (CH,
C-600), 127.3 (CH, C-20, C-60), 127.2 (CH, C-200), 121.1 (C,
C-100), 105.2 (CH, C-5); EI MS: m/z (rel. abund. %), 313
(M?, 25.1), 233 (91.3), 191 (100), 174 (70.3), 134 (93.6);
91(40.3), 43 (40.8). Anal. Calcd for C16H12ClN3S;
(313.04); C, 61.24; H, 3.85; Cl, 11.30; N, 13.39; S, 10.22;
Found; C, 61.22; H, 3.87; Cl, 11.28; N, 13.41; S, 10.20.
(E)-2-(2-(4-Chlorobenzylidene)hydrazinyl)-4-phenylthiazole
1
(9) Yield: (79 %); H-NMR (300 M Hz, DMSO-d6): d
12.25 (s, 1H, H–NH), 8.01 (s, 1H, CH=NAr), 7.84 (d, 2H,
J = 7.5 Hz, H-20,60), 7.66 (d, 2H, J = 8.7 Hz, H-200,600),
7.48 (d, 2H, J = 8.4 Hz, H-300,500) 7.40 (t, 2H, J = 7.2 Hz,
H-30,50), 7.31 (t, 1H, J = 7.8 Hz, H-40), 7.26 (s, 1H, H-5);
13C-NMR (DMSO-d6, 75 MHz): d 171.8 (C, C-2), 150.4
(C, C-4), 143.5 (C=N), 136.8 (CH, C-400), 135.1 (C, C-100),
133.1 (C, C-10), 130.4 (C, C-200, C-600), 129.5 (CH, C-30,
C-50), 129.1 (C, C-300, C-500), 128.9 (CH, C-40), 127.7 (CH,
C-20, C-60), 105.3 (CH, C-5); EI MS: m/z (rel. abund. %),
311 (M?, 23.0), 294 (7.9), 176 (100), 134 (66.3). Anal.
Calcd for C16H12ClN3S; (313.04); C, 61.24; H, 3.85; Cl,
11.30; N, 13.39; S, 10.22; Found; C, 61.26; H, 3.83; Cl,
11.28; N, 13.37; S, 10.24.
(E)-2-(2-(3-Nitrobenzylidene)hydrazinyl)-4-phenylthiazole
(6) Yield: (89 %); 1H-NMR (300 MHz, DMSO-d6): d
12.47 (s, 1H, H–NH), 8.46 (s, 1H, CH=NAr), 8.19 (dd, 1H,
J1 ,2 = 2 Hz, J1 ,3 = 8 Hz, H-300), 8.19 (s, 1H, H-200),
8.08 (d, 1H, J = 8 Hz, H-600), 7.85 (d, 2H, J = 7.6 Hz,
H-20,60), 7.71 (t, 1H, J = 7.6 Hz, H-500), 7.40 (t, 2H,
J = 7.6 Hz, H-30,50), 7.38 (s, 1H, H-5), 7.30 (t, 1H,
J = 7.2 Hz, H-40); 13C-NMR (DMSO-d6, 75 MHz): d
172.2 (C, C-2), 150.5 (C, C-4), 148.2 (C, C-300), 143.1
(C=N), 134.9 (C, C-100), 133.4 (C, C-10), 132.3 (CH, C-600),
130.2 (CH, C-30, C-50), 130.1 (CH, C-500), 129.1 (CH,
C-40), 128.1 (CH, C-20, C-60), 126.8 (CH, C-400), 121.4
(CH, C-200), 105.3 (CH, C-5); EI MS: m/z (rel. abund. %),
324 (M?, 35.1), 176 (100), 134 (89.9), 104 (12.3), 77 (19);
63 (5). Anal. Calcd for C16H12N4O2S; (324.36); C, 59.25;
H, 3.73; N, 17.27; O, 9.87; S, 9.89; Found; C, 59.27; H,
3.75; N, 17.25; O, 9.85; S, 9.91.
00 00
00 00
(E)-2-(2-(2,4-Dichlorobenzylidene)hydrazinyl)-4-phenylth-
1
iazole (10) Yield: (76 %); H-NMR (300 MHz, DMSO-
d6): d 12.47 (s, 1H, H–NH), 8.26 (s, 1H, CH=NAr), 7.84 (d,
2H, J = 7.2 Hz, H-20,60), 7.56 (s, 1H, H-300), 7.53 (s, 1H,
H-5), 7.42–7.29 (m, 5H, H-30,50,40, 500,600); 13C-NMR
(DMSO-d6, 75 MHz): d 171.8 (C, C-2), 150.1 (C, C-4),
143.5 (C=N), 133.1 (C, C-10), 131.2 (C, C-200), 129.6 (CH,
C-30, C-50), 129.4 (CH, C-300), 129.2 (CH, C-600), 128.8
(CH, C-40), 128.5 (C, C-400), 127.7 (CH, C-20, C-60), 127.1
(CH, C-500), 121.1 (C, C-100), 105.2 (CH, C-5); EI MS: m/z
(rel. abund. %), 347 (M?, 3.37), 176 (100), 134 (92.1), 45
(28.5). Anal. Calcd for C16H11Cl2N3S; (347.01); C, 55.18;
H, 3.18; Cl, 20.36; N, 12.07; S, 9.21; Found; C, 55.16; H,
3.16; Cl, 20.34; N, 12.05; S, 9.23.
(E)-2-(2-(4-Nitrobenzylidene)hydrazinyl)-4-phenylthiazole
(7) Yield: (91 %); 1H-NMR (300 MHz, DMSO-d6): d
10.47 (s, 1H, H-NH), 8.21 (d, 2H, J = 8.8 Hz, H-20,60),
7.79 (d, 2H, J = 7.6 Hz, H-300,500), 7.66 (d, 2H,
J = 8.8 Hz, H-200,600), 7.26 (s, 1H, CH = NAr), 7.40 (t,
2H, J = 7.6 Hz, H-30, 50), 7.33-7.31 (m, 1H, H-40), 6.92 (s,
1H, H-5); 13C-NMR (DMSO-d6, 75 MHz): d 171.9 (C,
C-2), 150.6 (C, C-400), 150.5 (C, C-4), 143.1 (C=N), 140.1
(C, C-100), 133.1 (C, C-10), 129.3 (CH, C-30, C-50), 128.9
(CH, C-40), 127.2 (CH, C-20, C-60), 124.4 (CH, C-200, C-600),
124.1 (C, C-300, C-500), 105.1 (CH, C-5); EI MS: m/z (rel.
abund. %), 324 (M?, 90.6), 176 (100), 134 (65.2), 104
(7.7), 77 (6.2); 44 (24.9). Anal. Calcd for C16H12N4O2S;
(324.36); C, 59.25; H, 3.73; N, 17.27; O, 9.87; S, 9.89;
Found; C, 59.23; H, 3.71; N, 17.23; O, 9.89; S, 9.87.
(E)-2-(2-(2,6-Dichlorobenzylidene)hydrazinyl)-4-phenyl
thiazole (11) Yield: (88 %); 1H-NMR (400 MHz,
DMSO-d6): d 12.20 (s, 1H, H–NH), 8.26 (s, 1H, CH=NAr),
7.85 (d, 2H, J = 7.2 Hz, H-20,60), 7.54 (d, 2H, J = 8.4 Hz,
H-300,500), 7.42–7.36 (m, 3H, H-30,50,400), 7.32 (s, 1H, H-5),
7.32-7.29 (m, 3H, H-40); 13C-NMR (DMSO-d6, 75 MHz):
d 171.6 (C, C-2), 150.1 (C, C-4), 143.2 (C = N), 133.8 (C,
C-200, C-600), 133.1 (C, C-10), 130.2 (C, C-100), 129.4 (CH,
C-30, C-50), 129.2 (CH, C-400), 128.9 (CH, C-40), 128.4
(CH, C-300, C-500), 127.4 (CH, C-20, C-60), 105.0 (CH, C-5);
EI MS: m/z (rel. abund. %), 348 (M?,1.2), 176 (100), 148
(71.6), 89 (1.5). Anal. Calcd for C16H11Cl2N3S; (347.01);
(E)-2-(2-(3-Chlorobenzylidene)hydrazinyl)-4-phenylthiazole
(8) Yield: (85 %); 1H-NMR (400 MHz, DMSO-d6): d
12.28 (s, 1H, H–NH), 8.01 (s, 1H, CH=NAr), 7.84 (d, 2H,
J = 7.2 Hz, H-20,60), 7.68 (s, 1H, H-200), 7.60 (d, 1H,
J = 7.2 Hz, H-400), 7.47–7.42 (m, 3H, H-30,50,500), 7.39 (d,
1H, J = 7.6 Hz, H-600), 7.34 (s, 1H, H-5), 7.29 (t, 1H,
123

Med Chem Res
C, 55.18; H, 3.18; Cl, 20.36; N, 12.07; S, 9.21; Found; C,
55.16; H, 3.16; Cl, 20.34; N, 12.05; S, 9.23.
(E)-4-((2-(4-Phenylthiazol-2-yl)hydrazono)methyl)benzene-
1,3-diol (15) Yield: (88 %); 1H-NMR (400 MHz,
DMSO-d6): d 11.84 (s, 1H, H–NH), 10.14 (s, 2H, –OH),
8.19 (s, 1H, CH = NAr), 7.83 (d, 2H, J = 7.2 Hz, H-20,60),
7.39 (t, 2H, J = 7.6 Hz, H-30,50), 7.39 (s, 1H, H-300),
7.30–7.25 (m, 2H, H-40,600), 6.32 (d, 1H, J = 6.8 Hz, 500),
6.31 (s, 1H, H-5); 13C-NMR (DMSO-d6, 75 MHz): d 171.9
(C, C-2), 162.4 (C, C-400), 162.3 (C, C-200), 150.1 (C, C-4),
143.5 (C=N), 133.6 (CH, C-600), 133.1 (C, C-10), 130.1
(CH, C-30, C-50), 128.9 (CH, C-40), 127.1 (CH, C-20, C-60),
111.2 (C, C-100), 108.3 (CH, C-500), 103.6 (CH, C-300), 105.3
(CH, C-5); EI MS: m/z (rel. abund. %), 311 (M?, 23.0), 176
(100), 134 (66.3). Anal. Calcd for C16H13N3O2S; (311.07);
C, 61.72; H, 4.21; N, 13.50; O, 10.28; S, 10.30; Found; C,
61.74; H, 4.23; N, 13.48; O, 10.30; S, 10.28.
(E)-2-(2-(2-Chloro-5-nitrobenzylidene)hydrazinyl)-4-phenylth
1
iazole (12) Yield: (89 %); H-NMR (300 MHz, DMSO-
d6): d 11.88 (s, 1H, H–NH), 8.62 (d, 1H, J = 2.7 Hz,
H-600), 8.38 (s, 1H, CH=NAr), 8.16 (dd, 1H, J1 ,2 = 3,
00 00
J1 ,3 = 9 Hz, H-400), 7.86 (d, 2H, J = 7.2 Hz, H-20,60),
00 00
7.81 (d, 1H, J = 8.7 Hz, H-300), 7.41 (t, 2H, J = 8.4 Hz,
H-30,50), 7.41 (s, 1H, H-5), 7.32 (t, 1H, J = 7.2 Hz, H-40);
13C-NMR (DMSO-d6, 75 MHz): d 171.9 (C, C-2), 150.4
(C, C-4), 146.3 (C, C-500), 143.5 (C = N), 140.1 (C, C-200),
134.1 (C, C-100), 133.2 (C, C-10), 129.8 (CH, C-400), 129.1
(CH, C-30, C-50), 128.9 (CH, C-40), 128.3 (CH, C-300),
127.4 (CH, C-20, C-60), 124.1 (CH, C-600), 105.2 (CH, C-5);
EI MS: m/z (rel. abund. %), 358 (M?, 22.4), 176 (88.3),
134 (100), 77 (18); 45 (5.7). Anal. Calcd for
C16H11ClN4OS; (347.01); C, 53.56; H, 3.09; Cl, 9.88; N,
15.61; O, 8.92; S, 8.94; Found; C, 53.58; H, 3.11; Cl, 9.90;
N, 15.59; O, 8.90; S, 9.23.
(E)-2-(2-(4-Ethoxybenzylidene)hydrazinyl)-4-phenylthiazole
1
(16) Yield: (85 %); H-NMR (300 MHz, DMSO-d6): d
8.16 (s, 1H, H–NH), 7.71 (t, 2H, J = 8.4 Hz, H-30,50), 7.62
(d, 2H, J = 8.7 Hz, H-20,60), 7.54–7.37 (m, 4H, H-40, 200,
600 and CH=NAr), 6.92 (d, 2H, J = 8.7 Hz, H-300, 500), 6.70
(s, 1H, H-5), 4.11 (q, 2H, J = 6.9 Hz, –CH2), 1.43 (t, 3H,
J = 6.9 Hz, –CH3); 13C-NMR (DMSO-d6, 75 MHz): d
171.5 (C, C-2), 130.2 (CH, C-200, C-600), 114.7 (CH, C-300,
C-500), 150.1 (C, C-4), 143.3 (C=N), 133.1 (C, C-10), 129.1
(CH, C-30, C-50), 128.5 (CH, C-40), 127.4 (CH, C-20, C-60),
125.2 (C, C-100), 161.8 (C, C-400), 105.1 (CH, C-5), 64.5
(CH2, –OCH2), 14.8 (CH3, –OCH2CH3); EI MS: m/z (rel.
abund. %), 323 (M?, 80.6), 176 (100), 134 (54.5). Anal.
Calcd for C18H17N3OS; (323.11); C, 66.85; H, 5.30; N,
12.99; O, 4.95; S, 9.91; Found; C, 66.87; H, 5.28; N, 13.01;
O, 4.93; S, 9.92.
(E)-2-(2-(2-Bromobenzylidene)hydrazinyl)-4-phenylthiazole
1
(13) Yield: (78 %); H-NMR (300 MHz, DMSO-d6): d
12.30 (s, 1H, H–NH), 8.51 (s, 1H, CH=NAr), 8.03 (dd, 1H,
J1 ,2 = 1.5, J1 ,3 = 6.3 Hz, H-300), 7.89 (d, 2H, J = 7.5 Hz,
00 00
00 00
H-20,60), 7.64 (dd, 1H, J1 ,2 = 0.9, J1 ,3 = 8.1 Hz, H-500),
7.45 (t, 1H, J = 7.5 Hz,H-400), 7.22 (s, 1H, H-5), 7.40–7.25
(m, 4H, H-30,40,50,600); 13C-NMR (DMSO-d6, 75 MHz): d
171.8 (C, C-2), 150.1 (C, C-4), 143.4 (C = N), 135.6 (C,
C-100), 133.1 (C, C-10), 132.6 (CH, C-300), 130.4 (CH, C-400),
129.3 (CH, C-30, C-50), 128.8 (CH, C-40), 127.9 (CH, C-500),
127.6 (CH, C-20, C-60), 127.3 (CH, C-600), 121.5 (C, C-200),
105.1 (CH, C-5); EI MS: m/z (rel. abund. %), 358 (M?, 29),
176 (100), 134 (89.9), 104 (26.2), 89, (24.1), 77 (14.9). Anal.
Calcd for C16H12BrN3S; (356.99); C, 53.64; H, 3.38; Br,
22.30; N, 11.73; S, 8.95; Found; C, 53.66; H, 3.40; Br, 33.28;
N, 11.71; S, 8.97.
00 00
00 00
(E)-2-Methoxy-5-((2-(4-phenylthiazol-2-yl)hydrazono)methyl)phe-
1
nol (17) Yield: (88 %); H-NMR (400 MHz, DMSO-d6):
d 11.92 (s, 1H, H–NH), 9.23 (s, 2H, –OH), 7.88 (s, 1H,
CH=NAr), 7.83 (d, 2H, J = 7.5 Hz, H-20,60), 7.39 (t, 2H,
J = 7.2 Hz, H-30,50), 7.30–7.27 (m, 1H, H-40), 7.28 (s, 1H,
H-5), 6.96 (d, 1H, J = 8.1 Hz, 500), 3.79 (s, 3H, –OCH3);
13C-NMR (DMSO-d6, 75 MHz): d 171.5 (C, C-2), 152.3
(C, C-400), 150.5 (C, C-4), 147.2 (C, C-300), 143.2 (C=N),
133.1 (C, C-10), 131.0 (C, C-100), 129.3 (CH, C-30, C-50),
128.7 (CH, C-40), 127.4 (CH, C-20, C-60), 122.7 (CH,
C-600), 116.0 (CH, C-200), 112.1 (CH, C-500), 105.2 (CH,
C-5), 56.1 (CH3, –OCH3); EI MS: m/z (rel. abund. %), 325
(M?, 30.3), 176 (100), 134 (23.3). Anal. Calcd for
C17H15N3O2S; (325.09); C, 62.75; H, 4.65; N, 12.91; O,
9.83; S, 9.85; Found; C, 62.73; H, 4.67; N, 1289; O, 9.81;
S, 9.87.
(E)-4-((2-(4-Phenylthiazol-2-yl)hydrazono)methyl)benzene-
1,2-diol (14) Yield: (78 %); 1H-NMR (400 MHz,
DMSO-d6): d 11.84 (s, 1H, H–NH), 9.22 (s, 2H, –OH),
7.84 (s, 1H, CH=NAr), 7.83 (d, 2H, J = 6.6 Hz, H-20,60),
7.39 (t, 2H, J = 7.2 Hz, H-30,50), 7.30–7.26 (m, 1H, H-40),
7.26 (s, 1H, H-5), 7.13 (s, 1H, H-200), 6.84 (s, 1H, H-500),
6.74 (d, 1H, J = 8.1 Hz, H-600); 13C-NMR (DMSO-d6,
75 MHz): d 171.5 (C, C-2), 150.3 (C, C-4), 149.8 (C,
C-400), 146.2 (C, C-300), 143.3 (C=N), 133.1 (C, C-10), 131.2
(C, C-100), 129.4 (CH, C-30, C-50), 128.9 (CH, C-40), 127.3
(CH, C-20, C-60), 123.1 (CH, C-600), 117.3 (CH, C-500),
116.2 (CH, C-200),105.2 (CH, C-5); EI MS: m/z (rel. abund.
%), 311 (M?, 46.9), 309(18.6), 176 (100), 134 (70.2). Anal.
Calcd for C16H13N3O2S; (311.07); C, 61.72; H, 4.21; N,
13.50; O, 10.28; S, 10.30; Found; C, 61.74; H, 4.23; N,
13.48; O, 10.30; S, 10.28.
(E)-2-(2-(3,4-Dimethoxybenzylidene)hydrazinyl)-4-phenylth-
1
iazole (18) Yield: (85 %); H-NMR (300 MHz, DMSO-
0
0
d6): d 12.10 (s, 1H, H–NH), 7.81 (d, 2H, J2 ,6 = 7.2 Hz,
H-20,60), 7.52 (s, 1H, CH=NAr), 7.38 (t, 2H, J = 7.2 Hz,
123

Med Chem Res
H-30,50), 7.29 (d, 1H, J = 7.2 Hz, 500), 7.20 (s, 1H, H-200),
6.92 (d, 1H, J = 8.1 Hz, H-600), 6.85 (s, 1H, H-5), 6.82 (t,
1H, J = 8.4 Hz, H-40), 3.92 (s, 1H, –OCH3), 3.89 (s, 1H,
–OCH3); 13C-NMR (DMSO-d6, 75 MHz): d 171.6 (C,
C-2), 152.1 (C, C-400), 150.1 (C, C-4), 150.0 (C, C-300),
143.1 (C=N), 132.9 (C, C-10), 130.5 (C, C-100), 129.1 (CH,
C-30, C-50), 128.9 (CH, C-40), 127.4 (CH, C-20, C-60), 122.4
(CH, C-600), 111.5 (CH, C-200), 109.1 (CH, C-500), 105.1
(CH, C-5), 56.0 (CH3, –OCH3), 56.0 (CH3, –OCH3); EI
MS: m/z (rel. abund. %), 339 (M?, 24.7), 176 (100), 134
(23.0). Anal. Calcd for C18H17N3O2S; (339.10); C, 63.70;
H, 5.05; N, 12.38; O, 9.43; S, 9.45; Found; C, 63.68; H,
5.03; N, 12.40; O, 9.45; S, 9.43.
131.5 (CH, C-300, C-500), 129.1 (CH, C-30, C-50), 128.5 (CH,
C-40), 128.4 (CH, C-200, C-600), 127.4 (CH, C-20, C-60),
125.3 (C, C-400), 105.2 (CH, C-5); EI MS: m/z (rel. abund.
%), 338 (M?,90.6), 176 (100), 134 (65.2), 104 (7.7), 77
(6.2); 44 (24.9). Anal. Calcd for C16H12BrN3S; (356.99);
C, 53.64; H, 3.38; Br, 22.30; N, 11.73; S, 8.95; Found; C,
53.66; H, 3.40; Br, 33.28; N, 11.71; S, 8.97.
Acknowledgments Authors would like to acknowledge the Higher
Education Commission (HEC), Pakistan, Project No. 20-2073 under
the National Research Program for Universities and the Organization
for Prohibition of Chemical Weapons (OPCW), The Netherlands
(Project No. L/ICA/ICB/173681/12), for financial supports.
(E)-2-(2-(1-(4-Nitrophenyl)ethylidene)hydrazinyl)-4-phenylth-
1
iazole (19) Yield: (81 %); H-NMR (400 MHz, DMSO-
References
d6): d 12.20 (s, 1H, H–NH), 8.24 (d, 2H, J = 8.8 Hz,
H-20,60), 7.92 (d, 2H, J = 9.2 Hz, H-300,500), 7.78 (d, 2H,
J = 7.2 Hz, H-200,600), 7.39 (t, 2H, J = 7.2 Hz, H-30,50),
7.32–7.24 (m, 1H, H-40), 6.94 (s, 1H, H-5); 13C-NMR
(DMSO-d6, 75 MHz): d 171.5 (C, C-2), 150.1 (C, C-400),
150.0 (C, C-4), 143.5 (C, C-100), 143.3 (C=N), 133.1 (C,
C-100), 129.4 (CH, C-30, C-50), 128.8 (CH, C-40), 127.6 (CH,
C-2 , C-60), 127.5 (CH, C-200, C-600), 127.1 (CH, C-300,
C-500), 105.1 (CH, C-5); EI MS: m/z (rel. abund. %), 323
(M?, 80.6), 176 (100), 134 (54.5). Anal. Calcd for
C17H14N4O2S; (338.08); C, 60.34; H, 4.17; N, 16.56; O,
9.46; S, 9.48; Found; C, 60.32; H, 4.15; N, 16.58; O, 9.48;
S, 9.50.
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(E)-4-(1-(2-(4-Phenylthiazol-2-yl)hydrazono)ethyl)phenol
1
(20) Yield: (85 %); H-NMR (300 MHz, DMSO-d6): d
8.56 (d, 2H, J = 7.8 Hz, H-20,60), 7.87 (d, 2H, J = 8.7 Hz,
H-200,600), 7.58-7.51 (m, 3H, H-30, 40, 50), 6.89 (s, 1H, H-5),
6.87 (d, 2H, J = 8.7 Hz, H-300,500), 2.57 (s, 3H, –CH3);
13C-NMR (DMSO-d6, 75 MHz): d 171.5 (C, C-2), 160.9
(C, C-400), 150.1 (C, C-4), 143.5 (C=N), 133.1 (C, C-10),
130.2 (C, C-100), 129.2 (CH, C-200, C-600), 129.1 (CH, C-30,
C-50), 128.5 (CH, C-40), 127.4 (CH, C-20, C-60), 116.1 (CH,
C-300, C-500), 105.1 (CH, C-5); EI MS: m/z (rel. abund. %),
309 (M?, 100), 176 (7.9), 134 (65.4). Anal. Calcd for
C17H15N3OS; (309.09); C, 66.00; H, 4.89; N, 13.58; O,
5.17; S, 10.36; Found; C, 58.98; H, 4.91; N, 13.46; O, 5.15;
S, 10.30.
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(E)-2-(2-(4-Bromobenzylidene)hydrazinyl)-4-phenylthiazole
1
(21) Yield: (81 %); H-NMR (300 MHz, DMSO-d6): d
10,10(s, 1H, H–NH), d 7.78 (d, 2H, J = 7.2 Hz, H-20,60),
7.47 (s, 1H, CH=NAr), 7.45–7.41 (m, 2H, –CH and 40),
7.373 (d, 1H, J = 7.2 Hz, H-600), 7.31–7.27 (dd, 1H,
J1,2 = 2.4 Hz, J1,3 = 8.8 Hz, H-400), 6.84 (t, 2H,
J = 8.8 Hz, H-30,50), 6.76 (d, 1H, J = 2.4 Hz, H-3);
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