Synthesis and anticancer evaluation of novel 2-cyclopropylimidazo[2,1-b][1, 3,4]-thiadiazole derivatives

Article abstract of DOI:10.1016/j.ejmech.2011.07.012

A series of 2,5,6-trisubstituted imidazo[2,1-b][1,3,4]-thiadiazole derivatives 4(a-k) have been prepared by reaction of 2-amino-5-cyclopropyl-1,3, 4-thiadiazole and an appropriate phenacyl bromide. Further 5-bromo 5(a-k) and 5-thiocyanato 6(a-k) derivativ

Full text of DOI:10.1016/j.ejmech.2011.07.012

European Journal of Medicinal Chemistry 46 (2011) 4411e4418
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and anticancer evaluation of novel 2-cyclopropylimidazo[2,1-b]
[1,3,4]-thiadiazole derivatives
,
a
a
b
Malleshappa N. Noolvi a , Harun M. Patel , Navjot Singh , Andanappa K. Gadad ,
*
Swaranjit Singh Cameotra c, Arvind Badiger d
a Department of Pharmaceutical Chemistry, ASBASJSM College of Pharmacy, Bela (Ropar) 140111, Punjab, India
b School of Pharmacy, Faculty of Medical Sciences, Mount Hope, The University of the West Indies, Trinidad and Tobago
c Environmental Biotechnology & Microbial Biochemistry, Institute of Microbial Technology, Chandigarh, India
d Shree Dhanvantary Pharmaceutical Analysis & Research Centre, Surat-394110, Gujrat, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 2,5,6-trisubstituted imidazo[2,1-b][1,3,4]-thiadiazole derivatives 4(aek) have been prepared by
reaction of 2-amino-5-cyclopropyl-1,3,4-thiadiazole and an appropriate phenacyl bromide. Further
5-bromo 5(aek) and 5-thiocyanato 6(aek) derivatives were synthesized in order to study the effect of these
substituents on antitumor activity. Structures of these compounds were established by IR,1H NMR,13C NMR
and Mass spectroscopy. Seven compounds were grantedNSC code at National Cancer Institute (NCI), USAfor
anticancer activity at a single high dose (10ꢀ5 M) in full NCI 60 cell panel. Among the compounds tested,
5-bromo-6-(4-chlorophenyl)-2-cyclopropylimidazo[2,1-b][1,3,4]thiadiazole 5b (NSC D-96022/1) was
found to be the most active candidate of the series at five dose level screening with degree of selectivity
toward Leukemic cancer cell line.
Received 18 June 2011
Accepted 4 July 2011
Available online 8 July 2011
Dedicated to Sardar Sangat Singh Longia on
his 86th Birthday for his contribution to
develop education in rural part of India.
Keywords:
Antitumor agents
Imidazo[2,1-b][1,3,4]thiadiazole derivatives
Five-dose assay
Ó 2011 Elsevier Masson SAS. All rights reserved.
NCI-USA
1. Introduction
cell lines [5]. Ibrahim in 2009 prepared 4-(3-substituted(1,2,4)tri-
azolo(3,4-b) [1,3,4]thiadiazole-6-yl) aniline derivatives as a novel
Cancer is a class of diseases in which cell, or a group of cells
display uncontrolled growth, invasion, and sometimes metastasis.
It affects people at all ages with the risk of most types increasing
with age. It caused about 13% (7.6 million) of all human deaths in
2007. Levamisole (I) an anthelmintic agent was found to be an
immuno-stimulant by Rebnoux in 1972. It appears to be most
effective in patients with small tumor burdens and it acts by
stimulating the responsiveness of lymphocytes to tumor antigen
[1]. An early report on 2-amino-1,3,4-thiadiazole derivatives deals
with the activity of these compounds against several transplanted
animal tumors is available [2]. Gadad et al., in 1999 reported
the antitumor effects of imidazo[2,1-b][1,3,4]-thiadiazoles [3].
Nalan et al., in 2003 have reported some hydrazone derivatives of
2,6-dimethylimidazo[2,1-b][1,3,4]-thiadiazole-5-carbohydrazide as
anticancer agents against ovarian cancer cell line OVCAR [4].
Andrew et al., in 2000 have studied on some imidazo[2,1-b]-thia-
zole guanyl hydrazones which were active against various cancer
class of potential antitumor agents [6]. Consequently, a large
number of imidazo thiadiazole derivatives have been reported to
possess diverse pharmacological properties such as antitubercular
[7], antibacterial [8], antifungal [9], anticonvulsant, analgesic [10],
antisecretory [11], anti-inflammatory [12], cardiotonic [13], diuretic
[14] and herbicidal [15] activities. In addition, the imidazo[2,1-b]
thiazole derivatives of the Levamisole have been reported as
potential antitumor agents (II) [16]. Later antitumor activity of
5-formyl-6-aryl imidazo [21-b][1,3,4]thiadiazole sulfonamides (III)
were also reported [3].
In view of the above facts and in continuation of our search
for novel anticancer agents [17e25] in the present study a new
series of 2-cyclopropylimidazo[2,1-b][1,3,4]thiadiazoles and their
5-bromo and 5-cyanato derivatives have been synthesized and
screened in vitro at NCI (National Cancer Institute))-USA (Fig. 1).
2. Chemistry
The synthetic route of the compound 5(aek) and 6(aek) is
outlined in Scheme 1. 2-Amino-5-cyclopropyl-1,3,4-thiadiazole 3
was prepared by refluxing cyclopropane carbonyl chloride 1 and
* Corresponding author. Tel.: þ91 9417563874; fax: þ91 1881263655.
E-mail address: mnoolvi@yahoo.co.uk (M.N. Noolvi).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.07.012

4412
M.N. Noolvi et al. / European Journal of Medicinal Chemistry 46 (2011) 4411e4418
H
N
Cl
O
NH2
+
H2N
S
R'
2
1
a
N
S
N
N
N
S
N
R
N
N
II
I
NH2
S
3
2,5 - disubstituted -6- phenyl
imidazo [2,1-b] thiadiazole
Levamisole
4a, R = H
4b, R = 4-Cl
b
4c, R = 4-Br
H
O C
4d, R = 4-F
4e, R = 2,4-di-Cl
4f, R = 2,4-di-OH
4g, R = 3-NH2
4h, R = 4-NH2
4i, R = 3-NO2
4 j, R = 4-NO2
4k, R = 2-OH
N
N
N
R
N
N
S
RHN
O2S
III
N
S
4 (a-k)
5-formyl-6-aryl imidazo[2,1-b]
[1,3,4]thiadiazole sulfonamide
c
d
N
r
B
S
R
R
N
N
N
N
N
N
S
S
5 (a-k)
6 (a-k)
6a, R = Hb,
6b, R = 4-Cl
6c, R = 4-Br
6d, R = 4-F
5a, R = H
5b, R = 4-Cl
5c, R = 4-Br
5d, R = 4-F
R
6e, R = 2,4-di-Cl
6f, R = 2,4-di-OH
5e, R = 2,4-di-Cl
5f, R = 2,4-di-OH
N
R
r
B
6g, R = 3-NH
2
5g, R=3-NH
5h, R=4-NH
5i, R=3-NO
5j, R=4-NO
2
2
2
2
S
6h, R = 4NH
6i, R = 3-NO
6j, R = 4-NO
2
2
2
N
S
N
N
N
N
N
6k, R = 2-OH
5k, R= v2-OH
S
Scheme 1. Reagent and conditions: a) POCl3, reflux b) substituted phenacyl bromide,
alcohol, reflux c) Br2, GAA d) KSCN, Br2, GAA.
Fig. 1. Reported and proposed antitumor imidazo[2,1-b][1,3,4]thiadiazole derivatives.
The formation of 2-aminothiadiazole 3 by the reaction between
cyclopropane carbonyl chloride and thiosemicarbazide was
confirmed by IR spectra, which showed the presence of amino
(eNH2) band w3200 and the absence of carbonyl stretching of
carboxylic acid w1700e1600. Structures of imidazo thiadiazole
derivatives 4(aek) were established by the absence of (eNH2) band
w3200 in IR spectra and appearance of imidazole proton (H-5)
thiosemicarbazide 2 in POCl3. The 2-cyclopropyl-6-substituted
phenylimidazo[2,1-b][1,3,4]thiadiazole derivatives 4(aek) repor-
ted in Scheme 1 were prepared by reaction of 2-amino-5-
cyclopropyl-1,3,4-thiadiazole 3 with the appropriate phenacyl
bromide, and neutralization with cold aqueous sodium carbonate
gave the free base in 40e60% yield. It is well established
that this reaction proceeds via the intermediate iminothiadiazole
[8], which undergoes dehydrocyclization to form the desired
fused heterocycle under reflux temperature spontaneously.
The electronic and steric factors at 5th position of 2-amino-5-
substituted-1,3,4-thiadiazole are crucial in determining the course
around
d
8 ppm in the 1H NMR spectra. The formation of title
compound 5(aek) and 6(aek) was confirmed by the absence of
signal for imidazole proton (H-5) in 1H NMR spectra and presence
of bromine (Br) band around 600 cmꢀ1 for 5(aek) and SCN band
around 2100 cmꢀ1 for 6(aek). The mass spectra of these
compounds further confirmed the assigned structure.
of its reaction with substituted
a-haloaryl ketones. The strongly
electronegative group impart less nucleophilic character to nitrogen
at 4th position of the 1,3,4-thiadiazole. The various phenacyl
bromides were prepared by bromination of the corresponding
ketones in glacial acetic acid. The substituted imidazo[2,1-b][1,3,4]
thiadiazole derivatives 4(aek) thus obtained were subjected to
electrophilic substitution reaction at the 5 position with bromine in
the presence of sodium acetate in acetic acid to obtain the 5-bromo
derivatives 5(aek) in good yield. Introduction of thiocyanate func-
tional group at the 5 position was carried out by reaction between
imidazo[2,1-b][1,3,4]-thiadiazoles 4(aek) and potassium thiocya-
nate in glacial acetic acid by drop wise addition of bromine in glacial
acetic acid to get 6(aek) in good yield.
3. Pharmacology
3.1. In vitro cancer screen at NCI-USA
The screening is a two-stage process, beginning with the eval-
uation of all compounds against the 60 cell lines at a single dose of
10ꢀ5 M. The output from the single dose screen is reported as
a mean graph and is available for analysis by the COMPARE
program. Compounds which exhibit significant growth inhibition
are evaluated against the 60 cell panel at five concentration levels.
The human tumor cell lines of the cancer screening panel are grown

M.N. Noolvi et al. / European Journal of Medicinal Chemistry 46 (2011) 4411e4418
4413
in RPMI 1640 medium containing 5% fetal bovine serum and 2 mM
-glutamine. For a typical screening experiment, cells are inocu-
lated into 96 well microtiter plates in 100 L at plating densities
ranging from 5000 to 40,000 cells/well depending on the doubling
time of individual cell lines. After cell inoculation, the microtiter
plates are incubated at 37 ꢁC, 5% CO2, 95% air and 100% relative
humidity for 24 h prior to addition of experimental drugs.
After 24 h, two plates of each cell line are fixed in situ with TCA,
to represent a measurement of the cell population for each cell line
at the time of drug addition (Tz). Experimental drugs are solubi-
lized in dimethyl sulfoxide at 400-fold the desired final maximum
test concentration and stored frozen prior to use. At the time of
drug addition, an aliquot of frozen concentrate is thawed and
diluted to twice the desired final maximum test concentration with
D-96022/1, NSC D-96019/1, D-96021/1, D-96155/1, D-96023/1,
D-96154/1 and D-96024/1 respectively among the synthesized
compounds 5(aek) and 6(aek) were screened on human tumor
cell lines at 10ꢀ5 M at the NCI, NIH, Bethesda, Maryland, USA, under
the drug discovery program of the NCI. Among the compounds
tested, compound 5b (NSC D-96022/1) was further screened for
5-log dose molar range as it has shown prominent cell growth
inhibition at 10ꢀ5 M concentration against variety of cell lines.
L
m
3.2.1. Primary single high dose (10ꢀ5 M) full NCI 60 cell panel
in vitro assay
All the selected compounds submitted to National Cancer Insti-
tute (NCI) for in vitro anticancer assay were evaluated for their
anticancer activity. Primary in vitro one dose anticancer assay was
performed in fullNCI 60cell panel representing leukemia, melanoma
and cancers of lung, colon brain breast, ovary, kidney and prostate in
accordance with the protocol of the NCI, USA. The compounds were
added at a single concentration (10ꢀ5 M) and the culture was incu-
bated for 48 h. End point determinations were made with a protein
binding dye, Sulforhodamine B. Results for each compound were
reported as a mean graph of the percent growth of the treated cells
when compared to the untreated control cells. There after obtaining
the results for one dose assay, analysis of historical Development
Therapeutics Programme (DTP) was performed and compound 5b
(NSC D-96022/1) which satisfied pre-determined threshold inhibi-
tion criteria was selected for NCI full panel 5 dose assay.
complete medium containing 50
10-fold or ½ log serial dilutions are made to provide a total of five
drug concentrations plus control. Aliquots of 100 l of these
different drug dilutions are added to the appropriate microtiter
wells already containing 100 l of medium, resulting in the
required final drug concentrations.
mg/ml gentamicin. Additional four,
m
m
Following drug addition, the plates are incubated for an addi-
tional 48 h at 37 ꢁC, 5% CO2, 95% air, and 100% relative humidity. For
adherent cells, the assay is terminated by the addition of cold TCA.
Cells are fixed in situ by the gentle addition of 50
v) TCA (final concentration, 10% TCA) and incubated for 60 min at
ꢁC. The supernatant is discarded, and the plates are washed five
times with tap water and air dried. Sulforhodamine B (SRB) solution
(100 l) at 0.4% (w/v) in 1% acetic acid is added to each well, and
ml of cold 50% (w/
4
m
3.2.2. In vitro 5 dose full NCI 60 cell panel assay and discussion
All the cell lines (about 60), representing nine tumor subpanels,
were incubated at five different concentrations (0.01, 0.1, 1, 10 &
plates are incubated for 10 min at room temperature. After staining,
unbound dye is removed by washing five times with 1% acetic acid
and the plates are air dried. Bound stain is subsequently solubilized
with 10 mM trizma (tris(hydroxymethyl)aminomethane) base, and
the absorbance is read on an automated plate reader at a wave-
length of 515 nm. For suspension cells, the methodology is the same
except that the assay is terminated by fixing settled cells at the
100 mM). The outcomes were used to create log concentration vs %
growth inhibition curves and three response parameters (GI50, TGI
and LC50) were calculated for each cell line. The GI50 value (growth
inhibitory activity) corresponds to the concentration of the
compound causing 50% decrease in net cell growth, the TGI value
(cytostatic activity) is the concentration of the compound resulting
in total growth inhibition and LC50 value (cytotoxic activity) is the
concentration of the compound causing net 50% loss of initial cells
at the end of the incubation period of 48 h. Compound under
investigation 5b (NSC D-96022/1) exhibited significant anticancer
activity against most of the tested cell lines representing nine
bottom of the wells by gently adding 50
ml of 80% TCA (final
concentration, 16% TCA). Using the seven absorbance measure-
ments [time zero, (Tz), control growth, (C), and test growth in the
presence of drug at the five concentration levels (Ti)], the
percentage growth is calculated at each of the drug concentrations
levels. Percentage growth inhibition is calculated as:
different subpanels with GI50 values between ‘‘1.79e43.4
mM’’.
[(Ti ꢀ Tz)/(C ꢀ Tz)] ꢂ 100 for concentrations for which Ti ꢃ Tz
[(Ti ꢀ Tz)/Tz] ꢂ 100 for concentrations for which Ti < Tz.
With regard to the sensitivity against some individual cell lines
(Table 1) the compound showed high activity against Leukemia K-
562, Colon Cancer HCT-15, Melanoma SK-MEL and Prostate Cancer
PC-3 with GI50 1.79, 2.02, 2.17, and 2.22 mM respectively. On the
Three dose response parameters are calculated for each experi-
mental agent. Growth inhibition of 50% (GI50) is calculated from
[(Ti ꢀ Tz)/(C ꢀ Tz)] ꢂ 100 ¼ 50, which is the drug concentration
resulting in a 50% reduction in the net protein increase (as measured
by SRB staining) in control cells during the drug incubation. The drug
concentration resulting in total growth inhibition (TGI) is calculated
from Ti ¼ Tz. The LC50 (concentration of drug resulting in a 50%
reduction in the measured protein at the end of the drug treatment
as compared to that at the beginning) indicating a net loss of cells
following treatment is calculated from [(TiꢀTz)/Tz] ꢂ 100 ¼ ꢀ50.
Values are calculated for each of these three parameters if the level
of activity is reached; however, if the effect is not reached or is
exceeded, the value for that parameter is expressed as greater or less
than the maximum or minimum concentration tested [26e28].
other hand compound showed least activity against Non-small cell
lung cancer: HOP-62 and NCI-H322M; CNS Cancer: SF-268 and
SNB-19; Melanoma: SK-MEL-28; Ovarian Cancer: IGROV 1, OVCAR-
5 and SK-OV-3; Renal Cancer: 786, A-498, SN-12C and UO-31;
Prostate Cancer: DU-145. Obtained data revealed an obvious
sensitivity profile toward Leukemic subpanel (GI50 value ranging
from 1.79 to 5.66 mM), least for K-562 and maximum for CCRF-CEM
cell line. The criterion for selectivity of a compound depends upon
the ratio obtained by dividing the full panel MID (the average
sensitivity of all cell lines toward the test agent) by their individual
subpanel MID (the average sensitivity of all cell lines of a particular
subpanel toward the test agent). Ratios between 3 and 6 refer to
moderate selectivity; ratios greater than 6 indicate high selectivity
toward the corresponding cell line, while compounds not meeting
either of these criteria rated non-selective [28]. As per this criterion,
compound in the study was found to be moderate selective toward
Leukemic cancer subpanel only with selectivity ratio of 3.36,
whereas it was found to be non-selective against remaining cell
panel (Table 1).
3.2. Pharmacological (in vitro anticancer activity)
The tumor growth inhibition properties of the selected seven
compounds 5bed, 5f, 6b, 6f and 6h with the NCI codes NSC

4414
M.N. Noolvi et al. / European Journal of Medicinal Chemistry 46 (2011) 4411e4418
Table 1
NCI in vitro testing result of compound 5b (NSC D-96022/1) at five dose level in mM.
Panel
Cell Line
GI50
TGI
LC50
Concentration per cell line
Subpanel MIDb
2.98
Selectivity ratio (MIDa:MIDb)
3.36
Leukemia
CCRF-CEM
HL-60(TB)
K-562
MOLT-4
RPMI-8226
SR
3.66
3.34
1.79
2.97
3.22
2.90
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
Non-Small Cell Lung Cancer
13.37
0.75
A549/ATCC
EKVX
HOP-62
HOP- 92
NCI-H226
NCI-H23
NCI-H322M
NCI-H460
NCI-H522
7.42
5.22
38.1
5.59
4.99
5.10
43.4
5.25
5.31
>100
>100
>100
37.9
>100
>100
>100
>100
55.4
>100
>100
>100
>100
>100
>100
>100
>100
>100
Colon Cancer
5.31
1.888
COLO 205
HCC-2998
HCT-116
HCT-15
HT 29
7.23
8.19
2.96
2.02
6.12
3.77
6.88
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
KM 12
SW-620
CNS Cancer
Melanoma
10.535
0.9759
1.0139
SF-268
SF-295
SF-539
SNB-19
SNB-75
U251
19.3
5.04
6.78
15.6
12.2
4.29
>100
>100
>100
>100
51.9
>100
>100
>100
>100
>100
>100
>100
9.89
LOX IMVI
MALME-3M
M14
MDA-MB-435
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-257
UACC-62
9.20
8.79
7.70
6.08
11.0
35.6
2.17
4.14
4.36
>100
>100
>100
>100
59.3
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
Ovarian Cancer
15.92
13.54
0.6458
0.7406
IGROV1
17.3
4.63
12.7
31.9
5.76
4.18
35.0
>100
>100
82.1
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
NCI/ADR-RES
SK-OV-3
Renal Cancer
786e0
A-498
ACHN
CAKI-1
RXF-393
SN-12C
UO-31
13.6
30.8
7.07
9.69
2.93
14.3
16.4
>100
>100
>100
>100
14.8
>100
>100
>100
>100
>100
>100
>100
>100
>100
Prostate Cancer
Breast Cancer
10.71
5.256
0.9363
1.90
PC-3
DU-145
2.22
19.2
>100
>100
>100
>100
MCF7
MDA-MB-231/ATCC
BT -549
T-47D
MDA-MB-468
8.18
6.59
4.07
4.49
2.95
>100
>100
>100
73.5
>100
69.5
>100
>100
>100
>100
>100
>100
MIDa
10.0282
a
MID ¼ Average sensitivity of all cell line in
m
M.
b
MID ¼ Average sensitivity of all cell line of a particular subpanel in
m
M.

M.N. Noolvi et al. / European Journal of Medicinal Chemistry 46 (2011) 4411e4418
4415
4. Experimental
imidazole); 13C NMR (DMSO-d6)
d
ppm: 166.8, 145.4, 137.2, 133.2,
132.1, 129.3, 124.7, 122.7, 13.8, 10.2; HRMS (EI) m/z calcd for
All chemicals and solvents were supplied by Merck, S.D. Fine
Chemical Limited, Mumbai. All the solvents were distilled and dried
before use. The reactions were monitored with the help of thin-
layer chromatography using pre-coated aluminum sheets with
GF254 silica gel, 0.2 mm layer thickness (E. Merck). Melting
points of the synthesized compounds were recorded on the Veego
(VMP-MP) melting point apparatus. IR spectrum was acquired on
a Shimadzu Infra Red Spectrometer, (model FTIR-8400S). Both 1H
NMR (DMSO) and 13C NMR (DMSO) spectra of the synthesized
compounds were performed with Bruker Avance-II 400 NMR
Spectrometer operating at 400 MHz in SAIF, Punjab University
(Chandigarh). Chemical shifts were measured relative to internal
C13H10BrN3S: 318.9779; found: 318.9784.
4.2.4. 2-Cyclopropyl-6-(4-fluorophenyl)imidazo[2,1-b][1,3,4]
thiadiazole (4d)
Yield 63%; mp 242e246 ꢁC; IR (KBr) nmax 3136.2, 3032.6, 1681.4,
1462.8, 1212.4 cmꢀ1; 1H NMR (DMSO-d6)
d
ppm: 1.35e2.31 (m, 5H,
cyclopropyl), 7.20e7.90 (m, 4H, AreH), 7.94 (s, 1H, C-5-H, imid-
azole); 13C NMR (DMSO-d6)
ppm: 166.6, 160.2, 145.2, 137.3, 130.2,
d
129.2, 124.3, 116.4, 13.7, 10.3; HRMS (EI) m/z calcd for C13H10FN3S:
259.0579; found: 259.0583.
4.2.5. 2-Cyclopropyl-6-(2,4-dichlorophenyl)imidazo[2,1-b][1,3,4]
thiadiazole (4e)
standard TMS (d: 0). Chemical shifts are reported in d scale (ppm).
Mass spectra of the synthesized compounds were recorded at MAT
120 in SAIF, Punjab University.
Yield 57%; mp 238e242 ꢁC; IR (KBr) nmax 3131.5, 3014.8, 1685.8,
1458.6, 641.6 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm: 1.15e2.45 (m, 5H,
cyclopropyl), 7.31e7.85 (m, 3H, AreH), 7.96 (s, 1H, C-5-H, imid-
azole); 13C NMR (DMSO-d6)
ppm: 166.6, 145.4, 137.2, 136.2, 134.2,
4.1. Synthesis of 5-cyclopropyl-1,3,4-thiadiazol-2-amine (3)
d
132.1, 130.2, 129.3, 128.4, 122.6, 13.2, 10.7; HRMS (EI) m/z calcd for
An equimolar mixture of cyclopropane carbonyl chloride
(0.01 M) 1 and thiosemicarbazide (0.1 M) 2 was refluxed in the
presence of phosphorous oxychloride (5 mL) for 4 h. After 4 h the
mixture was cooled and diluted with water (10 mL). Then the
mixture was filtered and filtrate was neutralized with potassium
hydroxide solution. The precipitate was filtered off and recrystal-
lized from ethanol.
C13H9Cl2N3S: 308.9894; found: 308.9898.
4.2.6. 4-(2-Cyclopropyl imidazo[2,1-b][1,3,4]thiadiazol-6-yl)
benzene-1,3-diol (4f)
Yield 72%; mp 264e266 ꢁC; IR (KBr) nmax 3410.4, 3139.8,
3018.4, 1671.6, 1462.6 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm:
1.21e2.21 (m, 5H, cyclopropyl), 6.12 (s, 2H, OH), 7.14e7.81 (m, 3H,
AreH), 7.91 (s, 1H, C-5-H, imidazole); 13C NMR (DMSO-d6)
ppm:
Yield 63%; mp 214e216 ꢁC; IR (KBr) nmax 3277.4, 3113.5, 2832.8,
d
1631.2, 1545 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm: 0.93e2.17 (m, 5H,
166.2, 162.3, 158.2, 145.8, 137.8, 135.2, 123.2, 113.2, 112.8, 111.2,
13.8, 10.4; HRMS (EI) m/z calcd for C13H11N3O2S: 273.0572; found:
273.0576.
cyclopropyl), 6.32 (s, 2H, NH2); 13C NMR (DMSO-d6)
d ppm: 166.6,
158.2, 13.1, 10.4.
4.2. Synthesis of 2-cyclopropyl-6-substituted phenylimidazo[2,1-b]
[1,3,4]thiadiazole 4(aek)
4.2.7. 3-(2-Cyclopropylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)aniline
(4g)
Yield 81%; mp 221e224 ꢁC; IR (KBr) nmax 3241.6, 3121.8,
A
mixture of equimolar quantities of 5-cyclopropyl-1,3,4-
3061.3, 1671.4, 1461.5 cmꢀ1 1H NMR (DMSO-d6)
; d ppm:
thiadiazol-2-amine (0.01 mol) and substituted phenacyl
3
1.21e2.01 (m, 5H, cyclopropyl), 6.42 (s, 2H, NH2), 7.13e7.76 (m,
bromides (0.01 mol) was refluxed in dry ethanol for 16 h. The excess
of solvent was distilled off and the solid hydrobromide that sepa-
rated was collected by filtration, suspended in water and neutral-
ized by aqueous sodium carbonate solution to get free base 4(aek).
It was filtered, washed with water, dried and recrystallized from
ethanol.
4H, AreH), 7.89 (s, 1H, C-5-H, imidazole); 13C NMR (DMSO-d6)
d
ppm: 166.8, 151.2, 145.4, 137.3, 135.3, 132.7, 123.4, 120.4, 118.2,
116.2, 13.8, 10.1; HRMS (EI) m/z calcd for C13H12N4S: 256.0783;
found: 256.0787.
4.2.8. 4-(2-Cyclopropylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)aniline
(4h)
4.2.1. 2-Cyclopropyl-6-phenylimidazo[2,1-b][1,3,4]thiadiazole (4a)
Yield 68%; mp 220e222 ꢁC; IR (KBr) nmax 3137.1, 3067.7, 1687.2,
Yield 77%; mp 228e232 ꢁC; IR (KBr) nmax 3256.6, 3119.6, 3058.6,
1678.2, 1459.2 cmꢀ1; 1H NMR (DMSO-d6)
d
ppm: 1.31e2.45 (m, 5H,
cyclopropyl), 6.39 (s, 2H, NH2), 7.17e7.86 (m, 4H, AreH), 7.96 (s, 1H,
C-5-H, imidazole); 13C NMR (DMSO-d6)
ppm: 166.6, 148.8, 145.2,
1439.5 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm: 1.19e2.31 (m, 5H, cyclo-
propyl), 7.26e7.28 (m, 5H, AreH), 7.92 (s, 1H, C-5-H, imidazole); 13C
NMR (DMSO-d6) ppm: 166.2, 145.8, 137.8, 134.8, 30.6, 128.6, 122.5,
d
d
137.1, 130.2, 125.3, 124.2, 116.4, 13.2, 10.6; HRMS (EI) m/z calcd for
13.1, 10.4; Mass (EI) m/z, 242.4557 (M þ 1).
C13H12N4S: 256.0783; found: 256.0786.
4.2.2. 6-(4-Chlorophenyl)-2-cyclopropylimidazo[2,1-b][1,3,4]
thiadiazole (4b)
4.2.9. 2-Cyclopropyl-6-(3-nitrophenyl)imidazo[2,1-b][1,3,4]
thiadiazole (4i)
Yield 62%; mp 230e234 ꢁC; IR (KBr) nmax 3131.2, 3056.7, 1666.4,
Yield 52%; mp 251e253 ꢁC; IR (KBr) nmax 3121.6, 3046.8,
1456.8, 648.4 cmꢀ1; 1H NMR (DMSO-d6)
d
ppm: 1.25e2.41 (m, 5H,
cyclopropyl), 7.18e7.80 (m, 4H, AreH), 7.96 (s, 1H, C-5-H, imid-
azole); 13C NMR (DMSO-d6)
ppm: 166.7, 145.1, 137.1, 135.2, 132.3,
1664.8, 1546.8, 1451.8, 1356.8 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm:
1.21e2.35 (m, 5H, cyclopropyl), 7.11e7.81 (m, 4H, AreH), 7.90 (s,
1H, C-5-H, imidazole); 13C NMR (DMSO-d6)
ppm: 166.2, 149.2,
d
d
129.5, 128.4, 122.8, 13.2, 10.5; HRMS (EI) m/z calcd for C13H10ClN3S:
275.0284; found: 275.0289.
145.4, 137.1, 135.6, 134.2, 132.4, 125.6, 123.6, 122.8, 13.7, 10.2;
HRMS (EI) m/z calcd for C13H10N4O2S: 286.0524; found:
286.0528.
4.2.3. 6-(4-Bromophenyl)-2-cyclopropylimidazo[2,1-b][1,3,4]
thiadiazole (4c)
4.2.10. 2-Cyclopropyl-6-(4-nitrophenyl)imidazo[2,1-b][1,3,4]
thiadiazole (4j)
Yield 66%; mp 260e264 ꢁC; IR (KBr) nmax 3129.8, 3042.6, 1685.4,
1461.8, 562.4 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm: 1.13e2.26 (m, 5H,
Yield 78%; mp 268e272 ꢁC; IR (KBr) nmax 3146.6, 3061.2, 1681.2,
cyclopropyl), 7.25e7.68 (m, 4H, AreH), 7.90 (s, 1H, C-5-H,
1561.8, 1461.9, 1335.2 cmꢀ1; 1H NMR (DMSO-d6)
d ppm: 1.14e2.38

4416
M.N. Noolvi et al. / European Journal of Medicinal Chemistry 46 (2011) 4411e4418
(m, 5H, cyclopropyl), 7.01e7.61 (m, 4H, AreH), 7.98 (s, 1H, C-5-H,
imidazole); 13C NMR (DMSO-d6)
ppm: 166.6, 151.2, 145.3, 137.4,
126.4, 125.8, 124.2, 13.2, 10.4; HRMS (EI) m/z calcd for C13H10N4O2S:
4.3.6. 4-(5-Bromo-2-cyclopropylimidazo[2,1-b][1,3,4]thiadiazol-6-
yl)benzene-1,3-diol (5f)
d
Yield 45%; mp 272e274 ꢁC; IR (KBr) nmax 3301.3, 3131.6, 3001.7,
286.0524; found: 286.0529.
1659.8, 1462.8, 512.8 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm: 1.18e2.24
(m, 5H, cyclopropyl), 6.01 (s, 2H, OH), 7.32e7.96 (m, 3H, AreH); 13C
NMR (DMSO-d6) ppm: 166.2, 162.3, 158.2, 139.8, 138.3, 135.2,
4.2.11. 2-(2-Cyclopropyl imidazo[2,1-b][1,3,4]thiadiazol-6-yl)
phenol (4k)
d
115.2, 112.2, 111.2, 96.1, 13.8, 10.6; HRMS (EI) m/z calcd for
C13H10BrN3O2S: 350.9677; found: 350.9681.
Yield 73%; mp 212e216 ꢁC; IR (KBr) nmax 3301.2, 3149.6, 3063.4,
1683.2, 1449.6 cmꢀ1; 1H NMR (DMSO-d6)
d
ppm: 1.10e2.61 (m, 5H,
cyclopropyl), 5.61 (s, 1H, OH), 7.09e7.82 (m, 4H, AreH), 7.99 (s, 1H,
C-5-H, imidazole); 13C NMR (DMSO-d6)
ppm: 166.2, 154.2, 145.4,
4.3.7. 3-(5-Bromo-2-cyclopropyl imidazo[2,1-b][1,3,4]thiadiazol-6-
yl)aniline (5g)
d
137.8, 132.6, 131.3, 124.6, 121.6, 120.3, 118.5, 13.5, 10.6; HRMS (EI)
m/z calcd for C13H11N3OS: 257.0623; found: 257.0627.
Yield 55%; mp 232e236 ꢁC; IR (KBr) nmax 3241.8, 3119.7, 3004.8,
1661.2, 1465.8, 561.2 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm: 1.16e2.21
(m, 5H, cyclopropyl), 6.91 (s, 2H, NH2), 7.32e7.91 (m, 4H, AreH); 13
NMR (DMSO-d6) ppm: 166.2, 150.2, 139.2, 138.2, 135.4, 132.8,
C
4.3. Synthesis of 5-bromo-2-cyclopropyl-6-substituted
d
phenylimidazo[2,1-b][1,3,4]thiadiazole 5(aek)
120.2, 119.2, 116.4, 96.4, 13.2, 10.1; HRMS (EI) m/z calcd for
C13H11BrN4S: 333.9888; found: 333.9892.
To a well stirred solution of 4(aek) (0.01 mol) in glacial acetic
acid (5 ml) and anhydrous sodium acetate (0.02 mol) was added
bromine (0.01 mol) drop wise with stirring at room temperature.
After the addition, stirring was continued for 2 h. The reaction
mixture was poured on ice cold water and basified with ammonia
solution. The separated solid was collected, washed with water,
dried and purified by column chromatography.
4.3.8. 4-(5-Bromo-2-cyclopropyl imidazo[2,1-b][1,3,4]thiadiazol-6-
yl)aniline (5h)
Yield 52%; mp 214e216 ꢁC; IR (KBr) nmax 3256.2, 3141.2, 3012.8,
1646.8, 1456.2, 591.8 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm: 1.15e2.18
(m, 5H, cyclopropyl), 6.85 (s, 2H, NH2), 7.35e7.98 (m, 4H, AreH); 13
NMR (DMSO-d6) ppm: 166.4,148.2,141.2,138.2,136.2,130.2,115.4,
C
d
13.4, 10.2; HRMS (EI) m/z calcd for C13H11BrN4S: 333.9888; found:
4.3.1. 5-Bromo-2-cyclopropyl-6-phenylimidazo[2,1-b][1,3,4]
thiadiazole (5a)
333.9891.
Yield 52%; mp 234e236 ꢁC; IR (KBr) nmax 3136.4, 3002.3, 1684.4,
4.3.9. 5-Bromo-2-cyclopropyl-6-(3-nitrophenyl)imidazo[2,1-b]
[1,3,4]thiadiazole (5i)
1476.2, 582.6 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm: 1.19e2.31 (m, 5H,
cyclopropyl), 7.26e7.82 (m, 5H, AreH); 13C NMR (DMSO-d6)
d
ppm:
Yield 49%; mp 260e264 ꢁC; IR (KBr) nmax 3139.6, 3014.6, 1651.4,
166.9, 145.9, 137.4.,134.0, 128.7, 127.4, 125.0, 99.9, 13.1, 10.4; Mass
(EI) m/z, 322.3154 (M þ 2).
1539.8, 1461.8, 1338.2, 588.2 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm:
1.17e2.23 (m, 5H, cyclopropyl),7.74e8.36 (m, 4H, AreH); 13C NMR
(DMSO-d6) ppm: 166.8, 150.2, 141.2, 138.2, 135.8, 132.8, 125.2,
d
4.3.2. 5-Bromo-6-(4-chlorophenyl)-2-cyclopropylimidazo[2,1-b]
[1,3,4]thiadiazole (5b)
124.8, 96.8, 13.2, 10.1; HRMS (EI) m/z calcd for C13H9BrN4O2S:
363.9630; found: 363.9634.
Yield 56%; mp 250e252 ꢁC; IR (KBr) nmax 3141.3, 3004.8, 1681.8,
1431.8, 602.5 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm: 1.20e2.23 (m, 5H,
4.3.10. 5-Bromo-2-cyclopropyl-6-(4-nitrophenyl)imidazo[2,1-b]
[1,3,4]thiadiazole (5j)
cyclopropyl), 7.26e7.96 (m, 4H, AreH); 13C NMR (DMSO-d6)
d
ppm:
166.2, 149.7, 138.3, 134.5, 133.2, 131.2, 130.2, 96.2, 13.2, 10.4; HRMS
(EI) m/z calcd for C13H9BrClN3S: 352.9389; found: 352.9392.
Yield 41%; mp 254e256 ꢁC; IR (KBr) nmax 3135.7, 3016.7, 1656.2,
1534.8, 1406.1, 1341.6, 601.4 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm:
1.11e2.10 (m, 5H, cyclopropyl), 7.64e8.16 (m, 4H, AreH); 13C NMR
(DMSO-d6) ppm: 166.2, 158.2, 149.2, 138.2, 136.2, 128.2, 126.2,
4.3.3. 5-Bromo-6-(4-bromophenyl)-2-cyclopropylimidazo[2,1-b]
[1,3,4]thiadiazole (5c)
d
96.8, 13.2, 10.6; HRMS (EI) m/z calcd for C13H9BrN4O2S: 363.9630;
found: 363.9635.
Yield 46%; mp 278e281 ꢁC; IR (KBr) nmax 3139.3, 3010.8, 1669.8,
1429.6, 613.6 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm: 1.17e2.21 (m, 5H,
cyclopropyl), 7.28e7.98 (m, 4H, AreH); 13C NMR (DMSO-d6)
d
ppm:
4.3.11. 2-(5-Bromo-2-cyclopropylimidazo[2,1-b][1,3,4]thiadiazol-6-
yl)phenol (5k)
166.3, 150.2, 139.2, 138.6, 134.8, 130.2, 123.4, 96.5, 13.7, 10.4; HRMS
(EI) m/z calcd for C13H9Br2N3S: 396.8884; found: 396.8888.
Yield 56%; mp 236e238 ꢁC; IR (KBr) nmax 3301.2, 3131.2, 3010.2,
1641.6, 1441.6, 610.2 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm: 1.12e2.12
(m, 5H, cyclopropyl),6.12 (s, 1H, OH), 7.38e8.15 (m, 4H, AreH); 13C
NMR (DMSO-d6) ppm: 166.2, 158.2, 139.2, 138.2, 132.6, 130.2,
4.3.4. 5-Bromo-2-cyclopropyl-6-(4-fluorophenyl)imidazo[2,1-b]
[1,3,4]thiadiazole (5d)
d
Yield 48%; mp 254e256 ꢁC; IR (KBr) nmax 3141.6, 3012.6, 1671.6,
122.4, 122.4, 118.3, 96.2, 13.8, 10.2; HRMS (EI) m/z calcd for
C13H10BrN3OS: 334.9728; found: 334.9732.
1431.8, 1021.8, 615.4 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm: 1.19e2.39
(m, 5H, cyclopropyl), 7.31e8.01 (m, 4H, AreH); 13C NMR (DMSO-d6)
ppm: 166.3, 164.2, 147.2, 139.2, 138.6, 132.8, 116.3, 96.8, 13.2, 10.4;
d
HRMS (EI) m/z calcd for C13H9BrFN3S: 336.9685; found: 336.9689.
4.4. Synthesis of 2-cyclopropyl-6-substituted phenyl-5-
thiocyanatoimidazo[2,1-b][1,3,4]thiadiazole 6(aek)
4.3.5. 5-Bromo-2-cyclopropyl-6-(2,4-dichlorophenyl)imidazo[2,1-
b][1,3,4]thiadiazole (5e)
To a well stirred solution of 4(aek) (0.01 mol) in glacial acetic
acid (5 ml) and potassium thiocyanate (0.02 mol) was added
bromine (0.01 mol) in glacial acetic acid, drop wise with stirring at
room temperature. Then stirring was continued for 1 h at 20e25 ꢁC
and then at room temperature for 30 min. The reaction mixture was
poured into ice water. The separated solid was collected, washed
with water, dried and recrystallized from ethanol.
Yield 56%; mp 276e278 ꢁC; IR (KBr) nmax 3129.6, 3018.2, 1671.8,
1434.8, 685.8, 503.6 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm: 1.21e2.29
(m, 5H, cyclopropyl), 7.31e7.92 (m, 3H, AreH); 13C NMR (DMSO-d6)
ppm: 166.2, 139.2, 138.2, 136.5, 134.8, 132.8, 130.2, 128.7, 126.3,
d
96.2, 13.2, 10.3; HRMS (EI) m/z calcd for C13H8BrCl2N3S: 386.8999;
found: 386.8996.

M.N. Noolvi et al. / European Journal of Medicinal Chemistry 46 (2011) 4411e4418
4417
4.4.1. 2-Cyclopropyl-6-phenyl-5-thiocyanatoimidazo[2,1-b][1,3,4]
thiadiazole (6a)
cyclopropyl), 6.41 (s, 2H, NH2), 7.11e8.31 (m, 4H, AreH); 13C NMR
(DMSO-d6) ppm: 166.4, 146.3, 140.2, 138.6, 130.2, 125.6, 122.6,
118.2, 114.2, 13.2, 10.1; HRMS (EI) m/z calcd for C14H11N5S2:
d
Yield 46%; mp 230e232 ꢁC; IR (KBr) nmax 3136.2, 3002.7, 2178.6,
1684.8, 1405.8 cmꢀ1; 1H NMR (DMSO-d6)
d
ppm: 1.17e2.27 (m, 5H,
313.0456; found: 313.0461.
cyclopropyl), 7.25e7.88 (m, 5H, AreH); 13C NMR (DMSO-d6)
d
ppm:
166.4, 140.2, 138.6, 135.6, 130.2, 128.6, 126.8, 122.6, 112.6, 13.2, 10.4;
HRMS (EI) m/z calcd for C14H10N4S2: 298.0347; found: 298.0351.
4.4.9. 2-Cyclopropyl-6-(3-nitrophenyl)-5-thiocyanatoimidazo[2,1-
b][1,3,4]thiadiazole (6i)
Yield 56%; mp 266e268 ꢁC; IR (KBr) nmax 3085.2, 2978.6, 2134.8,
4.4.2. 6-(4-Chlorophenyl)-2-cyclopropyl-5-thiocyanatoimidazo
[2,1-b][1,3,4]thiadiazole (6b)
1646.2, 1561.2, 1461.2, 1356.6 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm:
1.15e2.15 (m, 5H, cyclopropyl), 7.21e8.31 (m, 4H, AreH); 13C NMR
(DMSO-d6) ppm: 166.4, 151.2, 138.6, 136.2, 134.2, 132.2, 130.2,
Yield 58%; mp 240e242 ꢁC; IR (KBr) nmax 3131.2, 3004.6, 2156.8,
d
1671.2, 1441.8, 618.6 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm: 1.13e2.14
(m, 5H, cyclopropyl), 7.46e8.13 (m, 4H, AreH); 13C NMR (DMSO-d6)
ppm: 166.6,140.1,138.1,136.2, 132.8,131.8,128.8,122.6,114.6,13.2,
125.2, 124.2, 122.4, 114.2, 13.5, 10.6; HRMS (EI) m/z calcd for
C14H9N5O2S2: 343.0198; found: 343.0194.
d
10.2; HRMS (EI) m/z calcd for C14H9ClN4S2: 331.9957; found:
331.9961.
4.4.10. 2-Cyclopropyl-6-(4-nitrophenyl)-5-thiocyanatoimidazo[2,1-
b][1,3,4]thiadiazole (6j)
Yield 54%; mp 256e260 ꢁC; IR (KBr) nmax 3081.7, 2923.2, 2162.8,
4.4.3. 6-(4-Bromophenyl)-2-cyclopropyl-5-thiocyanatoimidazo
[2,1-b][1,3,4]thiadiazole (6c)
1616.7, 1433.2, 1556.4, 1345.2 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm:
1.18e2.20 (m, 5H, cyclopropyl), 7.39e8.15 (m, 4H, AreH); 13C NMR
(DMSO-d6) ppm: 166.4, 151.2, 140.6, 136.2, 134.2, 128.2, 126.2,
Yield 52%; mp 286e288 ꢁC; IR (KBr) nmax 3139.2, 2922.6, 2157.8,
d
1693.4, 1464.2, 503.2 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm: 1.15e2.27
(m, 5H, cyclopropyl), 7.26e7.68 (m, 4H, AreH); 13C NMR (DMSO-d6)
ppm: 166.4,140.2, 138.6, 134.4,132.8, 130.2, 122.6,114.8,13.2,10.6;
122.2, 13.6, 10.2; HRMS (EI) m/z calcd for C14H9N5O2S2: 343.0198;
found: 343.0195.
d
HRMS (EI) m/z calcd for C14H9BrN4S2: 375.9452; found: 375.9456.
4.4.11. 2-(2-Cyclopropyl-5-thiocyanatoimidazo[2,1-b][1,3,4]
thiadiazol-6-yl)phenol (6k)
4.4.4. 2-Cyclopropyl-6-(4-fluorophenyl)-5-thiocyanatoimidazo
[2,1-b][1,3,4]thiadiazole (6d)
Yield 36%; mp 270e272 ꢁC; IR (KBr) nmax 3312.2, 3041.2, 2931.6,
2114.5, 1656.2, 1461.2 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm: 1.16e2.18
(m, 5H, cyclopropyl), 6.01 (s, 1H, OH), 7.35e8.21 (m, 4H, AreH); 13C
NMR (DMSO-d6) ppm: 166.4, 158.2, 140.2, 138.6, 132.1, 123.2,
Yield 54%; mp 262e264 ꢁC; IR (KBr) nmax 3141.2, 2941.6, 2149.2,
1681.2, 1461.8, 1208.6 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm: 1.15e2.16
(m, 5H, cyclopropyl), 7.49e8.31 (m, 4H, AreH); 13C NMR (DMSO-d6)
ppm: 166.4, 161.6, 140.2, 138.6, 130.7, 128.6, 122.6, 118.3, 114.8,
d
122.4, 120.4, 118.4, 114.2, 13.2, 10.4; HRMS (EI) m/z calcd for
C14H10N4OS2: 314.0296; found: 314.0293.
d
13.5, 10.2; HRMS (EI) m/z calcd for C14H9FN4S2: 316.0253; found:
316.0257.
5. Conclusion
4.4.5. 2-Cyclopropyl-6-(2,4-dichlorophenyl)-5-thiocyanatoimidazo
[2,1-b][1,3,4]thiadiazole (6e)
In this paper, we report the synthesis, and anti-tumor activity
of series of 2-cyclopropylimidazo[2,1-b][1,3,4]thiadiazoles. These
compounds were prepared by the cyclodehydration process
between 2-amino-5-cyclpropyl-1,3,4-thiadiazole and an appropriate
phenacyl bromide. In light of the NCI-60 results, five dose selected
compound 5-bromo-6-(4-chlorophenyl)-2-cyclopropylimidazo[2,1-
b][1,3,4]thiadiazole 5b (NSC D-96022/1) was found to be the most
active candidate of the series against Leukemia K-562, Colon Cancer
HCT-15, Melanoma SK-MEL and Prostate Cancer PC-3 with GI50 1.79,
Yield 48%; mp 274e276 ꢁC; IR (KBr) nmax 3071.2, 2946.8, 2146.1,
1645.8, 1446.4, 681.2 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm: 1.24e2.31
(m, 5H, cyclopropyl), 7.12e7.89 (m, 3H, AreH); 13C NMR (DMSO-d6)
ppm: 166.3, 140.2, 138.6, 136.2, 134.2, 132.8, 130.2, 128.4, 122.6,
d
114.2, 13.8, 10.4; HRMS (EI) m/z calcd for C14H8Cl2N4S2: 365.9567;
found: 365.9571.
4.4.6. 4-(2-Cyclopropyl-5-thiocyanatoimidazo[2,1-b][1,3,4]
thiadiazol-6-yl)benzene-1,3-diol (6f)
2.02, 2.17, and 2.22 mM respectively with degree of selectivity toward
Leukemic cancer cell line based upon MG MID ratio (3.6). These
preliminary encouraging results of biological screening of the tested
compounds could offer an excellent framework in this field that may
lead to discovery of potent anti-tumor agent.
Yield 49%; mp 258e265 ꢁC; IR (KBr) nmax 3301.2, 3081.6, 2941.4,
2134.6, 1681.2, 1456.8 cmꢀ1; 1H NMR (DMSO-d6)
d
ppm: 1.21e2.19
(m, 5H, cyclopropyl), 6.14 (s, 2H, OH), 7.10e7.98 (m, 4H, AreH); 13C
NMR (DMSO-d6) ppm: 166.4, 161.2, 158.3, 140.2, 138.6, 122.6,
d
115.8, 112.8, 111.2, 109.8, 105.4, 13.2, 10.4; HRMS (EI) m/z calcd for
C14H10N4O2S2: 330.0245; found: 330.0249.
Acknowledgment
The authors would like to thank Director General, Department
of Science and Technology, New Delhi for funding the project
(Grant.No.SR/FT/LS-0024/2008), Chairman, Captain M.P. Singh and
Sardar Bhag Singh Bola, Secretary ASBASJSM College of Pharmacy
for providing the necessary facilities.
4.4.7. 3-(2-Cyclopropyl-5-thiocyanatoimidazo[2,1-b][1,3,4]
thiadiazol-6-yl)aniline (6g)
Yield 39%; mp 246e250 ꢁC; IR (KBr) nmax 3201.2, 3071.4, 2931.6,
2154.6, 1671.8, 1439.8 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm: 1.18e2.18
(m, 5H, cyclopropyl), 6.46 (s, 2H, NH2), 7.10e8.02 (m, 4H, AreH); 13
NMR (DMSO-d6) ppm: 166.4, 152.2, 140.2, 138.6, 135.2, 132.4,
C
d
References
122.6, 120.4, 118.2, 116.2, 13.6, 10.2; HRMS (EI) m/z calcd for
C14H11N5S2: 313.0456; found: 313.0460.
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