Synthesis and evaluation of unsymmetrical heterocyclic thioureas as potent β-glucuronidase inhibitors

Article abstract of DOI:10.1007/s00044-015-1369-x

Thiourea analogs 1-20 were synthesized and evaluated for their in vitro β-glucuronidase inhibitory potential. The compounds 9 (0.86 ± 0.01 μM), 6 (1.24 ± 0.01 μM), 16 (1.64 ± 0.02 μM) and 15 (2.12 ± 0.02 μM) showed potent activity. Other analogs 1-5, 7, 8

Full text of DOI:10.1007/s00044-015-1369-x

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-015-1369-x
ORIGINAL RESEARCH
Synthesis and evaluation of unsymmetrical heterocyclic thioureas
as potent b-glucuronidase inhibitors
Muhammad Taha1,2 Nor Hadiani Ismail1,2 Waqas Jamil3
•
•
•
Khalid Mohammed Khan4 Uzma Salar4 Syed Muhammad Kashif3
Fazal Rahim5 Yawar Latif6
•
•
•
•
Received: 3 November 2014 / Accepted: 15 April 2015
Ó Springer Science+Business Media New York 2015
Abstract Thiourea analogs 1–20 were synthesized and
evaluated for their in vitro b-glucuronidase inhibitory po-
tential. The compounds 9 (0.86 0.01 lM), 6 (1.24
0.01 lM), 16 (1.64 0.02 lM) and 15 (2.12 0.02 lM)
showed potent activity. Other analogs 1–5, 7, 8, 10, 11, 13,
17, 20 showed better activity than standard drug D-sac-
charic acid 1,4-lactone (47.34 0.21 lM) ranging
4.36–34.4 lM. All synthetic compounds were character-
ized by different spectroscopic methods. This study has
identified a new class of potent inhibitors b-glucuronidase.
Introduction
Urea derivatives have broad spectrum of biological activities
as colchicine-binding antagonist, (Fortin et al., 2007, 2009)
and CXCR3 antagonist, (Watson et al., 2008) anti-HIV,
antiviral, antibacterial, analgesic and HDL-elevating prop-
erties (Sivan et al., 2013; Venkatachalam et al., 2004;
ˇ
´
Holesova et al., 2014; Flieger et al., 2012; Bloom et al.,
2004; Seth et al., 2004; Lee et al., 2003). The urea analogs are
found to be very selective, and they are well suited to interact
with the viral proteases and showed no interaction with the
human proteases. Since, after first report of these inhibitors,
various derivatives have rapidly been synthesized, class of
cyclic compounds may soon become a feasible choice to the
currently available antiretroviral agents. The substituted
cyclic urea shown below has shown an increase in an-
Keywords Thioureas Á b-Glucuronidase inhibition Á
Heterocyclic
¨
tiretroviral potency (Backbro et al., 1997; Sham et al.,
´
1996a; Hulten et al., 1997; Ala et al., 1998).
& Muhammad Taha
taha_hej@yahoo.com;
muhamm9000@puncakalam.uitm.edu.my
Cyclic urea derivatives are also cytotoxic on a large
number of cancer cell lines and remain active on most
chemo-resistant cells (Fortin et al., 2007; Liu et al., 2014).
Chalcon reacts with isocyanate, thioisocyanate and amines
to produce important industrial products belonging to urea
and thiourea which posses a series of biological activities
including herbicidal activities, inhibition of nitric oxide,
antimicrobial, anti-HIV, antiviral, analgesic and HDL-
elevating properties (Yang et al., 2012). Derivatives of
1-phenyl-3-{4-[(2E)-3-phenylprop-2-enoyl]-phenyl}-urea
(2) exhibited anti-inflammatory and antimalarial activities
(Santos et al., 2008).
1
Atta-ur-Rahman Institute for Natural Product Discovery,
Universiti Teknologi MARA (UiTM), Puncak Alam Campus,
42300 Bandar Puncak Alam, Selangor, Malaysia
2
Faculty of Applied Science, UiTM, 40450 Shah Alam,
Selangor, Malaysia
3
Institute of Advance Research Studies in Chemical Sciences,
University of Sindh, Jamshoro, Pakistan
4
H. E. J. Research Institute of Chemistry, International Center
for Chemical and Biological Sciences, University of Karachi,
Karachi 75270, Pakistan
Classes of heterocyclic ureas, the azacyclic ureas, are
the potent inhibitors of HIV-1 protease; inhibition of HIV
protease is an important approach for the intervention of
HIV infection but possesses very low bioavailability
(Chrusciel and Strohbach, 2004; Sham et al., 1996b).
5
Department of Chemistry, Hazara University, Mansehra,
Pakistan
6
Department of Forensic Medicine and Toxiciology, Liaquat
University of Medical and Health Sciences, Jamshoro,
Hyderabad, Sindh, Pakistan
123

Med Chem Res
N-Acyl azide ureas 3 are excellent inhibitors of viral pro-
tease and have shown good antiviral activities against re-
sistant strains (Zhao et al., 2005).
The compounds 9, 6, 15 and 16 showed 0.86 0.01,
1.24 0.01, 2.12 0.02 and 1.64 0.02 lM activity far
better than standard drug D-saccharic acid 1,4-lactone 47.34
0.21 lM, respectively. 3-Chlorophenyl-2-methylpiper-
azinethiourea (9) showed potent activity that may be due to
3-chlorophenyl ring which can be proved by comparing the
activity of compound 5 (28.12 0.35 lM) having phenyl
ring with no substitution on 2-methylpiperazinethiourea.
The second most active compound also has 3-chlorophenyl
ring and 4-phenylpiperazinethiourea; when 3-chlorophenyl
is replaced with phenyl as in compound 4, the activity de-
creased almost two times. The compounds 15 and 16 have
quinoline ring and phenyl and 3-chlorophenyl, respectively;
the activity of 3-chlorophenyl is slightly better than phenyl
substituted. Compounds 3 and 17 have morpholine and
phenyl and 3-chlorophenyl thiourea, respectively; it was
observed that both compounds have almost same inhibition
potential.
b-Glucuronidase is an enzyme which catalyzes the
glucuronosyl-O-bonds cleavage (Sperker et al., 1997). This
is also up-regulated in different pathological conditions,
such as infection of urinary tract (Bank and Bailine, 1965;
Roberts et al., 1967; Ronald et al., 1971; Kallet and Lapco,
1967), renal disease (Gonick et al., 1973), rejection of
transplantation (Schapiro et al., 1968), epilepsy (Plum
1967), larynx and breast cancer (Boyland et al., 1957).
Besides, this enzyme is also involved in inflammatory joint
diseases, like rheumatoid arthritis (Caygill and Pitkeathly,
1966), and some hepatic diseases, and AIDS is also re-
ported due to over-expression of this enzyme. Literature
report showed that the bacterial b-glucuronidase inhibitor
leads to a decrease in carcinogen-induced colonic tumors
(Reddy, 1976). The current study is focused on the dis-
covery of b-glucuronidase inhibitors of pharmacological
importance. Some synthetic b-glucuronidase inhibitors re-
ported in recent past (Jamil et al., 2014; Khan et al., 2014a,
b, c; Cheng et al., 2015; Ahmad et al., 2012).
The compounds 2, 7, 10, 11 and 13 having piperidine
ring with different substitutions showed good activities.
The activity pattern is common, and 3-chlorophenylth-
iourea showed better activity than phenylthiourea. Phe-
nyl4-methylpiprazinethiourea (1) showed less activity as
compared to 3-chlorophenyl-4-ethylpiprazinethiourea (8)
which may be due to 3-chlrophenyl. The compound 20
showed fewer activities than compounds 1 and 8 because
4-acyl group replaces ethyl group. Compounds 12, 14, 18
and 19 showed less than 50 % inhibition and so considered
as inactive. Hence, we have discovered new potent
derivatives of thiourea for b-glucuronidase inhibition.
Further study on this compound could produce new
molecules for the b-glucuronidase inhibition.
Our research group is continuously working on the
chemistry and biology of new compounds (Aziz et al., 2014;
Musharraf et al., 2012; Anouar et al., 2013), sulfur-con-
taining compounds (Khan et al., 2008, 2009, 2010, 2011) and
hydrazones (Khan et al., 2012; Taha et al., 2013, 2014).
Results and discussion
Chemistry
We previously reported that unsymmetrical urea deriva-
tives are excellent antiglycating agent; therefore, we fur-
ther explored this class for discovering other biological
uses. The synthetic procedure which was adopted was quite
simple and required very short time to complete. Urea
derivatives 1–20 were synthesized from different amines
treating them with isocyanate (2 mmol). The crude prod-
ucts were recrystallized with ethanol afforded the pure
products (Scheme 1).
Experimental
Materials and methods
NMR experiments were performed on Avance Bruker AM
300 and 500 MHz machines. CHN analyses were carried
out on a Carlo Erba Strumentazione-Mod-1106, Italy.
Electron impact mass spectra (EI MS) were recorded on a
In continuation of our work on enzyme inhibition
(Rahim et al., 2015; Taha et al., 2015a; Taha et al.,
2015b; Khan et al., 2014d), the compounds 1–20 were
evaluated for in vitro b-glucuronidase inhibitory potential
(Table 1).
Finnigan MAT-311A (Germany) mass spectrometer. Thin-
layer chromatography (TLC) was monitored on pre-coated
silica gel aluminum plates (Kieselgel 60, 254, E. Merck,
Germany). Chromatograms were visualized by iodine va-
pors or UV at 254 and 365 nm.
123

Med Chem Res
Entry
No
Yield Entry
Yield
(%)
R1
R
R1
R
(%)
No
85
80
1
11
74
80
82
77
2
3
12
13
70
85
4
14
82
75
78
88
5
6
15
16
83
78
80
76
90
84
83
84
7
8
17
18
19
20
9
10
Scheme 1 Synthesis of heterocyclic thioureas 1–20
123

Med Chem Res
Table 1 In vitro b-glucuronidase activity of compounds 1–20
Compounds
IC50 (lM SEMa)
Compounds
IC50 (lM SEMa)
1
20.50 0.26
25.40 0.30
8.34 0.15
4.36 0.08
28.12 0.35
1.24 0.01
18.46 0.24
15.4 0.46
0.86 0.01
34.4 0.42
48.4 1.25 lM
11
12
13
14
15
16
17
18
19
20
–
31.40 0.54
NAb
2
3
11.21 0.26
NAb
4
5
2.12 0.02
1.64 0.02
8.42 0.36
NAb
6
7
8
9
NAb
10
D-Saccharic acid 1,4-lactonec
47.34 0.21
–
a
SEM is the standard error of the mean
b
NA Not active
c
D-saccharic acid 1,4-lactone, standard inhibitor for b-glucuronidase
General procedure for the synthesis of compounds
1–20
4-Methyl-N-phenylpiperazine-1-carbothioamide (1) Yield:
1
85 %; H NMR: (500 MHz, DMSO-d6): d 7.90 (s, 1H,
NH), 7.54 (dd, 2H, J = 6.4, J = 1.7 Hz, H-20/H-60), 7.23
(t, 2H, J = 7.8 Hz, H-30, H-50), 6.98 (t, 1H, J = 8.4 Hz,
H-40), 3.52 (t, 4H, J = 10.1 Hz, 2-CH2/6-CH2), 2.33 (t, 4H,
J = 10.0 Hz, 3-CH2/5-CH2), 2.50 (s, CH3); 13C NMR
(75 MHz, DMSO-d6): d 181.7 (C=S, C), 138.4 (C, C-10),
129.1 (CH, C-30), 129.1 (CH, C-50), 128.3 (CH, C-40),
126.6 (CH, C-20), 126.6 (CH, C-60), 56.7 (CH2, C-2), 56.7
(CH2, C-6), 51.6 (CH2, C-3), 51.6 (CH2, C-5), 46.5 (CH3,
C); EI MS: m/z (rel. abund%) 235.
Thiourea derivatives 1–20 were synthesized from different
heterocyclic amines by treating with isocyanate. Hetero-
cyclic amines (2 mmol) dissolved in dichloromethane
(10 mL), and temperature was maintained at 0 °C; then
isocyanate (2 mmol) was added drop-wise with constant
stirring. The formation of white solid after 1–1.5 h con-
firmed the completion of reaction. The resultant solid
products 1–20 were filtered and washed with hexane. Re-
crystallization with ethanol afforded the yield between 60
and 85 %.
N-Phenylpiperidine-1-carbothioamide (2) Yield: 74 %;
1H NMR: (500 MHz, DMSO-d6):d 8.42, (s, 1H, NH), 7.46(d,
2H, J = 8.0 Hz, H-20/H-60), 7.23 (t, 2H, J 8.0 Hz, H-30/H-50),
6.93 (t,1H, J = 7.0 Hz, H-40), 3.44 (t, 2H, J = 10.0 Hz,
2-CH2), 2.52 (t, 2H, J = 11 Hz, 6-CH2), 1.58 (m, 6H, 3-CH2/
4-CH2/5-CH2); 13C NMR (75 MHz, DMSO-d6): d 187.3
(C=S, C), 138.4 (C, C-10), 129.1 (CH, C-30), 129.1(CH, C-50),
128.5 (CH, C-40), 126.4 (CH, C-20), 126.4 (CH, C-60), 54.5
(CH2, C-2), 54.5 (CH2, C-6), 25.7 (CH2, C-3), 25.7 (CH2,
C-5), 24.9 (CH2, C-4); EI MS: m/z (rel. abund%) 220.
Biological assays
b-Glucuronidase (E.C. 3.2.1.31 from bovine liver, G-0251)
and p-nitrophenyl-b-D-glucuronide (N-1627) were pur-
chased from Sigma Chemical Co. (St. Louis, MO, USA).
Assay for b-D-glucuronidase
b-D-Glucuronidase inhibition was determined by measur-
ing the absorbance of the p-nitrophenol which is produced
from the substrate at 405 nm. The total reaction volume
was 250 lL. The reaction mixture contains 5 lL of test
compound solution, 185 lL of 0.1 M acetate buffer and
10 lL of enzyme, and it was incubated at 37 °C for
30 min. The plates were read on a multiplate reader at
405 nm after the addition of 50 lL of 0.4 mM p-nitro-
phenyl-b-D-glucuronide. All assays were performed in
triplicate.
N-Phenylmorpholine-4-carbothioamide (3) Yield: 80 %;
1H NMR: (500 MHz, DMSO-d6): d 7.38 (dd, 2H, J = 8.0,
J = 2.0, Hz, H-20/H-60) 7.29 (t, 2H, J = 8.0 Hz, H-30/H-
50), 7.07 (t, 1H, J = 8.0 Hz, H-40), 3.75 (t, 4H,
J = 10.4 Hz, 3-CH2, 5-CH2), 3.48 (t, 4H, J = 10.3 Hz,
2-CH2/6-CH2); 13C NMR (75 MHz, DMSO-d6): d 181.9
(C=S, C), 138.4 (C, C-10), 129.1 (CH, C-30), 129.1 (CH,
C-50), 128.5 (CH, C-40), 126.4 (CH, C-20), 126.4 (CH,
C-60), 66.3 (CH2, C-3), 66.3 (CH2, C-5), 50.1 (CH2, C-2),
50.1 (CH2, C-6); EI MS: m/z (rel. abund%) 222.
123

Med Chem Res
N-4-Diphenylpiperazine-1-carbothioamide
(4) Yield:
N-(3-Chlorophenyl)-4-ethylpiperazine-1-carbothioamide
(8) Yield: 78 %; 1H NMR: (500 MHz, DMSO-d6): d
7.52, (t,1H, J = 2.0 Hz, H-20), 7.28 (ddd, 1H, J = 8.0,
J = 2.0, J = 2.0 Hz, H-40), 7.27 (t, 1H, J = 8.5 Hz, H-50),
7.04 (ddd, 1H, J = 8.0, J = 2.0, J = 2.0 Hz, H-40), 3.56 (t,
4H, J = 10.0 Hz, H-2/H-6), 2.56-2.52 (m, 6H, 2xH-3/H-5/,
CH2), 1.20 (d, 3H, J = 8.0 Hz, CH3); 13C NMR (75 MHz,
DMSO-d6): d 181.7 (C=S, C), 138.6 (C, C-10), 134.5 (C,
C-30), 130.3 (CH, C-50), 128.2 (CH, C-40), 126.8 (CH,
C-20), 124.5 (CH, C-60), 57.2 (CH2, C-2), 57.2 (CH2, C-6),
56.6 (CH2, C-3), 56.6 (CH2, C-5), 49.7 (CH2, C), 13.4
(CH3, C); EI MS: m/z (rel. abund%) 283.
1
70 %; H NMR: (500 MHz, DMSO-d6): d 7.38, (dd, 2H,
J = 8.0, J = 2.0 Hz, H-20/H-60), 7.31 (m, 4H, H-30/H-50/
H-200/H-600), 7.06 (m, 3H, H-300/H-500/H-40), 6.91 (t, 1H,
J = 8.0 Hz, H-400), 3.72 (t, 4H, J = 10.0 Hz, 2-CH2/6-
CH2), 3.24 (t, 4H, J = 10.1 Hz, 3-CH2,5-CH2); 13C NMR
(75 MHz, DMSO-d6): d 181.7 (C=S, C), 149.5 (C, C-10),
138.4 (C, C-10), 129.7 (CH, C-30), 129.7 (CH, C-50), 128.9
(CH, C-30), 128.9 (CH, C-50), 128.5 (CH, C-40), 126.4 (CH,
C-20), 126.4 (CH, C-60), 121.8 (CH, C-40), 114.4 (CH,
C-20), 114.4 (CH, C-60), 56.8 (CH2, C-2), 56.8 (CH2, C-6),
53.6 (CH2, C-3), 53.6 (CH2, C-5); EI MS: m/z (rel.
abund%) 297.
N1, N14-Bis(3-chlorophenyl)-2-methyl-1,4-piperazinedicar-
boxamide (9) Yield: 80 %; 1H NMR: (500 MHz, DMSO-
d6): d 8.71 (s, 1H, NH), 8.62 (s, 1H, NH) 7.63 (s, 2H, H-20/
H-200), 7.40 (d, 2H, J = 8.0 Hz, H-50/H-500), 7.24 (dt, 2H,
J = 8.0, J = 2.0 Hz, H-40/H-400), 7.02 (dd, 2H, J = 2.0,
Hz, J = 2.0, H-60/H-600), 4.39 (s, 1H, H-3a), 4.06 (d,1H,
J = 12.0 Hz, H-3b), 3.97 (t, 2H, J = 13.0 Hz, H-5), 3.17
(t, 2H, J = 13.0 Hz, H-6), 2.98-2.91 (m, 1H, H-2); 13C
NMR (75 MHz, DMSO-d6): d 181.3 (C=S, C), 138.4 (C,
C-10), 134.5 (C, C-30), 130.3 (CH, C-50), 128.2 (CH, C-40),
126.8 (CH, C-20), 124.7 (CH, C-60), 66.6 (CH, C-2), 57.7
(CH2, C-3), 56.7 (CH2, C-6), 47.8 (CH2, C-5), 18.2 (CH3,
C); EI MS: m/z (rel. abund%) 422.
3-Methyl-N-phenyl-4-(phenylcarbamothioyl)piperazine-1-
carboxamide (5) Yield: 82 %; 1H NMR: (500 MHz,
DMSO-d6): d 8.56 (s, 1H, NH), 8.52 (s, 1H, NH), 7.50 (m,
4H, H-20/H-60/H-200/H-600), 7.29 (m, 4H, H-30/H-50/H-300/H-
500), 7.01-6.94 (m, 2H, H-40/H-400), 4.45(t, 1H, J = 6.5 Hz,
3a-CH), 4.16 (d, 1H, J = 11 Hz, 3b-CH), 3.97 (t, 4H,
J = 11 Hz, 6-CH2), 3.18 (t, 1H, J = 11 Hz, 5-CH2), 2.99
(m, 1H, 2-CH), 1.11 (d,3H, J = 7.2 Hz, CH3); 13C NMR
(75 MHz, DMSO-d6): d 181.3 (C=S, C), 138.6 (C, C-10),
129.1 (CH, C-30), 129.1 (CH, C-50), 128.5 (CH, C-40),
126.6 (CH, C-20), 126.6 (CH, C-60), 66.6 (CH, C-2), 57.5
(CH2, C-3), 56.9 (CH2, C-6), 47.8 (CH2, C-5), 18.5 (CH3,
C); EI MS: m/z (rel. abund%) 354.
3-Methyl-N-phenylpiperidine-1-carbothioamide (10) Yield:
1
76 %; H NMR: (500 MHz, DMSO-d6): d 8.36 (s, 1H,
N-(3-Chlorophenyl)-4-phenylpiperazine-1-carbothioamide
(6) Yield: 75 %; 1H NMR: (300 MHz, DMSO-d6): d 8.24
(s, 1H, NH), 7.86 (d, 1H, J = 2.0 Hz, H-20), 7.49 (dt, 1H,
J =0 8.0, J = 2.0, Hz, H-60), 7.32 (d, 1H, J = 2.0 Hz,
H-4 ), 7.29-7.22 (m, 2H, H-200/H-600), 7.04-6.98 (m, 3H,
H-400/H-600/H-60), 6.90 (t,1H, J = 7.0 Hz, H-400), 3.74 (t,
4H, J = 10.0 Hz, H-3/H-5), 3.24 (t, 4H, J = 10.0 Hz H-2/
H-6); 13C NMR (75 MHz, DMSO-d6): d 181.7 (C=S, C),
149.4 (C, C-10), 138.4 (C, C-10), 134.5 (C, C-30), 130.3
(CH, C-50), 129.5 (CH, C-30), 129.5 (CH, C-50), 128.2 (CH,
C-40), 126.8 (CH, C-20), 124.5 (CH, C-60), 121.8 (CH,
C-40), 114.4 (CH, C-20), 114.4 (CH, C-60), 56.8 (CH2, C-2),
56.8 (CH2, C-6), 53.4 (CH2, C-3), 53.5 (CH2, C-4); EI MS:
m/z (rel. abund%) 331.
NH), 7.46 (dd, 2H, J = 8.0, J = 1.5, Hz, H-20/H-60), 7.32
(t, 2H, J = 8.0, J = 8.0 Hz, H-30/H-50), 6.99 (t, 1H,
J = 8.0 Hz, H-40), 4.08 (t, 2H, J = 10.5 Hz, 6-CH2), 2.72
(dd 1H, J = 6.0, J = 8.0 Hz, H-2b) 2.52 (dd,1H, J = 7.0,
J = 6.5, Hz, H-2a), 1.78-1.67 (m, 2H, H-4b/H-4a),1.59-
1.38 (m, 2H, 5-CH2), 1.16-1.05 (m,1H, H-3), 0.91 (d, 3H,
J = 6.6 Hz, CH3); 13C NMR (75 MHz, DMSO-d6): d
187.3 (C=S, C), 138.4 (C, C-10), 128.9 (CH, C-30), 128.9
(CH, C-50), 128.3 (CH, C-40), 126.4 (CH, C-20), 126.4 (CH,
C-60), 60.3 (CH2, C-2), 54.6 (CH2, C-6), 32.7 (CH2, C-4),
28.8 (CH, C-3), 23.2 (CH2, C-5), 18.6 (CH3, C); EI MS: m/
z (rel. abund%) 234.
4-Methyl-N-phenylpiperidine-1-carbothioamide (11) Yield:
1
80 %; H NMR: (500 MHz, DMSO-d6): d 8.42 (s, 1H,
N-(3-Chlorophenyl)piperidine-1-carbothioamide (7) Yield:
83 %; 1H NMR: (500 MHz, DMSO-d6): d 7.50 (t,1H,
J = 4.0 Hz, H-20), 7.28 (dt, 1H, J = 8.5, = 2.0 Hz, H-40),
NH), 7.46 (dd, 2H, J = 8.0, J = 2.0, Hz, H-20/H-60) 7.31
(t, 2H, J = 8.0 Hz, H-30/H-50), 7.06 (t, 1H, J = 7.2 Hz,
H-40), 4.07 (d, 2H, J = 13.0 Hz, 2-CH2), 2.79 (t, 2H,
J = 13.0 Hz, 6-CH2) 1.66-1.58 (m, 3H, 4-CH/3-CH2),
0
7.28 (t, 1H, J = 8.0 Hz, H-50), 6.99 (dt, 1H, J6 , = 8.0 -
J = 2.0 Hz, H-60), 3.49 (t, 4H, J = 10.5 Hz, H-2,6), 1.68-
163 (m, 2H, H-4), 1.60-1.58 (m, 4H, H-3,5); 13C NMR
(75 MHz, DMSO-d6): d 187.1 (C=S, C), 138.6 (C, C-10),
134.5 (C, C-30), 130.6 (CH, C-50), 128.2 (CH, C-40), 126.8
(CH, C-20), 124.7 (CH, C-60), 54.3 (CH2, C-2), 54.3 (CH2,
C-6), 25.5 (CH2, C-3), 25.5 (CH2, C-5), 24.7 (CH2, C-4);
EI MS: m/z (rel. abund%) 254.
1.15-1.08 (m, 2H, 5-CH2) 1.02 (d, J = 13.0 Hz, CH3); 13
C
NMR (75 MHz, DMSO-d6): d 187.1 (C=S, C), 138.4 (C,
C-10), 129.1 (CH, C-30), 129.1 (CH, C-50), 128.3 (CH,
C-40), 126.4 (CH, C-20), 126.4 (CH, C-60), 51.8 (CH2, C-2),
51.8 (CH2, C-6), 34.2 (CH2, C-3), 34.2 (CH2, C-5), 32.2
(CH, C-4), 20.3 (CH3, C); EI MS: m/z (rel. abund%) 234.
123

Med Chem Res
N-(3-Chlorophenyl)-4-(2-methoxyphenyl)piperazine-1-car-
bothioamide (12) Yield: 82 %; 1H NMR: (500 MHz,
DMSO-d6): d 7.54, (t, 1H, J = 2 Hz, H-20) 7.31 (ddd,
1H, = J = 1.6, J = 8.0 Hz, H-40), 7.28 (t, 1H,
J = 8.0 Hz, H-50), 7.07-6.97 (m, 4H, H-300/H-400/H500/H-
600), 6.96 (dt, 1H, J = 8.4, J = 2.3 Hz, H-60), 3.89 (s, 3H,
OCH3), 3.71 (t, 4H, J = 10.0 Hz, 2-CH2/6-CH2), 3.08 (t,
4H, J = 10.0 Hz, 3-CH2/5-CH2); 13C NMR (75 MHz,
DMSO-d6): d 181.7 (C=S, C), 162.3 (C, C-100), 141.2 (C,
C-200), 138.4 (C, C-10), 134.5 (C, C-30), 130.3 (CH, C-50),
128.2 (CH, C-40), 126.8 (CH, C-20), 124.5 (CH, C-60),
123.1 (CH, C-600), 122.0 (CH, C-400), 121.8 (CH, C-500),
113.4 (CH, C-300), 56.6 (CH2, C-2), 56.6 (CH2, C-6), 55.7
(OCH3, C), 53.7 (CH2, C-3), 53.7 (CH2, C-5); EI MS: m/
z (rel. abund%) 361.
(75 MHz, DMSO-d6): d 179.8 (C=S, C), 148.5 (CH, C-2),
138.4 (C, C-10), 137.1 (C, C-10), 136.6 (CH, C-4), 133.7
(C, C-9), 129.1 (C, C-5), 129.1 (CH, C-30), 129.1 (CH,
C-50), 128.3 (CH, C-40), 127.4 (CH, C-7), 126.6 (CH, C-20),
126.6 (CH, C-60), 121.3 (CH, C-3), 116.6 (CH, C-8),113.7
(CH, C-6); EI MS: m/z (rel. abund%) 279.
1-(3-Chlorophenyl)-3-(quinolin-8-yl)thiourea (16) Yield:
88 %; 1H NMR: (500 MHz, Methanol-d4): d 8.80 (dd, 1H,
J = 2.0, J = 4.5 Hz, H-2), 8.52 (dd, 1H, J = 6.0,
J = 2.5 Hz, H-3), 8.29 (dd, 1H, J = 8.4, J = 1.7 Hz,
H-7), 7.74 (t, 1H, J = 2.0, Hz, H-20), 7.57-7.49 (m, 3H,
H-4/H-5/H-6), 7.38 (ddd, 1H, J = 8.4, J = 2.0,
J = 1.6 Hz H-40), 7.25 (t, 1H, J = 8.0 Hz, H-50), 7.04
(ddd, 1H, J = 7.0, J = 2.0 J = 1.6 Hz, H-6); 13C NMR
(75 MHz, DMSO-d6): d 179.8 (C=S, C), 148.5 (CH, C-2),
138.4 (C, C-10), 137.1 (C, C-10), 136.6 (CH, C-4), 134.7
(C, C-30), 133.9 (C, C-9), 130.5 (CH, C-50), 129.1 (C, C-5),
128.2 (CH, C-40), 127.2 (CH, C-7), 126.8 (CH, C-20), 124.5
(CH, C-60), 121.1 (CH, C-3), 116.4 (CH, C-8),113.7 (CH,
C-6); EI MS: m/z (rel. abund%) 313.
N-(3-Chlorophenyl)-2,6-dimethylpiperidine-1-carbothioamide
1
(13) Yield: 77 %; H NMR: (500 MHz, DMSO-d6): d
8.42 (s, 1H, NH), 7.72, (t,1H, J = 2.0 Hz, H-20), 7.47 (dd,
1H, J = 8.0 Hz, H-40), 7.28 (t, 1H, J = 8.0 Hz, H-50), 7.07
(dt, 1H, J = 8.0, J = 2 Hz,H-60),7.28 (t, J = 8.0 Hz, H-50)
6.99 (dt, 1H, J = 7.5, = 2.0 Hz, H-40), 4.36-4.30 (m, 2H,
4-CH2), 1.58-1.54 (m, 1H, 2-CH), 1.51-1.46 (m, 4H,
3-CH2/5-CH2), 1.42-1.37 (m, 1H, 6CH), 1.14 (d, 3H,
J = 7 Hz, CH3), 1.04 (d, 3H, J = 7 Hz, CH3); 13C NMR
(75 MHz, DMSO-d6): d 187.1 (C=S, C), 138.4 (C, C-10),
134.5 (C, C-30), 130.3 (CH, C-50), 128.2 (CH, C-40), 126.8
(CH, C-20), 124.5 (CH, C-60), 64.2 (CH, C-2), 64.2 (CH,
C-6), 30.0 (CH2, C-3), 30.0 (CH2, C-5), 20.2 (CH3, C),
20.2 (CH3, C), 14.0 (CH2, C-4); EI MS: m/z (rel. abund%)
284.
N-(3-chlorophenyl)morpholine-4-carbothioamide (17) Yield:
90 %; 1H NMR: (500 MHz, DMSO-d6): d 8.71 (s, 1H, NH)
7.66 (t, 1H, J = 2.0 Hz, H-2), 7.41 (dt, 1H, J = 8.0,
J = 2.0 Hz, H-4), 7.29 (t, 1H, J = 8.0 Hz, H-5), 7.02 (dd,
1H, J = 7.8, J = 2.0 Hz, H-6), 3.62 (t, 4H, J = 5.0 Hz, 20-
CH2/60-CH2), 3.52 (t, 4H, J = 5.0 Hz, 30-CH2, 50-CH2);
13C NMR (75 MHz, DMSO-d6): d 181.7 (C=S, C), 138.4
(C, C-10), 134.5 (C, C-30), 130.3 (CH, C-50), 128.2 (CH,
C-40), 126.8 (CH, C-20), 124.5 (CH, C-60), 66.3 (CH2, C-3),
66.3 (CH2, C-5), 50.1 (CH2, C-2), 50.1 (CH2, C-6); EI MS:
m/z (rel. abund%) 256.
N-(3-Chlorophenyl)-4-(4-methoxyphenyl)piperazine-1-car-
bothioamide (14) Yield: 85 %; 1H NMR: (500 MHz,
DMSO-d6): d 8.79, (s, 1H, H-NH), 7.68 (t,1H, J = 2.0 Hz,
H-20), 7.43 (dd, 1H, J = 8.0, J = 2.0 Hz, H-40), 7.25 (t,
1H, J = 8.0 Hz, H-50), 7.02 (d,1H, J = 2.0 Hz, H-20), 7.01
(d, 2H, J = 9 Hz, H-200/H-600) 6.87 (d, 2H, J = 6.0 Hz,
H-300/H-500), 3.69 (s, 3H, CH2), 3.60 (t, 4H, J = 9.5 Hz,
3-CH2/5-CH2), 3.06 (t, 4H, J = 2-CH2/6-CH2); 13C NMR
(75 MHz, DMSO-d6): d 181.7 (C=S, C), 152.9 (C, C-400),
146.2 (C, C-100), 138.4 (C, C-10), 134.5 (C, C-30), 130.3
(CH, C-50), 128.2 (CH, C-40), 126.8 (CH, C-20), 124.5 (CH,
C-60), 115.2 (CH, C-200), 115.2 (CH, C-600), 115.1 (CH,
C-300), 115.1 (CH, C-500), 56.6 (CH2, C-2), 56.6 (CH2, C-6),
55.7 (OCH3, C), 53.4 (CH2, C-3), 53.4 (CH2, C-5); EI MS:
m/z (rel. abund%) 361.
N-Phenyl-4-(pyridin-2-yl)piperazine-1-carbothioamide
1
(18) Yield: 84 %; H NMR: (500 MHz, DMSO-d6): d
8.15 (dd, 1H, J = 1.5, J = 5.0 Hz, H-600), 7.62 (ddd, 1H,
J = 5.0, J = 5.0, J = 1.5 Hz, H-500), 7.39 (d, 2H,
J = 8.5 Hz, H-20/H-60), 7.25 (t, 2H, J = 8.5 Hz, H-30/H-
50), 7.06 (t, 1H, J = 7.6 Hz, H-40), 6.88 (d, 1H,
J = 8.4 Hz, H-300), 6.72 (dd, 1H, J = 8.0, J = 1.5 Hz,
H-400), 3.62 (t, 4H, J = 9.2 Hz, 2-CH2/6-CH2), 3.59 (t, 4H,
J = 9.2 Hz, 3-CH2/5-CH2); 13C NMR (75 MHz, DMSO-
d6): d 181.9 (C=S, C), 158.2 (C, C-200), 148.0 (CH, C-600),
138.6 (C, C-10), 138.4 (CH, C-400), 128.9 (CH, C-30), 128.9
(CH, C-50), 128.3 (CH, C-40), 126.4 (CH, C-20), 126.4 (CH,
C-60), 117.8 (CH, C-500), 106.3 (CH, C-300), 56.9 (CH2,
C-2), 56.9 (CH2, C-6), 46.2 (CH2, C-3), 46.2 (CH2, C-5);
EI MS: m/z (rel. abund%) 298.
1
1-Phenyl-3-(quinolin-8-yl)thiourea (15) Yield: 78 %; H
NMR: (500 MHz, Methanol-d4): d 8.82 (dd, 1H, J = 2.0,
J = 5.0 Hz, H-2), 8.52 (dd, 1H, J = 7.0, J = 2.0 Hz,
H-4), 8.29 (dd, 1H, J = 8.0, J = 2.0 Hz, H-7), 7.54-7.48
(m, 5H, H-3, H-5/H-6, H-20/H-60), 7.33 (t, 2H, J = 7.6 Hz,
H-3/H-5), 7.06 (t 1H, J = 7.6 Hz, H-40); 13C NMR
N-(3-Chlorophenyl)-4-(pyridin-2-yl)piperazine-1-carboth-
ioamide (19) Yield: 83 %; 1H NMR: (500 MHz, DMSO-
d6): d 8.12 (dd, 1H, J = 5.0, J = 1.5 Hz, H-600), 7.62 (ddd,
1H, J = 5.0, J = 5.0, J = 1.5 Hz, H-500), 7.55 (t, 1H,
J = 4.5 Hz, H-20), 7.29 (dd, 1H, J = 7.0, J = 2.0 Hz,
123

Med Chem Res
H-40), 7.26 (t, 1H, J = 8.0 Hz, H-50), 7.02 (ddd 1H,
J = 8.0, J = 1.8, J = 2.0 Hz, H-60), 6.86 (d, 1H,
J = 8.8 Hz, H-300), 6.74(dd, 1H, J = 7.0, J = 5.0 Hz,
H-400), 3.69 (t, 4H, J = 10.0 Hz, 2-CH2/6-CH2), 3.56 (t,
4H, J = 10.0 Hz, 3-CH2/5-CH2); 13C NMR (75 MHz,
DMSO-d6): d 181.7 (C=S, C), 158.2 (C, C-200), 148.0 (CH,
C-600), 138.4 (C, C-10), 138.2 (CH, C-400), 134.5 (C, C-30),
130.3 (CH, C-50), 128.2 (CH, C-40), 126.8 (CH, C-20),
124.5 (CH, C-60), 117.8 (CH, C-500), 106.1 (CH, C-300),
56.6 (CH2, C-2), 56.6 (CH2, C-6), 46.2 (CH2, C-3), 46.2
(CH2, C-5); EI MS: m/z (rel. abund%) 332.
Boyland E, Gasson JE, Williams DC (1957) Enzyme activity in
relation to cancer; the urinary b-glucuronidase activity of
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120–129
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and acid phosphatase in pathological joint fluids. Ann Rheum
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_
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4-Acetyl-N-phenylpiperazine-1-carbothioamide (20) Yield:
84 %; 1H NMR: (500 MHz, Methanol-d4): d 7.37 (dd, 2H,
J = 7.6, J = 1.8, Hz, H-20/H-60), 7.32 (t, 2H, J = 8.5 Hz,
H-30/H-50), 7.07 (t, 1H, J = 8.5 Hz, H-40), 3.67 (t, 4H,
J = 10.0 Hz, 2-CH2/6-CH2), 3.56 (t, 4H, J = 10.0 Hz,
3-CH2/5-CH2), 2.12 (s, 3H, CH3); 13C NMR (75 MHz,
DMSO-d6): d 181.9 (C=S, C), 168.7 (C=O, C), 138.4 (C,
C-10), 129.1 (CH, C-30), 129.1 (CH, C-50), 128.5 (CH,
C-40), 126.4 (CH, C-20), 126.4 (CH, C-60), 56.7 (CH2, C-2),
56.7 (CH2, C-6), 49.4 (CH2, C-3), 49.4 (CH2, C-5), 21.2
(CH3, C); EI MS: m/z (rel. abund%), 263.
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oethyl)urea analogs of combretastatin A-4: is the N-phenyl-N0-
(2-chloroethyl)urea pharmacophore mimicking the trimethoxy
phenyl moiety. Bioorgan Med Chem 15:4456–4469
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Tokarsky J, Pazdziora E (2014) Antibacterial kaolinite/urea/
´
´ˇ
´
´ˇ
´
´
´
Acknowledgments Authors would like to acknowledge The Min-
istry of Agriculture (MOA) Malaysia and Universiti Teknologi
MARA under MOA Grant File No. 100-RMI/MOA 16/6/2 (1/2013)
and Higher Education Commission (HEC) Pakistan, under National
Research Program for Universities (Project No. 20-1910) for the fi-
nancial support.
´
chlorhexidine nanocomposites: experiment and molecular mod-
eling. Appl Surf Sci 305:783–791
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