Synthesis, in vitro antiproliferative and anti-HIV activity of new derivatives of 2-Piperazino-1,3-benzo[d]thiazoles

Article abstract of DOI:10.1515/znb-2010-1113

A series of N-{2-oxo-2-[4-(1,3-benzothiazol-2-yl)piperazin-1-yl]}-(het) arenecarboxamides 4a - l, sulfonamide derivatives 8a - i as well as benzothiazole-containing N¹-(2-oxoethyl)-N¹-arylthioureas 9a - c have been synthesized. Compo

Full text of DOI:10.1515/znb-2010-1113

Synthesis, in vitro Antiproliferative and Anti-HIV Activity of
New Derivatives of 2-Piperazino-1,3-benzo[d]thiazoles
Yaseen A. Al-Souda, Haitham H. Al-Sa’donia, Sadeekah O. W. Sabera,
Reem H. M. Al-Shaneeka, Najim A. Al-Masoudib, R. Loddoc, and P. La Collac
a Department of Chemistry, College of Science, University of Al al-Bayt, Al-Mafraq, Jordan
b Department of Chemistry, College of Science, University of Basrah, Basrah, Iraq
c Department of Biomedical Sciences and Technologies, University of Cagliari,
Cittadella Universitaria, 09042 Monserrato (CA), Italy
Reprint requests to Prof. N. A. Al-Masoudi. E-mail: najim.al-masoudi@gmx.de
Z. Naturforsch. 2010, 65b, 1372 – 1380; received May 28, 2010
A series of N-{2-oxo-2-[4-(1,3-benzothiazol-2-yl)piperazin-1-yl]}-(het)arenecarboxamides 4a – l,
sulfonamide derivatives 8a – i as well as benzothiazole-containing N1-(2-oxoethyl)-N1-arylthioureas
9a – c have been synthesized. Compounds 4a – l and 9a were evaluated, in vitro, for their antiprolifer-
ative activity against a large panel of human tumor-derived cell lines. Compounds 4l and 9a were the
most potent analogs in this series, showing remarkable effects on human splenic B-lymphoblastoid
cells (WIL-2NS) and human acute B-lymphoblastic leukemia (CCRF-SB) cell lines (4l: CC50 = 5.1
and 7.3 µM, respectively), and compound 5 against CCRF-SB cell lines with CC50 = 2.3 µM. These
compounds are leading candidates for further development. Compounds 6 – 7a – i were screened as
inhibitors against HIV-1 and HIV-2, and no activity has been witnessed.
Key words: Antiproliferative Activity, Anti-HIV Activity, Benzothiazole, Aryl Isothiocyanate,
Amide, Thiourea Derivatives
Introduction
Several benzothiadiazoles have shown selective
antiproliferative activity, especially the phenyl-sub-
stituted benzothiazoles [1 – 3]. Substituted 2-(4-amino-
phenyl)benzothiazoles were developed and comprised
a novel class of antitumor-active compounds, es-
pecially against sensitive breast tumor cell lines,
e. g., MCF-7 and MDA 468, and extended to cer-
tain colon, lung, melanoma, renal, and ovarian tu-
mor cell lines [4 – 7]. Pyrimidobenzothiazole and ben-
zothiazoloquinoline derivatives [5], imidazobenzothi-
azoles [8], polymerized benzothiazoles [9, 10] as
well as several derivatives of substituted benzoth-
iazoles [11] showed remarkable antitumor activity
against malignant cell lines.
Fig. 1. 2-(3,4-Dimethoxyphenyl)-5-fluoro-1,3-benzothiazole
(DMFB, 1).
azol-2-yl)-4-hydroxycyclohexa-2,5-dienone[21], have
been synthesized and exhibited potent antitumor ac-
tivity against renal and colon cancer cell lines with
prodrug Phortress [22], and human mammary tumor
xenografs [23], and is currently under pharmacological
investigation in phase I clinical trial in the UK. Yoshida
et al. [24] have synthesized a highly potent benzoth-
iazole derivative bearing an amido substituent that
displays excellent in vivo inhibitory effect on tumor
growth. Recently, Racane et al. [25] have described the
synthesis of bis-disubstituted amidinobenzothiazoles
as potential anti-HIV agents.
Some (arylamino)benzothiazoles, such as 2-(4-
amino-3-methylphenyl)-benzothiazole [12, 13], 2-(4-
aminophenyl)-benzothiazole [14, 15], the fluoro ana-
In continuation of our research on the synthesis
log (5F 203) [16 – 19] and 2-(3,4-dimethoxyphenyl)- and biological evaluation of benzothiazole analogs
5-fluoro-benzothiazole (1) [20] are considered as po- [26 – 29], we report here the synthesis and antipro-
tent ligands for the arylhydrocarbon receptor (AhR) liferative and anti-HIV evaluation of new benzo-
which translocates with the drug to cell nuclei (Fig. 1). thiazole derivatives bearing 2-(piperazin-1-yl)-2-oxo-
A further class of benzothiazoles, e. g. 4-(benzothi- ethyl-benzamide, sulfonamide and thiourea functions.
c
0932–0776 / 10 / 1100–1372 $ 06.00 ꢀ 2010 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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Y. A. Al-Soud et al. · New Derivatives of 2-Piperazino-1,3-benzo[d]thiazoles
1373
Scheme 1.
2
Results and Discussion
(CCH CH S = O, δC = 169.1 ppm) as well as a JC,H
2 2
coupling to the carbonyl carbon atom CNpiperazine =O,
Synthesis
(δC = 166.0 ppm). Furthermore, the CCH CH S = O car-
2
2
bon atom showed two couplings: a 3JC,H coupling with
In the present work, amine 2, prepared previ-
ously in our laboratory, has been selected for the
synthesis of new potentially active substituted amide
derivatives. Two methods have been employed in
the preparation of the corresponding amide deriva-
tives from the reaction of 2 with the appropriate
carboxylic acid 3a – l (Scheme 1). The first method
includes the preparation of amides 4a – c, l (23 –
38 % yield), by treatment of 2 with the benzoic
acids 3a – c or 3-(1-benzyl-2-ethyl-4-nitro-1H-imid-
azol-5-ylthio)propanoic [30] acid, using 1-hydroxy-
benzotriazole (HOBt) [31, 32] and N,Nꢀ-dicyclohex-
ylcarbodiimide (DCC)[33] as coupling reagents. The
second method proceeded by preparation of the amides
4d – k in 57 – 90 % yield, from treatment of 2 with
2
the CH2CH2S protons at δH = 3.20 ppm, and a JC,H
coupling with the CH2CH2S protons at δH = 2.55 ppm.
C-4 of the imidazole moiety (δC = 148.3 ppm) showed
a
3JC,H coupling to the CH2CH2S protons (δH
=
3.20 ppm).
Next, our target was the synthesis of N-{2-oxo-2-
[4-(1,3-benzothiazol-2-yl)piperazin-1-yl]}-(het)arene-
sulfonamides aiming to evaluate their HIV-inhibiting
potential. Thus, the hydrazide 6 was prepared (84%)
by treatment of the ester 5 with hydrazine hydrate.
Treatment of 6 with the arenesulfonyl chlorides 7a – i
afforded the corresponding sulfonamides 8a – i in
39 – 96 % yield (Scheme 2).
The structures of 6 and 8a – i were assigned on the
the carboxylic acid chlorides 3d – k in the presence basis of their H NMR, 13C NMR, and mass spec-
1
of Et3N.
tra. In the former the multiplets at higher field (δ =
The structures of the newly synthesized com- 8.56– 7.04 ppm) were attributed to the aryl protons.
pounds 4a – k are in agreement with the 1H NMR, The methylene protons of the piperazine moiety ap-
13C NMR, and mass spectra. In the H NMR spec- peared as multiplets in the region δ = 3.69 – 2.42 ppm.
1
tra, the piperazine protons showed a similar pattern The 13C NMR spectra of 6 and 8a – i were fully as-
in the region δ = 4.10 – 3.13 ppm for all compounds. signed (cf. Experimental Section), while compound 8b
The singlets in the region δ = 4.43 – 3.94 ppm were was selected for a detailed 13C NMR analysis. The
assigned to CH2NH protons. The 13C NMR spectra spectrum showed signals at δ = 169.9– 167.9 ppm and
of 4a – l contained similar resonance signals for the δ = 168.5– 164.0 ppm which were assigned to C=N
piperazine and benzothiazole carbon atoms. CH2NH and C=O, respectively. The COCH2 resonances were
carbon signals were observed in the region δ = 41.9– observed in the region δ = 60.8 – 59.9 ppm, and the
41.0 ppm. Compound 4l was selected for further NMR piperazine carbon atoms resonated in the regions δ =
studies. In the gradient-selected HMBC spectrum [34] 53.3– 51.4 ppm and δ = 48.5– 47.2 ppm. The aromatic
of 4l, the CH2NH methylene protons at δH = 4.11 ppm carbon atoms were observed in the region δ = 144.9 –
3
showed a JC,H coupling to the carbonyl carbon atom 114.5 ppm.
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1374
Y. A. Al-Soud et al. · New Derivatives of 2-Piperazino-1,3-benzo[d]thiazoles
Scheme 2. Reagents and conditions: i) EtOH, NH2NH2· H2O, reflux, 8 h; ii) CHCl3, 7a – i, Et3N, r. t., 20 – 24 h.
acute T-lymphoblastic leukaemia (CCRF-CEM), and
human splenic B-lymphoblastoid cells (WIL-2NS),
human acute B-lymphoblastic leukaemia (CCRF-
SB), human skin melanoma (SK-MEL-28), human
breast adenocarcinoma (MCF-7), human lung squa-
mous carcinoma (SK-MES-1), human hepatocellu-
Scheme 3.
lar carcinoma (Hep-G2), human prostate carcinoma
(DU-145), human foreskin fibroblast (CRL7065), and
Compounds 9a – c, combining a benzothiazole, a
human lung fibroblast (MRC-5). The microculture
piperazinecarbonyl and a thiourea residue were also
tetrazolium assay (MTT) method [35] was used for
prepared. Thus, treatment of 2 with phenyl, 4-chloro-
estimation of the in vitro tumor-inhibiting activ-
or 4-methylphenylisothiocyanate afforded the thiourea
ity of the tested compounds. The cell lines of tu-
derivatives 9a – c in 61, 69, and 59 % yield, respec-
mor subpanels were incubated within five concen-
tively (Scheme 3). The assignment of proton and car-
trations (0.01 – 100 mmol L−1) of each tested com-
bon atoms of the benzothiazole and piperazine rings
pound for 48 h. For comparative purposes, we eval-
were deduced from comparison with those of 4a – k.
uated the cytotoxic activities of the compounds rel-
The CH2NS protons resonated together with the piper-
ative to Doxorubicin. The compounds were dis-
azine protons in the region δ = 3.49– 3.31 ppm as mul-
solved in DMSO at 100 mmol L−1 and then diluted
tiplets. In the 13C NMR spectra of 9a – c, the C=S car-
in culture.
bon signals appeared at higher field (δ = 181.3, 181.6,
All compounds were inactive except 4l which
and 180.0 ppm, respectively), while the resonances at
showed activity against human splenic B-lympho-
δ = 167.5, 167.9, and 167.7 ppm were assigned to
blastoid cells (WIL-2NS) and human acute B-lympho-
C2benzothiazol, respectively. CNpiperazine = O carbons ap-
blastic leukemia (CCRF-SB) cell lines with CC50 = 5.1
peared at δ = 164.3, 164.7, and 164.1 ppm, respec-
and 7.3 µM, respectively. Compound 9a exhibited ac-
tively, and C4benzothiazol carbons resonated at δ = 149.2,
tivity against CCRF-SB cell lines with CC50 = 2.3 µM.
149.0, and 149.1 ppm, respectively. The CH2NS car-
In conclusion, introduction of a thiourea residue in the
bon atoms appeared together with the piperazine car-
backbones of 9a generally enhanced the activity of the
bons in the region δ = 48.5 – 43.1 ppm. The signals of
benzothiazole derivatives in comparison to the activity
aromatic carbon atoms were assigned.
of other analogs 4a – l.
In vitro antiproliferative activity
In vitro anti-HIV assay
Compounds 4a – l and 9a were selected for the an-
Compounds 5 – 8a – i were evaluated for their in
tiproliferative activity screening and tested in vitro vitro anti-HIV activity by using the IIIB strain for
against a panel of tumor cell lines consisting of CD4 HIV-1 and the ROD strain for HIV-2 in human T-
human T-cells containing integrated leukaemia, human lymphocyte (MT-4) cells, and the results are sum-
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Y. A. Al-Soud et al. · New Derivatives of 2-Piperazino-1,3-benzo[d]thiazoles
Table 1. In vitro anti-HIV-1a and HIV-2b of some new ben-
1375
Experimental Section
General
zothiazole derivatives.
Compound
Virus
strain
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
EC50
(µgmL−1
> 95.98
> 95.98
> 74.58
> 74.58
> 53.38
> 53.38
> 62.45
> 62.45
> 55.50
> 55.50
> 58.55
> 58.55
> 31.85
> 31.85
> 60.65
> 60.65
> 113.75
> 113.75
> 57.28
> 57.28
> 19.87
> 19.87
0.050
CC50
(µg mL−1
95.98
SIe
c
d
)
)
Melting points are uncorrected and were measured on a
Bu¨chi melting point apparatus B-545 (Bu¨chi Labortechnik
AG, Switzerland). Microanalytical data were obtained with
a Euro Vector EA 3000 Elemental apparatus. NMR spectra
were recorded on 300 MHz (1H) spectrometers with TMS
as internal standard and on 75 MHz (13C) spectrometers
(Bruker, Germany) with TMS as internal standard and on the
δ scale in ppm. Mass spectra were recorded at 70 eV on EI
(Shimadzu QP5050A). Silica gel (0.040 – 0.063 mm) used
for column chromatography and analytical silica gel TLC
plates 60 F254 were purchased from Merck.
5
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
3.5
2.1
< 1
< 1
< 1
< 1
< 1
< 1
> 80
< 1
95.98
74.58
74.58
53.38
53.38
62.45
62.45
55.50
55.50
58.55
58.55
31.85
31.85
60.65
60.65
113.75
113.75
57.58
57.28
> 19.87
19.87
6
8a
8b
8c
8d
8e
8f
General procedure for the preparation of N-[2-(4-(benzothi-
azol-2-yl)piperazin-1-yl)-2-oxoethyl]benzamides 4a – l
8g
Method A. (Synthesis of 4a – c, l). To a cold solution of 2
(400 mg, 1.50 mmol) in dry MeCN (25 mL) was added the
appropriate carboxylic acid 3a – c, l (1.50 mmol) followed by
the addition of HOBt (1.50 mmol) and DCC (1.50 mmol).
8i
8h
◦
◦
Nevirapine
> 4.00
> 4.00
The mixture was stirred at 0 C for 1 h, at 5 C for 1 h,
and then at 23 ◦C for 16 h. The mixture was filtered to
remove DCU, and the filtrate was evaporated to dryness.
The residue was partitioned successively between EtOAc
and 5 % NaHCO3, 1 M HCl and water. The organic layer
was dried (Na2SO4), filtered and evaporate to dryness. The
residue was purified by thin-layer chromatography, using
CHCl3-MeOH (9 : 1) as eluent to give the desired product.
ROD
> 4.00
a Anti-HIV-1 activity measured with strain IIIB; b anti-HIV-2 activity
measured with strain ROD; compound concentration required to
c
achieve 50 % protection of MT-4 cells from the HIV-1 and 2-induced
d
cytopathogenic effect; compound concentration that reduces the
viability of mock-infected MT-4 cells by 50 %; e SI: selectivity index
(CC50/EC50).
marized in Table 1. Cytotoxicity induced by these
compounds was also measured in MT-4 cells paral-
lel with the antiviral activity. The results are sum-
marized in Table 1, in which the data for Nevirap-
ine (BOE/BIRG587) [36] are included for compari-
son purposes. None of the new benthiazoles derivatives
were found to inhibit HIV-1 and HIV-2 replication in
vitro at EC50 lower than the CC50 in comparison to
Nevirapine. In conclusion, the reported data showed no
selective anti-HIV activity.
Method B. (Synthesis of 4d – k). To a solution of 2
(400 mg, 1.50 mmol) in CHCl3 (50 mL) was added the ap-
propriate carboxylic chloride 3 (1.50 mmol) followed by a
◦
few drops of Et3N, and the mixture was stirred at 23 C
for 24 h. The mixture was partitioned with water (50 mL),
and the organic layer was dried (Na2SO4), filtered and evap-
orated to dryness. The residue was purified by TLC, using
CHCl3-MeOH (9 : 1) as eluent, to give the pure product.
N-[2-(4-(Benzothiazol-2-yl)piperazin-1-yl)-2-oxoethyl]-
benzamide (4a)
Conclusion
From 3a (183 mg). Yield: 52 mg (38 %), m. p. 215 –
◦
220 C (dec.), colorless powder. – 1H NMR (CDCl3): δ =
In summary, in vitro screening led to the identifi-
cation of N-[2-(4-benzothiazol-2-yl-piperazin-1-yl)-
2-oxoethyl]-3-(1-benzyl-2-ethyl-4-nitro-1H-imidazol-
5-ylthio)propanamide (4l) and 1-(2-(4-(benzothiaz-
ol-2-yl)piperazin-1-yl)-2-oxoethyl)-3-phenylthiourea
(9a) as new antitumor candidates, which are promis-
ing agents for further structural modification and
pharmacological evaluation.
7.91 – 7.12 (m, 10H, NH + Ar-H); 4.32 (s, 2H, CH2NH);
3.94 – 3.62 (m, 8H, piperazine-H). – 13C NMR (CDCl3): δ =
168.1 (C2benzothiazol); 167.2 (Carom. =O); 166.9 (CNpiperazine
=O); 151.0 (C4benzothiazol); 133.7, 131.7, 128.6, 128.6,
127.1, 126.6, 126.4, 122.5, 122.3, 120.9, 119.3, 119.1
(Carom.); 48.4, 48.1, 43.8, 41.7 (Cpiperazine); 41.3 (CH2NH). –
MS (EI): m/z = 380 [M]+. – C20H20N4OS: calcd. C 63.14,
H 5.30, N 14.73; found C 62.97, H 5.31, N 14.52.
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1376
Y. A. Al-Soud et al. · New Derivatives of 2-Piperazino-1,3-benzo[d]thiazoles
N-[2-(4-(Benzothiazol-2-yl)piperazin-1-yl)-2-oxoethyl]-4-
chloro-3-nitro-benzamide (4b)
48.4, 47.9 42.8, 42.6 (Cpiperazine); 41.5 (CH2NH). – MS (EI):
m/z = 424 [M]+. – C21H20N4O4S: calcd. C 59.42, H 4.75,
N 13.20; found C 59.23, H 4.72, N 13.56.
From 3b (302 mg). Yield: 115 mg (23 %), m. p. 189 –
193 ◦C (dec.), yellow powder. – 1H NMR ([D6]DMSO): δ =
8.10 (br s., 1H, NH); 8.58 – 6.94 (m, 7H, Ar-H); 4.36 (s,
2H, CH2NH); 3.73 – 3.41 (m, 8H, piperazine-H). – 13C NMR
([D6]DMSO): δ = 164.1 (C2benzothiazol); 162.7 (Carom. =O);
N-[2-(4-(Benzothiazol-2-yl)piperazin-1-yl)-2-oxoethyl]thio-
phen-2-carboxamide (4f)
From 3f (220 mg). Yield: 240 mg (78 %), m. p. 217 –
161.5 (CNpiperazine =O); 151.1 (C4benzothiazol); 146.7 (Carom.
-
◦
222 C (dec.), colorless powder. – 1H NMR (CDCl3): δ =
NO2); 134.3, 133.1, 130.1, 130.0, 129.9, 126.5, 121.7, 121.6,
119.5 (Carom.), 48.4, 47.9, 42.8, 42.2 (Cpiperazine); 41.9
(CH2NH). – MS (EI): m/z = 459 [M]+. – C20H18ClN5O4S:
calcd. C 52.23, H 3.94, N 15.23; found C 52.01, H 4.01,
N 15.56.
7.90 (br s, 1H, NH), 7.71 – 7.02 (m, 7H, Ar-H); 4.43 (s, 2H,
CH2NH); 3.90 – 3.51 (m, 8H, piperazine-H). – 13C NMR
(CDCl3): δ = 168.3 (C2benzothiazol); 165.2 (CNpiperazine
=O); 161.5 (Cthiophen =O); 152.1 (C4benzothiazol); 134.7,
133.4, 129.5, 128.0, 127.0, 126.5, 122.5, 121.0, 119.1
(Carom.+ Cthiophen); 48.6, 47.7, 44.2, 41.2 (Cpiperazine); 41.0
(CH2NH). – MS (EI): m/z = 386 [M]+. C18H18N4O2S2:
calcd. C 55.94, H 4.64, N 14.50; found C 56.21, H 4.80,
N 14.78.
N-[2-(4-(Benzothiazol-2-yl)piperazin-1-yl)-2-oxoethyl]-2-
chloroacetamide (4c)
From 3c (142 mg). Yield: 58 mg (32 %), m. p. 176 –
180 ◦C (dec.), yellow powder. – 1H NMR ([D6]DMSO):
δ 7.71 – 7.11 (m, NH +4H, Ar-H); 4.20 (s, 2H, CH2Cl);
3.94 (s, 2H, CH2NH); 3.92 – 3.60 (m, 8H, piperazine-H). –
13C NMR ([D6]DMSO): δ = 169.1 (C2benzothiazol); 166.2
N-[2-(4-(Benzothiazol-2-yl)piperazin-1-yl)-2-oxoethyl]-
furan-2-carboxamide (4g)
From 3g (196 mg). Yield: 110 mg (82 %), m. p. 275 –
(CCH Cl =O); 163.5 (CNpiperazine =O); 152.1 (C4benzothiazol);
◦
278 C (dec.), colorless powder. – 1H NMR (CDCl3): δ =
2
131.4, 129.3, 128.6, 122.5, 121.2, 119.8 (Carom.); 48.7, 46.9,
42.3, 41.9 (Cpiperazine); 41.1 (CH2NH); 40.5 (CH2Cl). – MS
(EI): m/z = 352 [M]+. – C15H17ClN4O2S: calcd. C 51.06,
H 4.86, N 15.88; found C 51.31, H 4.85, N 15.66.
7.61 – 6.40 (m, 8H, NH +Ar-H); 4.20 (s, 2H, CH2NH); 3.92 –
3.60 (m, 8H, piperazine-H). – 13C NMR (CDCl3): δ = 168.1
(C2benzothiazol); 166.8 (CNpiperazine =O); 158.2 (Cfuran =O);
147.6 (C4benzothiazol); 147.5, 144.5 (C2furan + C5furan); 126.5,
+
122.2, 121.1, 121.0, 119.5, 114.5, 112.1 (Carom. Cfuran);
N-[2-(4-(Benzothiazol-2-yl)piperazin-1-yl)-2-oxoethyl]-2-
ethoxybenzamide (4d)
48.4, 48.2, 43.8, 41.5 (Cpiperazine); 41.0 (CH2NH). – MS (EI):
m/z = 370 [M]+. – C18H18N4O3S: calcd. C 58.36, H 4.90,
N 15.12; found C 58.09, H 4.88, N 15.10.
From 3d (276 mg). Yield: 242 mg (57 %), m. p. 168 –
◦
171 C (dec.), colorless powder. – 1H NMR (CDCl3): δ =
N-[2-(4-(Benzothiazol-2-yl)piperazin-1-yl)-2-oxoethyl]-
pyrrolidin-1-carboxamide (4h)
9.11 (br s., 1H, NH); 8.20 – 6.92 (m, 8H, Ar-H); 4.35 (s, 2H,
CH2NH); 4.31 (q, J = 7.0 Hz , 2H, CH2O); 3.82 – 3.51 (m,
8H, piperazine-H); 1.60 (t, J = 7.6 Hz, 3H, CH3). – 13C NMR
(CDCl3): δ = 168.2 (C2benzothiazol); 167.2 (Carom. =O);
165.1 (CNpiperazine =O); 157.4 (C4benzothiazol); 135.1, 133.9,
133.1, 132.1, 126.4, 122.3, 121.1, 121.1, 119.3, 112.6, 112.2
(Carom.); 65.7 (CH2O); 49.1, 48.4, 43.9, 42.2 (Cpiperazine);
41.5 (CH2NH); 14.6 (CH3). – MS (EI): m/z = 424 [M]+. –
C22H24N4O3S: calcd. C 62.24, H 5.70, N 13.20; found
C 61.97, H 5.78, N 12.99.
From 3h (204 mg). Yield: 247 mg (90 %), m. p. 141 –
◦
144 C (dec.), colorless powder. – 1H NMR (CDCl3): δ =
7.72 – 7.10 (m, 4H, NH +Ar-H); 4.32 (s, 2H, CH2NH); 3.91 –
3.44 (m, 16H, piperazine-H + pyrrolidin-H). – 13C NMR
(CDCl3): δ = 170.5 (Cpyrrolidin =O); 168.2 (C2benzothiazol);
164.2 (CNpiperazine =O); 150.9 (C4benzothiazol); 129.9, 128.8,
128.6, 122.4, 120.9, 119.3 (Carom.); 59.9 (C2pyrrolidin);
48.6, 48.5, 47.9, 47.8 (Cpiperazine); 42.8 (C5pyrrolidin); 41.5,
(CH2NH); 31.9, 25.1 (C3
+ C4pyrrolidin). – MS (EI):
N-[2-(4-(Benzothiazol-2-yl)piperazin-1-yl)-2-oxoethyl]-
benzo[1,3]dioxole-5-carboxamide (4e)
pyrrolidin
m/z = 373 [M]+. – C18H23N5O2S: calcd. C 57.89, H 6.21,
N 18.75; found C 57.74, H 6.48, N 18.82.
From 3e (277 mg). Yield: 312 mg (74 %), m. p. 188 –
◦
192 C (dec.), colorless powder. – 1H NMR (CDCl3): δ =
N-[2-(4-(Benzothiazol-2-yl)piperazin-1-yl)-2-oxoethyl]-
piperidin-1-carboxamide (4i)
7.42 – 6.81 (m, NH +7H, Ar-H); 4.40 (s, 2H, CH2NH); 4.03 –
3.44 (m, 8H, piperazine-H). – 13C NMR (CDCl3): δ = 170.5
(C2benzothiazol); 168.1 (Carom. =O); 161.0 (CNpiperazine =O);
From 3i (221 mg). Yield: 278 mg (90 %), m. p. 119 –
◦
+ Carom.OCH2O); 130.8, 130.0, 126.5, 122 C (dec.), colorless powder. – 1H NMR (CDCl3): δ =
151.8 (C4
benzothiazol
125.9, 122.3, 120.9, 120.1, 119.1 (Carom.); 97.9 (OCH2O); 7.76 – 7.14 (m, 4H, Ar-H); 4.81 (br s, 1H, NH), 3.95 (s, 2H,
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Y. A. Al-Soud et al. · New Derivatives of 2-Piperazino-1,3-benzo[d]thiazoles
1377
CH2NH); 4.10 – 3.13 (m, 12H, piperazine-H + piperidin-H), (C2imidazol); 149.8, 148.3 (C4
+ C5imidazol); 134.0,
imidazol
1.63 (m, 6H, piperidin-H). – 13C NMR (CDCl3): δ = 167.0 128.3, 128.3, 127.2, 127.2, 126.2, 125.2, 125.1, 125.0,
(C2benzothiazol); 163.0 (CNpiperazine =O); 156.0 (Cpiperidin 123.5, 122.3, 120.1, 117.5 (Carom.); 47.8, 46.9, 42.9, 41.6
=O); 125.5, 121.9, 121.1, 120.0, 118.3, 117.5 (Carom.); 48.2, (Cpiperazine); 40.2 (CH2NH); 31.2 (PhCH2); 24.8, 23.9
48.0 46.6, 45.2, 41.5 (Cpiperazine + C2piperidin+ C6piperidin); (CH2CH2S); 20.3 (CH2CH3); 10.2 (CH2CH3). – MS (EI):
m/z = 593 [M]+. – C28H31N7O4S2: calcd. C 56.64, H 5.26,
41.0 (CH2NH); 24.7, 23.5, 23.5 (C3piperidin+ C4
+
piperidin
C5piperidin). – MS (EI): m/z = 387 [M]+. – C19H25N5O2S:
calcd. C 58.89, H 6.50, N 18.07; found C 58.70, H 6.75,
N 17.80.
N 16.51; found C 56.38, H 5.37, N 16.45.
Preparation of (4-benzothiazol-2-yl-piperazin-1-yl)acetic
acid hydrazide (6)
N-[2-(4-(Benzothiazol-2-yl)piperazin-1-yl)-2-oxoethyl]-
morpholin-4-carboxamide (4j)
A mixture of 5 (3.20 g, 10.0 mmol) and hydrazine hy-
drate (5.0 g, 10 mmol) in EtOH (25 mL) was heated under
reflux for 8 h. On cooling, the solid hydrazide 6 was col-
lected and◦recrystallized from EtOH (2.58 g, 84 %), m. p.
187 – 189 C (dec.), yellow powder. – 1H NMR (CDCl3):
δ = 8.21 (br s., 1H, NH); 7.63 – 7.10 (m, 4H); 4.49 (br
s., 2H, NH2); 3.18 (s, 2H, CH2C=O); 3.70 – 2.67 (m, 8H,
piperazine-H). – 13C NMR (CDCl3): δ = 169.9 (C=N);
168.5 (C=O); 152.5 (C-3a); 130.7, 126.1, 121.6, 120.9, 119.2
(Ar); 60.6 (CH2C=O); 52.9, 48.3 (Cpiperazine). – MS (FAB):
m/z = 307 [M+H]+. – C14H21N5OS: calcd. C 54.70, H 6.89,
N 22.78; found C 54.87, H 6.66, N 22.91.
From 3j (224 mg). Yield: 268 mg (85 %), m. p. 130 –
133 ◦C (dec.), colorless powder. – 1H NMR (CDCl3):
δ = 8.22 (br s, 1H, NH); 7.81 – 7.10 (m, 4H, Ar-H);
4.31 (s, 2H, CH2NH); 4.05 – 3.42 (m, 16H, piperazine-
H + morpholine-H). – 13C NMR (CDCl3): δ = 170.5
(C2benzothiazol); 168.2 (CNpiperazine =O); 156.8 (Cmorpholine
=O); 130.5, 128.8, 126.4, 122.4, 120.9, 119.5 (Carom.);
66.6 (C2
+ C6morpholin); 59.9, 48.4, 47.8, 42.8
morpholin
(C3morpholine+ C5morpholine+ Cpiperazine); 41.6 (CH2NH). –
MS (EI): m/z = 389 [M]+. – C18H23N5O3S: calcd. C 55.51,
H 5.95, N 17.98; found C 55.78, H 6.13, N 18.13.
General procedure for the preparation of 2-[4-(1,3-benzothi-
azol-2-yl)piperazin-1-yl]-Nꢀ-(arylsulfonyl)acetohydrazides
8a – i
N-[2-(4-(Benzothiazol-2-yl)piperazin-1-yl)-2-oxoethyl]-4-
methyl-piperazin-1-carboxamide (4k)
A solution of 6 (1.0 mmol) and arylsulfonyl chlorides 7
(1.0 mmol) in CHCl3 (50 m◦L) containing Et3N (0.1 mL,
1.0 mmol) was stirred at 23 C for 22 h. The solvent was
evaporated to dryness, and the residue was purified by thin
layer chromatography, using CHCl3-MeOH (15 : 1) as eluent
to give the desired product which was purified by recrystal-
lization from EtOH.
From 3k (243 mg). Yield: 283 mg (80 %), m. p. 194 –
197 ◦C (dec.), colorless powder. – 1H NMR (CDCl3):
δ = 7.72 – 7.11 (m, 4H, Ar-H); 4.82 (br s, 1H, NH);
4.30 (s, 2H, CH2C=O); 4.02 – 3.22 (m, 16H, piper-
azine-H); 2.61 (s, 3H, NCH3). – 13C NMR (CDCl3):
δ = 170.5 (C2benzothiazol); 168.2 (CNpiperazine =O); 156.8
(CMe−piperazine =O); 130.4, 128.8, 126.5, 122.2, 120.9,
119.4 (Carom.); 59.9 (C3
+ C5Me-piperazine);
Me-piperazine
2-[4-(1,3-Benzothiazol-2-yl)piperazin-1-yl]-Nꢀ-[(4-methyl-
phenyl)sulfonyl]acetohydrazide (8a)
48.5, 48.3, 47.9, 47.8, 42.9 (Cpiperazine + C2
+
Me-piperazine
C6Me-piperazine); 41.4 (CH2NH); 40.9 (NCH3). – MS (EI):
m/z = 402 [M]+. – C19H26N6O2S: calcd. C 56.69, H 6.51,
N 20.88; found C 56.77, H 6.58, N 20.83.
From 7a (0.19 g). Yield: 0.22 g (50 %), m. p. 234 – 236 ◦C
(dec.), colorless powder. – 1H NMR ([D6]DMSO): δ =
10.01 (br s., 2H, NH); 7.78 – 7.04 (m, 8H); 3.32 (s, 2H,
CH2C=O); 2.50 – 2.42 (m, 8H, piperazine-H); 2.35 (s, 3H,
CH3). – 13C NMR ([D6]DMSO): δ = 168.0 (C=N); 167.3
(C=O); 152.4 (C-3a); 143.3, 135.9, 130.4, 129.2, 127.8,
125.9, 121.2, 121.1, 118.5 (Ar); 59.1 (CH2C=O); 51.8, 47.2
(Cpiperazine); 21.0 (CH3). – MS (FAB): m/z = 446 [M+H]+. –
C20H23N5O3S2: calcd. C 53.91, H 5.20, N 15.72; found
C 54.10, H 5.16, N 15.75.
N-[2-(4-(Benzothiazol-2-yl)piperazin-1-yl)-2-oxoethyl]-
3-(1-benzyl-2-ethyl-4-nitro-1H-imidazol-5-ylthio)propan-
amide (4l)
From 3-(1-benzyl-2-ethyl-4-nitro-1H-imidazol-5-ylthio)
propanoic acid (3l) (503 mg). Yield: 248 mg (23 %),
m. p. 120 – 123 ◦C (dec.), colorless powder. – 1H NMR
([D6]DMSO): δ = 7.80 – 6.92 (m, 9H, Ar-H); 6.27 (br s., 1H,
NH); 5.42 (s, 2H, PhCH2); 4.11 (s, 2H, CH2NH); 3.91 – 3.60
(m, 8H, piperazine-H); 3.20 (m, 2H, CH2CH2S), 2.72 (q, 2H,
J = 7.1 Hz, CH2CH3), 2.55 (m, 2H, CH2CH2S), 1.31 (t, 3H,
2-[4-(1,3-Benzothiazol-2-yl)piperazin-1-yl]-Nꢀ-[(4-meth-
oxyphenyl)sulfonyl]acetohydrazide (8b)
CH2CH3). – 13C NMR ([D6]DMSO): δ = 169.1 (CCH CH S
From 7b (0.21 g). Yield: 0.18 g (39 %), m. p. 232 – 234 ◦C
=O); 167.0 (C2benzothiazol); 166.0 (CNpiperazine =O); 1562.8 (dec.), colorless powder. – 1H NMR ([D6]DMSO): δ = 9.99
2
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1378
Y. A. Al-Soud et al. · New Derivatives of 2-Piperazino-1,3-benzo[d]thiazoles
(br s., 2H, NH); 7.77 – 7.05 (m, 8H); 3.81 (s, 3H, OCH3); CH2C=O); 3.50 – 2.44 (m, 8H, piperazine-H). – 13C NMR
2.96 (s, 2H, CH2C=O); 2.58 – 2.43 (m, 8H, piperazine-H). – ([D6]DMSO): δ = 167.9 (C=N); 167.7 (C=O); 152.3 (C-3a);
13C NMR ([D6]DMSO): δ = 168.5 (C=N); 167.9 (C=O); 151.3, 143.0, 137.1, 136.4, 134.1, 131.0, 130.3, 128.5, 125.9,
163.2, 152.9 (C-3a); 130.9, 130.8, 130.6, 126.4, 121.7, 125.4, 122.53, 121.2, 121.1, 118.5 (Ar); 59.1 (CH2C=O);
121.6, 119.4, 114.5 (Ar); 59.2 (CH2C=O); 56.1 (OCH3); 51.4, 47.7 (Cpiperazine). – MS (FAB): m/z = 482 [M+H]+. –
51.8, 48.3 (Cpiperazine). – MS (FAB): m/z = 462 [M+H]+. – C22H22N6O3S2: calcd. C 54.75, H 4.60, N 17.41; found
C20H23N5O4S2: calcd. C 52.04, H 5.02, N 15.17; found C 55.03, H 4.84, N 17.45.
C 52.27, H 5.12, N 15.48.
2-[4-(1,3-Benzothiazol-2-yl)piperazin-1-yl]-Nꢀ-(2-thienyl-
sulfonyl)acetohydrazide (8g)
2-[4-(1,3-Benzothiazol-2-yl)piperazin-1-yl]-Nꢀ-[(4-chloro-
phenyl)sulfonyl]acetohydrazide (8c)
From 7g (0.18 g). Yield: 0.293 g (67 %), m. p. 222 –
From 7c (0.21 g). Yield: 0.19 g (41 %), m. p. 232 – 234 ◦C 224 C (dec.), colorless powder. – 1H NMR ([D6]DMSO):
(dec.), colorless powder. – 1H NMR ([D6]DMSO): δ = δ = 10.09 (br s., 2H, NH); 7.96 – 7.04 (m, 7H, Ar-H);
10.12 (br s., 2H, NHNH); 7.82 – 7.07 (m, 8H); 2.97 (s, 2H, 3.01 (s, 2H, CH2C=O); 3.56 – 2.50 (m, 8H, piperazine-H). –
CH2C=O); 3.53 – 2.45 (m, 8H, piperazine-H). – 13C NMR 13C NMR ([D6]DMSO): δ = 168.5 (C=N); 168.1 (C=O);
([D6]DMSO): δ = 168.5 (C=N); 168.1 (C=O); 152.9 (C-3a); 152.9 (C-3a); 139.6, 134.4, 133.8, 130.9, 128.0, 126.4, 121.7,
138.4, 138.3, 130.9, 130.2, 129.4, 126.4, 121.7, 121.6, 119.0 121.6, 119.0 (Ar); 59.2 (CH2C=O); 51.9, 48.4 (Cpiperazine). –
(Ar); 59.1 (CH2C=O); 51.9, 48.3 (Cpiperazine). – MS (FAB): MS (FAB): m/z = 437 [M+H]+. – C17H19N5O3S3: calcd.
m/z = 465/467 [M+H]+. – C19H20ClN5O3S2: calcd. C 48.97, C 46.66, H 4.38, N 16.01; found C 46.93, H 4.47, N 16.17.
H 4.33, N 15.03; found C 49.15, H 4.39, N 15.06.
◦
2-[4-(1,3-Benzothiazol-2-yl)piperazin-1-yl]-Nꢀ-[(3-bromo-
5-chloro-2-thienyl)sulfonyl] acetohydrazide (8h)
2-[4-(1,3-Benzothiazol-2-yl)piperazin-1-yl]-Nꢀ-[(2,5-di-
chlorophenyl)sulfonyl]acetohydrazide (7d)
From 7h (0.3 g). Yield: 0.31 g (56 %), m. p. 166 – 168 ◦C
From 7d (0.25 g). Yield: 0.45 g (90 %), m. p. 207 – 209 ◦C (dec.), colorless powder. – 1H NMR ([D6]DMSO): δ = 9.05
(dec.), colorless powder. – 1H NMR ([D6]DMSO): δ = 10.15 (br s., 2H, NH); 7.77 – 7.06 (m, 5H, Ar-H); 2.90 (s, 2H,
(br s., 2H, NH); 7.93 – 7.07 (m, 7H, Ar-H); 3.02 (s, 2H, CH2C=O); 3.59 – 2.52 (m, 8H, piperazine-H). – 13C NMR
CH2C=O); 3.54 – 2.50 (m, 8H, piperazine-H). – 13C NMR ([D6]DMSO): δ = 168.5 (C=N); 164.0 (C=O); 152.9 (C-
([D6]DMSO): δ = 168.6 (C=N), 168.5 (C=O); 152.9 (C-3a); 3a); 131.4, 130.9, 129.6, 126.4, 126.4, 121.7, 121.6, 119.1,
139.1, 134.5, 134.0, 132.0, 131.4, 130.9, 130.8, 126.4, 121.7, 119.0 (Ar); 60.8 (CH2C=O); 52.3, 48.5 (Cpiperazinee). – MS
121.6, 119.1 (Ar); 59.0 (CH2C=O); 51.8, 48.2 (Cpiperazine). – (FAB): m/z = 550/552 [M+H]+. – C17H17BrClN5O3S3:
MS (FAB): m/z = 500/502 [M+H]+. – C19H19Cl2N5O3S2: calcd. C 37.06, H 3.11, N 12.71; found C 37.26, H 3.27,
calcd. C 45.60, H 3.83, N 13.99; found C 45.80, H 4.05, N 12.96.
N 14.23.
2-[4-(1,3-Benzothiazol-2-yl)piperazin-1-yl]-Nꢀ-[(2,5-di-
chloro-3-thienyl)sulfonyl]aceto-hydrazide (8i)
2-[4-(1,3-Benzothiazol-2-yl)piperazin-1-yl]-Nꢀ-{[(3-tri-
fluoromethyl)phenyl]sulfonyl}acetohydrazide (8e)
From 7i (0.25 g). Yield: 0.45 g (89 %), m. p. 176 – 178 ◦C
From 7e (0.25 g). Yield: 0.48 g (96 %), m. p. 201 – 203 ◦C (dec.), colorless powder. – 1H NMR ([D6]DMSO): δ = 9.04
(dec.), colorless powder. – 1H NMR ([D6]DMSO): δ = (br s., 2H, NH); 7.79 – 7.06 (m, 5H, Ar-H); 3.35 (s, 2H,
10.21 (br s., 2H, NH); 8.12 – 7.04 (m, 8H); 2.96 (s, 2H, CH2C=O); 3.69 – 3.29 (m, 8H, piperazine-H). – 13C NMR
CH2C=O); 3.51 – 2.43 (m, 8H, piperazine-H). – 13C NMR ([D6]DMSO): δ = 168.5 (C=N); 164.2 (C=O); 152.9 (C-
([D6]DMSO): δ = 168.5 (C=N); 168.3 (C=O); 152.9 (C-3a); 3a); 144.9, 130.9, 129.2, 126.4, 126.4, 123.2, 121.7, 121.6,
140.8, 132.3, 130.9, 130.2, 129.7 (CF3), 126.4, 124.8, 121.7, 119.0 (Ar); 60.6 (CH2C=O); 52.2, 48.5 (Cpiperazine). – MS
121.6, 119.0 (Ar); 59.1 (CH2C=O); 51.8, 48.2 (Cpiperazine). – (FAB): m/z = 506/504 [M+H]+. – C17H17Cl2N5O3S3: calcd.
MS (FAB): m/z = 499 [M+H]+. – C20H20F3N5O3S2: calcd. C 40.32, H 3.38, N 13.83; found C 40.17, H 3.59, N 14.03.
C 48.09, H 4.04, N 14.02; found C 45.28, H 4.17, N 14.24.
General procedure for the preparation of 1-[2-(4-(benzothi-
azol-2-yl)piperazin-1-yl)-2-oxoethyl]-3-arylthioureas 9a – c
2-[4-(1,3-Benzothiazol-2-yl)piperazin-1-yl]-Nꢀ-[(quinolin-
8-yl)sulfonyl]acetohydrazide (8f)
To a stirred solution of 2 (400 mg, 1.50 mmol) in MeCN
From 7f (0.23 g). Yield: 0.23 g (47 %), m. p. 128 – 130 ◦C (15 mL) was added aryl isothiocyanate (1.63 mmol), and the
(dec.), colorless powder. – 1H NMR ([D6]DMSO): δ = 9.14 mixture was heated under reflux for 6 h. The precipitate was
(br s., 2H, NH); 8.56 – 7.04 (m, 10H, Ar-H); 2.98 (s, 2H, filtered and then washed with ether to give a crude product.
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Y. A. Al-Soud et al. · New Derivatives of 2-Piperazino-1,3-benzo[d]thiazoles
1379
This was purified by column chromatography (SiO2) using 1-[2-(4-(Benzothiazol-2-yl)piperazin-1-yl)-2-oxoethyl]-3-
CHCl3-MeOH (19 : 1) as eluent to give the desired thiourea (4-methylphenyl)-thiourea (9c)
derivatives.
From 4-methylphenyl isothiocyanate (238 mg). Yield:
0.41 g (59 %); m. p. 150 – 152 ◦C. – 1H NMR ([D6]DMSO):
1-[2-(4-(Benzothiazol-2-yl)piperazin-1-yl)-2-oxoethyl]-3-
phenylthiourea (9a)
δ = 8.20 – 6.38 (m, 8H, Ar-H); 3.41 – 3.31 (m, 10H, piper-
azine-H + CH2NS). – 13C NMR ([D6]DMSO): δ = 181.0
(C=S); 167.7 (C2benzothiazol); 164.1 (CN-piperazine = O);
149.1 (C4benzothiazol); 133.9, 130.1, 129.1, 126.2, 125.0,
From phenyl isothio◦cyanate (220 mg). Yield: 0.34 g
(61 %); m. p. 160 – 163 C. – 1H NMR ([D6]DMSO): δ =
7.89 – 6.41 (m, 9H, Ar-H); 4.52 (br s, 1H, NH); 3.49 –
3.36 (m, 10H, piperazine-H + CH2NS). – 13C NMR
([D6]DMSO): δ = 181.3 (C=S); 167.5 (C2benzothiazol);
164.3 (CN-piperazine =O); 149.2 (C4benzothiazol); 136.3, 128.6,
126.2, 125.2, 125.1, 125.0, 123.8, 121.8 (Carom.); 47.9, 47.5,
43.3, 43.1 (Cpiperazine + CH2NH). – MS (FAB): m/z = 372
[M+H]+. – C18H19N4OS2 : calcd. C 58.19, H 5.16, N 15.08;
found C 57.93, H 5.02, N 14.88.
123.2, 121.6 (Carom.); 48.1, 48.3, 44.2, 43.8 (Cpiperazine
+
CH2NH); 24.1 (Me-Ph). – MS (FAB): m/z = 426 [M+H]+. –
C21H23N5OS2: calcd. C 59.27, H 5.45, N 16.46; found
C 59.01, H 5.40, N 16.12.
Cytotoxicity assays
Cell cultures were seeded at 1×105 cells mL−1 in 96 mul-
tiwall plates in specific media supplemented (5 %) with
◦
10 % FCS and antibiotics, then incubated at 37 C in a hu-
midified CO2 atmosphere in the absence or presence of serial
dilutions of test ◦compounds. Cell viability was determined
after 96 h at 37 C by the 3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyl-tetrazolium bromide (MTT) method. Compounds
were dissolved in DMSO at 100 mM and then diluted into
the culture medium.
1-[2-(4-(Benzothiazol-2-yl)piperazin-1-yl)-2-oxoethyl]3-(4-
chlorophenyl)-thiourea (9b)
From 4-chlorophenyl isothiocyanate (276 mg). Yield:
0.44 g (61 %); m. p. 172 – 174 ◦C. – 1H NMR ([D6]DMSO):
δ
= 8.21 – 6.43 (m, 8H, Ar-H); 3.49 – 3.35 (m, 10H,
piperazine-H + CH2NS). – 13C NMR ([D6]DMSO): δ =
181.6 (C=S); 167.9 (C2benzothiazol); 164.7 (CN-piperazine =O);
149.0 (C4benzothiazol); 135.2, 129.1, 126.8, 125.3, 125.0,
124.8, 121.9 (Carom.); 48.4, 48.5, 44.1, 43.7 (Cpiperazine
+ CH2NH). – MS (FAB): m/z = 446/448 [M+H]+. –
C20H20ClN5OS2: calcd. C 53.86, H 4.52, N 15.70; found
C 53.67, H 4.39, N 15.41.
Acknowledgements
We thank Dr. G. Gosselin, Laboratoires Idenix Sarl, Mont-
pellier cedex 4 (France), for helping in the antitumor screen-
ing and Prof. C. Pannecouque, Rega Institute for Medical
Research, Katholieke Universiteit Leuven, Belgium, for the
anti-HIV screening.
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