Novel benzothiazole derivatives with a broad antifungal spectrum: Design, synthesis and structure-activity relationships

Article abstract of DOI:10.1039/c3md00215b

N-Myristoyltransferase (NMT) is a new target for the development of novel antifungal agents. The benzothiazole derivative FR1335 is a highly potent NMT inhibitor with fungicidal activity. However, FTR1335 was only active against Candida albicans and its a

Full text of DOI:10.1039/c3md00215b

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Novel benzothiazole derivatives with a broad
antifungal spectrum: design, synthesis and structure–
activity relationships†
Cite this: Med. Chem. Commun., 2013,
, 1551
4
Yang Liu, Yan Wang, Guoqiang Dong, Yongqiang Zhang, Shanchao Wu,
Zhenyuan Miao, Jianzhong Yao, Wannian Zhang* and Chunquan Sheng*
N-Myristoyltransferase (NMT) is a new target for the development of novel antifungal agents. The
benzothiazole derivative FR1335 is a highly potent NMT inhibitor with fungicidal activity. However,
FTR1335 was only active against Candida albicans and its antifungal spectrum and solubility remained
to be improved. Thus, a series of benzothiazole derivatives were designed and synthesized by modifying
the scaffold and side chain of FTR1335. Interestingly, the antifungal spectrum of the target compounds
was significantly expanded and also new structure–activity relationship information was obtained.
Particularly, compound 6m showed good inhibitory activity against a wide range of fungal pathogens
including systemic fungus and dermatophytes. Its antifungal activity against Cryptococcus neoformans
and Candida glabrata was higher than that of fluconazole. Moreover, compound 6m also exhibited in
vivo antifungal activity in a Caenorhabditis elegans-Candida albicans infection model, which represents a
promising lead for further optimization.
Received 30th July 2013
Accepted 17th September 2013
DOI: 10.1039/c3md00215b
www.rsc.org/medchemcomm
a critical need to develop novel antifungal compounds that have
broad-spectrum activity, new mechanisms of action, and no
Introduction
Recently, the incidence of invasive fungal infections and asso- cross-resistance to the currently available antifungal drugs.
1,2
ciated mortality has been increasing dramatically. Clinically,
Myristoyl-CoA: protein N-myristoyltransferase (NMT) is a
Candida albicans (mortality rate: 20–40%), Cryptococcus neofor- new target enzyme for the development of novel fungicidal
mans (mortality rate: 20–70%), and Aspergillus fumigatus drugs, which catalyzes the transfer of the myristoyl group from
(
mortality rate: 50–90%) have been identied as three major
myristoyl CoA to the N-terminal glycine of a number of
3–5
12–14
causes of invasive fungal infections. There are four classes of
antifungal agents, namely polyenes (amphotericin B), 5-uo-
rocytosine, azoles (e.g. uconazole, itraconazole and vor- benzoheterocyclic inhibitors (Fig. 1), such as benzofuran,
iconazole), and echinocandins (e.g. caspofungin and benzothiazole
micafungin), that can be used for the treatment of systemic to possess potent antifungal activities. Particularly, the benzo-
infections. However, these antifungal agents have achieved thiazole NMT inhibitor FTR1335 showed good enzyme inhibi-
limited success in terms of severe resistance, limited efficacy tory activity and potent fungicidal activity with good selectivity.
eukaryotic cellular and viral proteins.
of NMT inhibitors have been reported. Among them, only the
Up To date, a number
6
12
15–19
7
19,20
21
and benzoxazole inhibitors, were reported
8
and spectrum, drug related toxicity, non-optimal pharmacoki-
netics, and serious drug–drug interactions. For example,
It represents a promising lead for the development of novel
antifungal agents. However, FTR1335 is only active against
Candida albicans and Candida tropicalis and its antifungal
9
amphotericin B has signicant nephrotoxicity and many other
9
side effects. Severe resistance to azoles is increasingly being spectrum remains to be expanded. Moreover, the structure–
10
reported. Echinocandins cannot be orally administrated and activity relationship (SAR) of FTR1335 also needs to be further
11
are not active against Cryptococcus neoformans. Hence, there is investigated. Continuing our efforts on the discovery of novel
21–23
NMT inhibitors,
herein the SAR of FTR1335 was extended by
modifying its benzothiazole scaffold and the terminal naphthyl
School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai group. Several target compounds showed a broader antifungal
2
00433, People's Republic of China. E-mail: zhangwnk@hotmail.com; shengcq@
spectrum and better solubility than FTR1335. In particular,
compound 6m had potent in vitro and in vivo antifungal activity,
which presents a promising lead for the development of novel
antifungal agents.
hotmail.com; Fax: +86-21-81870243; +86-21-81871233; Tel: +86-21-81870243; +86-
2
†
1
1-81871233
Electronic supplementary information (ESI) available. See DOI:
0.1039/c3md00215b
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Fig. 1 Representative structures of small-molecule NMT inhibitors.
presence of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (EDC$HCl) and 4-dimethylamiopryidine (DMAP)
in CH Cl to give compound 2a. Aer the reduction of the nitro
2 2
Results and discussion
Chemistry
The synthetic procedure of benzothiazole and benzoxazole group by SnCl in ethanol, compound 3a reacted with cis-3-(tert-
2
derivatives is shown in Scheme 1. 2-Amino-6-nitrobenzothiazole butoxycarbonylamino)-cyclohexane-carboxylic acid in the pres-
(
1a) was treated with cyclopentanecarboxylic acid in the ence of EDC$HCl and N-hydroxybenzotriazole (HOBt) in CH Cl2
2
Scheme 1 Reagents and conditions: (a). Cyclopentanecarboxylic acid, EDC$HCl, DMAP, CH
tert-butoxycarbonylamino)-cyclohexanecarboxylic acid, CH Cl , rt, 18 h; (d). TFA, CH Cl , rt, 1h; (e). NaBH
aldehyde, MeOH, rt 12 h.
2
Cl
2
, rt, 16 h; (b). SnCl
2 2
$2H O, EtOH, reflux, 2 h; (c). EDC$HCl, HOBt, cis-3-
(
2
2
2
2
3
CN, substituted naphthaldehyde or quinoline carbox-
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to afford compound 4a, which was subsequently transformed to compound 10. The subsequent reactions for the synthesis of the
compound 5a by removing its Boc group. Finally, target target compounds 13a–e were similar to those in Scheme 1. As
compounds 6a–o were obtained by reductive amination of shown in Scheme 3, the phenylthiazole derivative 20 was also
compound 5a with different kinds of naphthaldehyde or quin- synthesized by a similar procedure. The phenylthiazole scaffold
0
oline carboxaldehyde in the presence of NaBH
3
CN in methanol. 15 was obtained by reacting 2-bromo-4 -nitroacetophenone (14)
Compounds 6p–q were prepared by a similar procedure to that with thiourea in the presence of sodium acetate in EtOH.
described above using 2-amino-6-nitrobenzoxazole (1b) as the
starting material. The benzothiazole derivatives with reversed Design rationale
side chains (13a–e) were synthesized according to the route
outlined in Scheme 2. The amino group of 1a was rst protected
Previously, Kazuo and co-workers reported a highly potent
benzothiazole inhibitor FTR1335 and its racemate 6a having the
by (Boc) O to give compound 7. Aer reducing its nitro group,
2
19
same antifungal activity. However, the SARs about its scaffold
compound 8 was condensed with cyclopentanecarboxylic acid
to give intermediate 9, which was deprotected to afford
and the side chain naphthyl group have not been investigated in
detail. The present study designed three kinds of modications
Scheme 2 Reagents and conditions: (a). Di-tert-butyl dicarbamate, DMAP, Et
EDC$HCl, DMAP, CH Cl , rt, 12 h; (d). TFA, CH Cl , rt, 1 h; (e). cis-3-(tert-butoxycarbonylamino)-cyclohexanecarboxylic acid, EDC$HCl, HOBt, CH
CH Cl , rt, 1 h; (g). NaBH CN, naphthaldehyde or quinoline carboxaldehyde, rt, 12 h.
3
N, CH
2
Cl
2
, rt, 8 h; (b). SnCl
2
$2H
2
O, EtOH, reflux, 3 h; (c). Cyclopentanecarboxylic acid,
2
2
2
2
2
Cl , rt, 12 h; (f). TFA,
2
2
2
3
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Scheme 3 Reagents and conditions: (a). thiourea, sodium acetate, EtOH, reflux, 7 h; (b). cyclopentanecarboxylic acid, EDC$HCl, DMAP, CH
2
Cl
2
, rt, 15 h; (c). SnCl
2 2
$2H O,
EtOH, reflux, 2 h; (d). EDC$HCl, HOBt, cis-3-(tert-butoxycarbonylamino)-cyclohexanecarboxylic acid, CH
2
Cl
2
, rt, 12 h; (e) TFA, CH
2
Cl
2
, rt, 2 h; (f) NaBH
3
CN, 2-naph-
thaldehyde, rt, 10 h.
to extend the SAR of FTR1335. The racemate 6a was used as the 20 showed excellent activity against M. gypseum (MIC ¼ 0.125 mg
ꢀ1
lead compound. First, the 2-naphthyl group of 6a was replaced mL ), which was signicantly more potent than uconazole
ꢀ
1
by various substituted naphthyl groups or quinolines (MIC ¼ 32 mg mL ). The activity of compound 6m against T.
ꢀ
1
(
compounds 6a–o). Second, the C2 and C6 side chains of rubrum (MIC ¼ 4 mg mL ) is comparable to that of uconazole.
compound 6a was interchanged (compound 20). Third, the
benzothiazole scaffold was replaced by benzoxazole
(
compounds 6p and 6q) and phenylthiazole (compounds 13a–e) Table 1 Antifungal in vitro activity of the compounds (MIC80, mg mLꢀ
1 a
)
to nd out whether the benzothiazole scaffold was necessary for
the antifungal activity.
Compds
C. alb.
C. par.
C. gla.
C. neo.
T. rub.
M. gyp.
6
6
6
6
6
6
6
a
b
c
d
e
f
4
>64
>64
>64
>64
>64
>64
>64
8
>64
32
>64
4
>64
>64
>64
>64
>64
>64
>64
>64
8
>64
>64
>64
4
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
4
>64
>64
>64
4
>64
>64
>64
>64
32
>64
>64
16
>64
64
>64
>64
64
>64
64
>64
8
>64
>64
>64
4
>64
>64
>64
>64
32
>64
>64
>64
>64
32
>64
64
>64
>64
64
>64
64
>64
>64
>64
64
In vitro antifungal activity
In vitro antifungal activity of the synthesized compounds is
listed in Table 1. Compound 6a (racemate of FTR1335) and

uconazole were used as reference drugs. C. albicans ranks the
g
fourth cause of bacterial/fungal nosocomial infectious diseases. 6h
ꢀ
1
ꢀ1
Compound 6i (MIC ¼ 8 mg mL ), 6k (MIC ¼ 32 mg mL ), 6m 6i
ꢀ
1
ꢀ1
6j
6k
6
6
(
MIC ¼ 4 mg mL ), 6n (MIC ¼ 16 mg mL ) and 13a (MIC ¼ 8 mg
ꢀ1
mL ) showed potent inhibitory activity against C. albicans.
Among them, compound 6m showed the same activity as the
l
m
16
0.125
>64
>64
>64
1
1
32
64
64
>64
32
0.125
32
lead compound 6a. Interestingly, several designed compounds, 6n
such as 6i, 6m, 6n, and 13a, showed broad-spectrum inhibitory 6o
16
64
>64
>64
>64
>64
16
>64
>64
16
>64
>64
>64
8
>64
>64
>64
>64
>64
0.5
>64
>64
>64
>64
>64
>64
>64
>64
>64
2
6
6
1
1
p
q
3a
3b
activity against most of the tested fungal pathogens, whereas
compound 6a was only active against C. albicans. Compound
6m also showed good activity toward other Candida species.
Particularly, its activity against C. glabrata (MIC ¼ 0.125 mg 13c
ꢀ1
ꢀ1
mL ) was higher than that of uconazole (MIC ¼ 2 mg mL ). 13d
1
2
FLZ
3e
0
>64
>64
2
>64
>64
16
C. neoformans is the leading cause for cryptococcal meningitis,
which kills more than 650 000 people per year world-wide. Two
compounds, 6i and 6m, showed a MIC value of 4 mg mL
4
ꢀ1
,
a
ꢀ
1
Abbreviations: C. alb. - Candida albicans; C. par. - Candida parapsilosis;
C. gla. - Candida glabrata; C. neo. - Cryptococcus neoformans; A. fum. -
which was more potent than uconazole (MIC ¼ 16 mg mL ).
Moreover, several compounds were also active against derma-
Aspergillus fumigatus; T. rub.
- Trichophyton rubrum; M. gyp. -
tophytes (T. rubrum and M. gypseum). For example, compound Microsporum gypseum; FLZ - Fluconazole.
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Among the synthesized compounds, compound 6m showed In vivo antifungal activity by C. elegans–Candida-killing assay
good antifungal activity with a broad spectrum, which was
worthy of further optimization.
Since C. elegans–Candida compound screening assay was
proven to be a facile in vivo model for antifungal drug
24
discovery, we used this assay to evaluate the in vivo potency of
compound 6m with uconazole as the positive control.
Compound 6m exhibited signicant antifungal activity in vivo
in the C. elegans–Candida infection model (P < 0.002, Fig. 2).
More specically, 60% nematodes survived at the end of our
Structure–activity relationships
According to the in vitro antifungal activity data, preliminary
SARs of the synthesized compounds were obtained. Compared
with compound 6a, the replacement of its 2-naphthyl group
with other naphthyl or quinoline groups resulted in different
effects on the antifungal activity and antifungal spectrum. The
ꢀ
1
observation time (144 hours) with 16 mg mL compound 6m
ꢀ
1
treatment, showing a similar antifungal activity of 32 mg mL
uconazole.

2-naphthyl group was found to be important for the antifungal
activity. Introducing substitutions on the 2-naphthyl group
(
(
compounds 6b and 6c) or replacing it by 1-naphthyl groups
compounds 6d–g) led to the loss of the antifungal activity.
Conclusion
In conclusion, SAR of the benzothiazole NMT inhibitor
FTR1335 was extended by modifying its scaffold and C6-side
chain naphthyl group. As compared with the lead compound,
the antifungal spectrum was signicantly improved for the
designed compounds. The replacement of the naphthyl group
of FTR1335 by the 3-quinoline or 6-quinoline group was positive
for the solubility, antifungal activity and spectrum. The
While the 2-naphthyl group was replaced by various quinoline
groups, the antifungal spectrum was signicantly expanded for
the 3-quinoline derivative (compound 6i) and 6-quinoline
derivative (compound 6m). Particularly, the 6-quinoline group
was observed to be the most favorable substitution for the
antifungal activity and spectrum. Reducing the 3-quinoline or
6
(
-quinoline groups to the tetrahydroquinoline group
compound 6k and 6n) led to the decreased antifungal activity.
In contrast, the 2-quinoline (compound 6h), 4-quinoline
compound 6l) and 8-quinoline (compound 6n) derivatives were
6-quinoline derivative 6m showed good antifungal activity with
a broad spectrum and exhibited signicant in vivo antifungal
activity in the C. elegans–Candida infection model, which
represents a promising lead structure for the development of
novel antifungal agents.
(
totally inactive, indicating that the linking site of the quinoline
group was important for the antifungal activity. In comparison
with the benzothiazole compounds (6a and 6h), the activity of
the corresponding benzoxazole derivatives (6p and 6q) was lost
toward most of the tested fungal pathogens. For the compounds
with reversed side chains, different SAR was observed. The
Experimental protocols
In vitro antifungal activity assay
In vitro antifungal activity was measured by means of the
minimum inhibitory concentration (MIC) that achieved 80%
inhibition of the tested fungi using the serial dilution method
in 96-well microtest plates. Fluconazole and FTR1335 race-
2
-naphthyl derivative 13a exhibits higher inhibitory activity and
broader antifungal spectrum than other quinoline derivatives
13b–e). As compared with the lead compound 6a, compound
3a showed decreased activity against C. albicans, but its anti-
(
1
19
mate were used as the reference drugs. Test fungal strains
were obtained from the ATCC or were clinical isolates. The MIC
determination was performed according to the National
Committee for Clinical Laboratory Standards (NCCLS) recom-
mendations with RPMI 1640 (Sigma) buffered with
fungal spectrum was signicantly expanded (Table 1). When the
benzothiazole scaffold was changed to phenylthiazole
(compound 20), the antifungal activity was lost for C. albicans.
In contrast, compound 20 showed improved activity toward
dermatophytes.
0.165MMOPS (Sigma) as the test medium. Test compounds
were dissolved in DMSO serially diluted in growth medium. The
ꢁ
ꢁ
yeasts were incubated at 35 C and the dermatophytes at 28 C.
The growth MIC was determined at 24 h for Candida species
and at 72 h for C. neoformans.
In vivo antifungal activity assay
In vivo antifungal activity was measured using the nematode
Caenorhabditis elegans-Candida-killing assay which was
24
described by J. Breger et al. Freshly grown C. albicans SC5314
cells were inoculated into 2 mL of YPD broth and allowed to
ꢁ
grow overnight at 30 C. The following day, 100 ml of yeast was
spread into a square lawn on a 10 cm plate containing BHI agar
ꢀ
1
and kanamycin (45 mg mL ), followed by incubation for
Fig. 2 Compound 6m protected C. elegans from C. albicans infection. Survival
over 144 hours (n ¼ 30 worms per compound). Compared to the infection
ꢁ
approximately 20 h at 30 C. Synchronized adult C. elegans glp-4
and sek-1 nematodes grown at 25 C were carefully collected and
washed using sterile M9 buffer. Approximately 400 to 500
ꢁ
ꢀ1
without treatment, 16 mg mL compound 6m protected the nematodes from
fungal infection (P < 0.002).
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washed worms were then added to the center of the C. albicans (50 mL) at room temperature was added EDC$HCl (5.75 g, 0.03
ꢁ
lawns. The plates were incubated at 25 C for 4 h. Worms were mol) and DMAP (0.40 g, 2 mmol). The mixture was stirred at
then carefully washed into a 15 mL conical tube using 6 mL of room temperature for 16 h, then washed with 5% aqueous HCl
sterile M9. Worms were washed four times with sterile M9. (3 ꢃ 30 mL), 5% aqueous NaHCO (30 mL), and brine (30 mL),
3
2 4
Thirty worms were then pipetted into a single well of a 12-well dried with anhydrous Na SO . Purication by ash chroma-
tissue culture plate (Corning Inc.) containing 2 mL of liquid tography (n-hexane–ethyl acetate, 10 : 1) afforded 5.66 g of 2a as
ꢀ1
1
3
medium (80% M9, 20% BHI, and 45 mg mL kanamycin). Each a light yellow solid, yield: 97%. H-NMR (300 MHz, CDCl )
compound was added to a single well to test its antifungal d: 9.15 (br s, 1H), 8.76 (d, 1H, J ¼ 2.4 Hz), 8.34 (dd, 1H, J ¼ 9.0,
ꢁ
activity. The plates were incubated at 25 C and then examined 2.4 Hz), 7.82 (d, 1H, J ¼ 9.0 Hz), 2.80–2.96 (m, 1H), 1.90–2.11
at 24 h intervals for survival. Worms were considered dead and (m, 2H), 1.54–1.90 (m, 6H). ESI-MS (m/z): 290 [M ꢀ 1].
removed when they did not respond to being touched. Two
controls were used in the plate. The positive control was the
antifungal uconazole. Phosphate-buffered saline (PBS) was the
negative control. C. elegans survival was examined by using
the Kaplan–Meier method and differences were determined by
using the log-rank test (STATA 6; STATA, College Station, TX). A
P value of <0.05 was considered statistically signicant.
N-(6-nitrobenzoxazole-2-yl)cyclopentanecarboxamide (2b)
Titled compound 2b was prepared in a similar manner to that
described for 2a.
1
A yellow solid, yield: 84%. H-NMR (600 MHz, CDCl
3
) d: 9.51
(
7
1
br s, 1H), 8.39 (d, 1H, J ¼ 2.2 Hz), 8.32 (dd, 1H, J ¼ 8.7, 2.2 Hz),
.68 (d, 1H, J ¼ 8.7 Hz), 3.15–3.32 (m, 1H), 1.92–2.11 (m, 4H),
.77–1.88 (m, 2H), 1.62–1.75 (m, 2H). ESI-MS (m/z): 274 [M ꢀ 1].
Chemistry
All reagents and solvents were purchased from commercial
suppliers and used as received unless otherwise stated. Melting
points (mp) were determined by using a microscope melting-
point apparatus with an aromatic temperature control system
N-(6-aminobenzothiazol-2-yl)cyclopentanecarboxamide (3a)
A mixture of 2a (1.00 g, 3.4 mmol), SnCl $2H O (2.30 g, 10.2
mmol), and 50 mL of EtOH was stirred and reuxed for 2 h. The
solution was evaporated to near dryness. 5% aqueous NaOH (50
mL) and 100 mL EtOAc were added and the mixture was shaken.
The aqueous phase was extracted twice with the same EtOAc
2
2
1
13
(
XT4A). H NMR and C NMR spectra were recorded on a
Bruker 300 or 600 spectrometer with TMS as an internal stan-
dard and CDCl , CD OD or d -DMSO as the solvent. Chemical
3
3
6
shis (d values) and coupling constants (J values) are given in
ppm and Hz, respectively. ESI mass spectra were recorded on an
API-3000 LC-MS spectrometer. High-resolution mass spectros-
copy measurements were performed on a Kratos-concep mass
spectrometer under electron impact ionization (EI) conditions.
Elemental analyses were performed with a MOD-1106 instru-
ment and were consistent with theoretical values within ꢂ0.4%.
TLC analysis was carried out on silica gel plates GF254 (Qindao
Haiyang Chemical, China). Flash column chromatography was
carried out on a silica gel 300–400 mesh (Qindao Haiyang
(
100 mL). The organic phase was washed with brine, dried with
anhydrous Na SO , and evaporated. The residue was recrystal-
lized in EtOAc (20 mL) to give the 0.45 g of 3a as a colorless
2
4
1
6
solid, yield: 51%. H-NMR (300 MHz, DMSO-d ) d: 11.97 (s, 1H),
7
1
1
.37 (d, 1H, J ¼ 8.5 Hz), 6.97 (d, 1H, J ¼ 1.5), 6.68 (dd, 1H, J ¼ 8.5,
.5 Hz), 5.14 (s, 2H), 2.83–2.97 (m, 1H), 1.78–1.95 (m, 2H), 1.45–
.95 (m, 6H). ESI-MS (m/z): 262 [M + 1].
N-(6-aminobenzoxazole-2-yl)cyclopentanecarboxamide (3b)
Chemical, China). Commercial solvents were used without any Titled compound 3b was prepared in a similar manner to that
pretreatment.
described for 3a.
A colorless solid, yield: 60%. H-NMR (600 MHz, DMSO-d
11.16 (s, 1H), 7.19 (d, 1H, J ¼ 8.4 Hz), 6.71 (d, 1H, J ¼ 2.0), 6.55
1
6
) d:
2-Amino-6-nitrobenzoxazole (1b)
(
1
2
dd, 1H, J ¼ 8.4, 2.0 Hz), 5.17 (s, 2H), 2.81–3.00 (m, 1H), 1.81–
To a solution of 2-amino-5-nitrophenol (3.08 g, 0.02 mol) in
tetrahydrofuran (20 mL) was added cyanogen bromide (2.33 g,
.94 (m, 2H), 1.61–1.77 (m, 4H), 1.50–1.61 (m, 2H). ESI-MS (m/z):
46 [M + 1].
0.022 mol) in tetrahydrofuran (5 mL). The mixture was stirred at
room temperature for 1 day, then water (5 mL) was added to
dissolve the precipitate. Aer stirring for another 3 days at room tert-Butyl N-cis-3-[(2-[(cyclopentanylcarbonyl)aminol]-
temperature, water (10 mL) was added and then NaOH was benzothiazol-6-yl amino) carbonyl]cyclohexyl carbamate (4a)
added to make the mixture basic. Aer removing the THF in
vacuo, a precipitate was separated by ltration, and recrystal-
To a solution of 3a (1.00 g, 3.83 mmol) and cis-3-(tert-butoxy-
carbonylamino)-cyclohexanecarboxylic acid (0.93 g, 3.83 mmol)
lized from methanol (50 mL) to give compound 1b (2.80 g) as a
2 2
in CH Cl (25 mL) at room temperature was added EDC$HCl
1
brown solid, yield: 52%. H-NMR (600 MHz, DMSO-d ) d: 8.23
6
(1.10 g, 5.75 mmol) and HOBt (0.78 g, 5.75 mmol). The mixture
(
s, 1H), 8.21 (s, 2H), 8.08 (d, 1H, J ¼ 8.7), 7.30 (d, 1H, J ¼ 8.7 Hz).
was stirred at room temperature for 18 h, and the white
precipitate formed was ltered. The resulting solid was washed
with CH Cl to give the 0.91 g of 4a as a white solid, yield: 54%.
ESI-MS (m/z): 178 [M ꢀ 1].
2
2
N-(6-nitrobenzothiazol-2-yl)cyclopentanecarboxamide (2a)
1
H-NMR (300 MHz, DMSO-d ) d: 12.45 (s, 1H), 10.21 (s, 1H), 8.50
6
To a solution of 2-amino-6-nitrobenzothiazole (4.00 g, 0.02 mol) (d, 1H, J ¼ 1.8 Hz), 7.83 (d, 1H, J ¼ 8.7 Hz), 7.68 (dd, 1H, J ¼ 8.7,
and cyclopentane-carboxylic acid (2.28 g, 0.02 mol) in CH
2
Cl
2
1.8 Hz), 7.04 (s, 1H), 3.07–3.22 (m, 1H), 2.72–2.81 (m, 1H),
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2.55–2.66 (m, 1H), 1.67–2.17 (m, 12H), 1.57 (s, 9H), 1.20–1.53 Anal. calcd for C31
H
34
N
4
O
2
S: C, 70.69; H, 6.51; N, 10.64. Found:
(m, 4H). ESI-MS (m/z): 485 [M ꢀ 1]. C, 70.68; H, 6.49; N, 10.62.
tert-Butyl N-cis-3-[(2-[(cyclopentanylcarbonyl)aminol]-
cis-N-{2-[(Cyclopentanecarbony)aminol]-benzothiazol-6-yl}-3-[(1-
benzoxazole-6-yl amino) carbonyl]cyclohexyl carbamate (4b)
bromo-2-naphthylmethyl) amino]cyclohexanecarboxamide (6b)
Titled compound 4b was prepared in a similar manner to that Titled compound 6b–o was prepared in a similar manner to that
described for 4a.
described for 6a.
A light-brown solid, yield: 52%. H-NMR (300 MHz, DMSO-d )
A white solid, yield: 34%, mp: 172–177 C. H-NMR (300
d: 11.48 (s, 1H), 10.05 (s, 1H), 8.04 (d, 1H, J ¼ 1.7 Hz), 7.44 (d, 1H, MHz, DMSO-d ) d: 12.26 (s, 1H), 10.08 (s, 1H), 8.32 (s, 1H), 8.25
J ¼ 8.5 Hz), 7.68 (dd, 1H, J ¼ 8.5, 1.7 Hz), 6.79 (s, 1H), 2.91–3.01 (d, 1H, J ¼ 8.3 Hz), 7.95–8.12 (m, 3H), 7.59–7.80 (m, 4H), 7.50 (d,
1
ꢁ
1
6
6
(
1
m, 1H), 2.63–2.73 (m, 1H), 2.34–2.43 (m, 1H), 1.48–1.97 (m, 1H, J ¼ 8.7 Hz), 4.38 (s, 2H), 2.87–3.00 (m, 1H), 2.38–2.46 (m,
2H), 1.36 (s, 9H), 1.01–1.34 (m, 4H). ESI-MS (m/z): 469 [M ꢀ 1]. 1H), 2.06–2.32(m, 2H), 1.14–2.06 (m, 15H). ESI-MS (m/z): 606 [M
+
1]. Anal. calcd for C H BrN O S: C, 61.48; H, 5.49; N, 9.25.
3
1
33
4 2
Found: C, 61.41; H, 5.51; N, 9.30.
cis-3-Amino-N-[2-(cyclopentanecarbonyl)-amino]-
benzothiazol-6-ylcyclo hexanecarboxamide (5a)
cis-N-{2-[(Cyclopentanecarbony)aminol]-benzothiazol-6-yl}-3-
(6-methoxy -2-naphthylmethyl) amino]
cyclohexanecarboxamide (6c)
A light-yellow solid, yield: 46%, mp: 156–160 C. H-NMR (600
MHz, DMSO-d
To a suspension of 4a (0.35 g, 0.72 mmol) in CH
added TFA (3 mL). The mixture was stirred at room temperature
for 1 h, then evaporated to dryness. 5% aqueous Na CO (30 mL)
and EtOAc (50 mL) were added and the mixture was shaken. The
aqueous phase was extracted twice with the same EtOAc (20 mL).
The organic phase was washed with brine, dried with anhydrous
2 2
Cl (3 mL) was
[
2
3
ꢁ
1
6
) d: 12.24 (br s, 1H), 10.07 (s, 1H), 8.32 (d, 1H, J ¼
.9 Hz), 7.91 (s, 1H), 7.82–7.89 (m, 2H), 7.65 (d, 1H, J ¼ 8.7 Hz),
.56 (d, 1H, J ¼ 8.5 Hz), 7.50 (dd, 1H, J ¼ 8.7, 1.9 Hz), 7.34 (d, 1H,
1
7
Na
2 4
SO , and evaporated to give 5a (0.27 g) as a colorless solid,
1
J ¼ 2.2 Hz), 7.18–7.23 (dd, 1H, J ¼ 8.9, 2.5 Hz), 4.21 (s, 2H), 3.88
s, 3H), 2.93–2.99 (m, 1H), 2.41–2.49 (m, 1H), 2.08–2.30(m, 2H),
.18–1.98 (m, 15H). ESI-MS (m/z): 557 [M + 1]. Anal. calcd for
C H N O S: C, 69.04; H, 6.52; N, 10.06. Found: C, 69.00; H,
yield: 92%. H-NMR (300 MHz, DMSO-d
6
) d: 10.08 (s, 1H), 8.41
s, 1H), 7.73 (d, 1H, J ¼ 8.7 Hz), 7.62 (d, 1H, J ¼ 8.7 Hz), 4.58–5.52
br s, 2H), 2.99–3.16 (m, 1H), 2.43–2.69 (m, 2H), 1.60–2.16(m,
2H), 0.99–1.60 (m, 4H). ESI-MS (m/z): 385 [M ꢀ 1].
(
1
(
(
1
32 36 4 3
6.54; N, 10.10.
cis-3-Amino-N-[2-(cyclopentanecarbonyl)-amino]-benzoxazole-
-ylcyclo hexanecarboxamide (5b)
cis-N-{2-[(Cyclopentanecarbony)aminol]-benzothiazol-6-yl}-3-
(1-naphthy l methyl) amino]cyclohexanecarboxamide (6d)
6
[
Titled compound 5b was prepared in a similar manner to that
ꢁ
1
A white solid, yield: 81%, mp: 170–175 C. H-NMR (600 MHz,
described for 5a.
1
DMSO-d ) d: 12.24 (br s, 1H), 10.05 (s, 1H), 8.32 (d, 1H, J ¼ 2.0
6
A yellow solid, yield: 56%. H-NMR (600 MHz, DMSO-d ) d:
6
Hz), 8.20 (d, 1H, J ¼ 8.2 Hz), 7.88–7.99 (m, 2H), 7.49–7.67 (m,
1
0.00 (s, 1H), 7.97 (s, 1H), 7.42 (d, 1H, J ¼ 8.5 Hz), 7.30 (d, 1H,
J ¼ 8.5 Hz), 5.78 (s, 2H), 2.95–3.01 (m, 1H), 2.65–2.73 (m, 1H),
.35–2.43 (m, 1H), 1.41–1.96(m, 12H), 1.19–1.40 (m, 4H). ESI-MS
m/z): 371 [M + 1].
5
2
H), 4.44 (br s, 2H), 2.91–3.00 (m, 1H), 2.42–2.48 (m, 1H), 2.10-
.32(m, 2H), 1.14-1.94 (m, 15H). ESI-MS (m/z): 527 [M + 1]. Anal.
2
(
calcd for C H N O S: C, 70.69; H, 6.51; N, 10.64. Found: C,
3
1
34 4 2
70.71; H, 6.45; N, 10.68.
cis-N-{2-[(Cyclopentanecarbony)aminol]-benzothiazol-6-yl}6-
-[(2-naphthylmethyl)amino]cyclohexanecarboxamide (6a)
cis-N-{2-[(Cyclopentanecarbony)aminol]-benzothiazol-6-yl}-3-
(2-methoxy-1-naphthylmethyl) amino]
cyclohexanecarboxamide (6e)
A white solid, yield: 50%, mp: 167–171 C. H-NMR (300 MHz,
DMSO-d ) d: 12.25 (s, 1H), 10.14 (s, 1H), 8.33 (s, 1H), 8.06–8.17
3
[
To a solution of 5a (0.15 g, 0.39 mmol) in MeOH (10 mL) was
added 2-naphthaldehyde (0.061 g, 0.39 mmol). The mixture was
ꢁ
1
stirred at room temperature for 2 h, then NaBH
3
CN (0.025 g,
6
0.39 mmol) and 3–5 drops of AcOH were added and the mixture
(
4
2
m, 2H), 7.95 (d, 1H, J ¼ 8.3 Hz), 7.39–7.69 (m, 5H), 4.61 (s, 2H),
was further agitated for a period of 10 h. Purication by ash
chromatography (CH Cl –MeOH, 10 : 1) afforded 0.18 g of 6a as
.01 (s, 3H), 2.88–3.02 (m, 1H), 2.52–2.61 (m, 1H), 2.18–2.40(m,
H), 1.19–2.04 (m, 15H). ESI-MS (m/z): 557 [M + 1]. Anal. calcd
2
2
ꢁ
1
a light-yellow solid, yield: 86%, mp: 162–166 C. H-NMR (300
MHz, DMSO-d ) d: 12.49 (br s, 1H), 10.28 (s, 1H), 8.51 (s, 1H),
.19 (s, 1H), 8.09–8.18 (m, 3H), 7.85 (d, 1H, J ¼ 9.0 Hz), 7.72–7.82
for C32
36 4 3
H N O S: C, 69.04; H, 6.52; N, 10.06. Found: C, 69.10; H,
6
6.49; N, 10.10.
8
(
2
m, 3H), 7.69 (d, 1H, J ¼ 9.0 Hz), 4.47 (s, 2H), 3.08–3.22 (m, 1H),
1
3
cis-N-{2-[(Cyclopentanecarbony)aminol]-benzothiazol-6-yl}-3-
(4-methoxy-1-naphthylmethyl) amino]
cyclohexanecarboxamide (6f)
28.02, 127.84, 127.56, 121.69, 120.50, 113.64, 57.41, 49.94, A light-yellow solid, yield: 41%, mp: 172–174 C. H-NMR (300
6.10, 44.93, 32.65, 31.35, 31.35, 29.94, 29.96, 27.06, 27.06, MHz, DMSO-d ) d: 12.25 (s, 1H), 10.13 (s, 1H), 8.33 (s, 1H), 8.25
4.42. ESI-MS (m/z): 527 [M + 1]. HR ESI-MS [M + 1]: 527.2489. (d, 1H, J ¼ 8.4 Hz), 8.13 (d, 1H, J ¼ 8.4 Hz), 7.45–7.77 (m, 5H),
.59–2.67 (m, 1H), 2.27–2.53(m, 2H), 1.33–2.15 (m, 15H). C-
[
NMR (75 MHz, CD OD) d: 177.50, 175.32, 159.39, 146.64, 135.92,
3
1
1
4
2
34.83, 134.68, 133.84, 130.99, 130.41, 130.06, 129.06, 128.81,
ꢁ
1
6
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7
1
.06 (d, 1H, J ¼ 8.0 Hz), 4.58 (s, 2H), 4.00 (s, 3H), 2.88–3.03 (m, cis-N-{2-[(Cyclopentanecarbony)aminol]-benzothiazol-6-yl}-3-
H), 2.52–2.60 (m, 1H), 2.17–2.41(m, 2H), 1.18–2.01 (m, 15H). [(1,2,3,4-tetrahydroquinolin-3-yl) methylamino]-
ESI-MS m/z: 557 [M + 1]. Anal. calcd for C H N O S: C, 69.04; cyclohexanecarboxamide (6k)
3
2
36 4 3
H, 6.52; N, 10.06. Found: C, 69.08; H, 6.53; N, 10.02.
ꢁ
A white solid, yield: 8%, mp: 168–170 C. 6k was one of the by-
1
products in obtaining 6i. H-NMR (600 MHz, CD
3
OD) d: 8.22 (s,
1
6
2
H), 7.67 (d, 1H, J ¼ 8.6 Hz), 7.48 (dd, 1H, J ¼ 8.6, 1.9 Hz), 6.90–
cis-N-{2-[(Cyclopentanecarbony)aminol]-benzothiazol-6-yl}-3-
.97 (m, 2H), 6.51–6.60 (m, 2H), 3.39–3.50 (d, 2H, J ¼ 6.0 Hz),
[(2-ethoxy-1-naphthylmethyl) amino]cyclohexanecarboxamide
.95–3.23 (m, 6H), 2.52–2.65 (m, 2H), 1.37–2.37 (m, 16H). ESI-
(
6g)
MS (m/z): 532 [M + 1]. HR ESI-MS [M + 1]: 532.2756. Anal. calcd
for C H N O S: C, 67.77; H, 7.01; N, 13.17. Found: C, 67.69; H,
7
ꢁ
1
A light-yellow solid, yield: 50%, mp: 173–176 C. H-NMR (300
3
0
37 5 2
MHz, DMSO-d ) d: 12.25 (br s, 1H), 10.13 (s, 1H), 8.31 (d, 1H, J ¼
6
.06; N, 13.10.
2
5
.0 Hz), 8.03–8.17 (m, 2H), 7.93 (d, 1H, J ¼ 7.9 Hz), 7.39–7.70 (m,
H), 4.61 (s, 2H), 4.20–4.33 (m, 2H), 2.88–3.02 (m, 1H), 2.53–2.62
cis-N-{2-[(Cyclopentanecarbony)aminol]-benzothiazol-6-yl}-3-
(4-quinolinmethyl)amino]cyclohexanecarboxamide (6l)
(
[
m, 1H), 2.18–2.43(m, 2H), 1.18–2.04 (m, 18H). ESI-MS (m/z): 571
M + 1]. Anal. calcd for C33 S: C, 69.44; H, 6.71; N, 9.82.
Found: C, 69.46; H, 6.69; N, 9.86.
[
38 4 3
H N O
ꢁ
1
A yellow solid, yield: 23%, mp: 160–163 C. H-NMR (300 MHz,
DMSO-d
Hz), 8.31 (s, 1H), 8.22 (d, 1H, J ¼ 8.1 Hz), 8.03 (d, 1H, J ¼ 8.1 Hz),
7.43–7.84 (m, 5H), 4.37 (s, 2H), 2.87–3.02 (m, 1H), 2.35–2.46 (m,
1H), 2.08–2.30 (m, 2H), 1.10–1.97 (m, 15H). ESI-MS (m/z): 528 [M
6
) d: 12.23 (br s, 1H), 10.00 (s, 1H), 8.87 (d, 1H, J ¼ 4.2
cis-N-{2-[(Cyclopentanecarbony)aminol]-benzothiazol-6-yl}-3-
(2-quinolinmethyl) amino]cyclohexanecarboxamide (6h)
[
ꢁ
1
30 33 5 2
+ 1]. Anal. calcd for C H N O S: C, 68.28; H, 6.30; N, 13.27.
A yellow solid, yield: 29%, mp: 149–152 C. H-NMR (600 MHz,
DMSO-d
) d: 12.24 (br s, 1H), 10.02 (s, 1H), 8.39 (d, 1H, J ¼ 8.5
Hz), 8.31 (s, 1H), 8.03 (d, 1H, J ¼ 8.3 Hz), 7.99 (d, 1H, J ¼ 8.3 Hz),
.76–7.81 (m, 1H), 7.59–7.68 (m, 3H), 7.50 (dd, 1H, J ¼ 8.6, 1.9
Hz), 4.31 (s, 2H), 2.92–3.01 (m, 1H), 2.37–2.47 (m, 1H), 2.04–
.27(m, 2H), 1.20–1.96 (m, 15H). ESI-MS (m/z): 528 [M + 1]. Anal.
calcd for C30 S: C, 68.28; H, 6.30; N, 13.27. Found: C,
8.20; H, 6.32; N, 13.25.
Found: C, 68.19; H, 6.29; N, 13.36.
6
cis-N-{2-[(Cyclopentanecarbony)aminol]-benzothiazol-6-yl}-3-
7
[
(6-quinolin methyl)amino]cyclohexanecarboxamide (6m)
ꢁ
1
2
A light-yellow solid, yield: 11%, mp: 185–187 C. H-NMR (600
33 5 2
H N O
MHz, CD OD) d: 8.85 (dd, 1H, J ¼ 4.3 Hz, 1.6 Hz), 8.38 (d, 1H, J ¼
3
6
8
1
.3 Hz), 8.21 (d, 1H, J ¼ 2.0 Hz), 8.04 (d, 1H, J ¼ 8.4 Hz), 7.96 (s,
H), 7.85 (dd, 1H, J ¼ 8.6, 1.8 Hz), 7.66 (d, 1H, J ¼ 8.7 Hz), 7.57
(
2
2
dd, 1H, J ¼ 8.4, 4.3 Hz), 7.48 (dd, 1H, J ¼ 8.7, 2.0 Hz), 4.12 (s,
cis-N-{2-[(Cyclopentanecarbony)aminol]-benzothiazol-6-yl}-3-
(3-quinolin methyl) amino]cyclohexanecarboxamide (6i)
H), 2.94–3.03 (m, 1H), 2.70–2.78 (m, 1H), 2.41–2.49 (m, 1H),
[
1
3
.09–2.31 (m, 2H), 1.21–2.07 (m, 14H). C-NMR (75 MHz,
OD) d (ppm): 177.49, 176.36, 159.42, 151.17, 148.18, 146.52,
ꢁ
1
A light-yellow solid, yield: 7%, mp: 160–163 C. H-NMR (600
MHz, DMSO-d ) d: 12.24 (br s, 1H), 10.07 (s, 1H), 8.98 (s, 1H),
.42 (s, 1H), 8.32 (s, 1H), 8.05 (d, 1H, J ¼ 8.7 Hz), 8.01 (d, 1H, J ¼
.5 Hz), 7.76–7.84 (m, 1H), 7.61–7.71 (m, 2H), 7.50 (d, 1H, J ¼ 8.8
CD
3
6
1
1
3
38.86, 138.27, 136.17, 133.82, 131.99, 129.81, 129.32, 128.53,
22.78, 121.62, 120.46, 113.53, 56.57, 50.58, 46.10, 45.82, 35.85,
1.34, 31.34, 30.73, 30.20, 27.05, 27.05, 25.14. ESI-MS (m/z): 528
8
8
Hz), 4.30 (br s, 2H), 2.93–3.01 (m, 1H), 2.42–2.48 (m, 1H), 2.08–
[
M + 1]. HR ESI-MS [M + 1]: 528.2443. Anal. calcd for
C H N O S: C, 68.28; H, 6.30; N, 13.27. Found: C, 68.35; H,
1
3
2
1
1
1
3
.30 (m, 2H), 1.19–1.98 (m, 15H). C-NMR (75 MHz, CD OD) d:
3
3
0
33 5 2
77.51, 175.78, 159.40, 152.23, 148.37, 146.62, 138.70, 136.00,
33.85, 131.65, 129.97, 129.28, 129.28, 129.07, 128.68, 121.64,
20.42, 113.54, 57.33, 47.74, 46.10, 45.30, 34.05, 31.34, 31.34,
1.21, 30.07, 27.05, 27.05, 24.67. ESI-MS (m/z): 528 [M + 1]. HR
6.33; N, 13.39.
cis-N-{2-[(Cyclopentanecarbony)aminol]-benzoxazole-6-yl}-3-
(1,2,3,4-tetrahydroquinolin-6-yl) methylamino]-
cyclohexanecarboxamide (6n)
A white solid, yield: 8%, mp: 179–182 C, 6n was one of the by-
[
33 5 2
ESI-MS [M + 1]: 528.2443. Anal. calcd for C30H N O S: C, 68.28;
H, 6.30; N, 13.27. Found: C, 68.30; H, 6.25; N, 13.32.
ꢁ
1
3
products in obtaining 6m. H-NMR (600 MHz, CD OD) d: 8.26
cis-N-{2-[(Cyclopentanecarbony)aminol]-benzothiazol-6-yl}-3-
(2-chloro-3-quinolinmethyl) amino]cyclohexanecarboxamide
6j)
A white solid, yield: 32%, mp: 166–169 C. H-NMR (600 MHz,
DMSO-d ) d: 12.24 (br s, 1H), 10.04 (s, 1H), 8.55 (s, 1H), 8.31 (d,
H, J ¼ 1.9 Hz), 8.06 (d, 1H, J ¼ 8.2 Hz), 7.96 (d, 1H, J ¼ 8.4 Hz),
.76–7.86 (m, 1H), 7.60–7.72 (m, 2H), 7.49 (dd, 1H, J ¼ 8.8, 2.0
(d, 1H, J ¼ 1.9 Hz), 7.67 (d, 1H, J ¼ 8.7 Hz), 7.48 (dd, 1H, J ¼ 8.7,
1.9 Hz), 6.94–7.06 (m, 2H), 6.52 (d, 1H, J ¼ 8.7 Hz), 4.03 (s, 2H),
3.15–3.30 (m, 3H), 2.64–2.89 (m, 4H), 2.32–2.38 (m, 1H), 2.19–
[
(
ꢁ
1
2
.26 (m, 1H), 1.22–2.10 (m, 16H). ESI-MS (m/z): 532 [M + 1]. HR
ESI-MS [M + 1]: 532.2761. Anal. calcd for C30 S: C, 67.77;
H, 7.01; N, 13.17. Found: C, 67.85; H, 7.05; N, 13.09.
37 5 2
H N O
6
1
7
cis-N-{2-[(Cyclopentanecarbony)aminol]-benzothiazol-6-yl}-3-
(8-quinolin methyl)amino]cyclohexanecarboxamide (6o)
Hz), 4.14 (br s, 2H), 2.88–3.01 (m, 1H), 2.37–2.47 (m, 1H), 2.01–
.28 (m, 2H), 1.15–1.97 (m, 15H). ESI-MS (m/z): 562 [M + 1]. Anal.
calcd for C30 32ClN S: C, 64.10; H, 5.74; N, 12.46. Found: C, A yellow solid, yield: 29%, mp: 155–158 C. H-NMR (300 MHz,
4.05; H, 5.69; N, 12.50.
[
2
ꢁ
1
H
5 2
O
6
DMSO-d
6
) d: 12.26 (br s, 1H), 10.11 (s, 1H), 9.02 (dd, 1H, J ¼ 4.2
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1
Hz, 1.7 Hz), 8.49 (dd, 1H, J ¼ 8.3, 1.7 Hz), 8.31 (d, 1H, J ¼ 1.9 Hz),
6
A brown solid, yield: 53%. H-NMR (300 MHz, DMSO-d ) d:
8
.09 (d, 1H, J ¼ 8.3 Hz), 7.95 (d, 1H, J ¼ 8.0 Hz), 7.45–7.74 11.33 (s, 1H), 7.32 (d, 1H, J ¼ 8.6 Hz), 6.95 (s, 1H), 6.64 (d, 1H,
(
2
m, 4H), 4.77 (s, 2H), 2.88–3.03 (m, 1H), 2.40–2.47 (m, 1H), 2.14– J ¼ 8.6 Hz), 5.08 (s, 2H), 1.48 (m, 9H). ESI-MS (m/z): 266 [M + 1].
.37 (m, 2H), 1.16–2.00 (m, 15H). ESI-MS (m/z): 528 [M + 1]. Anal.
calcd for C30 S: C, 68.28; H, 6.30; N, 13.27. Found: C, tert-Butyl [6-(cyclopentanecarboxamido)benzothiazol-2-yl]-
8.33; H, 6.34; N, 13.31.
33 5 2
H N O
6
carbamate (9)
Titled compound 9 was prepared in a similar manner to that
cis-N-{2-[(Cyclopentanecarbony)aminol]-benzoxazole-6-yl}-3-
(2-naphthyl methyl) amino]cyclohexanecarboxamide (6p)
described for 2a.
1
[
A white solid, yield: 68%. H-NMR (600 MHz, DMSO-d
6
) d:
ꢁ
1
11.64 (br s, 1H), 9.96 (s, 1H), 8.30 (d, 1H, J ¼ 2.0 Hz), 7.58 (d, 1H,
A white solid, yield: 36%, mp: 198–201 C. H-NMR (600 MHz,
DMSO-d
) d: 11.50 (br s, 1H), 10.15 (s, 1H), 8.06 (d, 2H, J ¼ 8.9
Hz), 8.01 (d, 1H, J ¼ 8.2 Hz), 7.93–7.99 (m, 2H), 7.63 (d, 1H, J ¼
.1 Hz), 7.55–7.61 (m, 2H), 7.49 (d, 1H, J ¼ 8.7 Hz), 7.35 (d, 1H,
J ¼ 8.8 Hz), 7.45 (dd, 1H, J ¼ 8.8, 2.0 Hz), 2.75–2.85 (m, 1H),
6
1
9
.81–1.89 (m, 2H), 1.64–1.77 (m, 4H), 1.54–1.59 (m, 2H), 1.51 (s,
H). ESI-MS (m/z): 362 [M + 1].
8
J ¼ 8.3 Hz), 4.36 (s, 2H), 2.90–3.03 (m, 1H), 2.42–2.49 (m, 1H),
1
3
N-(2-Aminobenzothiazol-6-yl)cyclopentanecarboxamide (10)
2
.13–2.35 (m, 2H), 1.16–1.98 (m, 15H). C-NMR (75 MHz,
CD
3
OD) d: 177.58, 175.18, 159.58, 148.53, 138.04, 136.43, Titled compound 10 was prepared in a similar manner to that
1
1
4
34.92, 134.65, 132.12, 130.68, 130.13, 129.08, 128.81, 128.14, described for 5a.
27.90, 127.54, 118.09, 117.53, 103.39, 57.65, 49.89, 46.68,
A white solid, yield: 94%. H-NMR (600 MHz, DMSO-d ) d:
4.84, 32.26, 31.24, 31.24, 29.89, 29.63, 27.04, 27.04, 24.34. ESI- 9.77 (s, 1H), 8.02 (d, 1H, J ¼ 2.0 Hz), 7.31 (s, 2H), 7.27 (dd, 1H, J
1
6
MS (m/z): 511 [M + 1]. HR ESI-MS [M + 1]: 511.2706. Anal. calcd ¼ 8.5, 2.0 Hz), 7.23(d, 1H, J ¼ 8.5 Hz), 2.69–2.79 (m, 1H), 1.79–
for C H N O : C, 72.92; H, 6.71; N, 10.97. Found: C, 72.87; H, 1.87 (m, 2H), 1.63–1.75 (m, 4H), 1.50–1.58 (m, 2H). ESI-MS (m/z):
3
1
34 4 3
6.69; N, 10.93.
262 [M + 1].
tert-Butyl-N-cis-3-[(2-[(cyclopentanylcarbonyl)aminol]-
benzothiazol-6-yl amino) carbonyl]cyclohexyl carbamate (11)
cis-N-{2-[(Cyclopentanecarbony)aminol]-benzothiazol-6-yl}-3-
(2-quinolin methyl) amino]cyclohexanecarboxamide (6q)
[
ꢁ
1
Titled compound 11 was prepared in a similar manner to that
A yellow solid, yield: 29%, mp: 148–152 C. H-NMR (600 MHz,
DMSO-d
) d: 11.46 (br s, 1H), 10.04 (s, 1H), 8.33 (d, 1H, J ¼ 8.6
described for 4a.
6
1
A white solid, yield: 93%. H-NMR (600 MHz, DMSO-d ) d:
6
Hz), 8.06 (s, 1H), 7.98 (d, 1H, J ¼ 8.7 Hz), 7.95 (d, 1H, J ¼ 7.7 Hz),
1
2.25 (s, 1H), 10.06 (s, 1H), 8.3 (d, 1H, J ¼ 2.0 Hz), 7.63 (d, 1H, J
8.8 Hz), 7.52 (dd, 1H, J ¼ 8.8, 2.0 Hz), 6.82 (s, 1H), 2.97–3.03
m, 1H), 2.78–2.85 (m, 1H), 2.56–2.64 (m, 1H), 1.52–1.98 (m,
7
7
2
2
1
1
1
2
.70–7.77 (m, 1H), 7.65 (d, 1H, J ¼ 8.4 Hz), 7.55–7.60 (m, 1H),
.46 (d, 1H, J ¼ 8.3 Hz), 7.34 (d, 1H, J ¼ 7.2 Hz), 4.13 (s, 2H),
.91–3.01 (m, 1H), 2.56–2.67 (m, 1H), 2.33–2.42(m, 1H), 2.11–
¼
(
1
3
12H), 1.38 (s, 9H), 1.06–1.35 (m, 4H). ESI-MS (m/z): 485 [M ꢀ 1].
.18 (m, 1H), 1.20–2.03 (m, 15H). C-NMR (75 MHz, CD OD) d:
3
77.56, 174.76, 158.49, 155.01, 147.20, 146.92, 137.00, 136.68,
35.12, 130.10, 129.50, 127.54, 127.41, 126.12, 120.19, 117.34,
16.52, 101.84, 55.57, 50.63, 45.28, 44.25, 34.46, 31.11, 29.65,
cis-3-Amino-N-[6-(cyclopentanecarbonyl)-amino]-
benzothiazol-2-yl]cyclo hexanecarboxamide (12)
9.65, 28.57, 25.45, 25.45, 23.57. ESI-MS (m/z): 512 [M + 1]. HR Titled compound 12 was prepared in a similar manner to that
: C, 70.43; described for 5a.
33 5 3
ESI-MS [M + 1]: 512.2672. Anal. calcd for C30H N O
1
H, 6.50; N, 13.69. Found: C, 70.38; H, 6.48; N, 13.67.
A light-yellow solid, yield: 92%. H-NMR (300 MHz, DMSO-
d
1
2
6
) d: 10.08 (s, 1H), 8.41 (s, 1H), 7.73 (d, 1H, J ¼ 8.7 Hz), 7.62 (d,
H, J ¼ 8.7 Hz), 4.58–5.52 (br s, 2H), 2.99–3.16 (m, 1H), 2.43–
.69 (m, 2H), 1.60–2.16 (m, 12H), 0.99–1.60 (m, 4H). ESI-MS (m/
tert-Butyl-(6-nitrobenzothiazol-2-yl)carbamate (7)
To a solution of 2-amino-6-nitrobenzothiazole (1.00 g, 5.12
z): 385 [M ꢀ 1].
mmol), DMAP (0.11 g, 0.1 mmol) and Et N (3.55 mL, 25.6 mmol)
3
in CH
g, 7.68 mmol). The mixture was stirred at room temperature for
6 h, then washed with 5% aqueous HCl (3 ꢃ 30 mL) and brine
30 mL), dried with anhydrous Na SO . Purication by ash
2 2 2
Cl (50 mL) at room temperature was added Boc O (1.68
cis-N-{6-[(Cyclopentanecarbony)aminol]-benzothiazol-2-yl}-3-
[
(2-naphthyl methyl) amino]cyclohexanecarboxamide (13a)
1
(
Titled compound 13a–f was prepared in a similar manner to
that described for 6a.
2
4
chromatography (n-hexane–ethyl acetate, 20:1) afforded 0.45 g
ꢁ
1
1
A yellow solid, yield: 48%, mp: 160–164 C. H-NMR (600
MHz, DMSO-d ) d: 12.16 (br s, 1H), 10.01 (s, 1H), 8.35 (s, 1H),
.99 (s, 1H), 7.96 (d, 1H, J ¼ 8.5 Hz),7.90–95 (m, 2H), 7.65 (d, 1H,
J ¼ 8.7 Hz), 7.62 (dd, 1H, J ¼ 8.5, 1.3 Hz), 7.52–7.58 (m, 2H), 7.51
dd, 1H, J ¼ 8.7, 2.0 Hz), 4.23 (s, 2H), 2.76–2.85 (m, 1H), 2.59–
of 7 as a light yellow solid, yield: 30%. H-NMR (300 MHz,
CDCl ) d: 8.72 (d, 1H, J ¼ 2.3 Hz), 8.31 (dd, 1H, J ¼ 8.9, 2.3 Hz),
6
3
7
7.83 (d, 1H, J ¼ 8.9 Hz), 1.63 (s, 9H). ESI-MS (m/z): 294 [M ꢀ 1].
(
2
tert-Butyl-(6-aminobenzothiazol-2-yl)carbamate (8)
13
.68 (m, 1H), 2.09–2.39 (m, 2H), 1.14–1.97 (m, 15H). C-NMR
Titled compound 8 was prepared in a similar manner to that (75 MHz, CD
3
OD) d: 177.74, 175.11, 158.93, 146.36, 136.46,
described for 3a.
134.83, 134.71, 133.85, 131.26, 130.32, 130.05, 129.05, 128.81,
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1
4
2
27.99, 127.82, 127.56, 121.75, 120.55, 113.52, 57.27, 49.98, washed by water and vacuumed to dry to give 2.71 g of 15 as a
7.23, 44.00, 32.48, 31.61, 31.61, 30.00, 29.72, 27.11, 27.11, yellowish-brown solid, yield: 93%. H-NMR (300 MHz, DMSO-
1
4.55. ESI-MS (m/z): 527 [M + 1]. HR ESI-MS [M + 1]: 527.2489. d ) d: 8.24 (d, 2H, J ¼ 8.9), 8.05 (d, 2H, J ¼ 8.9), 7.43(s, 2H), 7.25
6
Anal. calcd for C H N O S: C, 70.69; H, 6.51; N, 10.64. Found: (s, 2H). ESI-MS (m/z): 222 [M + 1].
3
1
34 4 2
C, 70.66; H, 6.55; N, 10.67.
N-[4-(4-Nitrophenyl)thiazol-2-yl]cyclopentanecarboxamide (16)
Titled compound 16 was prepared in a similar manner to that
cis-N-{6-[(Cyclopentanecarbony)aminol]-benzothiazol-2-yl}-3-
[(2-quinolin methyl) amino]cyclohexanecarboxamide (13b)
described for 2a.
ꢁ
1
1
A white solid, yield: 7%, mp: 164–168 C. H-NMR (600 MHz,
DMSO-d
Hz), 8.35 (s, 1H), 8.00–8.16 (m, 2H), 7.84 (m, 1H), 7.76–7.81 (m, 2.72–2.87 (m, 1H), 1.56–2.06 (m, 8H). ESI-MS (m/z): 318 [M + 1].
H), 7.46–7.75 (m, 3H), 4.55 (s, 2H), 2.75–2.85 (m, 1H), 2.61–2.71
m, 1H), 2.15–2.41 (m, 2H), 1.18–2.00 (m, 15H). ESI-MS (m/z): N-[4-(4-Aminophenyl)thiazol-2-yl]cyclopentanecarboxamide (17)
A yellow solid, yield: 86%. H-NMR (300 MHz, CDCl
3
) d: 9.07 (br
6
) d: 12.29 (br s, 1H), 10.01 (s, 1H), 8.47 (d, 1H, J ¼ 8.3 s, 1H), 8.27(d, 2H, J ¼ 8.7 Hz), 7.97 (d, 2H, J ¼ 8.7 Hz), 7.35 (s, 1H),
1
(
5
1
28 [M + 1]. Anal. calcd for C H N O S: C, 68.28; H, 6.30; N,
30 33 5 2
3.27. Found: C, 68.19; H, 6.33; N, 13.19.
Titled compound 17 was prepared in a similar manner to that
described for 3a.
1
A colorless solid, yield: 60%. H-NMR (300 MHz, DMSO-d
6
) d:
cis-N-{6-[(Cyclopentanecarbony)aminol]-benzothiazol-2-yl}-3-
(3-quinolin methyl) amino]cyclohexanecarboxamide (13c)
1
¼
2.30 (s, 1H), 7.73 (d, 2H, J ¼ 8.5 Hz), 7.35 (s, 1H), 6.76 (d, 2H, J
8.5 Hz), 5.44 (s, 2H), 3.02–3.21 (m, 1H), 1.99–2.56 (m, 2H),
A white solid, yield: 9%, mp: 158–160 C. H-NMR (600 MHz, 1.79–1.99 (m, 4H), 1.65–1.79 (m, 2H). ESI-MS (m/z): 288 [M + 1].
DMSO-d ) d: 12.10 (br s, 1H), 9.99 (s, 1H), 8.90 (s, 1H), 8.31 (s,
[
ꢁ
1
6
1
7
3
1
+
H), 8.25 (s, 1H), 7.99 (d, 1H, J ¼ 8.9 Hz), 7.94 (d, 1H, J ¼ 8.4 Hz), tert-Butyl-N-cis-3-{4-[2-(cyclopentanecarboxamido)thiazol-4-
.69–7.74 (m, 1H), 7.55–7.67 (m, 2H), 7.50 (d, 1H, J ¼ 8.4 Hz), yl]phenyl carbamoyl}cyclohexylcarbamate (18)
.96 (s, 2H), 2.74–2.84 (m, 1H), 2.53–2.60 (m, 1H), 2.15–2.22 (m,
H), 1.93–2.00 (m, 1H), 1.16–1.92 (m, 15H). ESI-MS (m/z): 528 [M
Titled compound 18 was prepared in a similar manner to that
described for 4a.
A white solid, yield: 76%. H-NMR (300 MHz, DMSO-d
2.20 (s, 1H), 9.95 (s, 1H), 7.80 (d, 2H, J ¼ 8.7 Hz), 7.65 (d, 2H, J
8.7 Hz), 7.46 (s, 1H), 6.83 (s, 1H), 2.88–3.02 (m, 1H), 2.56–2.62
m, 1H), 2.33–2.45 (m, 1H), 1.49–1.98 (m, 12H), 1.38 (s, 9H),
.02–1.36 (m, 4H). ESI-MS (m/z): 511 [M ꢀ 1].
1]. Anal. calcd for C H N O S: C, 68.28; H, 6.30; N, 13.27.
1
3
0
33 5 2
6
) d:
Found: C, 68.20; H, 6.28; N, 13.35.
1
¼
cis-N-{6-[(Cyclopentanecarbony)aminol]-benzothiazol-2-yl}-3-
(
[(4-quinolin methyl) amino]cyclohexanecarboxamide (13d)
1
ꢁ
1
A light-yellow solid, yield: 8%, mp: 154–156 C. H-NMR (600
MHz, DMSO-d
) d: 12.23 (br s, 1H), 9.99 (s, 1H), 8.85 (d, 1H, J ¼ cis-3-Amino-N-{4-[2-(cyclopentanecarboxamido)thiazol-4-yl]
6
4
.3 Hz), 8.32 (s, 1H), 8.21 (d, 1H, J ¼ 8.4 Hz), 8.03 (d, 1H, J ¼ 8.2 phenyl}cyclo hexanecarboxamide (19)
Hz), 7.71–7.78 (m, 1H), 7.58–7.67 (m, 3H), 7.50 (d, 1H, J ¼ 8.7
Titled compound 19 was prepared in a similar manner to that
described for 5a.
Hz), 4.27 (s, 2H), 2.75–2.84 (m, 1H), 2.53–2.63 (m, 1H), 2.21–2.29
(m, 1H), 1.99–2.06 (m, 1H), 1.18–1.92 (m, 15H). ESI-MS (m/z):
1
A light-brown solid, yield: 93%. H-NMR (300 MHz, DMSO-
528 [M + 1]. Anal. calcd for C H N O S: C, 68.28; H, 6.30; N,
30 33 5 2
d
6
) d: 9.95 (s, 1H), 7.78 (d, 2H, J ¼ 8.5 Hz), 7.63 (d, 2H, J ¼ 8.5
Hz), 7.26 (s, 1H), 5.15 (br s, 2H), 2.73–2.90 (m, 1H), 2.2.28–2.48
m, 2H), 1.07–1.99 (m, 16H). ESI-MS (m/z): 413 [M + 1].
13.27. Found: C, 68.15; H, 6.29; N, 13.22.
(
cis-N-{6-[(Cyclopentanecarbony)aminol]-benzothiazol-2-yl}-3-
(6-quinolin methyl) amino]cyclohexanecarboxamide (13e)
[
cis-N-{4-[2-(cyclopentanecarboxamido)thiazol-4-yl]phenyl}-3-
ꢁ
1
A light-yellow solid, yield: 37%, mp: 168–172 C. H-NMR (600 [(naphthalen-2-ylmethyl)amino]cyclohexanecarboxamide (20)
MHz, DMSO-d ) d: 12.23 (br s, 1H), 9.99 (s, 1H), 8.89 (d, 1H, J ¼
6
Titled compound 20 was prepared in a similar manner to that
2
7
.5 Hz), 8.30–8.38 (m, 2H), 8.01 (d, 1H, J ¼ 8.9 Hz), 7.98 (s, 1H),
.82 (d, 1H, J ¼ 8.8 Hz), 7.61–7.67 (m, 1H), 7.51–7.56 (m, 1H), 7.50
described for 6a.
ꢁ
1
A white solid, yield: 21%, mp: 168-171 C. H-NMR (300 MHz,
(
(
dd, 1H, J ¼ 8.7, 2.2 Hz), 3.92 (s, 2H), 2.76–2.84 (m, 1H), 2.56–2.64
DMSO-d ) d: 12.18 (s, 1H), 10.02 (s, 1H), 7.88–8.06 (m, 4H), 7.76
6
m, 1H), 2.22–2.31 (m, 1H), 1.94–2.12 (m, 1H), 1.15–1.93 (m, 15H).
(
7
2
d, 2H, J ¼ 8.6 Hz), 7.65 (d, 2H, J ¼ 8.6 Hz), 7.50–7.62 (m, 3H),
33 5 2
ESI-MS (m/z): 528 [M + 1]. Anal. calcd for C30H N O S: C, 68.28;
.46 (s, 1H), 4.23 (s, 2H), 2.86–3.00 (m, 1H), 2.2.37–2.46 (m, 1H),
H, 6.30; N, 13.27. Found: C, 68.37; H, 6.33; N, 13.21.
13
.05–2.29 (m, 2H), 1.15–1.93 (m, 15H). C-NMR (75 MHz,
CD
34.69, 132.06, 130.74, 130.51, 130.08, 129.06, 128.80, 128.06,
To a solution of thiourea (1.00 g, 13.2 mmol), sodium acetate 127.85, 127.56, 127.47, 127.47, 121.17, 121.17, 107.79, 57.44,
3
OD) d: 176.99, 175.28, 159.50, 150.66, 139.39, 134.94,
4-(4-Nitrophenyl)thiazol-2-amine (15)
1
(
2.2 g, 26.4 mmol) in EtOH (25 mL) at room temperature was 49.80, 46.02, 44.96, 32.54, 31.37, 31.37, 29.89, 29.79, 27.04,
0
added 2-bromo-4 -nitroacetophenone (4.20 g, 17.2 mmol). The 27.04, 24.42. ESI-MS (m/z): 553 [M + 1]. HR ESI-MS [M + 1]:
mixture was stirred and reuxed for 7 h. Aer being cooled to 553.2634. Anal. calcd for C33
36 4 2
H N O S: C, 71.71; H, 6.56; N,
room temperature, the precipitate was separated by ltration, 10.14. Found: C, 71.66; H, 6.53; N, 10.12.
1560 | Med. Chem. Commun., 2013, 4, 1551–1561
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1
4 T. A. Farazi, G. Waksman and J. I. Gordon, J. Biol. Chem.,
Acknowledgements
2001, 276, 39501–39504.
This work was supported by the National Natural Science 15 H. Ebiike, M. Masubuchi, P. Liu, K. Kawasaki, K. Morikami,
Foundation of China (Grant no. 81222044), Science and Tech-
nology Commission of Shanghai (no. 13431900301), Shanghai
Rising-Star Program (grant 12QH1402600), Shanghai and
Shanghai Municipal Health Bureau (Grant XYQ2011038).
S. Sogabe, M. Hayase, T. Fujii, K. Sakata, H. Shindoh,
Y. Shiratori, Y. Aoki, T. Ohtsuka and N. Shimma, Bioorg.
Med. Chem. Lett., 2002, 12, 607–610.
16 K. Kawasaki, M. Masubuchi, K. Morikami, S. Sogabe,
T. Aoyama, H. Ebiike, S. Niizuma, M. Hayase, T. Fujii,
K. Sakata, H. Shindoh, Y. Shiratori, Y. Aoki, T. Ohtsuka
and N. Shimma, Bioorg. Med. Chem. Lett., 2003, 13, 87–91.
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