Synthesis of novel fluoro 1,2,3-triazole tagged amino bis(benzothiazole) derivatives, their antimicrobial and anticancer activity

Article abstract of DOI:10.1007/s00044-014-1006-0

A new series of fluoro 1,2,3-triazole tagged amino bis (benzothiazole) derivatives 8, 9 were prepared starting from 2-amino benzothiazole in four steps via amination, cyclization, alkylation followed by reaction with various azides under sharpless conditi

Full text of DOI:10.1007/s00044-014-1006-0

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-014-1006-0
ORIGINAL RESEARCH
Synthesis of novel fluoro 1,2,3-triazole tagged amino
bis(benzothiazole) derivatives, their antimicrobial
and anticancer activity
•
Ravindra M. Kumbhare Tulshiram L. Dadmal R. Pamanji
•
•
•
Umesh B. Kosurkar L. R. Velatooru K. Appalanaidu
•
•
•
Y. Khageswara Rao J. Venkateswara Rao
Received: 15 November 2013 / Accepted: 7 April 2014
Ó Springer Science+Business Media New York 2014
Abstract A new series of fluoro 1,2,3-triazole tagged
amino bis (benzothiazole) derivatives 8, 9 were prepared
starting from 2-amino benzothiazole in four steps via
amination, cyclization, alkylation followed by reaction
with various azides under sharpless conditions through
click chemistry approach. All newly synthesized com-
pounds were screened for their antimicrobial and cytotoxic
activity against four human cancer cell lines (U937,
THP-1, Colo205, and A549), and promising compounds
have been identified.
refrigerants (Sekiya and Misaki, 2000), pharmaceuticals
(Rowley et al., 2001; Isanbor and OHagan, 2006), agro-
chemicals (Hewitt and Silvester, 1988), polymers (Dear and
Gilbert, 1974), blowing agents (Takada et al., 1999),
lubricants, artificial blood substitutes (Maichiodi et al.,
1998), etc. The introduction of fluorine into a specific
position of bioactive compounds such as pharmaceutical or
agrochemical may remarkably reduce the toxicity, improve
the pharmacokinetics of the compounds, and improve the
overall efficiency. Around 20 % of all licensed pharma-
ceutical products over the last 50 years contain a fluorine
atom. In the recent past, it was found that fluorine is a
substitute of distinctive qualities and one of the most lipo-
philic functional groups known provides an extremely
useful way of making a molecule more easily delivered to
the active site in the body. Since there are very few naturally
occurring fluorine-containing compounds, and being a great
demand for fluorinated chemicals all over the world, it is
necessary to synthesize fluorinated organic compounds.
The presence of the benzothiazole nucleus of com-
pounds aimed at evaluating new products that possess
interesting biological activity. The 2-substituted benzo-
thiazole has emerged in its usage as a core structure in the
diversified therapeutic application. The structure–activity
relationship studies interestingly reveal that change in the
structure of substituent at C-2 position enhances the bio-
logical activities. Among those, 2-substituted benzothia-
zole derivatives with fluorine have received considerable
attention due to their potential bioactivities (Ge et al.,
2007). Most of the benzothiazole derivatives were repor-
ted for their diversified activity viz., anti-tumor, anti-
tubercular, antimalarial, anticonvulsant, anthelmintic,
analgesic, anti-inflammatory, antifungal, a topical car-
bonic anhydrase inhibitor, and an anti-hypoxic (Hutchin-
son et al., 2003; Yoshida et al., 2005; Latrofa et al., 2005;
Keywords Amino bis (benzothiazole) ꢀ
2-amino benzothiazole ꢀ Sharpless conditions ꢀ
Antibacterial activity ꢀ Antifungal activity ꢀ
Anticancer activity
Introduction
Fluorinated organic molecules often exhibit remarkable
physical and biological properties which originate from
C–F bond and with a wide range of applications, notably as
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-014-1006-0) contains supplementary
material, which is available to authorized users.
R. M. Kumbhare (&) ꢀ T. L. Dadmal ꢀ U. B. Kosurkar ꢀ
K. Appalanaidu ꢀ Y. Khageswara Rao
Fluoroorganic Division, CSIR - Indian Institute of Chemical
Technology, Tarnaka, Hyderabad 500007, India
e-mail: rakumbhare@yahoo.com; kumbhare@iict.res.in
R. Pamanji ꢀ L. R. Velatooru ꢀ J. Venkateswara Rao (&)
Biology Division, CSIR - Indian Institute of Chemical
Technology, Tarnaka, Hyderabad 500007, India
e-mail: jv@iict.res.in
123

Med Chem Res
N
N
S
N
N
CH3
NH2
H
N
OCH3
OCH3
N
N
N
R
N
N
N
N
S
F
N
N
S
CF3
HN
N
O
Ph
R = H ( DF 203) 2a
2b
N
CF120
F3C
R = F ( 5F 203)
610 (1)
PMX
FA030
4
3
Fig. 1 Structure of fluorinated benzothiazole and triazoles derivatives
Caryolle and Loiseau 1990). Some of the structurally
related benzothiazoles such as 2-(3,4-dimethoxyphenyl)-5-
fluorobenzothiazole (PMX 610) (Mortimer et al., 2006;
Aiello et al., 2008) 1 (Fig. 1), 2-(4-amino-3-methyl-
phenyl) benzothiazole (DF 203), and the 2-(4-amino-3-
methylphenyl)-5-fluoro benzothiazole (5F 203) (Loaiza-
Perez et al., 2002; Trapani et al., 2003; Leong et al.,
2004) (2a and 2b of Fig. 1) have been reported to possess
potent in vitro anti-tumor properties in human cancer cell
lines, particularly against colon, non-small cell lung, and
breast cancer lines of the National Cancer Institute (NCI)
60 human cancer cell line screen. Especially interesting
are bis-benzothiazole derivatives which exhibit their
importance in amyloid-imaging (Wu et al., 2007), vulca-
nization accelerators (Monsanto 1968), and starting
materials for various pharmaceutical industries (Papenfuhs
and Theodor, 1983; Bondock et al., 2009). N-Heterocyclic
compounds such as [1,2,3]-triazoles may display biologi-
cal activities, and there are several examples in the liter-
ature including antibacterial (Genin et al., 2000),
antifungal (Nilkanth et al., 2009), antiallergic (Buckle and
Rockell, 1982; Buckle et al., 1983, 1986), anti-HIV
(Alvarez et al., 1994), anticonvulsant (Kelley et al., 1995),
b-lactamase inhibitory (Micetich et al., 1987), and selec-
tive b3 adrenergic receptor agonism (Brockunier et al.,
2000).
scattering of MDCK (epithelial cells) and in vitro tumori-
genesis of H1437 (non-small-cell lung cancer) and GTL-16
(human gastric carcinoma) (Colombo et al., 2012). In con-
tinuation of our efforts on the design of novel anticancer and
antibacterial agents and keeping in mind the medicinal
importance of benzothiazole moiety (Kumbhare and Nagr-
agu 2011; Kumbhare et al., 2011;2012), we have synthesized
some new derivatives of novel fluoro 1,2,3-triazole tagged
amino bis(benzothiazole) molecules and evaluated for anti-
microbial and anticancer properties. Representatives of
some biologically important fluorinated triazole compounds
have been illustrated in Fig. 1.
Results and discussion
Chemistry
We first synthesized the compound 5 as our previous
reported method (Kumbhare et al., 2012). Compound 5
was further reacted with propargyl bromide in N,N-dime-
thyl formamide using potassium carbonate as a base
resulted in the formation of N-propargylated 6-fluoro-N-6-
methoxy-N-bis-benzothiazole 7. The sequence of reactions
outlined in Scheme 1.
It is quite evident that the favorable properties of 1,2,3-
triazole ring-like moderate dipole character, hydrogen
bonding capability, rigidity, and stability under in vivo
conditions are responsible for their enhanced biological
activities. In recent years, several attempts were made for
modifying the triazole nucleus to improve their biological
activity. Modifications on the triazole nucleus have resulted
in a large number of compounds having diverse pharmaco-
logical activities. Among them, triazole derivatives such as
(phenyl)pyrimidine-2-amine scaffold 3 which have impor-
tance for their in vitro potential use as inhabitor of breakpoint
cluster region (Bcr)-Abel-son kinase (Abl) (Arioli et al.,
2011; Peruzzotti et al., 2013). Similarly, fluorinated triazole
such as Triflorcas analog, having 1,2,3-triazole as a linkage
of imidazo[2,1-b]benzothiazol-2-ylphenyl and phenyl-N-
phenetyl acetamide moieties 4, inhibits the HGF-induced
Compound 7 was reacted with various fluorinated aro-
matic, aliphatic azides in THF, using Cu (I)-catalysed
[3?2] azide-alkyne cycloaddition reaction through click
chemistry under Sharpless conditions (Tornoe et al., 2002;
Himo et al., 2005), as a result an exclusive formation of
1,4-disubstituted-1,2,3-triazole tagged amino bis(benzo-
thiazole) derivatives 8, 9 are formed. The details of reac-
tion outlined in Scheme 2.
The azide-containing building blocks were synthesized
in a one-pot procedure Scheme 3 in which different amines
were reacted with the bromoacetyl bromide in N,N-dime-
thyl formamide followed by SN2 reaction with sodium
azide to generate the corresponding azides.
Several new triazole tagged bis-benzothiazole deriva-
tives 8a–e and 9a–i were synthesized and screened for
antimicrobial and anticancer activities.
123

Med Chem Res
Scheme 1 Synthesis of
N-propargylated amino bis
(benzothiazole)
O
F
O
F
N
N
N
N
K2CO3
Br
S
S
N
S
S
Dry DMF, r.t.
3-4 h.
N
H
6
7
5
Scheme 2 Synthesis of 1,2,3-
triazole tagged amino
bis(benzothiazole) derivatives
F
O
N
N
S
S
N
7
O
R2
N
N3
R1 N3
H
CuI (10 mol%)
CuI (10 mol%)
dry THF, rt
dry THF, rt
O
O
F
F
N
N
N
N
S
N
S
S
S
N
N
N
N
N
N
N
R1
O
HN
8a-e
R2
9a-i
9f = R2 = CH2-4-OCF3C6H4
8a = R1 = 4-FC6H4
9a = R2 = 4-FC6H4
9b = R2 = 2,4-FC6H3
9c = R2 = 3-CF3C6H4
8b = R1 = 2,4-F2C6H3
8c = R1 = 3-CF3C6H4
8d = R1 = 3-Cl, 4-FC6H3
9g = R2 = 5-(CF3)-1,3,4-thiadiazole
9h = R2 = Cyclopropane
9d = R2 = 3-Cl,4-FC6H3
9i
= R2 = Cyclohexane
= R1 = C8F17-CH2-CH2
= R = 4-SCF3C6H4
2
8e
9e
Scheme 3 Synthesis of azide-
tagged diversity elements
O
O
O
R2
NH2
NaN3
N3
R2
R2
Br
Br
N
Br
N
H
H
Pharmacology
strains. Moderate activity was shown by the compounds 8c,
9c, and 9f against the entire tested organism. Compounds
8d, 9a, 9b, 9d, and 9e showed some activity against few
bacterial strains. Compounds 9h and 9i were showed
similar activity against all tested strains except for K.
pneumonia. The compounds 8a and 8b have not been
shown any notable activity compared to other compounds.
Antibacterial activity
The minimum inhibitory concentrations (MIC) of various
synthetic compounds were screened against three repre-
sentative gram-positive microorganisms, viz. Bacillus
subtilis (MTCC 441) and Staphylococcus aureus (MTCC
96); and gram-negative organisms, viz. Escherichia coli
(MTCC 443), Pseudomonas aeruginosa (MTCC 741), and
Klebsiella pneumoniae (MTCC 618). The assays were
performed by broth dilution techniques according to the
National Committee for Clinical Laboratory (2000) stan-
dards. Standard antibacterial agents such as penicillin and
streptomycin were also screened under identical conditions
for comparison. The minimum inhibitory concentration
(MIC) values are resented in Table 1.
Antifungal activity
In vitro antifungal activity of the newly synthesized com-
pounds were studied against the fungal strains, Candida
albicans (MTCC 227), Candida rugosa (NCIM 3462),
Saccharomyces cerevisiae (MTCC 36), Rhizopus oryzae
(MTCC 262), and Aspergillus niger(MTCC 282) by Agar
Well Diffusion Method (2). The ready-made Potato Dex-
trose Agar (PDA) medium (Hi-media, 39 g) was suspended
in distilled water (1,000 ml) and heated to boil until it
dissolved completely; the medium and Petri dishes were
autoclaved at pressure of 15 lb/inc (Linday 1962) for
These results clearly indicate that compounds 8a–e and
9a–i displayed significant activity with a high degree of
variation. The results demonstrated that the compounds 8e
and 9g showed substantial activity against all the bacterial
123

Med Chem Res
Table 1 Antibacterial activity of compounds 8a–e and 9a–i
Compd code
MIC (lM)
B. subtilis
S. aureus
S. epidermidis
E. coli
P. aeruginosa
K. pneumoniae
8a
148.22
71.56
67.45
277.26
5.454
66.61
8.05
74.11
286.26
134.89
34.66
2.73
296.44
143.13
33.723
138.633
5.4543
133.213
32.273
61.173
15.673
58.14
74.11
286.26
67.45
69.32
10.92
33.30
16.12
30.58
31.35
29.07
58.32
15.08
73.67
68.06
37.38
10.75
296.44
71.56
134.89
17.32
2.73
148.22
286.26
16.85
34.66
10.92
16.64
32.27
15.28
7.83
8b
8c
8d
8e
9a
16.64
129.09
30.58
15.67
29.07
14.57
3.77
33.30
129.08
122.35
15.67
58.14
29.16
7.54
9b
9c
15.28
31.35
14.53
29.16
15.09
36.84
34.03
4.67
9d
9e
14.53
14.57
15.09
147.35
272.23
18.69
5.37
9f
14.57
9g
3.768
9h
18.41
17.01
4.67
18.41
36.84
34.03
37.38
2.68
9i
17.01
aPenicillin
aStreptomycin
9.35
10.75
10.75
5.37
MIC values are given in (lM) = Minimum inhibitory concentration, i.e. the lowest concentration of drug which completely inhibit bacterial
growth
a
Penicillin and Streptomycin with 98 % purity were used as positive control drugs
Table 2 Antifungal activity of compounds 8a–e and 9a–i
Zone of Inhibition (mm)
Compd code
R. oryzae
A. niger
C. rugosa
C. albicans
S. cerevisiae
10 lM
300 lM
10 lM
300 lM
10 lM
300 lM
10 lM
300 lM
10 lM
300 lM
8a
8b
8c
8d
8e
9a
9b
9c
9d
9e
9f
0
0
0
0
0
0
6
0
0
0
0
6
0
0
0
6
0
0
0
0
7
10
0
8
12
9
6
8
6
9
0
6
0
6
0
6
0
0
0
6
16
9
20
14
14
16
16
20
16
20
14
19
14
11
10
0
19
16
14
6
14
0
19
0
16
9
20
14
12
14
16
14
12
21
14
14
14
10
9
20
14
14
16
16
14
14
19
16
16
10
11
13
14
11
14
9
0
0
9
10
10
11
13
13
0
14
14
16
19
19
6
9
13
11
9
0
6
13
10
9
13
13
16
10
14
25
19
16
21
14
20
10
14
13
13
22
9g
9h
9i
16
9
13
24
11
22
16
10
23.5
aAmpotericin
B
MIC values are given in (lg/ml) = Minimum inhibitory concentration, i.e. the lowest concentration of drug which completely inhibit fungal
growth
a
Ampotericin B, 80 % was used as a positive control drug
123

Med Chem Res
20 min. Agar well bioassay was employed for testing
antifungal activity, and the results are shown in Table 2.
The medium was poured into sterile Petri dishes under
aseptic conditions in a laminar air flow chamber. When the
medium in the plates solidified, 0.5 ml of (week old) cul-
ture of test organism was inoculated and uniformly spread
over the agar surface with a sterile L-shaped rod. Solutions
were prepared by dissolving the compound in DMSO, and
different concentrations were made. After inoculation,
wells were scooped out with 6 mm sterile cork borer, and
the lids of the dishes were replaced. To each well, different
concentrations of test solutions were added. Controls were
maintained. The treated and the controls were kept at 27 °C
for 48 h. Inhibition zones were measured, and the diameter
was calculated in millimeter (mm). Three to four replicates
were maintained for each treatment.
as leukemia (U937, THP-1), colon and lung cancer cell
lines (Colo205 and A549, respectively). It is evident from
the results that these derivatives are not active on Colo205
and A549 cell lines at 200 lM concentration. However,
partial derivatives (3 out of 14) exhibited antiproliferative
activity.
Against U937, the highest activity (IC50 = 61.99 lM) is
observed in 9b followed by 9a and 9 h with IC50 values of
93.76 and 191.39 lM, respectively. Nonetheless, only one
derivative 9a exhibited activity (IC50 = 108.97 lM)
against THP1 cell line (Table 3). Remaining other deriv-
atives are not active at 200 lM concentration. The differ-
ential activity of active derivatives among the cell lines
may be due to the structure–activity relationship of the
molecules.
The antifungal screening data of compounds 8a–8e and
9a–9i revealed that the entire tested compounds showed
moderate to good antifungal activities against the tested
fungal strains. The compounds 8e and 9g showed better
antifungal activity against all fungal strains. The com-
pounds 8c, 9c, 9d, 9e, and 9f displayed antifungal activity
except on A. niger. Compounds 9a, 9b, 9h, and 9i exhibited
almost similar activity. The compounds 8a, 8b, and 8d
show no activity against all tested strains.
Conclusion
A series of novel 1,2,3-triazole tagged amino bis(benzo-
thiazole) derivatives 8 and 9 have been synthesized through
a facile strategy and screened for antimicrobial and anti-
cancer (cytotoxic) activity. The results of antibacterial
screening reveal that compounds 8e and 9g showed good
inhibition toward all the bacteria and fungi tested. Com-
parison with the IC50 values of positive control (Etoposide)
indicated that the U937 cells are more sensitive than the
other three (THP1, Colo205, and A549) cell lines. The
order of sensitivity of human cancer cell lines toward flu-
oro triazole tagged bis-(benzothiazole) derivatives is
U937 [ THP-1. Among the derivatives, 9a has exhibited a
good cytotoxic activity against the U937 and THP-1 cell
Cytotoxic activity
The fluoro 1,2,3-triazole tagged amino bis-(benzothiazole)
derivatives were evaluated by MTT assay (Mosmann,
1983) to investigate their antiproliferative/cytotoxic activ-
ities in four different types of human cancer cell lines such
Table 3 In vitro Cytotoxicity of fluoro 1,2,3-triazole tagged amino bis (benzothiazole) derivatives against U937, THP-1, COLO205, and A549
human cancer cells by MTT assay
Compounds
aIC50 (lM)
U937
THP1
Colo205
A549
9a
93.76 0.26
61.99 2.68
191.39 2.42
10.43 2.02
108.97 3.3
–
–
9b
–
–
–
9h
bEtoposide
–
–
–
3.67 0.25
0.42 0.22
18.19 2.14
The values represent the mean SE of three individual observations
Exponentially growing cells were treated with different concentrations of benzothiozole derivatives for 48 h and cell growth inhibition was
analyzed through MTT assay
a
IC50 is defined as the concentration, which results in a 50 % decrease in cell number as compared with that of the control cultures in the
absence of an inhibitor and were calculated using the respective regression analysis
b
Etoposide, 98 % was employed as positive control. Among the derivatives eleven compounds (8a, 8b, 8c, 8d, 8e, 9c, 9d, 9e, 9f, 9g, and 9i) did
not possess any cytotoxic activity at 200 lM concentration against four human cancer cell lines were used
Calculated the IC50 value by plotting, logarithm-transformed concentration–response versus percent growth inhibition, and fitted the data with a
straight line. IC50 value is then estimated using the formula of fitted line, i.e., Yscale (50) = A ? B 9 Xscale (X). [A = intercept; B = slope].
IC50 = antilogarithm of 50 - A/B
123

Med Chem Res
lines. However, most of the derivatives are comparatively
less potent than the commercially available drug molecule;
nevertheless, slight structural modification of these active
derivatives may yield as prospective anticancer drugs.
Based on the present results, it is warranted that these
derivatives to be further evaluated on other cancer cell
lines.
(5 % ethyl acetate in hexane) gave the desired product in
95 % isolated yield.
Synthesis of azide-tagged diversity elements
Commercially available amines (20 mmol) were dissolved
in dry DMF (40 ml) under nitrogen. To this solution, Et3N
(20 mmol) was added and bromoacetyl bromide (20 mmol)
via syringe at 0 °C under nitrogen. The mixture was stirred at
0 °C for 30 min and then at room temperature for another
2 h. Next, solid NaN3 (30 mmol) was added, and the reaction
mixture was stirred overnight. The mixture was poured into
water (100 ml) and extracted with EtOAc (3 9 100 ml). The
combined extracts were washed with water (3 9 50 ml) and
brine (50 ml). The organic layer was dried over Na2SO4,
filtered, and evaporated under reduced pressure. Silica gel
flash chromatography (10 % ethyl acetate in hexane) gave
the desired azide product in 70-90 % isolated yield.
Experimental
Materials and methods
All chemicals and reagents were purchased from Aldrich
(Sigma–Aldrich, St. Louis, MO, USA), Lancaster (Alfa
Aesar, Johnson Matthey Company, Ward Hill, MA, USA),
or Spectrochem Pvt. Ltd (Mumbai, India) with 80-98 %
purity and were used without further purification. Reac-
tions were monitored by TLC, performed on silica gel glass
plates containing 60 GF-254, and visualization on TLC was
achieved by UV light or iodine indicator. Column chro-
matography was performed with Merck 60–120 mesh silica
Synthesis of triazole derivatives of 6-fluoro-N-(6-methoxy
benzo[d]thiazol-2-yl) benzo[d]thiazol-2-amine (8 and 9)
1
gel. H, 13C, and 19F spectra were recorded Bruker UX-
The propargylated 6-fluoro-N-(6-methoxybenzo[d]thiazol-
2-yl)benzo[d]thiazol-2-amine 7 (0.27 mmol) was dissolved
in dry THF (5 ml), and catalytic amount of CuI was added.
Then, azides (0.27 mmol) in dry THF were slowly added at
room temperature under nitrogen atmosphere and contin-
ued stirring for 24 h. The solvent was removed under
reduced pressure; the residue was diluted with distilled
water and extracted with EtOAc (3 9 15 ml). The com-
bined organic layer was dried over anhydrous Na2SO4 and
concentrated to get the product. The crude product was
purified by column chromatography gave the desired
product 85-96 % isolated yield.
NMR/XWIN-NMR (300 MHz) instruments. Chemical
shifts (d) are reported in ppm down field from internal
TMS standard. ESI spectra were recorded on Micro mass,
Quattro LC using ESI?software with capillary voltage
3.98 kV and ESI mode positive ion trap detector. Melting
points were determined with an Electro thermal melting
point apparatus, and are uncorrected. The purities of all of
the compounds ([95 %) used for biological screening were
determined by analytical HPLC (SPD-M20A, make: Shi-
madzu) using an ODS column eluted with a gradient
mixture of acetonitrile–water.
General procedures
6-fluoro-N-((1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)
-N-(6-methoxybenzo[d]thiazol-2-yl)benzo[d]thiazol-2-amine
(8a) Yield 85 %; m.p. 158–160 °C. IR (KBr, mmax cm-1):
2,932, 1,515, 1,458, 1,263, 1,237, 1,046, 838, 805; 1H
NMR (CDCl3, 300 MHz): d 3.95 (s, 3H, –OCH3), 5.75 (s,
2H, –NCH2), 7.02 (d, 1H, J = 8.687 Hz), 7.08–7.33 (m,
4H, Ar–H), 7.41–7.51 (m, 1H, Ar–H), 7.58–7.86 (m, 4H,
Ar–H), 8.03 (s, 1H, Triazole–H); 13C NMR (CDCl3,
75 MHz): d 47.24 (N–CH2), 57.08 (OCH3), 104.38, 107.
45, 109.48, 111.25 (CH–Triazole), 114.85, 116.61, 116.70,
118.84, 119.92, 121.46, 122.61, 129.67, 131.14, 133.03,
133.30, 146.13, 152.38, 156.53, 160.43 (d, J = 251.60 Hz,
BT–C–F), 161.864 (d, J = 247.04 Hz, Ph–C–F); 19F NMR
(CDCl3, 400 MHz): d -112.01 to -112.43 (m, 1F), -118.
17 to -118.89 (m, 1F); ESI–MS: 507 (M?1)?; Anal.
calcd. For C24H16F2N6OS2: C 56.91, H 3.18, N 16.59 %.
Found: C 56.95, H 3.17, N 16.60 %.
Preparation of N-propargyl-6-fluoro-N-(6-methoxybenzo
[d]thiazol-2-yl)benzo[d] thiazol-2-amine (7)
6-fluoro-N-(6-methoxybenzo[d]thiazol-2-yl)benzo[d]thia-
zol-2-amine 5(3.0 mmol) was dissolved in dry N,N-dime-
thyl formamide (10 ml), and K2CO3 (6.0 mmol) was added
and the reaction mixture was stirred for 15 min at room
temperature. The propargyl bromide 6 (3.6 mmol) was
slowly added drop wise to the above mixture over a period
of 15 min and continued stirring for 4 h. The reaction was
quenched with water and extracted with EtOAc
(3 9 20 ml). The combined extracts were washed with
water (3 9 25 ml) and brine (20 ml). The organic layer
was dried over Na2SO4, filtered, and evaporated under
reduced pressure. Purification by silica gel chromatography
123

Med Chem Res
N-((1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-6-
fluoro-N-(6-methoxybenzo[d]thiazol-2-yl)benzo[d]thiazol-
2-amine (8b) Yield 89 %; m.p. 214–216 °C. IR (KBr,
mmax cm-1): 2,933, 1,536, 1,462, 1,328, 1,269, 1,254,
F), 156.92, 158.10 (d, J = 247.15 Hz, BT–C–F), 169.93;
19F NMR (CDCl3, 400 MHz): d -114.63 (s, 1F), -117.56
to -118.85 (m, 1F); ESI–MS: 542 (M?1)?; Anal. Calcd.
For C24H15ClF2N6OS2: C 53.28, H 2.79, N 15.53 %.
Found: C 53.27, H 2.81, N 15.55 %.
1
1,051, 842, 809; H NMR (CDCl3, 300 MHz): d 3.89 (s,
3H, –OCH3), 5.71 (s, 2H, –NCH2), 6.89–7.03 (m, 4H,Ar–
H), 7.10 (dt, 1H, J = 8.545 and 1.709 Hz, –Ar–H), 7.41 (s,
1H, Ar–H), 7.66 (d, 1H, J = 8.545 Hz, Ar–H), 7.71–7.83
(m, 2H, Ar–H), 8.13 (s, 1H, Triazole–H); 13C NMR
(CDCl3, 75 MHz): d 47.35 (N–CH2), 57.62 (OCH3), 107.
65 (CH–Triazole), 109.42, 110.51 (t, J = 25.31 Hz,
F–CH–F), 112.10, 115.10, 120.35, 124.10, 126.15, 127.35,
130.00, 131.18, 137.32, 147.10, 152.13, 156.23, 157.47
(d, J = 254.10 Hz, BT–C–F), 158.56 (d, J = 245.25 Hz,
Ph–4C–F), 160.22 (d, J = 248.23 Hz, Ph–2C–F); 19F
NMR (CDCl3, 400 MHz): d -106.83 to -106.95 (m, 1F),
-117.58 to -117.69 (m, 1F), -118.48 (q, 1F, J = 9.
426 Hz); ESI–MS: 525 (M?1)?; Anal. calcd. For
C24H15F3N6OS2: C 54.95, H 2.88, N 16.02 %. Found:
C 55.00, H 2.86, N 16.03 %.
6-fluoro-N-((1-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-hepta-
decafluorodecyl)-1H-1,2,3-triazol-4-yl)methyl)-N-(6-meth-
oxybenzo[d]thiazol-2-yl)benzo[d]thiazol-2-amine (8e) Yield
90 %; m.p. 164–166 °C. IR (KBr, mmax cm-1): 2,938, 1,538,
1,503, 1,462, 1,205, 1,146, 1,052, 809, 651; 1H NMR
(CDCl3?DMSO, 300 MHz): d 2.72–2.86 (m, 2H, –CH2–
CF2), 3.96 (s, 3H, –OCH3), 4.59 (t, 2H, J = 7.919 Hz,
–CH2–), 5.69 (s, 2H, –NCH2), 7.02–7.08 (m, 1H, Ar–H), 7.
13–7.19 (m, 1H, Ar–H), 7.44–7.50 (m, 1H, Ar–H), 7.68–7.
77 (m, 3H, Ar–H), 7.78–7.83 (m, 1H, Ar–H); 13C NMR
(CDCl3, 75 MHz): d 31.68 (N–CH2–CH2), 42.43 (N–CH2–
CH2), 47.12 (N–CH2), 57.06 (OCH3), 107.23, 109.12, 113.
92 (CH–Triazole), 112.63, 114.76, 116.94, 119.10, 120.00,
122.10, 122.93, 124.31, 125.03, 125.87, 126.10, 127.93,
132.76, 133.32, 133.67, 145.93, 150.71, 157.10, 158.14 (d,
J = 249.32 Hz, BT–C–F); 19F NMR (CDCl3?DMSO,
400 MHz): d -81.23 (t, 3F, J = 9.844 Hz), -114.43 to
-114.69 (m, 2F), -118.24 to -118.68 (m, 1F), -121.95 to
-122.55 (m, 6F), -123.20 (s, 2F, br), -123.89 (s, 2F, br),
-126.58 (t, 2F, J = 12.305 Hz); ESI–MS: 859 (M?1)?;
Anal. Calcd. For C28H16F18N6OS2: C 39.17, H 1.88, N 9.
79 %. Found: C 39.19, H 1.07, N 9.81 %.
6-fluoro-N-(6-methoxybenzo[d]thiazol-2-yl)-N-((1-(3-(tri-
fluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)benzo[d]
thiazol-2-amine (8c) Yield 83 %; m.p. 150–152 °C. IR
(KBr, mmax cm-1): 2,933, 1,534, 1,460, 1,324, 1,256, 1,174,
1
1,127, 1,043, 850, 802; H NMR (CDCl3, 300 MHz): d 3.
85 (s, 3H, –OCH3), 5.67 (s, 2H, –NCH2), 6.84–6.97 (m,
1H, Ar–H), 6.99–7.12 (m, 1H, Ar–H), 7.14–7.29 (m, 1H,
Ar–H), 7.35 (dt, 1H, J = 6.043 and 2.266 Hz, Ar–H), 7.
46–7.83 (m, 5H, Ar–H), 7.87 (s, 1H, Ar–H), 8.07 (s, 1H,
Triazole-H); 13C NMR (CDCl3, 75 MHz): d 47.15
(N–CH2), 57.05 (OCH3), 107.33, 109.50, 111.26
(CH–Triazole), 112.31, 114.86, 117.60, 119.95, 121.46,
123.16 (q, J = 273.37 Hz, –CF3), 123.68, 125.46, 130.43,
130.55, 132.3, 133. 21, 133.32, 145.15, 146.23, 152.60,
156.54, 157.32 (d, J = 251.60 Hz, BT–C–F); 19F NMR
(CDCl3, 400 MHz): d -63.35 (s, 3F), -118.15 to
-118.57 (m, 1F); ESI–MS: 557 (M?1)?; Anal. Calcd. For
C25H16F4N6OS2: C 53.95, H 2.90, N 15.10 %. Found: C
53.99, H 2.92, N 15.11 %.
2-(4-(((6-fluorobenzo[d]thiazol-2-yl)(6-methoxybenzo[d]
thiazol-2-yl)amino)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-fluoro
phenyl)acetamide (9a) Yield 92 %; m.p. 248–250 °C. IR
(KBr, mmax cm-1): 3,335, 2,941, 1,677, 1,536, 1,506, 1,460,
1
1,262, 1,221, 1,053, 837, 503; H NMR (CDCl3?DMSO,
300 MHz): d 3.97 (s, 3H, –OCH3), 5.20 (s, 2H, –CH2–CO),
5.72 (s, 2H, –NCH2), 6.89–7.24 (m, 4H, Ar–H), 7.48–7.62
(m, 3H, Ar–H), 7.64–7.85 (m, 3H, Ar–H), 8.05 (s, 1H,
Triazole-H), 10.28 (s, 1H, NH); 13C NMR (CDCl3,
75 MHz): d 46.70 (N–CH2), 52.02 (N–CH2–C=O), 56.47
(OCH3), 107.34, 111.00, 113.53 (CH–Triazole), 114.35
115.43, 119.23, 120.00, 122.20, 125.22, 129.08, 130.07,
132.63, 138.52, 154.20 (d, J = 247.60 Hz, Ph–C–F), 158.
06 (d, J = 246.50 Hz, BT–C–F), 160.33, 163.95 (C=O);
19F NMR (CDCl3?DMSO, 400 MHz): d -117.55 to
-118.19 (m, 2F); ESI–MS: 564 (M?1)?; Anal. Calcd. For
C26H19F2N7O2S2: C 55.41, H 3.40, N 17.40 %. Found: C
55.45, H 3.38, N 17.41 %.
N-((1-(3-chloro-4-fluorophenyl)-1H-1,2,3-triazol-4-yl)me-
thyl)-6-fluoro-N-(6- methoxybenzo[d] thiazol-2-yl)benzo[d]
thiazol-2-amine (8d) Yield 88 %; m.p. 217–219 °C. IR
(KBr, mmax cm-1): 2,930, 1,511, 1,457, 1,259, 1,050, 852,
1
804; H NMR (CDCl3, 300 MHz): d 3.95 (s, 3H, –OCH3),
5.77 (s, 2H, –NCH2), 7.08–7.25 (m, 2H, Ar–H), 7.37–7.45
(m, 1H, Ar–H), 7.50–7.90 (m, 4H, Ar–H), 7.98 (s, 1H, Ar–
H), 8.03–8.09 (m, 1H, Ar–H), 8.69 (s, 1H, Triazole-H); 13
C
N-(2,4-difluorophenyl)-2-(4-(((6-fluorobenzo[d]thiazol-2-yl)
(6-methoxybenzo[d]thiazol-2-yl)amino)methyl)-1H-1,2,3-
NMR (CDCl3, 75 MHz): d 47.35 (N–CH2), 57.07 (OCH3),
107.25, 109.52, 111.35 (CH–Triazole), 112.41, 115.15,
118.43, 119.52, 120.01, 120.13, 125.56, 131.50, 132.90,
133.51, 142.31, 146.53, 153.52 (d, J = 245.60 Hz, Ph–C–
triazol-1-yl)acetamide
(9b) Yield
95 %;
m.p.
213–215 °C. IR (KBr, mmax cm-1): 3,263, 2,931, 1,677,
123

Med Chem Res
1,536, 1,460, 1,261, 1,229, 1,051, 849, 809; 1H NMR
(CDCl3?DMSO, 300 MHz): d 3.97 (s, 3H, –OCH3), 5.32
(s, 2H, –CH2–CO), 5.72 (s, 2H, –NCH2), 6.77–6.96 (m, 2H,
Ar–H), 6.99–7.24 (m, 2H, Ar–H), 7.53 (dd, 1H, J = 8.120
and 2.077 Hz, Ar–H), 7.62 (s, 1H, Ar–H), 7.67–7.86 (m,
2H, Ar–H), 7.91–8.05 (m, 1H, Ar–H), 8.12 (s, 1H, Tria-
zole-H), 10.09 (s, 1H, NH); 13C NMR (CDCl3, 75 MHz): d
46.50 (N–CH2), 52.31 (N–CH2–C=O), 57.00 (OCH3), 106.
82 (t, J = 26.35 Hz, Ph–F–CH–F), 107.50, 111.14, 111.32,
113.92 (CH–Triazole), 114.61, 119.82, 120.32, 121.93,
125.31, 126.33, 130.34, 132.65, 149.53 (d, J = 245.35 Hz,
Ph–2C–F), 157.63 (d, J = 253.10 Hz, BT–C–F), 160.31
(d, J = 248.40 Hz, Ph–4C–F), 163.15 (C=O); 19F NMR
(CDCl3?DMSO, 400 MHz): d -113.98 to -114.13 (m,
1F), -117.54 to -118.83 (m, 1F), -121.17 (s, 1F, br.);
ESI–MS: 582 (M?1)?; Anal. Calcd. For C26H18F3N7O2S2:
C 53.69, H 3.12, N 16.86 %. Found: C 53.72, H 3.09, N 16.
87 %.
119.96, 121.10, 122.54, 124.11, 127.32, 131.65, 133.57,
141.24, 154.00 (d, v246.93 Hz, Ph–4C–F), 157.15, 159.31
(d, v251.90 Hz, BT–C–F), 165.34 (C=O); 19F NMR
(CDCl3?DMSO, 400 MHz): d -117.70 to -118.93 (m,
1F), -120.77 (s, 1F); ESI–MS: 599 (M?1)?; Anal. Calcd.
For C26H18ClF2N7O2S2: C 52.22, H 3.03, N 16.39 %.
Found: C 52.21, H 3.04, N 16.37 %.
2-(4-(((6-fluorobenzo[d]thiazol-2-yl)(6-methoxybenzo[d]
thiazol-2-yl)amino)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-tri-
fluoromethylthio)phenyl)acetamide (9e) Yield 94 %; m.
p. 183–185 °C. IR (KBr, mmax cm-1): 3,336, 2,936, 1,690,
1,599, 1,536, 1,460, 1,261, 1,117, 834, 514; 1H NMR
(CDCl3?DMSO, 300 MHz): d 3.83 (s, 3H, –OCH3), 5.21
(s, 2H, –CH2–CO), 5.66 (s, 2H, –NCH2), 6.88–7.82 (m,
10H, Ar–H), 8.02 (s, 1H, Triazole-H), 10.48 (s, 1H, NH);
13C NMR (CDCl3, 75 MHz): d 46.60 (N–CH2), 52.21 (N–
CH2–C=O), 56.41 (OCH3), 106.85, 110.93, 111.84, 113.33
(CH–Triazole), 114.11, 114.82, 117.60, 119.70, 120.75,
124.84, 125.75, 126.46 (q, J = 245.93 Hz, SCF3), 127.63,
129.74, 132.60, 136.56, 140.22, 143.30, 151.80, 155.76,
158.72, 159.94 (d, J = 283.36 Hz, BT–C–F), 161.55, 163.
42 (C=O); 19F NMR (CDCl3?DMSO, 400 MHz): d -41.
58 (s, 3F), -117.15 to -118.83 (m, 1F); ESI–MS: 646
(M?1)?; Anal. Calcd. For C27H19F4N7O2S3: C 50.22, H 2.
97, N 15.19 %. Found: C 50.23, H 2.94, N 15.23 %.
2-(4-(((6-fluorobenzo[d]thiazol-2-yl)(6-methoxybenzo[d]
thiazol-2-yl)amino)methyl)-1H-1,2,3-triazol-1-yl)-N-(3-tri-
fluoromethyl)phenyl)acetamide (9c) Yield 91 %; m.p.
194–196 °C. IR (KBr, mmax cm-1): 3,264, 2,924, 1,683,
1,532, 1,457, 1,329, 1,259, 1,167, 1,120, 1,056, 851, 799;
1H NMR (CDCl3?DMSO, 300 MHz): d 3.94 (s, 3H,
–OCH3), 5.23 (s, 2H, –CH2–CO), 5.69 (s, 2H, –NCH2), 6.
88–7.25 (m, 2H, Ar–H), 7.29 (d, 1H, J = 8.120 Hz, Ar–H),
7.35–7.48 (m, 2H, Ar–H), 7.54 (d, 1H, J = 7.743 Hz, Ar–
H), 7.60–7.85 (m, 3H, Ar–H), 7.94 (s, 1H, Ar–H), 8.07 (s,
1H, Triazole-H), 10.55 (s, 1H, NH); 13C NMR (CDCl3,
75 MHz): d 46.41 (N–CH2), 52.53 (N–CH2–C=O), 56.15
(OCH3), 107.65, 111.45, 113.15 (CH–Triazole), 114.81,
117.93, 119.20, 120.00, 122.21, 121.34, 122.95 (q, J =
252.32 Hz, –CF3), 127.30, 129.31, 131.63, 132.23, 134.32,
142.93, 157.63 (d, J = 248.95 Hz, BT–C–F), 160.70, 163.
66 (C=O); 19F NMR (CDCl3?DMSO, 400 MHz): d -62.
29 (s, 3F), -117.68 to -118.91 (m, 1F); ESI–MS: 614
(M?1)?; Anal. Calcd. For C27H19F4N7O2S2: C 52.85, H 3.
12, N 15.98 %. Found: C 52.89, H 3.10, N 15.96 %.
2-(4-(((6-fluorobenzo[d]thiazol-2-yl)(6-methoxybenzo[d]
thiazol-2-yl)amino)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-
trifluoromethoxy)benzyl)acetamide (9f) Yield 92 %; m.p.
221–223 °C. IR (KBr, mmax cm-1): 3,279, 2,931, 1,665,
1
1,535, 1,461, 1,265, 1,219, 1,163, 1,048, 804; H NMR
(CDCl3?DMSO, 300 MHz): d 3.84 (s, 3H, –OCH3), 4.32
(s, 2H, –CH2–CO), 5.07 (s, 2H, Ar–CH2), 5.68 (s, 2H,
–NCH2), 6.91–7.44 (m, 7H, Ar–H), 7.46–7.86 (m, 3H, Ar–
H), 8.05 (s, 1H, Triazole-H), 8.73 (s, 1H, NH); 13C NMR
(CDCl3, 75 MHz): d 42.15 (NH–CH2), 46.72 (N–CH2), 52.
39 (N–CH2–C=O), 56.43 (OCH3), 107.13, 111.35, 112.93
(CH–Triazole), 114.73, 118.34, 119.55, 120.84, 122.00
(q, J = 247.73 Hz, OCF3), 126.94, 129.53, 132.44, 133.83,
134.22, 149.93, 157.13 (d, J = 256.34 Hz, BT–C–F),
N-(3-chloro-4-fluorophenyl)-2-(4-(((6-fluorobenzo[d]thia-
zol-2-yl)(6-methoxybenzo[d]thiazol-2-yl)amino)methyl)-
1H-1,2,3-triazol-1-yl)acetamide (9d) Yield 89 %; m.p.
224–226 °C. IR (KBr, mmax cm-1): 3,261, 2,924, 1,681,
1,537, 1,502, 1,460, 1,264, 1,228, 1,054, 854, 818; 1H
NMR (CDCl3?DMSO, 300 MHz): d 3.85 (s, 3H, OCH3),
5.21 (s, 2H, –CH2–CO), 5.71 (s, 2H, –NCH2), 6.92–7.30
(m, 3H, Ar–H), 7.33–7.48 (m, 2H, Ar–H), 7.58–7.87 (m,
3H, Ar–H), 7.94 (s, 1H, Ar–H), 8.06 (s, 1H, Triazole-H),
10.45 (s, 1H, NH); 13C NMR (CDCl3, 75 MHz): d 46.33
(N–CH2), 52.43 (N–CH2–C=O), 56.71 (OCH3), 107.75,
111.92, 114.10 (CH–Triazole), 114.93, 117.93, 119.40,
160.00,
164.11
(C=O);
19F
NMR
(CDCl3?
DMSO, 400 MHz): d -56.98 (s, 3F), -117.12 to -118.80
(m, 1F); ESI–MS: 644 (M?1)?; Anal. Calcd. For
C28H21F4N7O3S2: C 52.25, H 3.29, N 15.23 %. Found: C
52.28, H 3.27, N 15.24 %.
2-(4-(((6-fluorobenzo[d]thiazol-2-yl)(6-methoxybenzo[d]
thiazol-2-yl)amino)methyl)-1H-1,2,3-triazol-1-yl)-N-(5-tri-
fluoromethyl)-1,3,4-thiadiazol-2-yl)acetamide (9 g) Yield
96 %; m.p. 218–220 °C. IR (KBr, mmax cm-1): 3,158,
2,941, 1,710, 1,535, 1,461, 1,328, 1,304, 1,262, 1,194,
123

Med Chem Res
1,157, 1,041, 851, 806; 1H NMR (CDCl3?DMSO,
300 MHz): d 3.94 (s, 3H, –OCH3), 5.48 (s, 2H, –CH2–CO),
5.69 (s, 2H, –NCH2), 6.87–7.28 (m, 2H, Ar–H), 7.34 (s,
1H, Ar–H), 7.40–7.90 (m, 3H, Ar–H), 8.11 (s, 1H, Tria-
zole-H), 13.65 (s, 1H, NH); 13C NMR (CDCl3, 75 MHz): d
46.60 (N–CH2), 51.21 (N–CH2–C=O), 56.30 (OCH3), 107.
14, 110.83, 113.63 (CH–Triazole), 114.23, 119.56, 120.76,
121.91 (q, J = 273.33 Hz, –CF3), 125.93, 132.42, 137.75,
145.463, 151.82, 155.53, 158.20 (d, J = 254.34 Hz, BT–
C–F), 160.17, 160.43, 165.00 (C=O); 19F NMR (CDCl3?
DMSO, 400 MHz): d -58.86 (s, 3F), -117.58 to -118.75
(m, 1F); ESI–MS: 622 (M?1)?; Anal. Calcd. For
C23H15F4N9O2S3: C 44.44, H 2.43, N 20.28 %. Found: C
44.45, H 2.41, N 20.26 %.
C26H26FN7O2S2: C 56.61, H 4.75, N 17.77 %. Found: C
56.60, H 4.77, N 17.78 %.
Acknowledgments Authors thankful to Dr. J. S. Yadav, Formal
Director, IICT for providing facilities, T.D. thank for UGC, and R.P,
L.R.V. and U.K. thank for CSIR, New Delhi, for the award of a
fellowship, and R.M.K thanks S.E.R.C., Department of Science &
Technology, Government of India for financial assistance under the
Fast Track Scheme for young scientists (SR/FT/CS-031/2010).
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acetamide (9i) Yield 92 %; m.p. 180–182 °C. IR (KBr,
mmax cm-1): 3,279, 2,926, 2,852, 1,658, 1,533, 1,458,
1,261, 1,049, 801; 1H NMR (CDCl3?DMSO, 300 MHz): d
1.04–1.40 (m, 5H, Cyh-H), 1.51–1.90 (m, 5H, Cyh-H), 3.
47–3.66 (m, 1H, Cyh–CH), 3.95 (s, 3H, –OCH3), 4.93 (s,
2H, –CH2–CO), 5.66 (s, 2H, –NCH2), 6.88–7.23 (m, 2H,
Ar–H), 7.32 (s, 1H, Ar–H), 7.45 (s, 1H, Ar–H), 7.52–7.82
(m, 2H, Ar–H), 7.90–8.05 (m, 2H, Ar–H); 13C NMR
(CDCl3, 75 MHz): d 26.92 (Cyhx-4-CH2), 28.50 (Cyhx-
3,5-CH2), 34.93 (Cyhx-2,6-CH2), 46.35 (N–CH2), 52.53
(N–CH2–C=O), 54.63 (Cyhx-1-CH), 57.09 (OCH3), 107.
93, 109.45, 111.53, 112.63 (CH–Triazole), 114.90, 120.03,
124.33, 129.05, 130.53, 134.13, 147.00, 152.15, 157.16,
159.10 (d, J = 254.10 Hz, BT–C–F), 163.15 (C=O); 19F
NMR (CDCl3?DMSO, 400 MHz): d -117.66 to -118.83
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