Synthesis and antimicrobial activities of novel quinoline derivatives carrying 1,2,4-triazole moiety

Article abstract of DOI:10.1016/j.ejmech.2009.06.031

A new class of quinoline derivatives containing 1,2,4-triazole moiety were synthesized from derivatives of 4-hydroxy-8-(trifluoromethyl)quinoline-3-carbohydrazide 4 through multi-step reactions. The compound 4, on treatment with substituted Isothiocyanates yielded quinoline-thiosemicarbazides 5a-c, which were conveniently cyclized to (5-mercapto-4H-triazol-3-yl)-quinolin-4-ols 6a-c in basic medium. These intermediates were then transformed to their respective chloro derivatives 7a-c by treatment with phosphorus oxychloride, which on further reaction with different biologically active rare amines yielded the target compounds 8a-g, 9a-h and 10a-h in good yield. The ultimate step, involving nucleophilic substitution reaction was achieved by microwave-induced technique, which has reduced the reaction time drastically as well as improved the yield when compared to conventional heating. The newly synthesized final compounds were evaluated for their in vitro antibacterial and antifungal activities against four strains each. Preliminary results indicated that most of the compounds demonstrated very good antimicrobial activity, comparable to the first line standard drugs. The most effective compounds have exhibited activity at MIC of 6.25 μg/mL.

Full text of DOI:10.1016/j.ejmech.2009.06.031

European Journal of Medicinal Chemistry 44 (2009) 4637–4647
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and antimicrobial activities of novel quinoline derivatives carrying
1,2,4-triazole moiety
,
c
Sumesh Eswaran a, Airody Vasudeva Adhikari b , N. Suchetha Shetty
*
a Anthem Biosciences Pvt. Ltd, 49 Bommasandra Industrial Area, Bommasandra, Bangalore 560099, Karnataka, India
b Department of Chemistry, National Institute of Technology Karnataka, Surathkal, Srinivasnagar, Mangalore 575025, Karnataka, India
c Department of Biochemistry, Justice K.S. Hegde Medical Academy, Deralakatte, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new class of quinoline derivatives containing 1,2,4-triazole moiety were synthesized from derivatives
Received 18 September 2008
Received in revised form
6 June 2009
Accepted 29 June 2009
Available online 3 July 2009
of 4-hydroxy-8-(trifluoromethyl)quinoline-3-carbohydrazide
4 through multi-step reactions. The
compound 4, on treatment with substituted Isothiocyanates yielded quinoline-thiosemicarbazides 5a–c,
which were conveniently cyclized to (5-mercapto-4H-triazol-3-yl)-quinolin-4-ols 6a–c in basic medium.
These intermediates were then transformed to their respective chloro derivatives 7a–c by treatment with
phosphorus oxychloride, which on further reaction with different biologically active rare amines yielded
the target compounds 8a–g, 9a–h and 10a–h in good yield. The ultimate step, involving nucleophilic
substitution reaction was achieved by microwave-induced technique, which has reduced the reaction
time drastically as well as improved the yield when compared to conventional heating. The newly
synthesized final compounds were evaluated for their in vitro antibacterial and antifungal activities
against four strains each. Preliminary results indicated that most of the compounds demonstrated very
good antimicrobial activity, comparable to the first line standard drugs. The most effective compounds
Keywords:
Quinoline
1,2,4-Triazole
Antibacterial activity
Antifungal activity
8-(Trifluoromethyl)quinoline derivatives
have exhibited activity at MIC of 6.25 mg/mL.
Ó 2009 Elsevier Masson SAS. All rights reserved.
1. Introduction
ideally suited for further modifications to obtain more efficacious
antibacterial compounds.
Quinoline moiety is of great importance to chemists as well as
biologists as it is found in a large variety of naturally occurring
compounds and also chemically useful molecules having diverse
biological activities. A large variety of quinoline derivatives have
been used as antimalarial [1], anti-inflammatory [2], anticancer [3],
antibiotic [4], antihypertensive [5], tyrokinase PDGF-RTK inhibiting
agents [6], and anti HIV [7,8]. In addition to the medicinal impor-
tance, multi-substituted quinolines are valuable synthons used for
the preparation of nano- and mesostructures with enhanced elec-
tronic and photonic properties [9–11].
It has been well established that fluorinated, in particular, CF3
substituted heterocycles have got a significant place in modern
medicinal chemistry [12]. Their biological studies clearly indicate
that the presence of trifluoromethyl group in position 8 of the
quinoline ring gives useful biological activity and are the subject of
considerable growing interest [13]. These effective derivatives are
On the other hand, it has been reported that 1,2,4-triazole
derivatives possess a wide spectrum of chemotherapeutic activities
including anti-inflammatory [14], anticancer [15], anti depressant
[16], antibacterial [17], antifungal [18] and anticonvulsant proper-
ties [19]. In fact, some of their derivatives are active constituents of
currently used drugs. Further, various amino derivatives of quino-
lines as well as 1,2,4-triazoles were shown to possess excellent
pharmacological properties such as antimicrobial, analgesic and
anti-inflammatory activities. On the basis of these observations, it
was thought of synthesizing a new class of heterocyclics, wherein
potent 1,2,4-triazole moiety is linked to position 3 while biologi-
cally active rare amines attached to position 4 of 8-trifluoromethyl
quinoline. These structures have been designed on the basis of
combinatorial synthesis, which is the current trend being practiced
in most of the drug discoveries. This communication reports the
synthesis of hitherto unknown 8a–g, 9a–h and 10a–h starting from
2-trifluoro aniline 1 and evaluation of their in vitro antimicrobial
properties. In the present synthesis, the ultimate step was achieved
using microwave technique. This has brought about drastic
reduction in reaction time and moreover, it has enhanced the yields
of target compounds (Table 1).
* Corresponding author. Tel.: þ91 (0)824 2474000x3203; fax: þ91 (0)824
2474033.
E-mail addresses: avchem@nitk.ac.in, avadhikari123@yahoo.co.in (A.V.
Adhikari).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.06.031

4638
S. Eswaran et al. / European Journal of Medicinal Chemistry 44 (2009) 4637–4647
Table 1
4-Subsituted-5-[4-(substituted amino)-8-(trifluoromethyl)quinolin-3-yl]-4H-1,2,4-triazole-3-thiols.
R1
R2
H N
2
H2N
HN
(CH ) OH
2 3
H2N
HN
O
–CH2Ph
–Ph
8a
9a
8b
9b
8c
9c
8d
9d
8e
9e
–CH2CH2OMe
10a
10b
10c
10d
10e
R1
R2
HN
N (CH ) NH
2 2 2
O
HN
HN
N
N
N
HN
N C6H11
H N
HN
O
–CH2Ph
–Ph
–CH2CH2OMe
8f
9f
10f
8g
–
–
–
9g
–
–
–
10g
–
–
10h
–
9h
–
2. Results and discussion
The mass spectrum of 2 showed a molecular ion peak at m/z
332.3 (100%), which matches with its molecular formula
2.1. Chemistry
C15H16F3NO4.
The cyclization of diethyl ester 2 to 4-hydroxyquinoline-3-
The reaction sequences employed for synthesis of title
compounds are shown in Scheme 1. Following the procedure
described by Price and Roberts [20], the starting material 2-(tri-
fluoromethyl) aniline 1 was conveniently converted to diethyl ({[2-
(trifluoromethyl) phenyl] amino} methylidene) propanedioate 2, by
condensing it with diethyl ethoxymethylene malonate. The diester
2, on heating at 250 ꢀC in Dowtherm medium, readily cyclized to
ethyl 4-hydroxy-8-(trifluoromethyl)quinoline-3-carboxylate 3,
which on condensation with hydrazine hydrate in alcoholic
medium gave 8-(trifluoromethyl)-4-hydroxyquinoline-3-carbohy-
drazide 4 in good yield. Further, the key intermediates, thio-
semicarbazides 5a–c were synthesized by refluxing the
carboxylate 3 was evidenced by its 1H NMR spectrum; the disap-
pearance of one triplet and one quartet of –CH2– and –CH3 protons
from
disappearance of a sharp doublet from
indicates the aromatization of quinoline ring. Appearance of
a broad singlet at 11.69 (which disappeared on D2O exchange)
d
1.38 and
d
4.45 clearly evidences the smooth cyclization, also
d
8.45 of >C]CH– proton
d
confirms the presence of –OH proton at the 4th position of quin-
oline. The entire aromatic proton shift towards downfield also gives
a strong indication of quinoline aromatization. In the FTIR spec-
trum, compound 3 exhibited a broad band at 3519 cmꢁ1 due to –OH
stretching. The mass spectrum of it showed a molecular ion peak at
m/z 285.96 (100%), which matches with its molecular formula
C13H10F3NO3.
carbohydrazide
4 with different isothiocyanates in alcoholic
medium using the procedure described by Silber and Cosma [21].
The compounds 5a–c were then conveniently cyclized in basic
medium to give (5-mercapto-4H-triazol-3-yl)-8-(trifluoromethyl)
quinolin-4-ol 6a–c, which on refluxing with phosphorus oxy-
chloride yielded the corresponding 4-chloro derivatives, 7a–c.
Interestingly, an unusual product, with a yield of 20–30%, was
isolated during the reaction, which was found to be a dimer of type
7d–f on analysis. Finally, the target compounds, viz. 5-(4-amino
The formation of 4-hydroxy-8-(trifluoromethyl)quinoline-3-
carbohydrazide 4 from ester 3 was confirmed by its FTIR, 1H NMR
and LC/MS spectra. FTIR spectrum of 4 showed strong bands at
3256 and 3293 cmꢁ1 indicating the presence of –NHNH2 group,
while the disappearance of triplet and quartet of –CH2– and –CH3
protons in 1H NMR spectrum clearly confirms the formation of 4.
Further the mass spectrum of 4 showed a molecular ion peak at m/z
271.9 (98%), which tallies with its molecular formula C11H8F3N3O2.
The structures of compounds 5a–c were elucidated by its FTIR,
NMR and LC/MS. FTIR spectrum of 5a reveals the presence of both
–NH groups due to absorbance bands at 3442 and 3491 cmꢁ1 while
that of >C]O and >C]S were observed at 1671 and 1269 cmꢁ1
respectively. The 1H NMR spectrum was in accordance with its
structure while the mass spectrum of it showed a molecular ion
peak at 421 (52%), which matches with its molecular formula
C19H15F3N4O2S.
substituted-8-(trifluoromethyl)quinolin-3-yl)-4-(un)
substituted
phenyl-4H-1,2,4-triazole-3-thiols (8a–g, 9a–h and 10a–h) were
synthesized from their precursors 7a–c by acetonitrile assisted
microwave-induced reaction using different rare and bio-active
amines. This reaction went on very fast and their yields were
excellent. The structures of all the newly synthesized compounds
were confirmed by FTIR, 1H and 13C NMR and mass spectral (ESI)
studies and elemental analysis.
The formation of ester 2 from 2-(trifluoromethyl) aniline 1 was
evidenced by its IR, 1H NMR and mass spectra. Its IR spectrum
showed strong bands at 1709, 1657 and 3467 cmꢁ1 indicating the
presence of ester >C]O, >C]C< and –NH– groups respectively,
while its 1H NMR spectrum showed two triplets and two quartets
The cyclization of 5a–c to form 6a–c was established byrecording
its FTIR, NMR and MS spectra. In FTIR spectrum of 6a absorbance
band of >C]S appeared at 1204 cmꢁ1 while that of >C]O dis-
appeared, this gives a strong indication of cyclization of 5a. Also, the
spectrum showed strong bands at 1623 and 3529 cmꢁ1 indicating
the presence of >C]N– and –OH group respectively. The mass
spectrum of 6a displayed a molecular ion peak at m/z 403 (100%),
which confirms to its molecular formula C19H13F3N4OS. In the 1H
at
–CH3 protons, indicating the presence of two –COOC2H5 groups.
The presence of a sharp doublet at 8.45 clearly reveal the pres-
ence of >C]CH– proton and a broad doublet at 11.45 (which
disappeared on D2O exchange) manifest the presence of –NH–C.
d 1.33, 1.38 and d 4.26, 4.45 respectively, due to two –CH2– and
d
d
NMR spectrum of 6a, it appeared a singlet at
d 14.08 integrating for
one proton of triazole ring. The smooth cyclization of 5a was further

S. Eswaran et al. / European Journal of Medicinal Chemistry 44 (2009) 4637–4647
4639
confirmed by the fact that the doublet peak of benzylic proton at
4.73 in 5a was shifted towards downfield to a singlet at 5.28.
quinoline ring. Its 1H NMR spectrum indicates the presence of two
multiplet due to two –CH2– groups at 0.41 and 0.55 and one
multipletdue to–CH– group at 2.21 ofcyclopropylring, and abroad
singlet at 7.86 clearly reveals the coupling of cyclopropyl amine
d
d
d
The structure of 4-benzyl-5-[4-chloro-8-(trifluoromethyl)quinolin-
d
3-yl]-4H-1,2,4-triazole-3-thiol 7a was determined by FTIR, MS, 1H and
13C NMR spectral studies. In FTIR spectrum of 7a the appearance of
medium band at 780 cmꢁ1 and disappearance of strong O–H stretching
band clearly indicates the replacement of O–H with Cl group. In the 1H
d
with 7a. Finally, the structure of the compound 8a was confirmed
by its mass spectrum, which showed molecular ion peak at m/z
442.1 (100%). This conforms to its molecular formula C22H18F3N5S.
Similarly, the structure of 5-(4-(4-(2-aminoethyl)piperazin-1-yl)-8-
(trifluoromethyl)quinolin-3-yl)-4-benzyl-4H-1,2,4-triazole-3-thiol
(8g) was evidenced by its mass spectrum. It displayed the molecular
ion peak at m/z 515 (45%), which is in agreement with the molecular
formula C25H26F3N7S. The major peaks at m/z 515 (M þ 2, 45%), 496
(19%), 470 (18%), 438 (37%), 395 (37%), 353 (37%), 351 (100%) and 239
(18%) were due to the fragmentation of molecular ion leading to
formation of important species with complex structures, as shown
in Scheme 2. Further, the mass spectral data of compounds 9b and
10d confirmed their structures (Table 2).
NMR shiftingof
to quinoline N clearly indicates the formation of 7a. Further, 13C NMR
showed signals at : 47.24 due to benzylic C, peak at 120.57 due to CF3,
127.58,128.18,130.09,135.46 due to benzene ring C, peaks at 125.81,
126.86, 127.25, 128.79, 131.51, 131.58, 146.78, 151.26, 168.47 due to
quinoline ring C and 144.37 and 145.37 due to triazole C2 and C5.
dfrom7.95 to 8.54 due to aromatic –CH– groupadjacent
d
d
d
d
d
Further, its mass spectrum showed molecular ion peak at m/z 421.0
(100%), which corresponds to its molecular formula C19H12 ClF3N4S.
The formation of unusual product 7d was confirmed by LC/MS
and 1H NMR and was in accordance with its structure as shown in
Scheme 1.
The formation of the title compound 8a by microwave-assisted
reaction with cyclopropyl amine with the corresponding chloro
compound 7a was evidenced by IR, 1H NMR and mass spectral
data. The IR spectrum of 8a showed a broad band at 3345 cmꢁ1
due to –NH– stretching, also the disappearance of C–Cl stretching
band indicates the chloro amine coupling at the 4th position of
2.2. Biological activities
2.2.1. Antibacterial studies
The newly synthesized compounds were screened for their anti-
bacterial activity against Escherichia coli (ATTC-25922), Staphylococcus
aureus (ATTC-25923), Pseudomonas aeruginosa (ATCC-27853) and
OH
COOEt
COOEt
a
b
NH COOEt
CF3
(2)
NH2
N
CF3
(1)
CF3
(3)
c
N
OH
N
OH
O
OH
O
H
H
N
SH
N
d
1
e
NH2
N
N
R
N
1
H
H
S
R
N
N
N
CF3
CF3
CF3
(6a-c)
(4)
(5a-c)
f
2
R
N
N
Cl
N
N
SH
SH
g
N
N
1
1
R
R
N
N
CF3
CF3
7(a-c)
8(a-g)
9(a-h)
10(a-h)
+
CF3
N
1
R
N
N
N
S
N
N
Cl
N
1
SH
R
= Ph, -CH2Ph, -CH2CH2OMe;
N
2
R
= substituted amines; Listed in Table 1
1
R
CF3
7(d-f)
(20 - 30%)
Dimer
Scheme 1. (a) 2-CF3 aniline, (COOEt)2C]C–OEt, 110 ꢀC, 4 h (b) Diphenylether, 250 ꢀC, 4 h (c) NH2NH2, 80 ꢀC, 6 h. (d) R1NCS, EtOH, 82 ꢀC. (e) KOH, 110 ꢀC, 2 h (f) POCl3, 60 ꢀC, 2 h (g)
NR2, K2CO3, ACN, 120 ꢀC,
W, 10 min.
m

4640
S. Eswaran et al. / European Journal of Medicinal Chemistry 44 (2009) 4637–4647
.
+
CH2
.
+
H
.
N
+
N
N
H
S
N
+
N
N
N
N
N
N
S
N
N
N
CF3
N
CF3
CF3
m/z 91
m/z 465
m/z 295
m/z 395
NH2
.
+
.
CH2
+
N
.
N
+
N
H
H
N
N
N
N
N
N
N
N
N
N
-NH
N
N
3
SH
S
S
N
N
N
CF3
CF3
CF3
m/z 470
-SH
m/z 515
m/z 496
NH2
.
H
+
.
+
N
N
N
N
N
N
N
N
N
N
N
CF3
N
m/z 438
CF3
.
+
m/z 389/391
NH2
N
N
N
N
HN
+
H2N
+
N
N
NH
N
N
CF3
CF3
m/z 397
N
CF3
m/z 239
m/z 351
.
+
N
N
N
N
CF3
m/z 353
Scheme 2. Mass fragmentation pattern of compound 8g.
Klebsiella pneumoniae (recultured) bacterial stains by serial plate
dilution method[22,23]. SerialdilutionsofthedruginMueller–Hinton
broth were taken in tubes and their pH was adjusted to 5.0 using
phosphate buffer. A standardized suspension of the test bacterium
was inoculated and incubated for 16–18 h at 37 ꢀC. The minimum
inhibitory concentration (MIC) was noted by seeing the lowest
concentration of the drug at which there was no visible growth.
A number of antimicrobial discs are placed on the agar for the
sole purpose of producing zones of inhibition in the bacterial lawn.
Twenty milliliters of agar media was poured into each Petri dish.
Excess of suspension was decanted and plates were dried by
placing in an incubator at 37 ꢀC for an hour. Using an agar punch,
wells were made on these seeded agar plates and minimum
inhibitory concentrations of the test compounds in dimethylsulf-
oxide (DMSO) were added into each labeled well. A control was also
prepared for the plates in the same way using solvent DMSO. The
Petri dishes were prepared in triplicate and maintained at 37 ꢀC for
3–4 days. Antibacterial activity was determined by measuring the
diameter of inhibition zone. Activity of each compound was
compared with ciprofloxacin as standard [24,25]. Zone of inhibition
was determined for 6a–c, 7a–c, 8a–g, 9a–h and 10a–h and the
results are summarized in Table 3.

S. Eswaran et al. / European Journal of Medicinal Chemistry 44 (2009) 4637–4647
4641
Table 2
Characterization data of compounds 6a–c, 7a–c, 8a–g, 9a–h and 10a–h.
Compound
R1
R2
Molecular formula/Mol. weight
M.P (ꢀC)
Yielda%
Analysis % found. Found (Calc.)
C
H
N
6a
6b
6c
7a
7b
7c
8a
8b
8c
8d
8e
8f
8g
9a
9b
9c
9d
9e
CH2–Ph
Ph
CH2CH2OMe
CH2–Ph
Ph
CH2CH2OMe
CH2–Ph
CH2–Ph
CH2–Ph
CH2–Ph
CH2–Ph
CH2–Ph
CH2–Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
OH
OH
OH
Cl
Cl
Cl
C19H13F3N4OS/402
C18H11F3N4OS/388
C15H13F3N4O2S/370
C19H12 ClF3N4S/420
C18H10 ClF3N4S/406
C15H12 ClF3N4OS/388
C22H18F3N5S/441
C25H24F3N5S/483
C25H26F3N5S/485
C27H28F3N4OS/527
C23H20F3N5OS/471
C29H31F3N6S/552
C25H26F3N7S/513
C21H16F3N5S/427
C24H22F3N5S/469
280
303
152
192
203
173
210
253
219
245
240
294
237
223
250
242
219
246
226
209
234
238
235
210
191
256
246
213
266
86
88
95
65
73
71
83
86
88
86
86
90
80
88
91
90
91
86
86
86
78
92
92
96
89
92
77
87
86
56.72 (56.71)
55.71 (55.67)
48.69 (48.65)
54.26 (54.23)
53.18 (53.14)
46.39 (46.34)
59.89 (59.85)
62.13 (62.10)
61.82 (61.84)
61.48 (61.46)
58.52 (58.59)
63.06 (63.02)
58.40 (58.47)
59.12 (59.01)
61.45 (61.39)
61.17 (61.13)
60.83 (60.80)
57.80 (57.76)
62.50 (62.44)
60.29 (60.23)
60.05 (59.99)
52.84 (52.80)
55.89 (55.86)
55.69 (55.61)
55.76 (55.74)
51.98 (51.93)
57.61 (57.68)
53.12 (53.09)
53.98 (53.95)
3.25 (3.26)
2.89 (2.85)
3.58 (3.54)
2.89 (2.87)
2.52 (2.48)
3.17 (3.11)
4.14 (4.11)
4.98 (5.00)
5.49 (5.40)
5.38 (5.35)
4.24 (4.28)
5.67 (5.65)
5.18 (5.10)
3.83 (3.77)
4.77 (4.72)
5.16 (5.13)
5.15 (5.10)
4.01 (3.97)
5.49 (5.43)
5.08 (5.05)
5.09 (5.03)
4.47 (4.43)
5.39 (5.36)
5.83 (5.78)
5.73 (5.70)
4.65 (4.59)
6.09 (6.00)
5.14 (5.12)
5.19 (5.17)
13.94 (13.92)
14.47 (14.43)
15.11 (15.13)
13.27 (13.31)
13.84 (13.77)
14.45 (14.41)
15.82 (15.86)
14.50 (14.48)
14.46 (14.42)
13.24 (13.27)
14.81 (14.85)
15.24 (15.21)
19.04 (19.09)
16.29 (16.38)
14.98 (14.92)
14.89 (14.85)
13.68 (13.64)
15.39 (15.31)
15.69 (15.60)
16.89 (16.86)
15.60 (15.55)
17.14 (17.11)
15.56 (15.51)
15.50 (15.44)
14.14 (14.13)
15.98 (15.94)
16.19 (16.14)
18.60 (18.57)
14.93 (14.98)
Cyclopropyl amine
Cyclohexyl amine
3,3 Dimethyl butylamine
Piperidine-4-propanol
Morpholine
1-Cyclohexyl piperazine
2-Piperazine ethyl amine
Cyclopropyl amine
Cyclohexyl amine
3,3 Dimethyl butylamine
Piperidine-4-propanol
Morpholine
1-Cyclohexyl piperazine
2-Piperazine ethyl amine
4-Piperidine morpholine
Cyclopropyl amine
Cyclohexyl amine
3,3 Dimethyl butylamine
Piperidine-4-propanol
Morpholine
C24H24F3N5S/471
C26H26F3N5OS/513
C22H18F3N5OS/457
C28H29F3N6S/538
C25H25F3N6S/498
C27H27F3N6OS/540
C18H18F3N5OS/409
C21H24F3N5OS/451
C21H26F3N5OS/453
C23H28F3N5O2S/495
C19H20F3N5O2S/439
C25H31F3N6OS/520
C21H25F3N6OS/466
C21H24F3N5O2S/467
9f
9g
9h
10a
10b
10c
10d
10e
10f
10g
10h
CH2CH2OMe
CH2CH2OMe
CH2CH2OMe
CH2CH2OMe
CH2CH2OMe
CH2CH2OMe
CH2CH2OMe
CH2CH2OMe
1-Cyclohexyl piperazine
4-Ethyl piperazine
3,5 Dimethyl morpholine
a
After column purification.
2.2.2. Antifungal studies
phenyl and alkyl group –CH2CH2OCH3 to the triazole ring at posi-
tion 3 of quinoline caused enhanced activity. The presence of –CF3
groups at position 8 of quinoline ring caused good antibacterial
activity while introduction of benzylic group at triazole caused
decrease in activity against most of the strains. The compounds 7c,
8b, 8c and 8d exhibited moderate activity compared to that of
standard against all the bacterial strains. Compounds 9f, 9g, 10f and
10g showed very good activity against E. coli, while compounds 8e,
8f, 8g, 9d and 10d showed very good activity against S. aureus. The
compounds 6b, 6c, 7b, 8a, 9a, 9b, 9c, 9e, 9h, 10a, 10b, 10c, 10e and
10h showed comparatively very good activity against all the fungal
strains. The structures of these compounds contain biologically
active –SH, –CH2CH2OCH3 and –Ph groups attached to triazole ring
in position 3 of the quinoline ring and aryl group such as phenyl and
alkyl group –CH2CH2OCH3 to the triazole ring at position 3 of
quinoline ring. The compounds 7c, 8b, 8c, 8d and 8e exhibited
moderate activity against all fungal strains. Results showed that
combination of quinoline with triazole ring gave an enhanced
biological effect against all the bacterial strains.
Newly prepared compounds were screened for their antifungal
activity against Aspergillus flavus (NCIM No. 524), Aspergillus fumi-
gatus (NCIM No. 902), Penicillium marneffei (recultured) and
Trichophyton mentagrophytes (recultured) in DMSO by serial plate
dilution method [26,27]. Sabourands agar media was prepared by
dissolving peptone (1 g), D-glucose (4 g) and agar (2 g) in distilled
water (100 mL) and adjusting the pH to 5.7. Normal saline was used
to make a suspension of spore of fungal strains for lawning. A
loopful of particular fungal strain was transferred to 3 mL saline to
get a suspension of corresponding species. Twenty milliliters of
agar media was poured into each Petri dish. Excess of suspension
was decanted and plates were dried by placing in incubator at 37 ꢀC
for 1 h. Using a punch, wells were made on these seeded agar plates
minimum inhibitory concentrations of the test compounds in
DMSO were added into each labeled well. A control was also
prepared for the plates in the same way using solvent DMSO. The
Petri dishes were prepared in triplicate and maintained at 37 ꢀC for
3–4 days. Antifungal activity was determined by measuring the
diameter of inhibition zone. Activity of each compound was
compared with Ciclopirox olamine as standard. Zones of inhibition
were determined for 6a–c, 7a–c, 8a–g, 9a–h and 10a–h and the
results are summarized in Table 4.
3. Conclusion
The research study reports the successful synthesis and anti-
microbial activity of new 5-(4-amino substituted-8-(tri-
2.2.3. Biological results
fluoromethyl)quinolin-3-yl)-4-(un)substituted
phenyl-4H-1,2,4-
The investigation of antibacterial and antifungal screening data
revealed that all the tested compounds 6a–c, 7a–c, 8a–g, 9a–h and
10a–h showed moderate to good inhibition at 6.25–12.5 mg/mL in
DMSO. The compounds 6b, 6c, 7b, 8a, 9a, 9b, 9c, 9e, 9h, 10a, 10b,
10e and 10h showed comparatively very good activity against all
the bacterial strains. The good activity is attributed to the presence
of pharmacologically active rare amine at position 4 of quinoline,
–SH, –CH2CH2OCH3 and –Ph groups attached to triazole moiety at
position 3 of the quinoline ring. Introduction of aryl group such as
triazole-3-thiols carrying biologically active groups. Their
antimicrobial activity study revealed that all the compounds tested
showed moderate to very good antibacterial and antifungal activ-
ities against pathogenic strains. Structure–biological activity rela-
tionship of title compounds showed that the presence of –CF3 at
position 8 and biologically active amines at position 4 of quinoline
ring and bioactive moieties such as –SH, –CH2CH2OCH3 and –Ph
groups at triazole ring of title compounds are responsible for
increased antimicrobial activity in newly synthesized title

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S. Eswaran et al. / European Journal of Medicinal Chemistry 44 (2009) 4637–4647
Table 3
Antibacterial activity of the title compounds 6a–c, 7a–c, 8a–g, 9a–h and 10a–h.
Compound
MIC in mg/mL and zone of inhibition in mm
S. aureus (ATCC-25923)
E. coli (ATCC 25922)
P. aeruginosa (ATCC-27853)
K. pneumoniae (recultured)
6a
6b
6c
7a
50 (<10)
50 (<10)
50 (<10)
6.25 (16–20)
6.25 (16–20)
50 (<10)
50 (<10)
6.25 (16– 20)
6.25 (16– 20)
50 (<10)
6.25 (16–20)
6.25 (16–20)
50 (<10)
6.25 (20–24)
6.25 (20–24)
50 (<10)
7b
7c
8a
8b
8c
8d
8e
8f
8g
9a
9b
9c
9d
9e
9f
9g
6.25 (16–20)
12.5 (10–15)
6.25 (16–20)
12.5 (10–15)
12.5 (10–15)
12.5 (10–15)
6.25 (16–20)
6.25 (16–20)
50 (<10)
6.25 (16–20)
6.25 (16–20)
6.25 (16–20)
6.25 (16–20)
6.25 (16–20)
50 (<10)
6.25 (20–24)
6.25 (16–20)
6.25 (20–24)
12.5 (16–20)
12.5 (16–20)
12.5 (16–20)
12.5 (16–20)
50 (<10)
6.25 (20–24)
6.25 (20–24)
6.25 (20–24)
6.25 (20–24)
12.5 (16–20)
6.25 (20–24)
6.25 (20–24)
6.25 (20–24)
6.25 (20–24)
6.25 (20–24)
6.25 (20–24)
50 (<10)
6.25 (16–20)
12.5 (10–15)
6.25 (16–20)
12.5 (10–15)
12.5 (10–15)
12.5 (10–15)
50 (<10)
6.25 (16–20)
12.5 (12–16)
6.25 (16–20)
12.5 (12–16)
12.5 (12–16)
12.5 (12–16)
50 (<10)
50 (<10)
50 (<10)
50 (<10)
50 (<10)
6.25 (16–20)
6.25 (16–20)
6.25 (16–20)
50 (<10)
6.25 (16–20)
50 (<10)
6.25 (16–20)
6.25 (16–20)
6.25 (16–20)
50 (<10)
6.25 (16–20)
50 (<10)
50 (<10)
50 (<10)
50 (<10)
9h
10a
10b
10c
6.25 (16–20)
6.25 (16–20)
6.25 (16–20)
50 (<10)
6.25 (16–20)
6.25 (16–20)
6.25 (16–20)
50 (<10)
6.25 (16–20)
6.25 (16–20)
6.25 (16– 20)
50 (<10)
10d
10e
10f
10g
6.25 (16–20)
6.25 (16–20)
50 (<10)
50 (<10)
6.25 (16–20)
6.25 (22–30)
6.25 (20–24)
6.25 (20–24)
6.25 (20–24)
6.25 (20–24)
6.25 (20–24)
6.25 (30–40)
50 (<10)
6.25 (16–20)
50 (<10)
50 (<10)
6.25 (16–20)
6.25 (25–33)
50 (<10)
6.25 (16–20)
50 (<10)
50 (<10)
6.25 (16–20)
6.25 (23–27)
10h
Ciprofloxacin (standard)
Note: The MIC values where evaluated at concentration range, 6.25–50
in mm.
m
g/mL. The figures in the table show the MIC values in
m
g/mL and the corresponding zone of inhibition
Table 4
Antifungal activity of title compounds 6a–c, 7a–c, 8a–g, 9a–h and 10a–h.
Compound
MIC in mg/mL and zone of inhibition in mm
P. marneffei (recultured)
T. mentagrophytes (recultured)
A. flavus (NCIM No. 524)
A. fumigatus (NCIM No. 902)
6a
6b
6c
7a
50 (<10)
6.25 (16–20)
6.25 (16–20)
50 (<10)
50 (<10)
6.25 (20–24)
6.25 (20–24)
50 (<10)
50 (<10)
6.25 (16–20)
6.25 (16–20)
50 (<10)
50 (<10)
6.25 (16–20)
6.25 (16–20)
50 (<10)
7b
7c
8a
8b
8c
8d
8e
8f
6.25 (16–20)
12.5 (10–15)
6.25 (16–20)
12.5 (10–15)
12.5 (10–15)
12.5 (10–15)
12.5 (10–15)
50 (<10)
6.25 (20–24)
12.5 (10–15)
6.25 (20–24)
12.5 (16–20)
12.5 (16–20)
12.5 (16–20)
12.5 (16–20)
50 (<10)
6.25 (16–20)
12.5 (10–15)
6.25 (16–20)
12.5 (10–15)
12.5 (10–15)
12.5 (10–15)
12.5 (10–15)
50 (<10)
6.25 (16–20)
12.5 (10–15)
6.25 (16–20)
12.5 (10–15)
12.5 (10–15)
12.5 (10–15)
12.5 (10–15)
50 (<10)
8g
50 (<10)
50 (<10)
50 (<10)
50 (<10)
9a
9b
9c
9d
6.25 (16–20)
6.25 (16–20)
6.25 (16–20)
50 (<10)
6.25 (20–24)
6.25 (20–24)
6.25 (20–24)
50 (<10)
6.25 (16–20)
6.25 (16–20)
6.25 (16–20)
50 (<10)
6.25 (16–20)
6.25 (16–20)
6.25 (16–20)
50 (<10)
9e
9f
6.25 (16–20)
50 (<10)
6.25 (20–24)
50 (<10)
6.25 (16–20)
50 (<10)
6.25 (16–20)
50 (<10)
9g
50 (<10)
50 (<10)
50 (<10)
50 (<10)
9h
10a
10b
10c
6.25 (16–20)
6.25 (16–20)
6.25 (16–20)
6.25 (16–20)
50 (<10)
6.25 (20–24)
6.25 (20–24)
6.25 (20–24)
6.25 (20–24)
50 (<10)
6.25 (16–20)
6.25 (16–20)
6.25 (16–20)
6.25 (16–20)
50 (<10)
6.25 (16–20)
6.25 (16–20)
6.25 (16–20)
6.25 (16–20)
50 (<10)
10d
10e
10f
10g
10h
6.25 (16–20)
50 (<10)
50 (<10)
6.25 (16–20)
6.25 (20–27)
6.25 (20–24)
6.25 (20–24)
6.25 (20–24)
6.25 (20–24)
3.125 (27–33)
6.25 (16–20)
50 (<10)
50 (<10)
6.25 (16–20)
3.125 (25–30)
6.25 (16–20)
50 (<10)
50 (<10)
6.25 (16–20)
6.25 (25–30)
Ciclopirox olamine (standard)
Note: The MIC values where evaluated at concentration range, 6.25–50
in mm.
m
g/mL. The figures in the table show the MIC values in
m
g/mL and the corresponding zone of inhibition

S. Eswaran et al. / European Journal of Medicinal Chemistry 44 (2009) 4637–4647
4643
compounds. In the final step of synthesis we made use of micro-
wave initiator, which not only made reaction time less but also gave
very good yields. It can be concluded that a combination of two
different heterocyclic systems namely quinoline and triazole has
enhanced the pharmacological effect and hence they are ideally
suited for further modifications to obtain more efficacious anti-
bacterial compounds.
4. Experimental section
4.1. General
All reagents were purchased from Aldrich. Some of the amines
which were used for final coupling were synthesized in the labo-
ratory. Solvents used were extra dried. Final purifications were
carried out using Quad biotage Flash purifier (A Dyax Corp.
Company). Microwave-assisted syntheses were performed in
Biotage initiator. TLC experiments were performed on alumina-
backed silica gel 40 F254 plates (Merck, Darmstadt, Germany). The
plates were illuminated under UV (254 nm) and molybidinic acid.
Melting points were determined using Buchi B-540 and are
uncorrected. Elemental analyses were carried out on an automatic
Flash EA 1112 Series, CHNSO Analyzer (Thermo). All 1H and 13C NMR
spectra were recorded on a Bruker AM-300 (300.12 MHz) and AM-
400 (400.13 MHz), Bruker BioSpin Corp., Germany. Molecular
weights of unknown compounds were checked by LCMS 6200
series Agilent Technology. The mass spectra of a few were recorded
on a 410 Prostar binary PDA detector (Varian Inc, USA). Chemical
shifts are reported in ppm (d) with reference to internal standard
TMS. The signals are designated as follows: s, singlet; d, doublet;
dd, doublet of doublets; t, triplet; m, multiplet; brs, broad singlet,
brt, broad triplet.
The microwave reaction was carried out in a 5 mL vial type. The
absorption level was kept high with a pre-stirring of 30 s and
stirring rate at 600 rpm. Initially the power was kept zero, followed
by a gradual increase to 175 W, the reaction proceeded at a constant
power of 35 W with temperature 120 ꢀC and 2-bar pressure. The
microwave irradiation was continued at 35 W for 10 min wherein
the reaction was completed. Fig. 1 show graphs A, B and C which
summarize variation of power, temperature and pressure against
time during the reaction.
4.2. Preparation of diethyl({[2-
(trifluoromethyl)phenyl]amino}methylene)malonate (2)
A suspension of 2-(trifluoromethyl)aniline 5 g (31 mmol) and
diethyl ethoxymethylene malonate 8 g (37.2 mmol) was heated to
110 ꢀC for 4 h. The reaction mixture was cooled to room tempera-
ture, the solid thus formed was taken in pet ether and stirred for
15 min and filtered to get compound 2 as a white crystalline solid
9.7 g (95% yield).
Fig. 1. Graphs A, B and C which summarize variation of power, temperature and
pressure against time respectively during the reaction.
thus precipitated was filtered and dried to get compound 3 as
a white solid 3.5 g (45% yield).
IR (KBr, cmꢁ1
) y: 3467 (>NH),1709 (>C]O),1657 (>C]C<), 1164
IR (KBr, cmꢁ1
)
y
: 3519 (O–H), 3449 (>NH), 1709 (>C]O), 1164
(>C–F).1HNMR(300 MHz, CDCl3)
d
ppm;1.35(t, –CH3, 3H, J ¼ 5.3 Hz),
(>C–F). 1H NMR (300 MHz, CDCl3)
d
ppm; 1.29 (t, –CH3, 3H,
1.38 (t, –CH3, 3H, J ¼ 5.3 Hz), 4.25(q, –CH2, 2H), 4.34(q, –CH2, 2H), 7.25
(m, –CH, 1H), 7.36 (d, –CH, 1H, J ¼ 6.1 Hz), 7.62 (m, –CH, 2H), 8.45 (d,
–NCH],1H, J ¼ 9.6 Hz). Anal. Calcd forC15H16F3NO4; C, 54.38; H, 4.87;
N, 4.23; found; C, 54.31; H, 4.79; N, 4.17.
J ¼ 7.2 Hz), 4.23 (q, –CH2, 2H), 7.59 (t, –CH, 1H, J ¼ 6.9 Hz), 8.13 (d,
–CH, 1H, J ¼ 7.5 Hz), 8.47 (m, –CH, 2H), 11.69 (brs, –OH, 1H, dis-
appeared on D2O exchange). LC/MS: (ESI) m/z 286 (M þ 1). Anal.
Calcd for C13H10F3NO3; C, 54.74; H, 3.53; N, 4.91; found; C, 54.71; H,
3.43; N, 4.97.
4.3. Preparation of ethyl 8-(trifluoromethyl)-4-hydroxyquinoline-3-
carboxylate (3)
4.4. Synthesis of 4-hydroxy-8-(trifluoromethyl)quinoline-3-
carbohydrazide (4)
Compound 2, 9 g (27 mmol) was heated at 250 ꢀC for 4 h in
Dowtherm medium. The reaction mixture was cooled to room
temperature and added hexane and stirred for 15 min, the solid
A
mixture of 10 g (35 mmol) ethyl 4-hydroxy-8-(tri-
fluoromethyl)quinoline-3-carboxylate and 5.2 g (105 mmol)of

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S. Eswaran et al. / European Journal of Medicinal Chemistry 44 (2009) 4637–4647
hydrazine hydrate 60% in 50 mL of ethanol was heated under
reflux for 2.5 h. Completion of the reaction was monitored by
TLC. The reaction mixture was concentrated and allowed to
cool. The solid product obtained was filtered, washed with
water and recrystallized from ethanol: diethyl ether (1:3) to
give product 4 as white solid 8 g (85% yield).
7.59 (t, –CH, 1H, J ¼ 7.8 Hz), 8.12 (s, –CH, 1H), 8.19 (d, –CH, 1H,
J ¼ 7.5 Hz), 8.51 (d, –CH, 1H, J ¼ 7.8 Hz), 11.90 (s, –SH, 1H), 14.06 (s,
–OH,1H,disappearedonD2Oexchange).LC/MS:(ESI)m/z371 (M þ 1).
4.7. General procedure for the synthesis of 4-chloro-8-
(trifluoromethyl) quinolin-3-yl triazole-3-thiole (7a–c)
IR (KBr, cmꢁ1
1164 (>C–F). 1H NMR (300 MHz, CDCl3)
)
y: 3519 (O–H), 3256 & 3293 (>NH), 1653 (>C]O),
d
ppm; 7.61 (t, –CH, 1H,
Compound 6a–c (1 mmol) was taken in 10 mL of distilled POCl3
and heated for 3 h at 60 ꢀC. Reaction completion was monitored by
TLC. Excess of POCl3 was distilled off and to the distillate was added
crushed ice. After stirring for 15 min, the aqueous layer was
extracted with ethyl acetate (2 times with 100 mL). Combined
organic extract was washed with brine, dried over Na2SO4, filtered
and concentrated. Crude product thus obtained was purified by
column chromatography on silica gel eluting with ethyl acetate/pet
ether (1:9) to get product as a yellow crystalline solid. Character-
ization data of 7a–c are given below.
J ¼ 7.8 Hz), 8.16 (d, –CH, 1H, J ¼ 7.5 Hz), 8.55 (d, –CH, 1H, J ¼ 7.8 Hz),
8.65 (s, –CH,1H),10.52 (brs, –OH,1H disappeared on D2O exchange).
LC/MS: (ESI) m/z271.9 (M þ 1). Anal. Calcd for C11H8F3N3O2;C, 48.72;
H, 2.97; N, 15.49; found; C, 48.78; H, 2.93; N, 15.55.
4.5. General procedure for the synthesis of 4-hydroxy-8-
(trifluoromethyl)quinoline thiosemicarbazide (5a–c)
A suspension of 4 (1 mmol), isothiocyanate (1.5 mmol) and
a catalytic amount of pyridine (0.2 mmol) in ethanol (10 mL) was
heated under reflux on oil bath for 3 h. Reaction completion was
monitored by TLC. The solvent was concentrated and the solid thus
obtained was taken in minimum quantity of ethanol, stirred for
10 min and filtered. The compounds were recrystallized from
ethanol to afford products 5a–c as white crystalline solid (85–90%
yield). Purity of all the quinoline-thiosemicarbazide derivatives
obtained were judged through TLC and MS and were taken as such
for the next step without any further purification.
4.7.1. 4-Benzyl-5-(4-chloro-8-(trifluoromethyl)quinolin-3-yl)-4H-
1,2,4-triazole-3-thiol (7a)
Compound 7a was obtained as a pale yellow solid. Yield 65%. IR
(KBr, cmꢁ1
)
y
: 3335 (>NH), 1623 (>C]N), 1204 (>C]S), 1164 (>C–
F), 780 (C–Cl). 1H NMR (300 MHz, CDCl3)
d
ppm; 5.27 (s, –CH2, 2H),
6.87 (d, –CH, 2H, J ¼ 7.8 Hz), 7.07 (t, –CH, 2H, J ¼ 6.9 Hz), 7.17 (m,
–CH, 1H), 7.85 (t, –CH, 1H, J ¼ 7.8 Hz), 8.27 (d, –CH, 1H, J ¼ 7.5 Hz),
8.51 (d, –CH, 1H, J ¼ 9 Hz), 8.54 (s, –CH, 1H), 12.25 (brs, –SH, 1H). 13C
NMR (300 MHz, CDCl3) d ppm: 47.24, 120.57, 125.81, 126.86, 127.25,
4.6. General procedure for the synthesis of (5-mercapto-4H-triazol-
3-yl)-8-(trifluoromethyl)quinolin-4-ol (6a–c)
127.58, 128.18, 128.79, 130.09, 131.51, 131.58, 135.46, 144.37, 145.37,
146.78, 151.26, 168.47. LC/MS: (ESI) m/z 421 (M þ 1).
A suspension of 5a–c (1 mmol) in 50 mL of aqueous potassium
hydroxide (4 mmol) was gently heated to 105 ꢀC for 2 h. The reac-
tion mixture was cooled to room temperature, was added 10 mL of
water and aqueous layer was extracted with diethyl ether (2 times
with 100 mL). Then the aqueous layer was cooled to 0 ꢀC, acidified
to pH z 4, the precipitate thus obtained was filtered, dried and
finally recrystallized from diethyl ether to get the desired product
as white fluffy solid. Characterization data of 6a–c are given below.
4.7.2. 5-(4-Chloro-8-(trifluoromethyl)quinolin-3-yl)-4-phenyl-4H-
1,2,4-triazole-3-thiol (7b)
Compound 7b was obtained as a yellow solid. Yield 73%. IR (KBr,
cmꢁ1
)
y
: 3335 (>NH), 1623 (>C]N), 1204 (>C]S), 1164 (>C–F),
780 (C–Cl). 1H NMR (300 MHz, CDCl3)
d
ppm; 7.32–7.45 (m, –CH,
5H), 7.77 (t, –CH, 1H, J ¼ 7.8 Hz), 8.22 (d, –CH,1H, J ¼ 7.2 Hz), 8.44 (d,
–CH, 1H, J ¼ 8.4 Hz), 8.92 (s, –CH, 1H), 12.34 (brs, –SH, 1H). 13C NMR
(300 MHz, CDCl3)
d ppm; 120.66, 125.51, 126.84, 127.23, 128.48,
128.88, 129.61, 129.96, 131.6, 133.79, 143.71, 145.21, 146.69, 152.08,
4.6.1. 3-(4-Benzyl-5-mercapto-4H-1,2,4-triazol-3-yl)-8-
(trifluoromethyl)quinolin-4-ol (6a)
168.98. LC/MS: (ESI) m/z 407 (M þ 1).
Compound 6a was obtained as a white solid. Yield 91%. IR (KBr,
4.7.3. 5-(4-Chloro-8-(trifluoromethyl)quinolin-3-yl)-4-(2-
methoxyethyl)-4H-1,2,4-triazole-3-thiol (7c)
cmꢁ1
)
y
: 3529 (O–H), 3345 (>NH), 1623 (>C]N), 1204 (>C]S),
1164 (>C–F). 1H NMR (300 MHz, DMSO-d6)
d
ppm; 5.28 (s, –CH2,
Compound 7c was obtained as a white solid. Yield 71%. IR (KBr,
2H), 6.98 (m, –CH, 2H), 7.00 (m, –CH, 3H), 7.62 (t, –CH, 1H,
J ¼ 7.8 Hz), 7.95 (s, –CH, 1H), 8.18 (d, –CH, 1H, J ¼ 7.8 Hz), 8.53 (d,
–CH, 1H, J ¼ 8.7 Hz), 11.82 (s, –SH, 1H), 14.08 (s, –OH, 1H, dis-
appeared on D2O exchange). LC/MS: (ESI) m/z 403 (M þ 1).
cmꢁ1
)
y
: 3335 (>NH), 1623 (>C]N), 1204 (>C]S), 1164 (>C–F),
1124 (>C–O–), 780 (C–Cl). 1H NMR (300 MHz, CDCl3)
d
ppm; 3.12 (s,
–CH3, 3H), 3.61 (t, –CH2, 2H, J ¼ 4.8 Hz), 4.17 (t, –CH2, 2H, J ¼ 4.8 Hz),
7.84 (t, –CH, 1H), 8.27 (d, –CH, 1H, J ¼ 7.2 Hz), 8.56 (d, –CH, 1H,
J ¼ 8.7 Hz), 8.97 (s, –CH, 1H), 11.88 (brs, –SH, 1H). 13C NMR
4.6.2. 8-(Trifluoromethyl)-3-(5-mercapto-4-phenyl-4H-1,2,4-
triazol-3-yl)quinolin-4-ol (6b)
(300 MHz, CDCl3) d ppm: 44.48, 58.40, 68.37, 121.06, 125.97, 126.89,
128.74, 130.19, 131.41, 144.11, 145.32, 147.56, 152.11, 167.52. LC/MS:
Compound 6b was obtained as an off white solid. Yield 93%. IR
(ESI) m/z 389 (M þ 1).
(KBr, cmꢁ1
)
y
: 3525 (O–H), 3345 (>NH), 1623 (>C]N), 1204
(>C]S), 1164 (>C–F). 1H NMR (300 MHz, DMSO-d6)
d
ppm; 7.31–
4.8. General procedure for the synthesis of title compounds (8a–g,
9a–h and 10a–h)
7.37 (m, –CH, 5H), 7.43 (t, –CH, 1H, J ¼ 7.8 Hz), 8.12 (d, –CH, 1H,
J ¼ 7.5 Hz), 8.24 (d, –CH, 1H, J ¼ 6.3 Hz), 8.28 (s, –CH, 1H), 11.73 (d,
–SH, 1H, J ¼ 6.6 Hz), 14.08 (s, –OH, 1H, disappeared on D2O
exchange). LC/MS: (ESI) m/z 389 (M þ 1).
To a suspension of compound 7a–c (1 mmol) in dry acetonitrile,
taken in a 5 mL microwave vial was added dry potassium carbonate
(2 mmol). The reaction mixture was purged with argon gas for
1 min and was added substituted amine (1 mmol). The vial was
irradiated with microwave for 10 min at 35 W constant power and
120 ꢀC temperature. Reaction was monitored by TLC. Reaction
mixture was then added to water followed by neutralized with
1.5 N HCl, then extracted with ethyl acetate (75 mL ꢂ 2). Combined
organic layer was dried over magnesium sulphate, concentrated
4.6.3. 8-(Trifluoromethyl)-3-(5-mercapto-4-(2-methoxyethyl)-4H-
1,2,4-triazol-3-yl) quinolin-4-ol (6c)
Compound 6c was obtained as white solid. Yield 92%. IR (KBr,
cmꢁ1
)
y
: 3529 (O–H), 3345 (>NH), 1623 (>C]N),1204 (>C]S), 1164
(>C–F), 1121 (>C–O–). 1H NMR (300 MHz, DMSO-d6)
ppm; 3.03 (s,
–OMe, 3H), 3.51 (t, –CH2, 2H, J ¼ 5.4 Hz), 4.07 (t, –CH2, 2H, J ¼ 5.4 Hz),
d

S. Eswaran et al. / European Journal of Medicinal Chemistry 44 (2009) 4637–4647
4645
and the solvent was evaporated under reduced pressure. The crude
4.8.6. 4-Benzyl-5-(4-(4-cyclohexylpiperazin-1-yl)-8-
compound thus obtained was purified by biotage column. The
compound comes out with 60–80% of pet ether/ethyl acetate.
(trifluoromethyl)quinolin-3-yl)-4H-1,2,4-triazole-3-thiol (8f)
Compound 8f was obtained as a yellow solid. 1H NMR (400 MHz,
DMSO-d6) d ppm; 1.06–1.28 (m, –C(CH2)3, 6H of cyclohexyl moiety),
4.8.1. 4-Benzyl-5-[4-(cyclopropylamino)-8-
1.73 (m, –C(CH2)2, 4H of cyclohexyl moiety), 2.24 (m, –N–CH, 1H,
junction proton of cyclohexyl moiety), 2.79 (brs, –N(CH2)2, 4H of
piperazine moiety), 3.34 (m, –N(CH2)2, 4H of piperazine moiety),
5.26 (brs, –CH2, 2H of benzylic moiety), 6.99 (d, –CH, 2H, J ¼ 7.2 Hz),
7.19 (m, –CH, 3H), 7.74 (t, –CH, 1H, J ¼ 8), 8.23 (d, –CH, 1H,
J ¼ 7.2 Hz), 8.36 (d, –CH, 1H, J ¼ 8.6 Hz), 8.60 (s, –CH, 1H), 14.30 (brs,
(trifluoromethyl)quinolin-3-yl]-4H-1,2,4-triazole-3-thiol (8a)
Compound 8a was obtained as a white solid. IR (KBr, cmꢁ1
) y:
3345 (>NH), 1623 (>C]N), 1204 (>C]S), 1164 (>C–F). 1H NMR
(300 MHz, DMSO-d6) ppm; 0.41 (m, –CH2, 2H of cyclopropyl ring),
d
0.55 (m, –CH2, 2H of cyclopropyl ring), 2.21 (m, –CH, 1H of cyclo-
propyl ring) 5.15 (s, CH2, 2H of benzylic moiety), 6.97 (d, –CH, 2H,
J ¼ 7.5 Hz), 7.18 (m, –CH, 3H), 7.63 (t, –CH, 1H, J ¼ 7.8 Hz), 7.86 (brs,
NH, 1H), 8.04 (s, –CH, 1H), 8.11 (d, –CH, 1H, J ¼ 7.2 Hz), 8.72 (d, –CH,
1H, J ¼ 9 Hz), 14.09 (brs, –SH, 1H). 13C NMR (300 MHz, CDCl3)
–SH, 1H). 13C NMR (400 MHz, CDCl3)
d ppm: 25.76, 26.33, 28.77,
47.13, 49.05, 52.69, 63.19, 120.15, 126.06, 128.15, 128.43, 128.95,
130.38, 135.62, 146.37, 148.57, 152.50, 156.58, 168.28. LC/MS: (ESI)
m/z 553.2 (M þ 1).
d
ppm: 8.42, 29.54, 47.24, 120.57, 125.81, 126.86, 127.25, 127.58,
128.18, 128.79, 130.09, 131.51, 131.58, 135.46, 144.37, 145.37, 146.78,
151.26, 168.47. LC/MS: (ESI) m/z 442.1 (M þ 1).
4.8.7. 5-(4-(4-(2-Aminoethyl)piperazin-1-yl)-8-
(trifluoromethyl)quinolin-3-yl)-4-benzyl-4H-
1,2,4-triazole-3-thiol (8g)
4.8.2. 4-Benzyl-5-[4-(cyclohexylamino)-8-
Compound 8g was obtained as a pale yellow solid. IR (KBr, cmꢁ1
)
(trifluoromethyl)quinolin-3-yl]-4H-1,2,4-triazole-3-thiol (8b)
y
: 1623 (>C]N), 1204 (>C]S), 1164 (>C–F). 1H NMR (300 MHz,
DMSO-d6) ppm; 2.12 (brs, –NH2, 2H), 2.20 (brt, –N(CH2)2, 4H of
Compound 8b was obtained as a white solid. IR (KBr, cmꢁ1
)
y:
d
3345 (>NH), 1623 (>C]N), 1204 (>C]S), 1164 (>C–F). 1H NMR
(400 MHz, DMSO-d6) ppm; 0.82–1.25 (m, –CH, 5H of cyclo-
piperazine ring), 2.32 (t, N–CH2, 2H, attached to piperazine ring,
J ¼ 6.6 Hz), 2.74 (t, N–CH2, 2H, attached to NH2 group, J ¼ 6 Hz), 3.48
(brt, –N(CH2)2, 4H of piperazine ring attached to quinoline ring)
5.16 (s, –CH2, 2H of benzylic moiety), 6.93 (d, –CH, 2H, J ¼ 6.9 Hz),
7.15 (m, –CH, 3H), 7.68 (t, –CH, 1H, J ¼ 7.8 Hz), 8.14 (d, –CH, 1H,
J ¼ 7.2 Hz), 8.27 (s, –CH, 1H), 8.52 (d, –CH, 1H, J ¼ 8.7 Hz), 14.22 (brs,
–SH, 1H). MS: (ESI) (m/z, %): 515 (M þ 2, 45), 496 (19), 470 (18), 438
(37), 395 (37), 353 (37), 351 (100), 239 (18).
d
hexane), 1.46–1.6 (m, –CH, 5H of cyclohexane), 2.29 (m, –CH, 1H of
cyclohexane), 5.08 (s, CH2, 2H of benzylic moiety), 6.97 (m, –CH, 2H
and –NH, 1H), 7.16 (m, –CH, 3H), 7.63 (t, –CH, 1H, J ¼ 8 Hz), 8.13 (d,
–CH, 1H, J ¼ 7.2 Hz), 8.22 (s, –CH, 1H), 8.70 (d, –CH, 1H, J ¼ 8.5 Hz),
14.18 (brs, –SH, 1H). 13C NMR (400 MHz, CDCl3)
d ppm: 25.42, 28.66,
34.54, 47.24, 51.8, 120.57, 125.81, 126.86, 127.25, 127.58, 128.18,
128.79, 130.09, 131.51, 131.58, 135.46, 144.37, 145.37, 146.78, 151.26,
168.47. LC/MS: (ESI) m/z 484.1 (M þ 1).
4.8.8. 5-(4-(Cyclopropylamino)-8-(trifluoromethyl)quinolin-
3-yl)-4-phenyl-4H-1,2,4-triazole-3-thiol (9a)
4.8.3. 5-(4-(3,3-Dimethylbutylamino)-8-(trifluoromethyl)quinolin-
Compound 9a was obtained as off white solid. IR (KBr, cmꢁ1
) y:
3-yl)-4-benzyl-4H-1,2,4-triazole-3-thiol (8c)
3345 (>NH), 1630 (>C]N), 1210 (>C]S), 1164 (>C–F). 1H NMR
(300 MHz, DMSO-d6) ppm; 0.62 (m, –CH2, 2H of cyclopropyl ring),
Compound 8c was obtained as an off white solid. IR (KBr, cmꢁ1
)
y:
d
3340 (>NH), 1623 (>C]N), 1204 (>C]S), 1164 (>C–F). 1H NMR
(300 MHz, DMSO-d6) ppm; 0.73 (s, –C(CH3)3, 9H of tert butyl),1.31
0.63 (m, –CH2, 2H of cyclopropyl ring), 1.26 (m, –CH, 1H of cyclo-
propyl ring), 4.46 (brs, –NH, 1H), 7.33 (d, –CH, 2H, J ¼ 7 Hz), 7.39 (m,
–CH, 3H), 7.64 (m, –CH, 1H), 8.05 (d, –CH, 1H, J ¼ 7.2 Hz), 8.51 (s,
–CH, 1H), 8.57 (d, –CH, 1H, J ¼ 8.7 Hz), 14.15 (brs, –SH, 1H). LC/MS:
(ESI) m/z 428.2 (M þ 1).
d
(t, –CH2, 2H of isobutyl moiety, J ¼ 8.4 Hz), 2.54 (m, –N–CH2, 2H of
isobutyl moiety), 5.12 (s, CH2, 2H of benzylic moiety), 6.97 (d, –CH,
2H, J ¼ 7.2 Hz), 7.15 (m, –CH, 3H), 7.19 (brs, –NH,1H), 7.64 (t, –CH,1H,
J ¼ 7.8 Hz), 8.12 (d, –CH,1H, J ¼ 7.2 Hz), 8.19 (s, –CH,1H), 8.65 (d, –CH,
1H, J ¼ 8.7 Hz), 14.18 (brs, –SH, 1H). LC/MS: (ESI) m/z 486.1 (M þ 1).
4.8.9. 5-(4-(Cyclohexylamino)-8-(trifluoromethyl)quinolin-
3-yl)-4-phenyl-4H-1,2,4-triazole-3-thiol (9b)
4.8.4. 2-(1-(3-(4-Benzyl-5-mercapto-4H-1,2,4-triazol-3-yl)-8-
(trifluoromethyl)quinolin-4-yl)piperidin-4-yl) propan-1-ol (8d)
Compound 9b was obtained as a white solid. 1H NMR (400 MHz,
DMSO-d6)
d ppm; 0.92–1.4 (m, –CH, 5H of cyclohexane), 1.73–1.83
Compound 8d was obtained as yellow solid. IR (KBr, cmꢁ1
)
y:
(m, –CH, 5H of cyclohexane), 2.82 (m, –CH, 1H of cyclohexane), 6.90
(brs, –NH, 1H), 7.27–7.42 (m, –CH, 5H), 7.56 (t, –CH, 1H, J ¼ 7.8 Hz),
8.07 (d, –CH, 1H, J ¼ 7.2 Hz), 8.56 (s, –CH, 1H), 8.58 (d, –CH, 1H,
3495 (O-H), 1623 (>C]N), 1204 (>C]S), 1164 (>C–F). 1H NMR
(400 MHz, DMSO-d6) ppm; 1.39–1.45 (m, (CH2)4 and –CH, 9H),
d
1.57 (m, –OCH2, 2H of propanol moiety), 2.74 (m, N–CH2, 2H, CH2 of
piperidine moiety), 3.33 (m, –NCH2, 2H of piperidine moiety), 4.37
(t, –OH, 1H of propanol moiety, J ¼ 5.1 Hz), 5.25 (s, CH2, 2H of
benzylic moiety), 7.00 (d, –CH, 2H, J ¼ 6.8 Hz), 7.18 (m, –CH, 3H),
7.73 (t, –CH,1H, J ¼ 7.8 Hz), 8.12 (d, –CH,1H, J ¼ 7.2 Hz), 8.29 (d, –CH,
1H, J ¼ 8.4 Hz), 8.58 (s, –CH, 1H), 14.26 (brs, –SH, 1H). LC/MS: (ESI)
m/z 528.1 (M þ 1).
J ¼ 8.6 Hz), 14.25 (brs, –SH, 1H). 13C NMR (400 MHz, CDCl3)
d ppm:
25.55, 32.98, 39.77, 54.29, 99.47, 115.99, 120.21, 124.19, 128.28,
129.37, 129.60, 129.70, 129.81, 134.15, 145.59, 149.65, 149.89, 153.80,
168.30. MS: (ESI) (m/z, %): 470.3 (M þ 1, 9), 469.3 (18), 468.4 (100).
4.8.10. 5-(4-(3,3-Dimethylbutylamino)-8-
(trifluoromethyl)quinolin-3-yl)-4-phenyl-
4H-1,2,4-triazole-3-thiol (9c)
4.8.5. 4-Benzyl-5-(8-(trifluoromethyl)-4-morpholinoquinolin-3-
yl)-4H-1,2,4-triazole-3-thiol (8e)
Compound 9c was obtained as off white solid. IR (KBr, cmꢁ1
) y:
3340 (>NH), 1630 (>C]N), 1210 (>C]S), 1164 (>C–F).1H NMR
(300 MHz, DMSO-d6) ppm; 0.82 (s, –C(CH3)3, 9H of tert butyl),
Compound 8e was obtained as a white solid. 1H NMR (300 MHz,
d
DMSO-d6)
d
ppm; 2.68 (brt, –N(CH2)2, 4H of morpholine ring), 3.62
1.49 (t, –CH2, 2H of isobutyl moiety, J ¼ 5.4), 3.05 (m, –N–CH2, 2H of
isobutyl moiety), 7.19 (brs, –NH, 1H), 7.38 (m, –CH, 5H, benzene
ring), 7.52 (t, –CH, 1H, J ¼ 7.8 Hz), 8.07 (d, –CH, 1H, J ¼ 7.5 Hz), 8.47
(s, –CH, 1H), 8.53 (d, –CH, 1H, J ¼ 9 Hz), 14.25 (brs, –SH, 1H). 13C
(brt, –O(CH2)2, 4H of morpholine ring), 5.29 (s, –CH2, 2H of benzylic
moiety), 7.02 (d, –CH, 2H, J ¼ 6 Hz), 7.17 (m, –CH, 3H), 7.77 (t, –CH,
1H, J ¼ 7.8 Hz), 8.26 (d, –CH, 1H, J ¼ 6.9 Hz), 8.42 (d, –CH, 1H,
J ¼ 8.4 Hz), 8.66 (s, –CH, 1H), 14.34 (brs, –SH, 1H). LC/MS: (ESI) m/z
472.1 (M þ 1).
NMR (300 MHz, CDCl3)
d ppm: 29.66, 32.46, 41.20, 46.35, 120.66,
125.51, 126.84, 127.23, 128.48, 128.88, 129.61, 129.96, 131.6, 133.79,

4646
S. Eswaran et al. / European Journal of Medicinal Chemistry 44 (2009) 4637–4647
143.71, 145.21, 146.69, 152.08, 168.98. LC/MS: (ESI) m/z 472.2
(M þ 1).
4.8.17. 5-(4-(Cyclohexylamino)-8-(trifluoromethyl)quinolin-3-yl)-
4-(2-methoxyethyl)-4H-1,2,4-triazole-3-thiol (10b)
Compound 10b was obtained as a white solid. IR (KBr, cmꢁ1
) y:
4.8.11. 3-(1-(8-(Trifluoromethyl)-3-(5-mercapto-4-phenyl-4H-
1,2,4-triazol-3-yl)quinolin-4-yl)piperidin-4-yl)propan-1-ol (9d)
Compound 9d was obtained as yellow solid. 1H NMR (400 MHz,
3345 (>NH), 1623 (>C]N), 1204 (>C]S), 1164 (>C–F), 1122 (>C–
O–). 1H NMR (300 MHz, DMSO-d6)
d
ppm; 0.83 (m, –CH, 2H of
cyclohexane), 1.28–1.73 (m, –(CH2)4, 8H of cyclohexane), 2.82 (m,
N–CH, 1H of cyclohexane), 3.00 (s, –OCH3, 3H), 3.53 (m, –OCH2, 2H
of methoxyethyl moiety), 3.98 (t, –NCH2, 2H of methoxyethyl
moiety, J ¼ 4.8 Hz), 7.75 (t, –CH, 1H, J ¼ 8.1 Hz), 8.12 (brs, –NH, 1H),
8.24 (d, –CH, 1H, J ¼ 7.5 Hz), 8.42 (s, –CH, 1H), 8.97 (d, –CH, 1H,
J ¼ 8.4 Hz), 14.21 (brs, –SH, 1H). LC/MS: (ESI) m/z 452.1 (M þ 1).
DMSO-d6)
d ppm; 1.43–1.48 (m, (CH2)4 and –CH, 9H), 1.74 (m,
–OCH2, 2H of propanol moiety), 2.61 (m, N–CH2, 2H, CH2 of
piperidine moiety), 3.40 (m, –NCH2, 2H of piperidine moiety), 4.40
(t, –OH, 1H of propanol moiety, J ¼ 5.1 Hz), 7.43 (m, –CH, 5H,
benzene ring), 7.69 (t, –CH, 1H, J ¼ 7.8 Hz), 8.16 (d, –CH, 1H,
J ¼ 7.2 Hz), 8.29 (d, –CH, 1H, J ¼ 8.5 Hz), 8.74 (s, –CH, 1H), 14.34 (brs,
–SH, 1H). LC/MS: (ESI) m/z 514.2 (M þ 1).
4.8.18. 5-(4-(3,3-Dimethylbutylamino)-8-(trifluoromethyl)quinolin-
3-yl)-4-(2-methoxy ethyl)-4H-1,2,4-triazole-3-thiol (10c)
Compound 10c was obtained as a white solid. IR (KBr, cmꢁ1
) y:
4.8.12. 5-(8-(Trifluoromethyl)-4-morpholinoquinolin-3-yl)-4-
phenyl-4H-1,2,4-triazole-3-thiol (9e)
3345 (>NH), 1623 (>C]N), 1204 (>C]S), 1164 (>C–F), 1124 (>C–
Compound 9e was obtained as a off white solid. IR (KBr, cmꢁ1
) y:
O–). 1H NMR (300 MHz, DMSO-d6)
d
ppm; 0.80 (s, –C(CH3)3, 9H of
1630 (>C]N), 1210 (>C]S), 1164 (>C–F). 1H NMR (400 MHz,
DMSO-d6) ppm; 2.95 (brt, –N(CH2)2, 4H of morpholine ring), 3.80
tert butyl), 1.47 (brt, –CH2, 2H of isobutyl moiety), 2.87 (brt, –N–
CH2, 2H of isobutyl moiety), 2.98 (s, –OCH3, 3H), 3.53 (m, –OCH2, 2H
of methoxyethyl moiety), 3.99 (t, –NCH2, 2H of methoxyethyl
moiety, J ¼ 4.6 Hz), 4.25 (t, –NH, 1H, J ¼ 4.5 Hz), 7.71 (t, –CH, 1H,
J ¼ 8 Hz), 8.19 (d, –CH, 1H, J ¼ 7.2 Hz), 8.40 (s, –CH, 1H), 8.80 (d, –CH,
1H, J ¼ 8.4 Hz), 14.13 (brs, –SH, 1H). LC/MS: (ESI) m/z 454.2 (M þ 1).
d
(brt, –O(CH2)2, 4H of morpholine ring), 7.46 (m, –CH, 5H, benzene
ring), 7.70 (t, –CH, 1H, J ¼ 7.8 Hz), 8.19 (d, –CH, 1H, J ¼ 7.2 Hz), 8.39
(d, –CH, 1H, J ¼ 8.4 Hz), 8.76 (s, –CH, 1H), 14.42 (brs, –SH, 1H). LC/
MS: (ESI) m/z 458.1 (M þ 1).
4.8.13. 5-(4-(4-Cyclohexylpiperazin-1-yl)-8-
(trifluoromethyl)quinolin-3-yl)-4-phenyl-
4H-1,2,4-triazole-3-thiol (9f)
4.8.19. 3-(1-(8-(Trifluoromethyl)-3-(5-mercapto-4-(2-
methoxyethyl)-4H-1,2,4-triazol-3-yl) quinolin-4-yl)piperidin-4-
yl)propan-1-ol (10d)
Compound 9f was obtained as a off white solid. IR (KBr, cmꢁ1
) y:
Compound 10d was obtained as off white solid. 1H NMR
1630 (>C]N), 1210 (>C]S), 1164 (>C–F). LC/MS: (ESI) m/z 539.2
(M þ 1).
(400 MHz, DMSO-d6)
d ppm; 1.45–1.48 (m, (CH2)4 and –CH, 9H),
1.74 (m, –OCH2, 2H of propanol moiety), 2.74 (m, N–CH2, 2H of
piperidine moiety), 3.01 (s, –OCH3, 3H), 3.36 (m, –NCH2 , 2H of
piperidine moiety), 3.61 (m, –OCH2, 2H of methoxyethyl moiety),
4.06 (m, –NCH2 , 2H of methoxyethyl moiety), 4.39 (t, –OH, 1H of
propanol moiety, J ¼ 5.1 Hz), 7.77 (t, –CH, 1H, J ¼ 7.8 Hz), 8.24 (d,
–CH, 1H, J ¼ 7.2 Hz), 8.39 (d, –CH, 1H, J ¼ 8.5 Hz), 8.73 (s, –CH, 1H),
4.8.14. 5-(8-(Trifluoromethyl)-4-(4-isopropylpiperazin-1-
yl)quinolin-3-yl)-4-phenyl-4 H-1,2,4-triazole-3-thiol (9g)
Compound 9g was obtained as a pale yellow solid. IR (KBr, cmꢁ1
)
y
: 1630 (>C]N), 1210 (>C]S), 1164 (>C–F). 1H NMR (300 MHz,
DMSO-d6)
ppm; 1.15 (d, –C(CH3)2, 6H, J ¼ 6.6 Hz), 2.62 (m,
d
14.16 (brs, –SH, 1H). 13C NMR (400 MHz, CDCl3)
d ppm: 29.99, 30.22,
–N(CH2)2, 4H of piperazine ring), 2.96 (m, N–CH, 1H, junction
proton of isopropyl group), 3.09 (brs, N–(CH2)2, 4H of piperazine
ring connected to quinoline ring), 7.45 (m, –CH, 5H, benzene ring),
7.73 (t, –CH,1H, J ¼ 7.9 Hz), 8.18 (d, –CH,1H, J ¼ 7.5 Hz), 8.36 (d, –CH,
1H, J ¼ 8.1 Hz), 8.79 (s, –CH, 1H), 14.23 (brs, –SH, 1H). LC/MS: (ESI)
m/z 499.2 (M þ 1).
32.84, 32.99, 35.36, 44.64, 58.27, 61.38, 63.42, 68.29, 111.77, 125.41,
125.78, 128.82, 129.67, 129.77, 130.45, 146.43, 149.47, 153.34, 157.11,
167.23. MS: (ESI) (m/z, %): 496.2 (M þ 1, 12), 495.3 (31), 494.4 (100).
4.8.20. 5-(8-(Trifluoromethyl)-4-morpholinoquinolin-3-yl)-4-(2-
methoxyethyl)-4H-1,2,4-triazole-3-thiol (10e)
Compound 10e was obtained as an off white solid. IR (KBr, cmꢁ1
)
4.8.15. 5-(8-Trifluoromethyl-4-(4-morpholinopiperidin-1-
y
: 1623 (>C]N),1204 (>C]S),1164 (>C–F),1124 (>C–O–). 1H NMR
(300 MHz, DMSO-d6) ppm; 2.35 (brt, –N(CH2)2, 4H of morpholine
yl)quinolin-3-yl)-4-phenyl-4H-1,2,4-triazole-3-thiol (9h)
Compound 9h was obtained as a off white solid. IR (KBr, cmꢁ1
) y:
d
1630 (>C]N), 1210 (>C]S), 1164 (>C–F). 1H NMR (400 MHz,
DMSO-d6) ppm; 1.24 (m, –C(CH2)2, 4H of piperidine), 1.67–1.87
ring), 3.00 (s, –OCH3, 3H), 3.31 (brt, –O(CH2)2, 4H of morpholine
ring), 3.58 (m, –OCH2, 2H of methoxyethyl moiety), 4.00 (m, –N–
CH2, 2H of methoxyethyl moiety attached to triazole ring), 7.77 (t,
–CH, 1H, J ¼ 8.1 Hz), 8.25 (d, –CH, 1H, J ¼ 6.9 Hz), 8.45 (d, –CH, 1H,
J ¼ 7.8 Hz) , 8.76 (s, –CH, 1H), 14.16 (brs, –SH, 1H). LC/MS: (ESI) m/z
440.1 (M þ 1).
d
(m, –N(CH2)2, 4H of morpholine ring), 2.65 (m, N–(CH2)2, N–CH
junction proton of piperidine, 5H), 3.60 (brs, O(CH2)2, 4H of mor-
pholine ring), 7.45 (m, –CH, 5H, benzene ring), 7.71 (t, –CH, 1H,
J ¼ 7.8 Hz), 8.18 (d, –CH, 1H, J ¼ 7.3 Hz), 8.26 (d, –CH, 1H, J ¼ 8.6 Hz),
8.76 (s, –CH, 1H), 14.37 (brs, –SH, 1H). MS: (ESI) m/z 541.2 (M þ 1).
4.8.16. 5-[4-(Cyclopropylamino)-8-(trifluoromethyl)quinolin-3-yl]-
4.8.21. 5-(4-(4-Cyclohexylpiperazin-1-yl)-8-(trifluoromethyl)quinolin-
4-(2-methoxyethyl)-4H-1,2,4-triazole-3-thiol (10a)
3-yl)-4-(2-methoxy ethyl)-4H-1,2,4-triazole-3-thiol (10f)
Compound 10a was obtained as an off white solid. IR (KBr, cmꢁ1
)
Compound 10f was obtained as a pale green solid. IR (KBr, cmꢁ1
)
y
: 3345 (>NH), 1623 (>C]N), 1204 (>C]S), 1164 (>C–F), 1120
y
: 1623 (>C]N),1204 (>C]S),1164 (>C–F),1124 (>C–O–). 1H NMR
(300 MHz, DMSO-d6) ppm; 1.06–1.30 (m, –C(CH2)3, 6H of cyclo-
(>C–O–). 1H NMR (300 MHz, DMSO-d6)
d
ppm; 0.45 (m, –CH2, 2H of
d
cyclopropyl ring), 0.57 (m, –CH2, 2H of cyclopropyl ring), 1.25 (m,
–CH, 1H of cyclopropyl ring), 3.01 (s, –OCH3, 3H), 3.59 (m, –OCH2,
2H of methoxyethyl moiety), 3.98 (t, –NCH2, 2H of methoxyethyl
moiety, J ¼ 5.1 Hz), 4.22 (brt, –NH, 1H), 7.63 (m, –CH, 1H), 8.15 (d,
–CH, 1H, J ¼ 7.2 Hz), 8.43 (s, –CH, 1H), 8.71 (d, –CH, 1H, J ¼ 8.4 Hz),
13.96 (brs, –SH, 1H). LC/MS: (ESI) m/z 410.1 (M þ 1).
hexyl moiety), 1.79–1.75 (m, –C(CH2)2, 4H of cyclohexyl moiety),
2.30 (m, –N–CH, 1H, junction proton of cyclohexyl moiety), 2.68
(brs, –N(CH2)2, 4H of piperazine moiety), 3.01(s, –OCH3, 3H), 3.06
(m, –N(CH2)2, 4H of piperazine moiety), 3.61 (m, –OCH2, 2H of
methoxyethyl moiety), 4.06 (m, –N–CH2, 2H of methoxyethyl
moiety attached to triazole ring), 7.77 (t, –CH, 1H, J ¼ 8.1 Hz), 8.25

S. Eswaran et al. / European Journal of Medicinal Chemistry 44 (2009) 4637–4647
4647
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1H), 14.20 (brs, –SH, 1H). LC/MS: (ESI) m/z 521.2 (M þ 1).
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4.8.22. 5-(8-(Trifluoromethyl)-4-(4-ethylpiperazin-1-yl)quinolin-
3-yl)-4-(2-methoxy ethyl)-4H-1,2,4-triazole-3-thiol (10g)
Compound 10g was obtained as an off white solid. IR (KBr, cmꢁ1
)
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: 1623 (>C]N), 1204 (>C]S), 1164 (>C–F), 1120 (>C–O–). MS:
(ESI) m/z 467.1 (M þ 1).
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4.8.23. 5-(8-(Trifluoromethyl)-4-(2,6-dimethylmorpholino)quinolin-
3-yl)-4-(2-methoxy ethyl)-4H-1,2,4-triazole-3-thiol (10h)
Compound 10h was obtained as a off white solid. IR (KBr, cmꢁ1
) y:
3345 (>NH),1623 (>C]N),1204 (>C]S),1164 (>C–F),1122 (>C–O–
). 1H NMR (300 MHz, DMSO-d6)
d
ppm; 1.25 (m, (CH3)2, 6H of mor-
pholine), 2.40 (brt, –N(CH2)2, 4H of morpholine ring), 3.00 (s, –OCH3,
3H), 3.61–3.82 (m, –OCH2, 2H of methoxyethyl moiety and 3,5–CH,
2H of morpholine), 4.20 (m, –N–CH2, 2H of methoxyethyl moiety
attached to triazole ring), 7.83 (t, –CH,1H, J ¼ 8 Hz), 8.26 (d, –CH,1H,
J ¼ 6.9 Hz), 8.48 (d, –CH, 1H, J ¼ 7.8 Hz) , 8.81 (s, –CH, 1H), 14.21 (brs,
–SH, 1H). 13C NMR (300 MHz, CDCl3)
d ppm: 35.36, 44.64, 60.22,
66.56, 68.29, 120.19, 124.43, 124.732 128.82, 129.34, 129.45, 130.45,
150.43,152.47, 154.34, 157.11, 161.23. LC/MS: (ESI) m/z 468.1 (M þ 1).
Acknowledgment
Authors are thankful to Dr. Ganesh Sambhasivam, CEO, Anthem
biosciences, Bangalore, India, for his invaluable support and allo-
cation of resources for this work. They are also grateful to the Head,
Chemistry Department, NITK for providing necessary laboratory
facilities for the research work and valuable support.
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