Different heterocycles functionalized s-triazine analogues: Design, synthesis and in vitro antimicrobial, antituberculosis, and anti-HIV assessment

Article abstract of DOI:10.1002/jhet.1769

Some new quinolone condensed s-triazine derivatives endowed with different heterocycles and 4-aminobenzonitrile moiety has been synthesized and examined for their bioactivities against eight bacteria (Staphylococcus aureus, Bacillus cereus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella typhi, Proteus vulgaris, and Shigella flexneri), two fungi (Aspergillus niger, Candida albicans) by using agar streak dilution method, and Mycobacterium tuberculosis H37Rv by using Lowenstein and Jensen MIC method. Upon preliminary biological screening, it was observed that the majority of the compounds were found to possess a significant broad spectrum antimicrobial (MICs: 6.25-25 μg/mL) and antitubercular (MIC: 12.5 μg/mL) potential. Hence, anti-HIV activity against two types of HIV viral strains [HIV-1 (III_B) and HIV-2 (ROD)] has been carried out using the MTT assay. From this bioassay, we have identified some potent inhibitors acting as anti-HIV-1 agents (IC₅₀: 4.45_g/mL) with promising therapeutic index of 16 for analogue 7 h. The structural assignments of the new products were carried out on the basis of IR, ₁HNMR, ₁₃CNMR spectroscopy, and elemental analysis.

Full text of DOI:10.1002/jhet.1769

Month 2014
Different Heterocycles Functionalized s-Triazine Analogues:
Design, Synthesis and In Vitro Antimicrobial, Antituberculosis, and
Anti-HIV Assessment
Paresh K. Patel,a Rahul V. Patel,a Dharmesh H. Mahajan,b Parimal A. Parikh,c Girish N. Mehta,a
d
d
e
*
Christophe Pannecouque, Erik De Clercq, and Kishor H. Chikhalia
aDepartment of Applied Chemistry, Sardar Vallabhbhai National Institute of Technology (SVNIT), Surat, 395 007 Gujarat, India
bDepartment of Chemistry (CGBIBT), Uka Tarsadia University, Maliba Campus, Bardoli-Mahuva Road, Bardoli, 394 350
Dist: Surat, Gujarat, India
cDepartment of Chemical EngineeringSardar Vallabhbhai National Institute of Technology (SVNIT), Surat, 395007
Gujarat, India
dRega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium
eDepartment of Chemistry, School of Science, Gujarat University, Ahmedabad, 380009 Gujarat, India
*
E-mail: chikhalia_kh@yahoo.com
Received February 1, 2012
DOI 10.1002/jhet.1769
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
Some new quinolone condensed s-triazine derivatives endowed with different heterocycles and 4-aminobenzo-
nitrile moiety has been synthesized and examined for their bioactivities against eight bacteria (Staphylococcus
aureus, Bacillus cereus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella typhi,
Proteus vulgaris, and Shigella flexneri), two fungi (Aspergillus niger, Candida albicans) by using agar streak
dilution method, and Mycobacterium tuberculosis H37Rv by using Lowenstein and Jensen MIC method. Upon
preliminary biological screening, it was observed that the majority of the compounds were found to possess a sig-
nificant broad spectrum antimicrobial (MICs: 6.25–25 mg/mL) and antitubercular (MIC: 12.5 mg/mL) potential.
Hence, anti-HIV activity against two types of HIV viral strains [HIV-1 (IIIB) and HIV-2 (ROD)] has been carried
out using the MTT assay. From this bioassay, we have identified some potent inhibitors acting as anti-HIV-1
agents (IC50: 4.45mg/mL) with promising therapeutic index of 16 for analogue 7 h. The structural assignments
of the new products were carried out on the basis of IR, 1H NMR, 13C NMR spectroscopy, and elemental analysis.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
the progression of recent or remotely acquired TB infection
to active disease. The deadly synergy between TB and HIV
has led to a quadrupling of TB cases in several African and
Asian countries [4]. Thus, both the current HIV pandemic
and multidrug-resistant M. tuberculosis have emerged as
major obstacles for public health control. The reverse tran-
scriptase of the HIV type-1 (HIV-1) that causes acquired
immune deficiency syndrome (AIDS) in humans is an essen-
tial enzyme for the life cycle of the virus [5]. Non-nucleoside
RT inhibitors (NNRTIs) are a variety of hydrophobic
compounds that are potent noncompetitive inhibitors of the
DNA polymerase activity of HIV-1 RT. Unfortunately, HIV-
1 RT is a flexible protein with an outstanding ability to tolerate
mutations (that develop quite rapidly in virions in AIDS
patients treated with anti-HIV-1 drugs), while still remaining
functionally active. As a result, many of these RT mutants
are resistant to the commonly used anti-RT drugs. Conse-
quently, new inhibitors are constantly required to increase
the available arsenal against HIV-1 and to fight AIDS. Hence,
an effort has been made to synthesize and screen novel s-tria-
zinyl derivatives towards the envisaged biological targets.
Heterocyclic compounds offer a high degree of structural
diversity and have proven to be broadly and economically
useful as therapeutic agents. One possible explanation is that
Throughout history, there has been a continual battle
between humans and the multitude of microorganisms that
cause infection and disease. [1]. The contemporary treatment
of such opportunistic microbial infectious diseases involves
administration of a multidrug regimen over a long period,
which has led to the rapid emergence of multidrug-resistant
strains and a high level of patient noncompliance [2]. Several
reports have shown that antibacterial resistance is increasing
at a rapid pace in both community and hospital settings [3].
The therapeutic problem has achieved increasing importance
in hospitalized patients, in immune-suppressed patients with
AIDS, or undergoing anticancer therapy or organ transplan-
tation. Furthermore, tuberculosis is retrieving its place
among theses infectious diseases, and today, nearly one-third
of the world’s population is infected with Mycobacterium
tuberculosis with approximately three million patients
decreasing every year. The mortality and spread of this
disease have been further aggravated by its synergy
with HIV. By destroying the two most important cells to
the containment of tubercle bacilli (macrophages and CD4-
receptor-bearing lymphocytes), HIV vigorously promotes
© 2014 HeteroCorporation

P. K. Patel, R. V. Patel, D. H. Mahajan, P. A. Parikh, G. N. Mehta,
C. Pannecouque, E. De Clercq, and K. H. Chikhalia
Vol 000
heterocyclic rings have hydrogen bond donors and acceptors
in a semirigid framework and they can therefore present a
diverse array of pharmacophores [6]. Hence in a view of
aforementioned facts, we were directed to substitute various
heterocycles to the C-6 position of the s-triazine ring in the
form of thiazole, benzothioazole, coumarin, quinoline,
pyridine, pyrimidine, and oxadiazoles. A vast number of
nitrogen-containing heterocyclic building blocks have appli-
cations in pharmaceuticals and agrochemical research and
drug discovery. Therefore, an attempt has been made to use
the well known medicinally important [7–9] 1,3,5-triazine
ring as a nucleus of the resultant analogues. Benzothiazole
derivatives hold a broad potential for various bioactivities
as inhibitors of HIV-1 [10] and antimicrobial agents
[11,12]. Furthermore, we have recently reported the antimi-
crobial efficacies of the combination of quinoline/couma-
rin–triazine ring systems [13]. In addition, we have also
reported the importance of incorporation of oxadiazole
nucleus to the s-triazine ring as antimicrobial agents [14].
In a view of the aforementioned findings, we have synthe-
sized some novel s-triazine bases derivatives involving sub-
stitution of biolabile pharmacophores.
RESULTS AND DISCUSSION
Chemistry.
The synthesis of compounds 7a–q was
undertaken as in Scheme 1. The first step expressed the
formation of intermediate 3 in very good yield 90% by
Scheme 1. Reagents and conditions: (a) 4-aminobenzonitrile, acetone, K2CO3, 0–5ꢀC, 4–5 h; (b) 4-hydroxy-N-methylquinolin-2(1H)-one acetone, K2CO3,
40–45ꢀC, 6–7 h; (c) substituted heterocycles, THF, K2CO3, reflux, 6–24h.
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the nucleophilic displacement of one chlorine atom of s-
triazine ring by 4-aminobenzonitrile in the presence of
anhydrous potassium carbonate in acetone solvent at
0–5ꢀC. Compound 3 displayed an absorption band at
2228 cm─1 confirming the presence of a CꢁN group, and
a strong band near 3277 cmÀ1 further confirmed the
presence of an –NH group. The synthesis of disubstituted
s-triazine intermediate 4-(4-chloro-6-(1-methyl-2-oxo-1,2-
dihydroquinilin-4-yloxy)-1,3,5-triazin-2-ylamino)-benzonitrile
5 was achieved in 88% of yield by the reaction between
significantly affected the bioprofiles of the resultant
analogues. Final derivative with alkyl methyl functional
group either in the form of thiazole 7l, benzothiazole
7g, or nitro-heterocycle 7m moiety showed diminished
antibacterial efficacies against Klebsiella pneumoniae at an
MIC level of 50 mg/mL, whereas the presence of an alkoxy
group in the benzothiazole 7h and oxadiazole 7n moieties
condensed to the s-triazine ring indicated improved activity
against both the Gram-positive strain and Gram-negative
Escherichia coli (MIC range: 6.25–25 mg/mL). In the
present research work, the condensation of nitrogen rich
pyridine and pyrazine moieties was also attempted, and the
said analogues 7i and 7j were found potentially active
against Gram-negative Shigella flexneri at an MIC of
25 mg/mL. The analogues 7p and 7q can be viewed as a
combination of two similar quinolone moiety in the s-triazine
ring: they gave excellent activity against Salmonella typhi
(MIC: 12.5 mg/mL); however, replacement of the quinolone
moiety by a coumarin made the molecule strongly active
against P. aeruginosa and Proteus vulgaris (MIC:
25 and 50 mg/mL, respectively), along with anti P. vulgaris
activity of 7a at an MIC of 50 mg/mL. The large number
of remaining analogues displayed good to moderate
antimicrobial activities against the mentioned panel of
microorganisms at an MIC range of 50–100 mg/mL.
4-(4,6-dichloro-1,3,5-triazin-2-ylammino)benzonitrile
3
and 4-hydroxy-N-methylquinolin-2(1H )-one in the presence
of anhydrous potassium carbonate in acetone solvent Àa1t
45–50ꢀC. A characteristic band appearing at 1256 cm
corresponded to the C– O– C linkage in the IR spectra of
compound 5. Subsequent coupling of the so-formed
compound 5 with the desired substituted heterocycles in
the presence of anhydrous potassium carbonate in
tetrahydrofuran solvent at reflux temperature provided the
target compounds 7a–q. This reaction proceeded in good
yield and is general for different substituted heterocycles.
The correct synthesis of 7a–q was confirmed on the basis
1
of IR, H NMR, and 13C NMR spectral analyses, and the
purity was ascertained by elemental analysis.
Pharmacology.
In vitro antituberculosis activity. In vitro antituberculosis
activity of the newer analogues was examined using
Lowenstein and Jensen (LJ) MIC method, and the results are
presented in mg/mL of MIC and percentage inhibition of
M. tuberculosis H37Rv at the respective concentration in
Table 3. The majority of the analogues were active against
H37Rv. An analogue with three electron-donating methoxy
groups in addition to oxadiazole ring system 7n showed the
highest inhibition of mycobacteria with 99% inhibition
efficacy at 12.5 mg/mL of MIC. This compound was
considered as the most potent antituberculosis agents among
the 17 studied. The analogue with the electron-withdrawing
fluoro substituent 7e was the second most active analogue in
this bioassay with a similar percentage inhibition potency at
an MIC of 25 mg/mL. Furthermore, two of the analogues
namely 7d with a bromo-benzothiazole substituent and
7p with a quinolone substituent provided 97% and
96%, respectively, inhibition of H37Rv at 50 mg/mL.
Additionally, three of the molecules, such as 7h with a
methoxy substituent, 7m with two methyl groups, and 7o
with pyridyl oxadiazole moieties, showed 96–97% of
mycobacterial inhibition at 62.5 mg/mL of MIC. All the
In vitro antimicrobial activity.
The newer analogues
were investigated for their antimicrobial activities, and the
results are summarized in Tables 1 and 2. Furthermore, we
have studied the effects of various functional groups
attached to the s-triazine-condensed heterocycles towards
the different bacteria, fungi, and viral strains, and from
these results, it can be stated that bioactivities can vary by
varying the functional groups to a large extent. The
presence of electron-withdrawing or electron-donating
substituent significantly affects the relative bioactivities.
In case of antibacterial activity of the final scaffolds, those
with halogen substituents 7c, 7d, and 7e showed significant
growth inhibitory potential against both the Gram-positive
bacteria at an MIC of 6.25–12.5 mg/mL and against Gram-
negative strain Pseudomonas aeruginosa at an MIC of
25mg/mL. However, it can be said that analogues with the
highly electronegative fluoro substituent 7e were more
active when compared with other derivatives with
remaining halogens. The order of increased activity against
the mentioned panel of microorganisms was F > Br > Cl.
Additionally in case of antifungal activity, both the final
analogues with bromo 7d or fluoro 7e substituent showed
potential inhibition towards the growth of Candida
albicans fungi at 25 mg/mL of MIC, whereas an analogue
with strong electron-withdrawing nitro functional group 7f
displayed potential bioactivity against Aspergillus niger
fungi at an MIC of 12.5 mg/mL. Final derivatives contained
heterocycles bearing electron-donating alkyl or alkoxy
substituents, and it can be seen that their presence
remaining analogues exhibited moderate to poor activity
against the mycobacterial strain used.
In vitro anti-HIV activity. In the present research work,
the in vitro anti-HIV activity of the analogue was
determined by MTT bioassay method against HIV-1 (IIIB)
and type-2 (ROD), and the results are summarized in
Table 4. The data are given as EC50 values (compound
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P. K. Patel, R. V. Patel, D. H. Mahajan, P. A. Parikh, G. N. Mehta,
C. Pannecouque, E. De Clercq, and K. H. Chikhalia
Vol 000
Table 1
In vitro antibacterial activity.
MIC in mg/mL
Gram-positive
Gram-negative
Compounds
R
S.a
B.c
E.c
P.a
K.p
S.t
P.v
S.f
7a
200
100
50
100
100
500
50
50
7b
7c
250
100
200
100
500
100
200
250
500
100
100
200
100
100
25
50
7d
7e
7f
12.5
6.25
50
25
12.5
25
50
25
25
50
100
100
200
200
100
250
100
100
100
50
50
50
100
100
7g
7h
100
250
100
250
500
100
50
200
100
250
200
250
100
50
25
100
(Continued)
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Table 1
(Continued)
MIC in mg/mL
Gram-negative
Gram-positive
Compounds
R
S.a
B.c
E.c
P.a
K.p
S.t
P.v
S.f
7i
250
500
500
100
500
500
500
25
7j
200
500
500
200
250
500
500
25
7k
7l
100
100
250
250
250
200
100
500
500
500
200
250
500
100
500
50
7m
50
100
100
100
50
100
200
250
7n
6.25
6.25
25
50
100
100
250
50
7o
12.5
6.25
50
200
250
250
200
100
(Continued)
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P. K. Patel, R. V. Patel, D. H. Mahajan, P. A. Parikh, G. N. Mehta,
C. Pannecouque, E. De Clercq, and K. H. Chikhalia
Vol 000
Table 1
(Continued)
MIC in mg/mL
Gram-positive
Gram-negative
Compounds
R
S.a
B.c
E.c
P.a
K.p
S.t
P.v
S.f
7p
100
200
100
50
200
12.5
100
250
7q
250
100
250
25
500
500
50
500
DMSO
—
12.5
6.25
1.0
—
12.5
6.25
1.0
—
6.25
12.5
1.0
—
25
12.5
1.0
—
25
25
1.0
—
25
12.5
1.0
—
12.5
6.25
1.0
—
50
25
≤3
Ampicillin
Gentamicin
Ciprofloxacin
Table 2
In vitro antifungal activity.
MIC in mg/mL
Compounds
R
A. niger
C. albicans
7a
50
500
7b
200
500
50
7c
100
50
7d
25
(Continued)
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Table 2
(Continued)
MIC in mg/mL
Compounds
R
A. niger
C. albicans
7e
25
25
7f
12.5
50
7g
500
500
7h
7i
100
500
250
100
>500
>500
7j
7k
7l
500
500
500
500
7m
7n
200
500
25
50
(Continued)
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P. K. Patel, R. V. Patel, D. H. Mahajan, P. A. Parikh, G. N. Mehta,
C. Pannecouque, E. De Clercq, and K. H. Chikhalia
Vol 000
Table 2
(Continued)
MIC in mg/mL
Compounds
R
A. niger
C. albicans
7o
50
200
250
7p
7q
100
200
250
DMSO
Fluconazole
Ketoconazole
—
6.25
≤3
—
12.5
1.0
from Merck, India and were used without further purification. Coupled
heterocycles as 6a, 6b, and 6m were purchased from Spectrochem Pvt.
Ltd, Vadodara, India and 6i, 6j, and 6k were purchased from ACS
chemicals Pvt. Ltd, Ahmedabad, India. Heterocycle 6l and 6q were
gifts from Nivika Chemo Pharma Pvt. Ltd, Ankleshwar, India and
Ami Organics Pvt. Ltd, Sachin, India, respectively.
concentration required to protect MT-4 cells against
viral cytopathogenicity by 50%), CC50 value (compound
concentration that decreases the uninfected MT-4 cell
viability by 50%), and selectivity index (ratio of CC50
/
EC50). The analogue with the 6-methoxy benzothiazole
substituent 7h linked through an amino linkage to the basic
s-triazine core displayed activity at an EC50 level of 4.45 mg/
mL against HIV-1 (IIIB), whereas being minimal cytotoxic
at 72.13 mg/mL, thus achieving a selectivity index of 16.
This compound was the most potent and (and only) selective
anti-HIV analogue. Some of the derivatives studied such as
7c, 7d, and 7e with halo-substituents (–Cl, –Br, and –F)
showed EC50 values of >2.19, >14.50, and >2.26 mg/mL
but were cytotoxic at these concentrations. In addition, a
single analogue from those bearing an alkyl functional group
(7g) displayed an EC50 of >3.88 mg/mL against HIV-1
(IIIB) but again, was cytotoxic at this concentration. All the
remaining analogues were inactive against HIV and
cytotoxic at concentrations of >65 to >125 mg/mL.
Melting points were determined in open capillaries on a Veego
electronic apparatus VMP-D (Veego Instrument Corporation,
Mumbai, India) and are uncorrected. IR spectra (4000–400 cm–1)
of synthesized compounds were recorded on a Shimadzu 8400–S
FTIR spectrophotometer (Shimadzu India Pvt. Ltd., Mumbai, India)
using KBr pellets. TLC was performed on object glass slides
(2Â 7.5 cm) coated with silica gel G, and spots were visualized
under UV irradiation. 1H NMR and 13C NMR spectra were
recorded on a Varian 400 MHz model spectrometer (Varian India
Pvt. Ltd., Mumbai, India) by using DMSO as a solvent and TMS
1
as internal standard with H resonant frequency of 400 MHz and
13C resonant frequency of 100 MHz. The 1H NMR and 13C NMR
chemical shifts (d) were reported as parts per million (ppm) down-
field from TMS (Me4Si) and were performed at Center for Excel-
lence, Vapi, India. The splitting patterns are designated as follows;
s, singlet; br s, broad singlet; d, doublet; m, multiplet. Elemental
analyses (C, H, N) were performed using a Heraeus Carlo Erba
1180 CHN analyzer (Hanau, Germany).
General synthetic procedure for 2-amino-6-substituted
EXPERIMENTAL
benzothiazoles (6c–h).
A mixture of (0.1 mol) of 4-
2,4,6-Trichloro-1,3,5-triazine, 4-hydroxy-N-methylquinolin-2(1H )-
one, and 4-aminobenzonitrile were purchased from Sigma-Aldrich,
Germany. Acetone and tetrahydrofuran were AR grade and purchased
substituted aniline and 19.43 g (0.2 mol) of potassium
thiocyanate (KCNS) in 100 mL glacial acetic acid (AcOH) was
cooled in an ice bath and stirred for 10–20 min, and then,
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Pharmacologically Active s-Triazines
Table 3
In vitro antituberculosis activity.
LJ MIC methoda
Compounds
R
MIC (mg/mL)
Inhibition (%)
96
7a
100
7b
7c
7d
200
95
95
97
100
50
7e
7f
25
99
95
100
7g
250
94
7h
7i
62.5
500
97
94
(Continued)
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P. K. Patel, R. V. Patel, D. H. Mahajan, P. A. Parikh, G. N. Mehta,
C. Pannecouque, E. De Clercq, and K. H. Chikhalia
Vol 000
Table 3
(Continued)
LJ MIC methoda
Compounds
R
MIC (mg/mL)
Inhibition (%)
7j
250
96
7k
7l
200
100
94
96
96
7m
7n
62.5
12.5
99
7o
7p
62.5
50
97
96
7q
100
96
Isoniazid
Rifampicin
Ethambutol
Pyrazinamide
0.20
0.25
3.12
6.25
99
99
99
99
aEach value is the mean of three independent experiments.
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Table 4
In vitro anti-HIV activity.
EC50 (mg/mL)a
CC50 (mg/
SIc (HIV-1
IIIB)
Compounds
R
HIV-1 (IIIB)
HIV-2 (ROD)
mL)b
7a
>72.78
>72.78
72.78
82.93
<1
7b
7c
7d
>82.93
>2.19
>82.93
<1
>2.19
2.19
<1
>14.50
>2.26
>14.50
>2.26
14.50
2.26
<1
<1
7e
7f
>69.28
>3.88
4.45
>69.28
>3.88
69.28
3.88
<1
<1
16
7g
7h
>72.13
72.13
7i
7j
>74.10
>83.58
>74.10
>83.58
≥74.10
≤1
<1
83.58
(Continued)
(Continued)
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Vol 000
Table 4
(Continued)
EC50 (mg/mL)a
CC50 (mg/
SIc (HIV-1
IIIB)
Compounds
R
HIV-1 (IIIB)
HIV-2 (ROD)
mL)b
7k
>107.88
>107.88
107.88
<1
7l
>125.00
>125.00
>125.00
>125.00
>125.00
1
7m
>125.00
1
7n
>65.13
>65.13
65.13
<1
7o
7p
>68.75
>79.48
>68.75
>79.48
68.75
79.48
<1
<1
7q
>69.20
>69.20
69.20
<1
Nevirapine
Zidovudine
Dideoxycytidine
Efavirenz
0.040
0.0032
0.37
0.0018
0.025
>4.00
>25.00
>20.00
>2.00
>101
>7899
>55
>1133
>81
0.0036
0.49
Delaviridine
>2.00
aCompound concentration required to protect MT-4 cells against viral cytopathogenicity by 50%.
bCompound concentration that decreases the uninfected MT-4 cell viability by 50%.
cSelectivity index: CC50/EC50 ratio (WT).
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5.1 mL (0.1 mol) bromine in 25 mL glacial acetic acid was added
dropwise at such a rate to keep the temperature below 10ꢀC
throughout the addition. The reaction mixture was stirred at
room temperature for 2–4 h, the hydrobromide (HBr) salt
thus separated out was filtered, washed with acetic acid,
dried, dissolved in hot water, and brought up to pH 11.0
with ammonia solution (NH4OH), and the resulting
precipitate was filtered, washed with water, and dried to
obtain the desired product 6c–h [15,16]. The progress of the
reaction was monitored by TLC using toluene:acetone (8:2)
solvent system.
Compounds 2-(methylthio)-5-(3,4,5-trimethoxyphenyl)-1,3,4-oxa-
diazole (6n) and 5-Pyridin-4-yl-1,3,4-oxadiazole-2-thiol (6o) were
synthesized by following the procedure described earlier [17,18].
Compounds 4-(4,6-dichloro-1,3,5-triazin-2-ylamino)benzoni-
trile (3) and 4-(4-chloro-6-(1-methyl-2-oxo-1,2-dihydroquinilin-4-
yloxy)-1,3,5-triazin-2-ylamino)-benzonitrile (5) were synthesized
according to the procedure described in the literature [19].
General procedure for the synthesis of 4-(substituted
phenylamine)-6-(4-cyanophenylamino)-1,3,5,-triazine-2-yloxy)-
1-methylquinolin-2(1H )-one (7a–q). Mixture of compound 5
(1.01 g, 2.5mmol), anhydrous potassium carbonate (0.35 g,
2.5 mmol), and substituted heterocycles 6a–q (2.5mmol) in 50 mL
tetrahydrofuran. The reaction mixture was refluxed for 5–24 h in a
water bath; progress of the reaction was monitored by TLC using
toluene/acetone (7:3, v/v) solvent system as an eluent. After the
completion of the reaction, the resultant mixture was poured in
crushed ice. The solid product was obtained, filtered, washed with
distilled water, and dried and purified by column chromatography
using toluene:acetone system as an eluent.
and benzothiazole linkage), 10.08 (s, 1H, –NH proton of
s-triazine to benzothiazole linkage), 8.20 (d, J = 7.2 Hz, 1H,
C-8 proton of quinoline), 7.71 (t, J = 7.6 Hz, 1H, C-7 proton of
quinoline), 7.64 (d, J = 8.2 Hz, 1H, C-5 proton of quinoline),
7.56 (t, J = 7.9 Hz, 1H, C-6 proton of quinoline), 7.47–7.19 (m,
8H, Ar–H proton of aromatic), 6.83 (s, 1H, –CH–(C═O)–N
proton of quinoline moiety), 3.66 (s, 3H, –N–CH3 proton
of quinoline moiety); 13C NMR (DMSO-d6): d 173.10 (1C, C–
O–C, s-triazine to 4-HMQ linkage), 165.98, 164.28 (2C, C–NH
of s-triazine to aminobenzonitrile linkage and benzothiazole
linkage), 161.88 (1C, –C═O of hydroxy quinoline moiety),
158.33 (1C, C–S, of benzothiazole), 152.34, 150.98, 149.08,
147.68, 145.86, 141.88, 140.01, 138.98, 137.05, 135.69,
133.68, 131.47, 128.88, 127.01, 125.63, 123.58, 122.01, 121.39
(18C, Ar–C of aromatic), 105.49 (1C, –CꢁN of aminobenzonitrile
moiety), 103.98 (1C, –C–(C═O)–N of hydroxy quinoline moiety),
96.58 (1C, –C–CꢁN of aminobenzonitrile moiety), 31.67
(1C, –N–CH3 of hydroxy quinoline moiety). Anal. Calcd for
C27H18N8O2S: C, 62.54; H, 3.50; N, 21.61. Found: C, 62.63;
H, 3.44; N, 21.57.
4-(4-(6-Chlorobenzo[d]thiazol-2-ylamino)-6-(1-methyl-2-oxo-
1,2-dihydroquinolin-4-yloxy)-1,3,5-triazin-2-ylamino)benzonitrile
(7c). This compound was obtained as off-white solid, yield 0.91 g
(71%), mp195ꢀC; IR (KBr): 3272 (N–H), 2228 (CꢁN), 1649
(C═O), 1579 (C═N in BT), 1338 (C–N), 1267 (C–O–C), 834
(C3N3, s-triazine), 738 (C–Cl), 651 (C–S) cmÀ1 1H NMR
;
(DMSO-d6): d 10.59, (s, 1H, –NH proton of s-triazine to
aminobenzonitriles linkage and benzothiazole linkage), 9.91 (s, 1H,
–NH proton of s-triazine to aminobenzothiazole linkage) 8.16
(d, J = 7.4 Hz, 1H, C-8 proton of quinoline), 7.81 (t, J= 7.3 Hz, 1H,
C-7 proton of quinoline), 7.67 (d, J =8.2Hz, 1H, C-5 proton of
quinoline), 7.55 (t, J= 7.8 Hz, 1H, C-6 proton of quinoline), 7.50
(d, J = 1.7 Hz, 1H, C-5 proton of benzothiazole), 7.44–7.19 (m, 6H,
Ar–H proton of aromatic), 6.82 (s, 1H, –CH–(C═O)–N proton of
quinoline moiety), 3.68 (s, 3H, –N–CH3 proton of quinoline
moiety); 13C NMR (DMSO-d6): d 171.98 (1C, C–O–C, s-triazine
to 4-HMQ linkage), 167.12, 164.28 (2C, C–NH of s-triazine to
aminobenzonitrile linkage and benzothiazole linkage), 160.99 (1C,
–C═O of hydroxy quinoline moiety), 156.88 (1C, C–S, of
benzothiazole), 150.58, 149.03, 147.95, 145.62, 144.09, 141.88,
140.01, 139.07, 137.83, 136.09, 133.28, 131.67, 130.01, 128.12,
125.06, 122.19, 120.44, 117.39 (18C, Ar–C of aromatic), 104.98
(1C, –CꢁN of aminobenzonitrile moiety), 102.09 (1C, –C–
(C═O)–N of hydroxy quinoline moiety), 96.88 (1C, –C–CꢁN of
aminobenzonitrile moiety), 30.69 (1C, –N–CH3 of hydroxy
quinoline moiety). Anal. Calcd for C27H17ClN8O2S: C, 58.64; H,
3.10; N, 20.26. Found: C, 58.57; H, 3.16; N, 20.34.
4-(4-(Benzo[d]thiazol-2-ylthio)-6-(1-methyl-2-oxo-1,2-dihydroquinolin-
4-yloxy)-1,3,5-triazin-2-ylamino)benzonitrile (7a).
This compound
was obtained as off-white solid, yield 1.29 g (96%), mp 230ꢀC;
IR (KBr): 3275 (N–H), 2223 (CꢁN), 1648 (C═O), 1570 (C═N
in BT), 1348 (C–N), 1259 (C–O–C), 835 (C3N3, s-triazine),
1
648 (C–S) cmÀ1; H NMR (DMSO-d6): d 10.76 (s, 1H, –NH
proton of s-triazine to aminobenzonitrile linkage), 8.16
(d, J = 7.5 Hz, 1H, C-8 proton of quinoline), 7.75 (t, J = 7.6 Hz,
1H, C-7 proton of quinoline), 7.66 (d, J = 8.3 Hz, 1H, C-5
proton of quinoline), 7.58 (t, J = 8.1 Hz, 1H, C-6 proton of
quinoline), 7.46–7.20 (m, 8H, Ar–H proton of aromatic), 6.78
(s, 1H, –CH–(C═O)–N proton of quinoline moiety), 3.71
(s, 3H, –N–CH3 proton of quinoline moiety); 13C NMR (DMSO-
d6): d 172.42 (1C, C–O–C, s-triazine to 4-HMQ linkage), 166.12,
165.08 (2C, C–NH of s-triazine to aminobenzonitrile linkage and
C–S of s-triazine to mercaptobobenzothiazole linkage), 162.98
(1C, –C═O of hydroxy quinoline moiety), 157.13 (1C, C–S, of
mercaptobenzothiazole), 151.28, 149.83, 148.09, 146.8, 144.39,
142.98, 141.01, 138.78, 136.43, 134.69, 130.28, 128.47, 126.01,
124.89, 121.63, 120.09, 119.01, 116.20 (18C, Ar–C of aromatic),
105.1 (1C, –CꢁN of aminobenzonitrile), 103.00 (1C, –C–
(C═O)–N of hydroxy quinoline moiety), 96.5 (1C, –C–CꢁN of
aminobenzonitrile), 30.67 (1C, –N–CH3 of hydroxy quinoline
moiety). Anal. Calcd for C27H17N7O2S2: C, 60.55; H, 3.20; N,
18.31. Found: C, 60.48; H, 3.12; N, 18.36.
4-(4-(6-Bromobenzo[d]thiazol-2-ylamino)-6-(1-methyl-2-oxo-
1,2-dihydroquinolin-4-yloxy)-1,3,5-triazin-2-ylamino)benzonitrile
(7d).
This compound was obtained as off-white solid, yield
0.99 g (66%); mp 227ꢀC; IR (KBr): 3277 (N–H), 2222 (CꢁN),
1658 (C═O), 1566 (C═N in BT), 1332 (C–N), 1268 (C–O–C),
832 (C3N3, s-triazine), 643 (C–S); 568 (C–Br) cmÀ1 1H NMR
;
(DMSO-d6): d 10.69 (s, 1H, –NH proton of s-triazine to
aminobenzonitriles linkage), 9.72 (s, 1H, –NH proton of s-triazine
to benzothiazole linkage), 8.20 (d, J = 7.5 Hz, 1H, C-8 proton of
quinoline), 7.79 (t, J = 7.6Hz, 1H, C-7 proton of quinoline), 7.71
(d, J = 1.4Hz, 1H, C-5 proton of benzothiazole), 7.63
(d, J = 8.2 Hz, 1H, C-5 proton of quinoline), 7.59 (t, J = 7.8Hz,
1H, C-6 proton of quinoline), 7.45–7.21 (m, 6H, Ar–H proton of
aromatic), 6.83 (s, 1H, –CH–(C═O)–N proton of quinoline
moiety), 3.66 (s, 3H, –N–CH3 proton of quinoline moiety); 13C
4-(4-(Benzo[d]thiazol-2-ylamino)-6-(1-methyl-2-oxo-1,2-
dihydroquinolin-4-yloxy)-1,3,5-triazin-2-ylamino)benzonitrile (7b). This
compound was obtained as brown solid, yield 0.82 g (63%), mp
224–226ꢀC; IR (KBr): 3278 (N–H), 2221 (CꢁN), 1656 (C═O),
1565 (C═N in BT), 1329 (C–N), 1262 (C–O–C), 843 (C3N3,
s-triazine), 654 (C–S) cmÀ1 1H NMR (DMSO-d6): d 10.66
;
(s, 1H, –NH proton of s-triazine to aminobenzonitriles linkage
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

P. K. Patel, R. V. Patel, D. H. Mahajan, P. A. Parikh, G. N. Mehta,
C. Pannecouque, E. De Clercq, and K. H. Chikhalia
Vol 000
NMR (DMSO-d6): d 171.69 (1C, C–O–C, s-triazine to 4-HMQ
linkage), 166.46, 165.25 (2C, C–NH of s-triazine to
aminobenzonitrile linkage and benzothiazole linkage), 162.01
(1C, –C═O of hydroxy quinoline moiety), 156.46 (1C, C–S, of
benzothiazole), 151.78, 150.01, 148.89, 147.11, 145.63, 143.98,
142.21, 140.26, 138.49, 136.09, 135.02, 133.14, 130.01, 128.89,
126.47, 124.09, 121.69, 118.87 (18C, Ar–C of aromatic), 105.68
(1C, – CꢁN of aminobenzonitrile moiety), 103.20 (1C, –C–
(C═O)–N of hydroxy quinoline moiety), 97.51 (1C, –C–CꢁN of
aminobenzonitrile moiety), 30.56 (1C, –N–CH3 of hydroxy
quinoline moiety). Anal. Calcd for C27H17BrN8O2S: C, 54.28; H,
2.87; N, 18.76. Found: C, 54.21; H, 2.83; N, 18.82.
4-(4-(6-Fluorobenzo[d]thiazol-2-ylamino)-6-(1-methyl-2-oxo-
1,2-dihydroquinolin-4-yloxy)-1,3,5-triazin-2-ylamino)benzonitrile
(7e). This compound was obtained as brown solid, yield 1.01 g
75%, mp 225ꢀC; IR (KBr): 3275 (N–H), 2225 (CꢁN), 1643
(C═O), 1579 (C═N in BT), 1359 (C–N), 1259 (C–O–C), 1043
(C–F), 839 (C3N3, s-triazine), 648 (C–S) cmÀ1; 1H NMR (DMSO-
d6): d 10.84 (s, 1H, –NH proton of s-triazine to aminobenzonitriles
linkage), 10.16 (s, 1H, –NH proton of s-triazine to benzothiazole
linkage), 8.14 (d, J = 7.3 Hz, 1H, C-8 proton of quinoline), 7.75
(t, J= 7.4 Hz, 1H, C-7 proton of quinoline), 7.65 (d, J= 7.9 Hz, 1H,
C-5 proton of quinoline), 7.57 (t, J= 8.2 Hz, 1H, C-6 proton of
quinoline), 7.54 (dd, J= 8.4, 2.4 Hz, 1H, C-7 proton of
benzothiazole), 7.46–7.21 (m, 5H, Ar–H proton of aromatic), 7.12
(dt, J= 8.1, 2.2 Hz, 1H, C-5 proton of benzothiazole), 6.70 (s, 1H,
–CH–(C═O)–N proton of quinoline moiety), 3.63 (s, 3H, –N–CH3
proton of quinoline moiety); 13C NMR (DMSO-d6): d 173.40
(1C, C–O–C, s-triazine to 4-HMQ linkage), 166.12, 165.08
(2C, C–NH of s-triazine to aminobenzonitrile linkage and
benzothiazole linkage), 162.96 (1C, –C═O of hydroxy quinoline
moiety), 157.83 (1C, C–S, of benzothiazole), 150.69, 149.13,
147.91, 145.78, 144.03, 142.87, 141.15, 139.95, 137.43, 134.99,
133.12, 130.84, 127.46, 125.89, 124.03, 122.44, 120.01, 118.98
(18C, Ar–C of aromatic), 105.25 (1C, –CꢁN of aminobenzonitrile
moiety), 102.66 (1C, –C–(C═O)–N of hydroxy quinoline moiety),
97.35 (1C, –C–CꢁN of aminobenzonitrile moiety), 29.99 (1C, –––
N–CH3 of hydroxy quinoline moiety). Anal. Calcd for
C27H17FN8O2S: C, 60.44; H, 3.19; N, 20.88. Found: C, 60.38; H,
3.24; N, 20.79.
CꢁN of aminobenzonitrile moiety), 33.04 (1C, –N–CH3 of hydroxy
quinoline moiety). Anal. Calcd for C27H17N9O4S: C, 57.54; H, 3.04;
N, 22.37. Found: C, 57.61; H, 2.99; N, 22.43.
4-(4-(1-Methyl-2-oxo-1,2-dihydroquinolin-4-yloxy)-6-(6-methylbenzo
[d]thiazol-2-ylamino)-1,3,5-triazin-2-ylamino)benzonitrile (7g). This
compound was obtained as light brown solid, yield 1.01 g
(76%), mp 225–227ꢀC; IR (KBr): 3282 (N–H), 2955 (C–H),
2224 (CꢁN), 1654 (C═O), 1561 (C═N in BT), 1328 (C–N),
1261 (C–O–C), 838 (C3N3, s-triazine), 647 (C–S) cmÀ1 1H
;
NMR (DMSO-d6): d 10.78 (s, 1H, –NH proton of s-triazine
to aminobenzonitriles linkage), 9.98 (s, 1H, –NH proton of
s-triazine to benzothiazole linkage), 8.12 (d, J = 7.5 Hz, 1H,
C-8 proton of quinoline), 7.77 (t, J = 7.4 Hz, 1H, C-7 proton
of quinoline), 7.65 (d, J = 8.2 Hz, 1H, C-5 proton of quinoline),
7.52 (t, J = 8.1 Hz, 1H, C-6 proton of quinoline), 7.49–7.23
(m, 7H, Ar–H proton of aromatic), 6.85 (s, 1H, –CH–(C═O)–
N proton of quinoline moiety), 3.70 (s, 3H, –N–CH3 proton of
quinoline moiety), 1.99 (s, 3H, –CH3 proton of benzothiazole);
13C NMR (DMSO-d6): d 170.87 (1C, C–O–C, s-triazine to
4-HMQ linkage), 167.31, 165.08 (2C, C–NH of s-triazine to
aminobenzonitrile linkage and benzothiazole linkage), 162.01
(1C, –C═O of hydroxy quinoline moiety), 158.21(1C, C–S, of
benzothiazole), 150.88, 148.79, 147.25, 146.38, 144.59,
142.78, 141.01, 139.69, 137.04, 135.79, 133.02, 130.59,
127.91, 125.06, 122.89, 120.59, 118.76, 116.89 (18C, Ar–C of
aromatic), 105.43 (1C, –CꢁN of aminobenzonitrile moiety),
101.86 (1C, –C–(C═O)–N of hydroxy quinoline moiety),
97.07 (1C, –C–CꢁN of aminobenzonitrile moiety), 32.61
(1C, –N–CH3 of hydroxy quinoline moiety), 22.87 (1C, –CH3
of benzothiazole). Anal. Calcd for C28H20N8O2S: C, 63.15; H,
3.79; N, 21.04. Found: C, 63.09; H, 3.75; N, 20.98.
4-(4-(6-Methoxybenzo[d]thiazol-2-ylamino)-6-(1-methyl-2-oxo-
1,2-dihydroquinolin-4-yloxy)-1,3,5-triazin-2-ylamino)benzonitrile
(7h).
This compound was obtained as light yellow solid, yield
1.03 g (75%), mp 217ꢀC; IR (KBr): 3277 (N–H), 2824 (O–CH3),
2221 (CꢁN), 1648 (C═O), 1566 (C═N in BT), 1338 (C–N), 1269
(C–O–C), 831 (C3N3, s-triazine), 644 (C–S) cmÀ1 1H NMR
;
(DMSO-d6): d 10.34 (s, 1H, –NH proton of s-triazine to
aminobenzonitriles linkage), 10.07 (s, 1H, –NH proton of s-triazine
to benzothiazole linkage), 8.19 (d, J= 7.6 Hz, 1H, C-8 proton of
quinoline), 7.78 (t, J= 7.5 Hz, 1H, C-7 proton of quinoline), 7.68
(d, J= 8.0 Hz, 1H, C-5 proton of quinoline), 7.55 (t, J=7.8Hz, 1H,
C-6 proton of quinoline), 7.47–7.19 (m, 7H, Ar–H proton of
aromatic), 6.81 (s, 1H, –CH–(C═O)–N proton of quinoline
moiety), 3.81 (s, 3H, –O–CH3 proton of benzothiazole), 3.59
(s, 3H, –N–CH3 proton of quinoline moiety); 13C NMR (DMSO-
d6): d 171.83 (1C, C–O–C, s-triazine to 4-HMQ linkage), 166.43,
165.20 (2C, C–NH of s-triazine to aminobenzonitrile linkage and
benzothiazole linkage), 161.91 (1C, – C═O of hydroxy quinoline
moiety), 157.49 (1C, C–S, of benzothiazole), 149.91, 148.15,
147.68, 145.78, 144.11, 142.83, 141.12, 139.59, 137.93, 135.09,
132.90, 131.17, 129.01, 126.89, 125.13, 122.88, 120.18, 118.71
(18C, Ar–C of aromatic), 105.81 (1C, –CꢁN of aminobenzonitrile
moiety), 103.12 (1C, –C–(C═O)–N of hydroxy quinoline moiety),
96.25 (1C, –C–CꢁN of aminobenzonitrile moiety), 64.98 (1C, –O–
CH3 of benzothiazole), 30.61 (1C, –N– CH3 of hydroxy quinoline
moiety). Anal. Calcd for C28H20N8O3S: C, 61.30; H, 3.67; N,
20.43. Found: C, 61.40; H, 3.70; N, 20.39.
4-(4-(1-Methyl-2-oxo-1,2-dihydroquinolin-4-yloxy)-6-(6-nitrobenzo
[d]thiazol-2-ylamino)-1,3,5-triazin-2-ylamino)benzonitrile (7f). This
compound was obtained as light yellow solid, yield 1.03 g (73%), mp
200ꢀC; IR (KBr): 3279 (N–H), 2228 (CꢁN), 1652 (C═O), 1569
(C═N in BT), 1536 and 1349 (N═O), 1330 (C–N), 1263 (C–O–C),
1
833 (C3N3, s-triazine), 654 (C–S) cmÀ1; H NMR (DMSO-d6): d
10.56 (s, 1H, –NH proton of s-triazine to aminobenzonitriles linkage),
10.09 (s, 1H, –NH proton of s-triazine to benzothiazole linkage), 8.21
(d, J= 7.5 Hz, 1H, C-8 proton of quinoline), 7.79 (t, J=7.6Hz, 1H, C-
7 proton of quinoline), 7.67 (d, J= 8.3 Hz, 1H, C-5 proton of
quinoline), 7.60 (d, J= 2.2 Hz, 1H, C-5 proton of benzothiazole), 7.54
(t, J= 7.9 Hz, 1H, C-6 proton of quinoline), 7.43–7.19 (m, 6H, Ar–H
proton of aromatic), 6.86 (s, 1H, –CH–(C═O)–N proton of quinoline
moiety), 3.66 (s, 3H, –N–CH3 proton of quinoline moiety); 13C NMR
(DMSO-d6): d 172.23 (1C, C–O–C, s-triazine to 4-HMQ linkage),
165.92, 164.68 (2C, C–NH of s-triazine to aminobenzonitrile linkage
and benzothiazole linkage), 163.08 (1C, –C═O of hydroxy quinoline
moiety), 158.09 (1C, C–S, of benzothiazole), 152.34, 150.46, 148.89,
146.99, 145.09, 143.18, 140.97, 138.78, 135.81, 134.02, 132.68,
129.86, 125.01, 124.11, 122.63, 120.76, 118.55, 116.98 (18C, Ar–C
of aromatic), 106.03 (1C, –CꢁN of aminobenzonitrile moiety), 102.29
(1C, –C–(C═O)–N of hydroxy quinoline moiety), 96.88 (1C, –C–
4-(4-(1-Methyl-2-oxo-1,2-dihydroquinolin-4-yloxy)-6-(pyridin-
2-ylamino)-1,3,5-triazin-2-ylamino)benzonitrile (7i).
This
compound was obtained as light yellow solid, yield 0.90g (78%),
mp 215ꢀC; IR (KBr): 3279 (N–H), 2229 (CꢁN), 1645 (C═O),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Pharmacologically Active s-Triazines
1561 and 1413 (C═C and C═N in pyridine), 1331 (C–N), 1259
166.18 (2C, –C–NH of s-triazine to aminobenzonitrile linkage
and thiazole linkage), 160.99 (1C, –C═O of hydroxy quinoline
moiety), 158.13 (1C, –NH–C, of thiazole moiety), 149.13,
146.08, 144.19, 142.18, 139.25, 137.71, 135.69, 132.45, 129.99,
127.01, 124.89, 121.03, 119.01, 117.25 (14C, Ar–C of aromatic),
105.11 (1C, –CꢁN of aminobenzonitrile moiety), 102.78 (1C, –
C–(C═O)–N of hydroxy quinoline moiety), 95.91 (1C, –C–CꢁN
of aminobenzonitrile moiety), 33.02 (1C, –N–CH3 of hydroxy
quinoline moiety). Anal. Calcd for C23H16N8O2S: C, 58.97; H,
3.44; N, 23.92. Found: C, 59.07; H, 3.41; N, 23.87.
1
(C–O–C), 837 (C3N3, s-triazine) cmÀ1; H NMR (DMSO-d6): d
10.68 (s, 1H, –NH proton of s-triazine to aminobenzonitriles
linkage), 9.97 (s, 1H, –NH proton of s-triazine to pyridyl linkage),
8.13 (d, J = 7.6 Hz, 1H, C-8 proton of quinoline), 7.78 (t,
J = 7.2 Hz, 1H, C-7 proton of quinoline), 7.68 (d, J = 8.3 Hz, 1H,
C-5 proton of quinoline), 7.53 (t, J = 7.7 Hz, 1H, C-6 proton of
quinoline), 7.46–7.21 (m, 7H, Ar–H proton of aromatic), 7.08
(dd, J = 7.9, 2.0 Hz, 1H, pyridyl), 6.83 (s, 1H, –CH–(C═O)–N
proton of quinoline moiety), 3.67 (s, 3H, –N–CH3 proton of
quinoline moiety); 13C NMR (DMSO-d6): d 173.09 (1C, C–O–C,
s-triazine to 4-HMQ linkage), 165.96, 164.68 (2C, C–NH of
s-triazine to aminobenzonitrile linkage and pyridyl linkage),
161.78 (1C, –C═O of hydroxy quinoline moiety), 151.01,
149.09, 146.81, 144.95, 143.01, 141.61, 139.25, 138.07, 135.87,
133.45, 131.21, 128.67, 126.46, 123.77, 120.69, 118.07,
116.88 (17C, Ar–C of aromatic), 105.26 (1C, –CꢁN of
aminobenzonitrile moiety), 102.59 (1C, –C–(C═O)–N of hydroxy
quinoline moiety), 97.19 (1C, –C–CꢁN of aminobenzonitrile
moiety), 32.61 (1C, –N–CH3 of hydroxy quinoline moiety). Anal.
Calcd for C25H18N8O2: C, 64.93; H, 3.92; N, 24.23. Found: C,
64.98; H, 3.88; N, 24.19.
4-(4-(1-Methyl-2-oxo-1,2-dihydroquinolin-4-yloxy)-6-(5-methylthiazol-
2-ylamino)-1,3,5-triazin-2-ylamino)benzonitrile (7l). This compound
was obtained as brown solid, yield 0.73 g (60%), mp 211–214ꢀC;
IR (KBr): 3282 (N–H), 2948 (C–H), 2221 (CꢁN), 1654 (C═O),
1332 (C–N), 1264 (C–O–C), 833 (C3N3, s-triazine), 651(C–S)
cmÀ1 1H NMR (DMSO-d6): d 10.68 (s, 1H, –NH proton of
;
s-triazine to aminobenzonitriles linkage), 10.02 (s, 1H, –NH
proton of s-triazine to thiazole linkage), 8.12 (d, J = 7.6Hz, 1H,
C-8 proton of quinoline), 7.75 (t, J = 7.7 Hz, 1H, C-7 proton of
quinoline), 7.66 (d, J = 8.3 Hz, 1H, C-5 proton of quinoline), 7.58
(t, J = 8.2Hz, 1H, C-6 proton of quinoline), 7.45–7.21 (m, 5H,
Ar–H proton of aromatic), 6.78 (s, 1H, –CH–(C═O)–N proton of
quinoline moiety), 3.79 (s, 3H, –N–CH3 proton of quinoline
moiety), 2.23 (s, 3H, –CH3, proton of thiazole); 13C NMR
(DMSO-d6): d 172.05 (1C, C–O–C, s-triazine to 4-HMQ linkage),
165.79, 166.08 (2C, –C–NH of s-triazine to aminobenzonitrile
linkage and thiazole linkage), 162.08 (1C, –C═O of hydroxy
quinoline moiety), 157.13 (1C, –NH–C of thiazole moiety),
150.88, 148.25, 146.69, 143.15, 139.98, 137.13, 135.69, 132.98,
129.04, 127.46, 124.09, 121.63, 119.01, 117.19 (14C, Ar–C of
aromatic), 104.19 (1C, –CꢁN of aminobenzonitrile moiety),
103.36 (1C, –C–(C═O)–N of hydroxy quinoline moiety), 95.69
(1C, –C–CꢁN of aminobenzonitrile moiety), 33.02 (1C, –N–CH3
of hydroxy quinoline moiety), 19.92 (1C, –CH3, thiazole). Anal.
Calcd for C24H18N8O2S: C, 59.74; H, 3.76; N, 23.22. Found: C,
59.81; H, 3.79; N, 23.26.
4-(4-(1-Methyl-2-oxo-1,2-dihydroquinolin-4-yloxy)-6-(pyrazin-
2-ylamino)-1,3,5-triazin-2-ylamino)benzonitrile (7j).
This
compound was obtained as light yellow solid, yield 0.93 g (80%),
mp 224–226ꢀC; IR (KBr): 3282 (N–H), 2224 (CꢁN), 1654
(C═O), 1568 and 1433 (C═C and C═N), 1336 (C–N), 1261
(C–O–C), 839 (C3N3, s-triazine) cmÀ1 1H NMR (DMSO-d6):
;
d 10.84, (s, 1H, –NH proton of s-triazine to aminobenzonitriles
linkage), 10.13 (s, 1H, –NH proton of s-triazine to pyrazine
linkage), 8.21 (d, J = 7.1 Hz, 1H, C-8 proton of quinoline), 7.76
(t, J = 7.7 Hz, 1H, C-7 proton of quinoline), 7.63 (d, J = 7.9Hz,
1H, C-5 proton of quinoline), 7.60 (t, J = 8.1Hz, 1H, C-6 proton
of quinoline), 7.49–7.14 (m, 7H, Ar–H proton of aromatic), 6.86
(s, 1H, ÀCH–(C═O)–N proton of quinoline moiety), 3.64 (s, 3H,
–N–CH3 proton of quinoline moiety); 13C NMR (DMSO-d6):
d 173.27 (1C, C–O–C, s-triazine to 4-HMQ linkage), 164.10,
165.25 (2C, C–NH of s-triazine to aminobenzonitrile linkage and
pyrazine linkage), 161.78 (1C, –C═O of hydroxy quinoline
moiety), 150.55, 147.61, 145.36, 143.09, 140.81, 140.01, 138.78,
135.98, 133.58, 130.66, 128.01, 125.81, 122.77, 119.01, 118.25,
116.87 (16C, Ar–C of aromatic), 106.01 (1C, –CꢁN of
aminobenzonitrile moiety), 101.69 (1C, –C–(C═O)–N of hydroxy
quinoline moiety), 97.09 (1C, –C–CꢁN of aminobenzonitrile
moiety), 31.86 (1C, –N–CH3 of hydroxy quinoline moiety). Anal.
Calcd for C24H17N9O2: C, 62.20; H, 3.70; N, 27.20. Found: C,
62.13; H, 3.74; N, 27.25.
4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-
ylamino)-6-(1-methyl-2-oxo-1,2-dihydroquinolin-4-yloxy)-1,3,5-
triazin-2-ylamino)benzonitrile (7m).
This compound was
obtained as off-white solid, yield 1.24 g (87%), mp 178–180ꢀC;
IR (KBr): 3508 and 3348 (N–CH3 in 4-aminoantipyrine), 3277
(N–H), 2940 (C–H), 2223 (CꢁN), 1652 (C═O), 1436 and 1401
(C–CH3 in 4-aminoantipyrine), 1339 (C–N), 1270 (C–O–C), 836
(C3N3, s-triazine) cmÀ1 1H NMR (DMSO-d6): d 10.81 (s, 1H,
;
ÀNH proton of s-triazine to aminobenzonitriles linkage), 10.12
(s, 1H, –NH proton of s-triazine to pyrazole linkage), 8.12
(d, J = 7.3 Hz, 1H, C-8 proton of quinoline), 7.78 (t, J = 7.5Hz,
1–H, C-7 proton of quinoline), 7.68 (d, J = 8.1Hz, 1H, C-5 proton
of quinoline), 7.59 (t, J =7.9 Hz, 1H, C-6 proton of quinoline),
7.45–7.28 (m, 9H, Ar–H proton of aromatic), 6.86 (s, 1H, –CH–
(C═O)–N proton of quinoline moiety), 3.63 (s, 3H, –N–CH3
proton of quinoline moiety), 2.43 (s, 3H, –N–CH3 proton of
pyrazole), 2.31 (s, 3H, –C–CH3 proton of pyrazole); 13C NMR
(DMSO-d6): d 171.49 (1C, C–O–C, s-triazine to 4-HMQ linkage),
167.19, 166.21 (2C, –C–NH of s-triazine to aminobenzonitrile
linkage and pyrazole linkage), 163.10 (1C, –C═O of hydroxy
quinoline moiety), 158.33 (1C, –NH–C of pyrazole moiety),
152.34, 150.89, 149.10, 148.01, 146.88, 144.45, 142.12, 140.66,
139.18, 137.43, 135.16, 133.88, 130.87, 129.01, 127.89, 124.99,
123.29, 121.01, 119.11, 117.20 (20C, Ar–C of aromatic), 105.16
(1C, –CꢁN of aminobenzonitrile moiety), 103.08 (1C, –C–
(C═O)–N of hydroxy quinoline moiety), 97.77 (1C, –C–CꢁN of
4-(4-(1-Methyl-2-oxo-1,2-dihydroquinolin-4-yloxy)-6-(thiazol-
2-ylamino)-1,3,5-triazin-2-ylamino)benzonitrile (7k).
This
compound was obtained as brown solid, yield 0.79g (67%), mp
226ꢀC; IR (KBr): 3274 (N–H), 2229 (CꢁN), 1649 (C═O), 1335
(C–N), 1259 (C–O–C), 835 (C3N3, s-triazine), 647(C–S) cmÀ1
;
1H NMR (DMSO-d6): d 10.76 (s, 1H, –NH proton of s-triazine to
aminobenzonitriles linkage), 9.88 (s, 1H, –NH proton of s-triazine
to thiazole linkage), 8.23 (d, J = 7.5 Hz, 1H, C-8 proton of
quinoline), 7.80 (t, J = 7.2 Hz, 1H, C-7 proton of quinoline), 7.68
(d, J = 8.2 Hz, 1H, C-5 proton of quinoline), 7.52 (t, J = 7.8 Hz,
1H, C-6 proton of quinoline), 7.44–7.17 (m, 5H, Ar–H proton of
aromatic), 6.83 (d, J = 7.8 Hz, 1H, C-5 proton of thiazole), 6.76
(s, 1H, –CH–(C═O)–N proton of quinoline moiety), 3.61 (s, 3H,
–N–CH3 proton of quinoline moiety); 13C NMR (DMSO-d6):
d 172.01 (1C, C–O–C, s-triazine to 4-HMQ linkage), 165.70,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

P. K. Patel, R. V. Patel, D. H. Mahajan, P. A. Parikh, G. N. Mehta,
C. Pannecouque, E. De Clercq, and K. H. Chikhalia
Vol 000
1H NMR
aminobenzonitrile moiety), 29.99 (1C, –N–CH3 of hydroxy
quinoline moiety), 21.67, 19.82 (2C, –N–CH3 and –C–CH3 of
pyrazole moiety). Anal. Calcd for C31H25N9O3: C, 65.14; H, 4.41;
N, 22.05. Found: C, 65.08; H, 4.46; N, 22.09.
4-(4-(1-Methyl-2-oxo-1,2-dihydroquinolin-4-yloxy)-6-(5-(3,4,5-
trimethoxyphenyl)-1,3,4-oxadiazol-2-ylthio)-1,3,5-triazin-2-ylamino)
(C–N), 1268 (C–O–C), 837 (C3N3, s-triazine) cmÀ1
;
(DMSO-d6): d 10.83 (s, 1H, –NH proton of s-triazine to
aminobenzonitriles linkage), 8.20 (d, J = 7.6Hz, 2H, C-8 proton of
quinoline), 7.79 (t, J = 7.1Hz, 2H, C-7 proton of quinoline), 7.67
(d, J = 7.8 Hz, 2H, C-5 proton of quinoline), 7.53 (t, J = 8.2Hz,
2H, C-6 proton of quinoline), 7.48–7.19 (m, 4H, Ar–H proton of
aromatic), 6.79 (s, 2H, –CH–(C═O)–N proton of quinoline
moiety), 3.73 (s, 6H, –N–CH3 proton of quinoline moiety); 13C
NMR (DMSO-d6): d 170.88 (2C, C–O–C, s-triazine to 4-HMQ
linkage), 167.12 (1C, –C–NH of s-triazine to aminobenzonitrile
linkage), 161.90 (2C, –C═O of hydroxy quinoline moiety),
152.30, 150.26, 148.89, 146.39, 143.88, 142.10, 140.86, 139.52,
137.33, 135.79, 134.02, 131.77, 130.01, 128.25, 125.63, 123.79,
120.25, 118.54, 116.88 (19C, Ar–C of aromatic), 106.11 (1C, –
CꢁN of aminobenzonitrile moiety), 102.09 (2C, –C–(C═O)–N of
hydroxy quinoline moiety), 97.05 (1C, –C–CꢁN of
aminobenzonitrile moiety), 31.62 (2C, –N–CH3 of hydroxy
quinoline moiety). Anal. Calcd for C30H21N7O4: C, 66.29; H,
3.89; N, 18.04. Found: C, 66.23; H, 3.94; N, 17.98.
benzonitrile (7n).
This compound was obtained as off-white
solid, yield 1.32 g (83%), mp 152–154ꢀC; IR (KBr): 3284 (N–H),
2837 (O–CH3), 2225 (CꢁN), 1655 (C═O), 1633, 1542 (2C═N,
oxadiazole), 1348 (C–N), 1261 (C–O–C), 1070 (C–O–C,
oxadiazole), 831 (C3N3, s-triazine), 743 (C–S) cmÀ1 1H NMR
;
(DMSO-d6): d 10.71 (s, 1H, –NH proton of s-triazine to
aminobenzonitriles linkage), 8.11 (d, J=7.1Hz, 1H, C-8 proton of
quinoline), 7.76 (t, J= 7.7 Hz, 1H, C-7 proton of quinoline), 7.65
(d, J= 8.3 Hz, 1H, C-5 proton of quinoline), 7.61 (t, J= 7.7 Hz, 1H,
C-6 proton of quinoline), 7.44–7.12 (m, 6H, Ar–H proton of
aromatic), 6.73 (s, 1H, –CH–(C═O)–N proton of quinoline moiety),
3.66 (s, 3H, –N–CH3 proton of quinoline moiety), 1.84 (s, 9H, –O–
CH3 oxadiazole); 13C NMR (DMSO-d6): d 170.81 (1C, C–O–C,
s-triazine to 4-HMQ linkage), 168.54 (1C, C–5 (C–C) of
oxadiazole), 166.08 (1C, C–2 (C–S) of oxadiazole), 165.36, 163.98
(2C, –C–NH of s-triazine to aminobenzonitrile linkage and –C–S of
s-triazine to oxadiazole linkage), 162.08 (1C, –C═O of hydroxy
quinoline moiety), 150.89, 149.21, 147.18, 145.36, 143.66, 141.48,
139.78, 137.55, 136.16, 133.99, 130.47, 128.81, 126.80, 124.77,
121.61, 120.01, 118.41, 117.11 (18C, Ar–C of aromatic), 105.64
(1C, –CꢁN of aminobenzonitrile moiety), 102.05 (1C, – C–(C═O)–
4-(4-(1-Methyl-2-oxo-1,2-dihydroquinolin-4-yloxy)-6-(2-oxo-2H-
chromen-4-yloxy)-1,3,5-triazin-2-ylamino)benzonitrile (7q). This
compound was obtained as light brown solid, yield 1.13 g (85%),
mp 248ꢀC; IR (KBr): 3272 (N–H), 2227 (CꢁN), 1727 (C═O of
cumarin), 1649 (C═O of quinoline), 1335 (C–N), 1272 (C–O–C),
833 (C3N3, s-triazine) cmÀ1 1H NMR (DMSO-d6): d 10.72
;
(s, 1H, –NH proton of s-triazine to aminobenzonitriles linkage),
8.25 (s, 1H, – CH–(C═O)–C proton of coumarin), 8.13
(d, J = 7.5 Hz, 1H, C-8 proton of quinoline), 7.75 (t, J= 7.3 Hz, 1H,
C-7 proton of quinoline), 7.68 (d, J =8.2Hz, 1H, C-5 proton of
quinoline), 7.56 (t, J = 7.9 Hz, 1H, C-6 proton of quinoline), 7.47–
7.21 (m, 8H, Ar–H proton of aromatic), 6.85 (s, 1H, –CH–(C═O)–
N proton of quinoline moiety), 3.67 (s, 3H, –N–CH3 proton of
quinoline moiety); 13C NMR (DMSO-d6): d 172.39 (1C, C–O–C,
s-triazine to 4-HMQ linkage), 166.45 (C, –C–NH of s-triazine to
aminobenzonitrile linkage linkage), 163.51 (1C, –C═O of
coumarin moiety), 163.06 (1C, – C═O of hydroxy quinoline
moiety), 151.85, 150.13, 148.69, 146.78, 145.15, 143.26, 141.91,
139.88, 138.09, 136.86, 135.16, 133.28, 130.67, 128.97, 125.98,
124.23, 121.76, 120.56, 119.11, 117.25 (20C, Ar–C of aromatic),
104.89 (1C, –CꢁN of aminobenzonitrile moiety), 103.33 (1C, –C–
(C═O)–N of hydroxy quinoline moiety), 96.59 (1C, –C–CꢁN of
aminobenzonitrile moiety), 94.56 (1C, –C–(C═O)–C of coumarin
moiety), 33.19 (1C, –N–CH3 of hydroxy quinoline moiety). Anal.
Calcd for C29H18N6O5: C, 66.29; H, 3.89; N, 18.04. Found: C,
66.35; H, 3.86; N, 18.10.
N
of hydroxy quinoline moiety), 96.61 (1C, –C–CꢁN of
aminobenzonitrile moiety), 66.54 (3C, –O–CH3 of oxadiazole
moiety), 30.79 (1C, –N–CH3 of hydroxy quinoline moiety). Anal.
Calcd for C31H24N8O6S: C, 58.48; H, 3.80; N, 17.60. Found: C,
58.55; H, 3.76; N, 17.66.
4-(4-(1-Methyl-2-oxo-1,2-dihydroquinolin-4-yloxy)-6-(5-(pyridin-
4-yl)-1,3,4-oxadiazol-2-ylthio)-1,3,5-triazin-2-ylamino)benzonitrile
(7o). This compound was obtained as brown solid, yield 1.07 g
(78%), mp 218–220ꢀC; IR (KBr): 3274 (N–H), 2222 (CꢁN), 1648
(C═O), 1621, 1532 (2C═N, oxadiazole), 1548 and 1438 (C═C
and C═N in pyridine), 1343 (C–N), 1272 (C–O–C), 1082 (C–O–C,
oxadiazole), 839 (C3N3, s-triazine), 756 (C–S) cmÀ1 1H NMR
;
(DMSO-d6): d 10.66 (s, 1H, –NH proton of s-triazine to
aminobenzonitriles linkage), 8.21 (d, J=7.5Hz, 1H, C-8 proton of
quinoline), 7.80 (t, J= 7.2 Hz, 1H, C-7 proton of quinoline), 7.64
(d, J= 8.2 Hz, 1H, C-5 proton of quinoline), 7.59 (t, J=8.2Hz, 1H,
C-6 proton of quinoline), 7.43–7.17 (m, 8H, Ar–H proton of
aromatic), 6.80 (s, 1H, –CH–(C═O)–N proton of quinoline
moiety), 3.70 (s, 3H, –N–CH3 proton of quinoline moiety); 13C
NMR (DMSO-d6): d): 173.04 (1C, C–O–C, s-triazine to 4-HMQ
linkage), 167.36 (1C, C–5 (C– C) of oxadiazole), 166.34 (1C, C–2
(C–S) of oxadiazole), 165.08, 164.83 (2C, – C–NH of s-triazine to
aminobenzonitrile linkage and –C– S of s-triazine to oxadiazole
linkage), 162.68 (1C, –C═O of hydroxy quinoline moiety), 151.75,
150.01, 148.99, 146.18, 144.87, 142.18, 140.95, 139.17, 137.48,
135.90, 134.12, 130.87, 129.01, 127.85, 125.60, 122.45, 119.97
(17C, Ar–C of aromatic), 106.11 (1C, –CꢁN of aminobenzonitrile
moiety), 101.29 (1C, –C–(C═O)–N of hydroxy quinoline moiety),
97.26 (1C, –C–CꢁN of aminobenzonitrile moiety), 31.98 (1C, –N–
CH3 of hydroxy quinoline moiety). Anal. Calcd for C27H17N9O3S:
C, 59.23; H, 3.13; N, 23.02. Found: C, 59.17; H, 3.17; N, 23.07.
4-(4,6-bis(1-Methyl-2-oxo-1,2-dihydroquinolin-4-yloxy)-1,3,5-
BIOLOGICAL ASSAY
In vitro evaluation of antimicrobial activity. The synthesized
derivatives (7a–q) were examined for antimicrobial activity
against several bacteria, two Gram-positive bacteria
(Staphylococcus aureus MTCC 96 and Bacillus cereus
MTCC 430), six Gram-negative bacteria (E. coli MTCC
739, P. aeruginosa MTCC 741, S. typhi MTCC 733, P.
vulgaris MTCC 1771, K. pneumoniae MTCC 109, and S.
flexneri MTCC 1457), and two fungal species (A. niger
MTCC 282, C. albicans MTCC 183) species. All MTCC
cultures were collected from the Institute of Microbial
Technology, Chandigarh. MIC of the compound was
determined by agar streak dilution method [20]. In vitro
triazin-2-ylamino)benzonitrile (7p).
This compound was
obtained as light brown solid, yield 1.14 g (84%), mp 209–210ꢀC;
IR (KBr): 3279 (N–H), 2222 (CꢁN), 1658 (C═O), 1313
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Pharmacologically Active s-Triazines
evaluation of antituberculosis activity was carried out using
LJ MIC method [21] for the measurement of MIC as
reported earlier [22].
In vitro evaluation of anti-HIV assay. Evaluation of the
control drugs. Attempt has been made to determine the effi-
cacy of various pharmacophores involving different electron-
withdrawing/donating functional groups towards particular
bacteria, fungi, mycobacteria, or viral strains. In the anti-HIV
bioassay, only one compound (7h) showed selective anti-
HIV-1 activity with minimum cytotoxicity and promising
therapeutic index compared with the control drugs. Thus, such
scaffolds provide an important starting point for the develop-
ment of novel lead molecules with increased potency by suit-
able structural optimization. Such studies are underway in our
laboratory, and the results will be published in due course.
antiviral activity of the test compounds against HIV-1
strain (IIIB) and HIV-2 strain (ROD) in MT-4 cells were
performed using the MTT assay method as previously
described [23,24]. Briefly, stock solutions (10Â final
concentration) of test compounds were added in 25mL
volumes to two series of triplicate wells so as to allow
simultaneous evaluation of their effects on mock-infected
and HIV-infected cells at the beginning of each
experiment. Serial fivefold dilutions of test compounds
were made directly in flat-bottomed 96-well microtiter trays
by using a Biomek 3000 robot (Beckman instruments).
Untreated control HIV-infected and mock-infected cell
samples were included for each sample. HIV-1 (IIIB) [25]
or HIV-2 (ROD) [26] stock (50 mL) at 100 –300 CCID50
(50% cell culture infectious dose) or culture medium was
added to either the HIV-infected or mock-infected wells of
the microtiter tray. Mock-infected cells were used to
evaluate the effect of test compound on uninfected cells in
order to assess the cytotoxicity of the test compound.
Exponentially growing MT-4 cells [27] were centrifuged
for 5 min at 1000 rpm (220 g), and the supernatant was
discarded. The MT-4 cells were resuspended at
6 Â 105 cells/mL, and 50 mL volumes were transferred to
the microtiter tray wells. Five days after infection, the
viability of mock-infected and HIV-infected cells was
examined spectrophotometrically by the MTT assay.
The MTT assay is based on the reduction of yellow-
colored 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazo-
lium bromide (MTT) (Acros Organics) by mitochondrial
dehydrogenase of metabolically active cells to a blue-purple
formazan that can be measured spectrophotometrically. The
absorbances were read in an eight-channel computer-
controlled photometer (Safire, Tecan), at two wavelengths
(540 and 690 nm). All data were calculated using the median
optical density (OD ) value of tree wells. The 50% cytotoxic
concentration (CC50) was defined as the concentration of the
test compound that reduced the absorbance (OD540) of the
mock-infected control sample by 50%. The concentration
achieving 50% protection from the cytopathic effect of the
virus in infected cells was defined as the 50% effective
concentration (EC50).
Acknowledgments. The authors are thankful to the Applied
Chemistry Department of S. V. National Institute of Technology,
Surat for the scholarship, encouragement, and facilities. The authors
wish to offer their deep gratitude to the Rega Institute for Medical
Research, Belgium, Europe for the evaluation of anti-HIV activity.
CONFLICT OF INTEREST
The authors have declared no conflict of interest.
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CONCLUSION
The work was focused on the development of some novel s-
triazine-based analogues having different structural character-
istics and their bioevaluations against multiple targets. From
the results, it is worth to note here that majority of the final ana-
logues revealed good antimicrobial and antituberculosis activ-
ities with appreciable MIC values as compared with the
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

P. K. Patel, R. V. Patel, D. H. Mahajan, P. A. Parikh, G. N. Mehta,
C. Pannecouque, E. De Clercq, and K. H. Chikhalia
Vol 000
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet