Synthesis and antibacterial evaluation of series of novel tri-substituted-s-triazine derivatives

Article abstract of DOI:10.1007/s00044-010-9446-7

Two novel series of s-triazine derivatives (6a-e and 7a-f) were synthesized with various aromatic and heterocyclic amines. The synthesized compounds were subsequently evaluated for their in vitro antibacterial activity against three gram-positive viz. Bacillus subtilis (NCIM- 2063), Bacillus cereus (NCIM-2156), Staphylococcus aureus (NCIM-2079) and gram-negative bacteria viz. Pseudomonas aeruginosa (NCIM-2036), Escherichia coli (NCIM-2065) and Klebseilla pneumoniae (NCIM-2706) by the broth dilution method as recommended by the National Committee for Clinical Laboratory Standards (NCCLS) using streptomycin as reference standard. Structures of the synthesized compounds were elucidated on the basis of elemental analyses and spectral data. Springer Science+Business Media, LLC 2010.

Full text of DOI:10.1007/s00044-010-9446-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:1603–1610
DOI 10.1007/s00044-010-9446-7
ORIGINAL RESEARCH
Synthesis and antibacterial evaluation of series of novel
tri-substituted-s-triazine derivatives
•
Udaya Pratap Singh Ramendra Kumar Singh
•
•
Hans Raj Bhat Yadav Pankajkumar Subhashchandra
•
•
Vikas Kumar Mukesh Kumar Kumawat Prashant Gahtori
•
Received: 7 March 2010 / Accepted: 17 September 2010 / Published online: 29 September 2010
Ó Springer Science+Business Media, LLC 2010
Abstract Two novel series of s-triazine derivatives (6a–e
and 7a–f) were synthesized with various aromatic and het-
erocyclic amines. The synthesized compounds were subse-
quently evaluated for their in vitro antibacterial activity
against three gram-positive viz. Bacillus subtilis (NCIM-
2063), Bacillus cereus(NCIM-2156), Staphylococcus aureus
(NCIM-2079) and gram-negative bacteria viz. Pseudomonas
aeruginosa (NCIM-2036), Escherichia coli (NCIM-2065)
and Klebseilla pneumoniae (NCIM-2706) by the broth dilu-
tion method as recommended by the National Committee for
Clinical Laboratory Standards (NCCLS) using streptomycin
as reference standard. Structures of the synthesized com-
pounds were elucidated on the basis of elemental analyses
and spectral data.
Introduction
Since the discovery of chemotherapeutic agents, there was a
belief in the medical fraternity that this would lead to the
eradication of infectious disease. But these agents are now
returning in new resistant forms to antibiotic therapies
(Qadri et al., 2005, Devasia et al., 2006). The global
emergence of multi-drug resistant microbial strains is
increasing and has become the limiting factor to the effec-
tiveness of current drugs. It has resulted in significant
morbidity and mortality from treatment failures and
increased health care cost (Projan and Bradford, 2007).
Development of new, cost effective and innovative drugs is
one of the most common scientific strategies to combat drug
resistant microorganisms.
Keywords s-triazines ꢀ Amines ꢀ Antibacterial ꢀ
s-Triazine derivatives have been focus of attention for
the chemists and biologists for long time due to their wide
array of biological activities associated with them, such as,
antiplasmodial (Klenke et al., 2003), antibacterial (Srinivas
et al., 2006), anticancer (Mandal et al., 2007) and carbonic
anhydrase inhibitors (Garaj et al., 2005). The purpose of
this study was to synthesize various substituted s-triazine
derivatives attached with substituted thiazoles as bioactive
scaffold (Khalil et al., 2009, Bharti et al., 2010) in search
of exploring the potential of this skeleton as antibacte-
rial drugs against some gram-positive and gram-negative
microorganisms.
MIC
U. P. Singh (&) ꢀ H. R. Bhat ꢀ Y. P. Subhashchandra ꢀ
V. Kumar
Department of Pharmaceutical Sciences, Allahabad Agricultural
Institute-Deemed University, Allahabad, Uttar Pradesh 211007,
India
e-mail: udaysingh98@gmail.com
R. K. Singh
Nucleic Acids Research Laboratory, Department of Chemistry,
University of Allahabad, Allahabad 211002, Uttar Pradesh, India
Materials and method
M. K. Kumawat
NIMS Institute of Pharmacy, NIMS University, Jaipur 303001,
Rajasthan, India
Structural investigation
P. Gahtori
Devsthali Vidyapeeth College of Pharmacy, Rudrapur 263148,
Uttarakhand, India
All chemicals were of analytical grade and used directly.
Melting points were determined in open capillary tubes
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with electrothermal melting point apparatus (MP-1) and are
uncorrected. The completion of reaction was checked by
thin layer chromatography (TLC) using silica gel-G coated
Al-plates (0.5 mm thickness; Merck) and the plates were
illuminated under UV (254 nm) and evaluated in iodine
vapor. The solubility of all the compounds were tested by
using water, chloroform, ethanol, DMF, DMSO, benzene,
acetic acid, ethyl acetate, and dilute acids. FT-IR (in
2.0 cm-1, flat, smooth, abex, KBr) spectra were recorded
on Perkin Elmer-Spectrum RX-I spectrometer. Elemental
analysis was carried out on a Vario EL III CHNOS ele-
mentor analyzer. 1H NMR spectra were recorded on Bruker
Avance II 400 NMR Spectrometer in DMSO-d6 using TMS
as internal standard (chemical shift in d, ppm). Mass
spectra were obtained on VG-AUTOSPEC spectrometer.
Solvents were purified prior to use according to standard
procedure.
(9 9 108 cells/ml) and each bacterium was incubated on a
rotary shaker at 37°C for 24 h at 150 rpm. The final vol-
ume in each tube was 1.0 ml. The incubation chamber was
kept humid. At the end of the incubation period, MIC
values were recorded as the lowest concentration of the
substance that gave no visible turbidity, i.e. no growth of
inoculated bacteria.
Result
The molecular modification of all the compounds is shown
in Table 1. The physicochemical properties, Rf values
(Table 2), Calculated log P values (ClogP) (Table 3), and
elemental composition of all the elements are reported
(Table 4). The entire spectral data are of individual com-
pound reported in Table 5. Antibacterial investigation of
this new series of s-triazines derivatives (6a–e, 7a–f)
showed moderate to excellent MIC against tested gram-
positive and gram-negative organisms. Their inhibition
values are included in Table 1.
Biological evaluation
All synthesized compounds were screened for their mini-
mum inhibitory concentration (MIC, lg/mL) against
selected gram-positive organisms viz. Bacillus subtilis
(NCIM-2063), Bacillus cereus (NCIM-2156), Staphylo-
coccus aureus (NCIM-2079) and gram-negative organisms
viz. Pseudomonas aeruginosa (NCIM-2036), Escherichia
coli (NCIM-2065) and Klebseilla pneumoniae (NCIM-
2706) bacteria by the broth dilution method as recom-
mended by the National Committee for Clinical Laboratory
Standards (National Committee for Clinical Laboratory
Standards, 1982) with minor modifications. Streptomycin
was used as standard antibacterial agent. Solutions of the
test compounds and reference drug were prepared in
dimethylsulfoxide (DMSO) at concentrations of 100, 50,
25, 12.5, 6.25, 3.125 lg/ml. Eight tubes were prepared in
duplicate with the second set being used as MIC reference
controls (16–24 h visual). After sample preparation, the
controls were placed in a 37°C incubator and read for
macroscopic growth (clear or turbid) the next day.
Discussion
From the structural investigation, FT-IR spectra showed
the stretching frequency range between region 1550–
1200 cm-1 due to –C=C–, –C=N stretching. 1H-NMR
spectra of class of compounds showed a singlet at d 4.4–4.6
due to –NH group of phenyl thiazolyl-2-amine groups and
aromatic C–NH lies at about 4.3–3.3 ppm, disappearance of
primary amine peak associated with substituted phenyl thi-
azole-2-amine further confirmed the formation of this
class of derivatives. Estimated elemental compositions were
with in 0.4% of the calculated values. The antibacterial
screening of all compounds showed an excellent to no
activity against both grampositive and gram-negative bac-
teria tested in comparison to standard streptomycin. The di-
(6a–e) and tri-substituted derivatives (7a–f) of s-triazines
series exhibited stronger inhibition of gram-negative
organism compared with gram-positive and the tri-substi-
tuted derivatives showed better results than di-substituted
derivatives.
Into each tube, 0.8 ml of nutrient broth was pipetted
(tubes 2–7), tube 1 (negative control) received 1.0 ml of
nutrient broth and tube 8 (positive control) received 0.9 ml
of nutrient. Tube 1, the negative control, did not contain
bacteria or antibiotic. The positive control, tube 8, received
0.9 ml of nutrient broth since it contained bacteria but not
antibiotic. The test compound is dissolved in dimethyl-
sulphoxide (100 lg/ml), 0.1 ml of increasing concentration
of the prepared test compounds which are serially diluted
from tube 2 to tube 7 from highest (100 lg/ml) to lowest
(3.125 lg/ml) concentration (tube 2–7 containing 100, 50,
25, 12.5, 6.25, 3.125 lg/ml). After this process, each tube
was inoculated with 0.1 ml of the bacterial suspension
whose concentration corresponded to 0.5 McFarland scale
As depicted in Table 1, none of the synthesized com-
pounds proved to be effective antibacterial against tested
microorganisms, except a few tri-substituted s-triazine
derivatives. Among the compounds (7a–f), 7c was found to
be equipotent to the standard drug streptomycin in the case
of all microorganisms, except Bacillus cereus. The com-
pound 7b was found to be equipotent to the standard
against Pseudomonas aeruginosa and was found posses
mild to moderate activity against tested microorganisms. In
terms of Klebseilla pneumoniae, 7f, is the only compound
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Table 1 Molecular modification and MIC value of individual compounds against gram-positive and gram-negative bacteria
Compounds
R1
R2
MIC (lg ml-1
Gram-positive bacteria
)
Gram-negative bacteria
Bacillus
subtilis
Bacillus
cereus
Staphylococcus
aureus
Pseudomonas
aeruginosa
Escherichia
coli
Klebseilla
pneumoniae
3a
Cl
–
NP
NP
100
100
100
50
NP
NP
NP
50
NP
NP
NP
NP
100
100
100
50
3b
NO2
–
–
NP
NP
NP
6a
3-Chloro,4-fluoro
4-Nitro
100
100
100
50
100
25
100
50
6b
–
50
6c
–
4-Bromo
4-Fluoro
4-Chloro
3-Chloro,4-fluoro
3-Chloro,4-fluoro
4-Nitro
100
100
50
100
100
50
100
50
6d
–
6e
–
50
100
100
25
25
25
7a
Cl
50
25
25
12.5
12.5
6.25
100
25
12.5
25
7b
NO2
NO2
NO2
NO2
NO2
100
6.25
100
50
50
3.125
3.125
50
7c
6.25
100
100
12.5
3.125
3.125
100
50
6.25
100
50
7d
4-Bromo
4-Fluoro
4-Chloro
7e
25
7f
25
25
6.25
3.125
12.5
6.25
6.25
6.25
Streptomycin
6.25
3.125
NP not performed
found equipotent to the standard drug like 7c. Nearly all
synthesized derivatives from both the series, viz. (6a–e,
7a–f) were found inactive against Bacillus subtilis. Rest of
the compounds was found either inactive or presented MIC
value more than 100 lg/ml.
tolerated at 6-position of tri-substituted triazine. By close
perlustration of the in vitro antibacterial activity, we proceed
to survey that electron withdrawing groups (NO2, Cl, Br, F)
are necessary for compounds to be effective antibacterials.
Further, the presence of nitro group leads to increased in
activity in comparison to the other electron withdrawing
groups. In next instance, we can see that the presence of
chloro is the second most influencing electron withdrawing
group, which can further be confirmed by antibacterial
profile of compound 7b (3-chloro, 4-fluoro benzyl amine)
against P. aeruginosa. The importance of electron with-
drawing group in enhancing the antimicrobial activity was
supported by similar results observed by Sharma et al., 2004.
These atoms (electron withdrawing groups) are very
useful to modulate the steric effect on phenyl ring of drug
and which in turn alter the ease of penetration of molecule
in bacterial cell wall and this may be the plausible cause for
variation in antibacterial profile of substituted derivatives.
Moreover, these atoms may also influence hydrophilic–
hydrophobic balance of the target molecules which would
further evidenced by SAR analysis.
LogP value is a measure of hydrophobic/lipophilic
balance of the molecule. It was believed that the lipophilic
nature of the compound plays a very vital role for gener-
ation of antimicrobial effect by increasing the membrane
permeation and hence, a strong correlation exists between
lipophilicity and activity. In this context, lipophilicity of
compound expressed as ClogP (octanol/water partition
coefficient) value explains the main predictor of activity
and was calculated by using the methodology developed by
Molinspiration as a sum of fragment-based contributions
and correction factors as shown in Table 3. The method is
very robust and is able to process practically all organic
and most organometallic molecules.
On close inspection of ClogP value and MIC of test
compound, it was observed that ClogP is the main factor
influencing physico-chemical parameter for generation of
antibacterial activity. Pronounced antibacterial activity
was observed in compound with having high ClogP, e.g., tri-
substituted derivatives were found more active than
di-substituted derivatives. And it was also confirmed that the
inhibition pattern of tri-substituted derivative on gram-
negative organism were more influencing than di-substitu-
tion due to high ClogP values.
Conclusion
In our study, we have synthesized various di- and tri-
substituted derivatives of s-triazine, which again proves the
novelty of biological efficacy of new s-triazines derivatives
as synthetic antibiotics. On the basis of result obtained, it
has been concluded that tri-substituted s-triazine provided a
In the light of above structure activity relationship stud-
ies, it could be suggested that thiazole amine pendent is well
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Table 3 Calculated log P
(miLog P) of test compounds
4-(4-subsitutedphenyl)-thiazole-2-amine groups on s-tri-
azine moiety towards antibacterial activity. The s-triazine
derivatives were synthesized from 2,4,6-trichloro-1,3,5-
triazine by consecutive aromatic nucleophilic substitution
(SNAr) reactions under controlled conditions by treating
two equivalents of substituted amine derivatives 5 with
s-triazine 4 in presence of NaOH as activating bases to give
di- substituted monochloro-s-triazines 6a–e. 4-(4-substi-
tutedphenyl)thiazole-2-amine were synthesized by cyclo-
condensation reaction between substituted acetophenone 1,
and thiourea 2 with the help of bromine to give compounds
3a and b (Scheme 1). And 3a and b were further used as
intermediate for synthesizing a series of compound by
reacting with 6a–e under harsh condition to form final
corresponding compounds 7a–f because third nucleophilic
attack is difficult to perform (Scheme 2).
Compounds
ClogP
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
7f
6.46
4.04
6.54
5.25
6.28
8.78
8.06
5.63
8.13
6.85
7.88
Table 4 Values obtained by elemental analysis for individual com-
pounds (in %)
General procedure for synthesis of 4-(4-subsituted
Compounds
Carbon
A
Hydrogen
Nitrogen
A
phenyl)thiazole-2-Yl)amine (3a, b)
B
A
B
B
Substituted acetophenone (1) (110 mmol) and thiourea (2)
(220 mmol) were mixed completely; then added bromine
(110 mmol) in small fractions (0.5 ml) over 3 h with
continuous stirring and heated on a steam bath for 9 h. The
sufficient quantity of water was added, heated until most of
the solid had gone into solution and filtered while hot. The
filtrate was cooled and concentrated ammonia solution was
added till the precipitation ceases off. Recrystallized with
pyridine–water (1:1) mixture to achieved pure products 3a
and b.
3a
3b
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
7f
51.31
48.86
44.75
46.46
39.55
53.99
49.14
49.97
49.07
50.35
45.02
55.59
52.28
51.01
48.88
44.79
46.48
39.53
53.96
49.17
49.99
49.15
50.28
45.10
55.65
52.26
3.35
3.19
2.00
2.60
2.21
3.02
2.75
2.45
2.40
2.82
2.52
3.11
2.92
3.36
3.20
1.97
2.65
2.20
3.02
2.77
2.42
2.35
2.86
2.55
3.15
2.95
13.30
18.99
17.39
25.29
15.37
20.99
19.10
17.00
19.08
24.47
17.50
21.61
20.32
13.25
18.22
17.38
25.26
15.34
20.95
19.15
16.98
19.04
24.40
17.48
21.68
20.28
General procedure for synthesis of 2,4-bis(substituted
amine)-6-chloro-s-triazine (6a–e)
(A) Calculated; (B) Found
Various substituted anilines (5) (0.2 mol) were added into
100 ml of acetone maintaining temperature 40–45°C. The
solution of 2,4,6-tri chloro-s-triazine (4) (0.1 mol) in 25 ml
acetone was added constantly, stirred for 3 h followed by
drop-wise addition of NaOH solution (0.1 mol) taking care
that reaction mixture does not become acidic. The product
was filtered and washed with cold water and recrystallized
with ethanol to afford pure products 6a–e.
new class of bioactive scaffolds, but in future compounds
will be modified further to reduce molar mass and toxi-
cological barriers.
This study also showed broad spectrum activity of
s-triazines containing thiazole units, that are comparatively
equipotent to the antibiotic agent (streptomycin) in the
comparison test, may be due to the synergistic antibacterial
effect of thiazole and triazine nuclei. Further, these mole-
cules may act as lead for further synthetic and biological
evaluation towards pursuit to discover novel class of anti-
bacterial agents.
General procedure for synthesis of 2,4-bis(substituted
amine)-6-(4-(4-subsituted phenyl)thiazole-2-Yl)-s-
triazine-2,4,6-triamine (7a–f)
2,4-Bis(substituted amine)-6-chloro-s-triazine (6a–e) (0.1 mol)
was added into 50 ml of 1,4-dioxane maintaining tempera-
ture 40–45°C. The solution of 4-(4-substituted phenyl)-
thiazole-2-amine (3a, b) (0.1 mol) in 35 ml 1,4-dioxane
was added constantly to above solution and stirred for
90 min followed by drop-wise addition of NaHCO3
Experimental
The compounds were synthesized to understand the role
of di- and tri-substitutions of substituted amines and
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Table 5 Spectral data for individual compounds
IR wave number (in cm-1
)
1H NMR (in ppm)
Mass [M ? H]?
Compound 3a
m 3389.72 (NH strech, –NH2), 3120.89 (aromatic C–H),
1627.11 (–C=N), 1092.77 (aromatic-Cl), 572.50 (C–S
strech)
d 7.34 (d, 2H, 3,5-CH aromatic), d 7.46 (d, 2H, 2,6-CH
aromatic), d 6.72 (s, 1H, CH thiazolyl), d 4.12 (s, 2H,
NH amino)
211.01 (10.1%) [M ? H]?, 210.00
(100.0%), 212.00 (36.6%), 213.00
(4.1%)
Compound 3b
m 3400.39 (NH strech, –NH2), 1607.97 (aromatic-C=N),
1525.08 (–NO2), 1345.28 (aromatic-NO2), 585.33
(C–S strech).
d 8.26 (d, 2H, 3,5-CH aromatic), d 7.75 (d, 2H, 2,6-CH
aromatic), d 6.80 (s, 1H, CH, thiazolyl), d 4.15 (s, 2H,
NH, amino).
222.03 (11.0%) [M ? H]?, 221.03
(100.0%), 223.02 (4.4%)
Compound 6a
m 3332.34 (N–H secondary), 3052.32(C–H broad),
1453.25(aromatic-C=N)
d 6.98 (d, 2H, 2-CH aromatic), d 6.54 (d, 2H,
2-CH aromatic), d 6.84(d, 2H, 2-CH, aromatic), d
4.66(d, 2H,-NH, amino)
403.90 (96.3%) [M ? H]?, 400.76
(100.0%), 404.09 (31.0%),
Compound 6b
m 3289.56 (N–H secondary), 3055.70 (C–H broad),
1548.28-1446.06 (aromatic-C=N)
d 7.40 (t, 4H, 4=CH-aromatic), d 7.32(t, 4H, 4=CH-
aromatic), d 3.62 (d, 2H, 2-NH aromatic)
388.04 (100.0%) [M?H]?, 389.12
(34.5%), 388.09 (19.6%)
Compound 6c
m 3350.62 (N–H secondary), 3015.43 (C–H broad),
1656.15 (C=C stretch)
d 7.26(d, 4H, 3,5-CH aromatic), d 7.06 (d, 4H, 2,6-
aromatic), d 4.81 (s, 2H, NH)
456.90 (43.3%) [M ? H]?, 454.90
(100.0%), 452.90 (44.1%)
Compound 6d
3054.72(C–H broad), 1548.58 (C=N), 1448.25 (C–N
aromatic)
d 7.68 (d, 4H, 2-CH, aromatic), d 7.14 (d, 4H,
2-CH aromatic), d 4.84(t, 2H, -NH amino)
334.38 (18.5%) [M ? H]?, 333.56
(100.0%), 335.63 (32.3%)
Compound 6e
m 3243.26 (N–H secondary), 2965.46 (C–H broad),
1387.38 (aromatic –C=N)
d 7.32 (d, 4H, 3,5-CH aromatic), d 7.08 (d, 4H, 2,6-CH
aromatic), d 4.82 (s, 2H, NH)
367.15 (96.2%) [M ? H]?, 365.70
(100.0%), 368.99 (30.7%)
Compound 7a
m 3393.6 (N–H stretch, –NH2), 3282.6, 3110.7 (C–H
stretch, aromatic), 1626.7 (N–H bend), 1406.2 (C–N
stretch), 1260.5 (C–N stretch; aromatic-NH-
d 7.93–7.91 (d, 1H, J=10.8 Hz, aromatic-H), d
7.77–7.75 (d, 1H, J = 8.8 Hz, aromatic-H), d 7.68 (s,
1H, NH), d 7.55 (s, 1H, NH), d 7.44 (s, 1H, NH), d (s,
1H, thiazolyl), d 7.07–7.02 (dd, 1H, J = 20 Hz,
aromatic-H)
578.1 (1.84%) [M?H]?, 274.3(100%),
331.3 (52.21%), 330.4 (45.32%)
aromatic), 1128.9 (aromatic-F stretch), 1088.3
(aromatic-Cl stretch), 693.1, 668.8 (C–S stretch)
Compound 7b
m 3395.2 (N–H stretch, –NH2), 3110.8 (C–H stretch,
aromatic), 1260.3, 1209.7 (C–N stretch, [NH),
1107.4 (aromatic-F stretch), 1055.8 (aromatic-Cl
stretch), 853.8 (C–N stretch, aromatic-NO2), 694.3
(C–S stretch)
d 8.27–8.25 (d, 1H, J = 7.2 Hz, aromatic-H), d
8.18–8.16 (d, 1H, J = 8.8 Hz, aromatic-H), d
8.11–8.09 (d, 1H, J = 8.8 Hz, aromatic-H), d
7.99–7.97 (d, 1H, J = 7.2 Hz, aromatic-H), d 7.68 (s,
1H, NH), d 7.60 (s, 1H, NH), d 7.56 (s, 1H, NH), d
7.25–7.22 (d, 1H, J = 11.2 Hz, aromatic-H), d
6.53–6.51 (d, 1H, J = 8.8 Hz, aromatic-H)
587.03 (2.45%) [M ? H]?, 331.3
(100%), 228.3 (85.67%), 381.4
(84.73%)
Compound 7c
m 3399.3 (N–H stretch, -NH2), 3360.2, 3217.9 (C–H
stretch, aromatic), 1594.2, 1502.8 (N–Hbend, [NH),
1478.4, 1325.3 ((N=O)2 stretch, aromatic-NO2),
842.0 (C–N stretch, aromatic-NO2), 698.2 (C–S
stretch)
d 8.35–8.29 (m, 1H, aromatic -H), d 8.21–8.19 (d, 1H,
J = 8.8 Hz, aromatic-H), d 8.16–8.14 (d, J = 8.8,
aromatic-H), d 8.10–8.08 (d, 1H, J = 9.8 Hz,
aromatic-H), d 8.20–7.99 (d, 1H, J = 8.4 Hz,
aromatic-H), d 7.91–7.89 (d, 1H, J = 8.8 Hz,
aromatic-H), d 7.84–7.82 (d, 1H, J = 9.2, aromatic-
H), d 7.68 (s, 1H, NH), d 7.55 (s, 1H, NH), d 7.38 (s,
1H, NH), d 7.33
573.51 (1.84%) [M ? H]?, 353.4
(100%), 274.3 (71%), 381.4
(67.79%), 330.4 (31.01%)
(s, 1H, thiazolyl), d 6.57–6.50 (m, aromatic-H)
Compound 7d
m 3394.8 (N–H stretch, –NH2), 3105.6 (C–H stretch,
aromatic), 1567.8, 1512.1 (N–H bend,[NH), 1485.1,
1327.0 ((N=O)2 stretch, aromatic-NO2), 1230.4 (C–N
stretch, aromatic -NH- aromatic), 645.3 (C–S stretch)
d 8.35–8.33 (d, 1H, J = 6.8 Hz, aromatic–H), d 8.30-
8.28 (d, 1H, J = 5.5 Hz, aromatic-H), d 8.20–8.18 (d,
1H, J = 8 Hz, aromatic-H), d 8.14–8.12 (d, 1H,
J = 9.2 Hz, aromatic-H), d 8.01–7.99 (d, 1H,
J = 6.8 Hz, 1H, aromatic-H), d 7.78 (s, 1H, NH), d
7.50 (s, 1H, NH), d 7.43–7.411 (d, 1H, J = 8.4 Hz,
aromatic-H), d 7.36 (s, 1H, NH), d 7.21 (s, 1H,
thiazolyl), d 7.02–6.98 (m, 1H, aromatic-H), d
6.93–6.91 (d, 1H, J = 6 Hz, aromatic-H)
640.95 (1.84%) [M ? H]?, 274.3
(100%), 330.4 (36.45%), 302.4
(27.76%), 419.4 (25.73%)
123

Med Chem Res (2011) 20:1603–1610
1609
Table 5 continued
IR wave number (in cm-1
)
1H NMR (in ppm)
Mass [M ? H]?
Compound 7e
m 3399.3 (N–H stretch, –NH2), 3124.4 (C–H stretch,
aromatic), 1538.0, 1504.2 (N–H bend,[NH), 1420.3,
1385.0, 1329.2 ((N=O)2 stretch, aromatic-NO2),
1203.3, 1157.9 (aryl fluoro, aromatic-F), 1107.8,
1039.2 (C–N stretch, aromatic-NH-aromatic), 632.3
(C–S stretch)
d 8.72–8.35 (d, 1H, J = 8.8 Hz, aromatic-H), d
8.31–8.29 (d, 1H, J = 8.4 Hz, aromatic-H), d 8.20-
8.18 (d, 1H, J = 8.8 Hz, aromatic-H), d 8.15–8.13 (d,
1H, J = 7.2 Hz, aromatic-H), d 8.10-8.08 (d, 1H,
J = 8.4 Hz, 1H, aromatic-H), d 8.01-7.99 (d, 1H,
J = 8.8 Hz, 1H, aromatic-H), d 7.94–7.92 (d, 1H,
J = 8.4 Hz, aromatic-H), d 7.76 (s, 1H, NH), d
7.66–7.67 (d, 1H, J = 8.8 Hz, aromatic-H), d 7.56 (s,
1H, NH), d 7.38 (s, 1H, NH), d 7.33 (s, 1H, NH), d
7.33 (s, 1H, thiazolyl), d 7.10–7.07 (d, 1H,
519.1 (1.8%) [M ? H]?, 274.3 (100%),
331.3 (44.45%), 330.4 (30.16%),
381.4 (27.68%)
J = 8.8 Hz, aromatic-H)
Compound 7f
m 3374.1 (N–H stretch, –NH2), 3112.4 (C–H stretch,
aromatic), 1571.5 (N–H bend,[NH), 1488.8, 1404.9,
1328.3 ((N=O)2 stretch, aromatic-NO2), 1232.7 (C-
Nstretch, aromatic-NH-aromatic), 632.3 (C–S
stretch).
d 8.10–8.18 (d, 1H, J = 8.4 Hz, aromatic-H), d
8.02–8.00 (d, 1H, J = 8.4 Hz, aromatic-H), d 7.44 (s,
1H, NH), d 7.60 (s, 1H, NH), d 7.38 (s, 1H, NH), d
7.32–7.30 (d, 1H, J = 8.4 Hz, aromatic-H), d 7.21 (s,
1H, thiazolyl)
551.05 (3.4%) [M ? H]?, 331.3
(91.39%), 353.4 (84.73%), 228.3
(66.58%)
S
Scheme 1 Reagents and
condition: a Br2, reflux
O
NH2
N
CH3
S
a
H2N
NH2
C
R1
R1
2
1
3a,b
Scheme 2 Reagents and
condition: a NaOH, 40–50°C;
b NaHCO3, 135–145°C
R2
H
Cl
N
Cl
N
N
Cl
R2
a
NH2
2
N
N
N
N
R2
5
NH
Cl
6a-e
4
b
3a,b
R2
S
H
H
N
N
N
N
N
N
R2
R1
NH
7a-f
Acknowledgment The authors are thankful to Lonza Chemicals,
Switzerland for providing a gift sample of cyanuric chloride (2,4,6-tri
chloro-1,3,5-triazine) for the work included in this paper, S.A.I.F.,
Punjab University for carrying out spectral analysis of reported
compounds. They are also grateful to the editor and an anonymous
(0.1 mol) and refluxed this mixture at 135–145°C for 9 h.
The product was filtered and washed with cold water and
recrystallized with ethanol to afford the corresponding pure
products 7a–f.
123

1610
Med Chem Res (2011) 20:1603–1610
reviewer for their invaluable comments and suggestions on their
work.
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activity of a series of 1,3,5-triazine-substituted polyamines.
J Antimicrob Chemother 52:290–293
Mandal S, Be0rube0 G, Asselin E, Mohammad I, Richardson VJ,
Gupta A, Pramanik SK, Williams AL, Mandal SK (2007) A
novel series of potent cytotoxic agents targeting G2/M phase of
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4955–4960
Conflict of interest None.
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