An eco-friendly water mediated synthesis of 1,2,3-triazolyl-2- aminopyrimidine hybrids as highly potent anti-bacterial agents

Article abstract of DOI:10.1016/j.cclet.2013.12.017

An elegant and efficient synthesis of novel 1,2,3-triazole fused 2-aminopyrimidine hybrids has been accomplished for the first time in the green solvent viz. water. The hybrid molecules exhibit significant anti-bacterial activity when screened against three human pathogens viz. Staphylococcus aureus, Pseudomonas aeruginosa and Klebsiella pneumoniae. In comparison to the commercially marketed drug tetracycline, some of them are equally potent and a few are more potent.

Full text of DOI:10.1016/j.cclet.2013.12.017

Accepted Manuscript
Title: An eco-friendly water mediated synthesis of
1,2,3-triazolyl-2-aminopyrimidine hybrids as highly potent
anti-bacterial agents
Author: Sangaraiah Nagarajan Poovan Shanmugavelan
Murugan Sathishkumar Ramasamy Selvi Alagusundaram
Ponnuswamy Hariharan Harikrishnan Vellasamy
Shanmugaiah
PII:
S1001-8417(13)00578-0
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.cclet.2013.12.017
CCLET 2817
To appear in:
Chinese Chemical Letters
Received date:
Revised date:
Accepted date:
11-9-2013
2-12-2013
10-12-2013
Please cite this article as: S. Nagarajan, P. Shanmugavelan, M. Sathishkumar, R. Selvi,
A. Ponnuswamy, H. Harikrishnan, V. Shanmugaiah, An eco-friendly water mediated
synthesis of 1,2,3-triazolyl-2-aminopyrimidine hybrids as highly potent anti-bacterial
agents, Chinese Chemical Letters (2013), http://dx.doi.org/10.1016/j.cclet.2013.12.017
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Graphical Abstract
An eco-friendly water mediated synthesis of 1,2,3-triazolyl-2-aminopyrimidine
hybrids as highly potent anti-bacterial agents
Sangaraiah Nagarajana, Poovan Shanmugavelana, Murugan Sathishkumara, Ramasamy Selvia,
Alagusundaram Ponnuswamya,∗, Hariharan Harikrishnanb, Vellasamy Shanmugaiahb,*
a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625021, India
b Department of Microbial Technology, School of Biological Sciences, Madurai Kamaraj University, Madurai 625021, India
N
O
N
N
.
NH HCl
CH3
NH2
N
CH3
N
H2N
NH2
N
N
NaOH, water
O
N
N
N
N
O
NaOH, water
reflux
grinding4-7 min
CH3
CH3
2a-l
3a-l
R
R
R
An elegant green synthesis of 1,2,3-triazolyl linked 2-aminopyrimidine hybrids in water has been accomplished for the first time. Their
antibacterial activities are comparable with that of tetracycline.
∗ Corresponding authors.
E-mail addresses: ramradkrish@yahoo.co.in (A. Ponnuswamy), shanmugaiahv@gmail.com (V. Shanmugaiah).
Page 1 of 5

Original article
An eco-friendly water mediated synthesis of 1,2,3-triazolyl-2-aminopyrimidine
hybrids as highly potent anti-bacterial agents
Sangaraiah Nagarajana, Poovan Shanmugavelana, Murugan Sathishkumara, Ramasamy Selvia,
Alagusundaram Ponnuswamya,∗, Hariharan Harikrishnanb, Vellasamy Shanmugaiahb,*
a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, India
b Department of Microbial Technology, School of Biological Sciences, Madurai Kamaraj University, Madurai 625021, India
ARTICLE INFO
ABSTRACT
Article history:
An elegant and efficient synthesis of novel 1,2,3-triazole fused 2-aminopyrimidine hybrids has
been accomplished for the first time in the green solvent viz. water. The hybrid molecules
exhibit significant anti-bacterial activity when screened against three human pathogens viz.
Staphylococcus aureus, Pseudomonas aeruginosa and Klebsiella pneumoniae. In comparison
to the commercially marketed drug tetracycline, some of them are equally potent and a few are
more potent.
Received 11 September 2013
Received in revised form 2 December 2013
Accepted 10 December 2013
Available online
Keywords:
Water promoted
Antibacterial
1,2,3-Triazole
Pyrimidine
1. Introduction
Microbial infections are a growing problem in contemporary medicine. According to statistical evidence provided by WHO, many of
the drug treatment breakthroughs of the last century could be lost through the spread of antimicrobial resistance [1]. For instance,
Staphylococcus aureus, Pseudomonas aeruginosa and Klebsiella pneumoniae are important pathogens causing invasive diseases such
as sepsis, meningitis, necrotising fasciitis, pneumonia [2], nosocomial pneumonia [3], cystic fibrosis, acute leukemia, organ transplants,
and intravenous-drug addiction [4]. Some of these pathogens have been reported to develop resistance [5] to the well-known
commercially available drugs. As a result, many infectious diseases may one day become uncontrollable and could rapidly spread
throughout the world. Consequently, the discovery of potent antibiotic drugs is considered to be one of the greatest scientific and
medical goals.
There is a growing interest pertaining to the synthesis of bioactive heterocyclic compounds in pharmacy. Among various
heterocyclic compounds, pyrimidine derivatives have apparently gained considerable importance owing to their varied biological
activities such as adenosine receptor antagonist [6], anti-inflammatory [7], CDK inhibitor [8], calcium channel antagonist [9], anti-
tumor [10] activities, etc. On the other hand, a promising diverse pharmacological activity is shown by the 1,2,3-triazole nucleus such
as anti-biotic, anti-fungal [11], anti-cancer [12], HIV protease inhibitor [13], and chemotherapeutic activities [14], etc.
In view of the bioactivity profiles of the individual heterocycles, the synthesis of hybrid molecules containing both of the above
said moieties in a single frame was attempted. Thus, the present study was undertaken to synthesize and investigate the anti-microbial
activities of a series of novel 1,2,3-triazolyl-2-aminopyrimidine hybrids against three human pathogenic bacteria viz. Klebsiella
pneumoniae, Staphylococcus aureus and Pseudomonas aeruginosa, the details of which are presented vide infra.
2. Experimental
Typical procedure: A mixture of (E)-1-(1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl)-3-phenylprop-2-en-1-one, 2a (0.2 g, 0.65 mmol),
guanidine hydrochloride (0.18 g, 1.88 mmol) and NaOH (0.04 g, 0.75 mmol) in water or ethanol (10 mL) was refluxed for 30-40 min.
Then, the reaction mixture was poured onto excess crushed ice and neutralized with dilute hydrochloric acid. The precipitated 1,2,3-
triazolyl-2-aminopyrimidine (3a) was filtered and recrystallized from ethanol. Yield 0.19 g (85%) in ethanol, 0.18 g (82%) in water.
4-(1-Benzyl-5-methyl-1H-1,2,3-triazol-4-yl)-6-phenylpyrimidin-2-amine (3a): Obtained as white solid in 82% yield, mp 152 °C; IR
(KBr, cm-1): v 3411, 3192, 1677, 1552, 1462, 1355, 1181, 834, 729, 700; 1H NMR (300 MHz, CDCl3): δ 8.12-8.09 (m, 2H, ArH), 7.98
(s, 1H, =CH), 7.49-7.18 (m, 8H, ArH), 5.56 (s, 2H, C6H5-CH2), 5.07 (brs, 2H, NH2), 2.62 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3): δ
∗ Corresponding authors.
E-mail addresses: ramradkrish@yahoo.co.in (A. Ponnuswamy), shanmugaiahv@gmail.com (V. Shanmugaiah).
Page 2 of 5

165.87, 163.14, 160.56, 142.30, 137.57, 134.51, 134.00, 133.94, 130.48, 130.42, 129.06, 128.71, 128.66, 128.41, 127.17, 104.50,
51.80, 9.82. MS (ESI): m/z 343.33 (M + H); Anal. Calcd. for C20H18N6: C, 70.16; H, 5.30; N, 24.54; Found: C, 70.09; H, 5.32; N,
24.50.
By a similar procedure, 4-(1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl)-6-arylpyrimidin-2-amines (3b-l) were synthesized. Their
characterization data and copies of NMR (1D& 2D), FT-IR and LC-MS spectra of representative compounds can be found in
Supporting information.
3. Results and discussion
Over the past decades, many protocols have been developed for the synthesis of pyrimidine derivatives [15], and most of these
involve the use of hazardous organic solvents [16-17]. Hence, eco-fiendly organic reactions that occur under solvent-free conditions or
use water have attained much importance and are of current interest. In particular, as a reaction medium, water offers many practical
and economic advantages including low cost, environmental compatibility, and safety among all available solvents, thus leading to
environmentally-friendly chemical processes [18]. In view of this, recently we have accomplished the synthesis of amides and various
heterocycles/hybrid heterocycles under solvent-free/water medium conditions [19-30].
Perusal of literature suggests that there are no reports on the synthesis of 1,2,3-triazolyl-2-aminopyrimidine hybrids. In connection
with our goal to conduct organic reactions in water medium and in continuation of our earlier report on the water promoted synthesis of
1,2,3-triazolyl-pyrimidine-2-thione hybrids [28] as a highly potent antibacterial agent, we hereby submit the first report on the eco-
friendly synthesis of 1,2,3-triazolyl-2-aminopyrimidine hybrids and their anti-bacterial activity.
At the outset, synthesis of 1,2,3-triazolyl-2-aminopyrimidine (3a) was attempted while varying the bases (Scheme1, Table 1) i.e. a
mixture of 1,2,3-triazolyl chalcone [26] (2a, 1 equiv.), guanidine hydrochloride (3 equiv) and base (1.5 equiv) was refluxed in ethanol
or water (10 mL). Completion of the reaction was monitored by TLC. It is noted that basicity is one of the key points behind the
success of the reaction (Table 1). Moreover, water seems to be the proper solvent to fulfill the reaction by achieving the best solubility
of the salts viz. guanidine hydrochloride and sodium hydroxide, thus promoting the reaction. The yields in ethanol and water were
comparable.
All twelve compounds exhibit different levels of inhibition against the previously mentioned human pathogens (both Gram-positive
& Gram-negative) (Scheme 2, Table 2). Among them, compounds coded 3a (-H), 3b (-4OMe), 3c (-2,4 diOMe), 3g (-2OMe), 3i (-4F),
3k (-2,4 diCl) (MIC 2 µg/mL) and 3d (-4Br) (MIC 5 µg/mL) were more potent against P. aeruginosa than tetracycline (MIC 10
µg/mL). Meanwhile, the compounds 3j (-3OMe) and 3l (2-thiophenyl) show equal inhibition (MIC 10 µg/mL) to tetracycline.
However, the rest of the compounds showed lower levels of inhibitions (MIC 25-35µg/mL). In the case of Klebsiella pneumonia,
compounds 3b and 3c were equally potent (MIC 2 µg/mL) as tetracycline. The compounds 3a and 3e (-3Br) exhibited moderate
potency (MIC 5 µg/mL) and the others showed less potency (MIC >5µg/mL). On the other hand, all the compounds exhibited less
potency (MIC ≥30 µg/mL) towards Staphylococcus aureus than tetracycline (MIC 15 µg/mL). This may be attributed to the thick
peptidoglycan layer of the cell wall of Gram positive S. aureus. Also, the binding of the cell-surface proteins of the Gram positive S.
aureus might have inactivated the compounds. The above results project 3b and 3c as highly potent compounds with remarkable
antibacterial activity in comparison to the commercial control.
Structure–activity relationship (SAR) in these compounds demonstrated that compounds 3b and 3c with substituents viz. -4OMe
and -2, 4 diOMe in the phenyl ring attached to the C-6 carbon of 2-amino pyrimidine moiety are more potent against all the tested
pathogens. Subsequently, various substituents were introduced in either of the -ortho, -meta or -para position of the phenyl ring to
evaluate their effect on biological activity. Their order of activity compared to compound (3a) with the unsubstituted phenyl ring
linked to C-6 carbon of 2-amino pyrimidine is in the order -4OMe ≥ -2,4-diOMe > -H > -4Br > -2OMe > -4F > -2,4 diCl > -3OMe > -
thiophene > -3Br. However, compounds 3f with -4Me and 3h with -4Cl substituents did not show notable activity against all the tested
pathogens.
4. Conclusion
In conclusion, an elegant, environmentally-friendly water promoted synthesis of a library of 1,2,3-triazolyl-2-aminopyrimidine
hybrids has been achieved. All the synthesized compounds were evaluated for antibacterial activity. Many of them exhibited potent
activity, and some of them were equally potent or of higher potency than the commercially marketed tetracycline.
Acknowledgments
The authors thank the UGC (BSR) and DST-PURSE for financial support and Department of Science and Technology, New Delhi,
India for funds under the IRHPA program for the purchase of a NMR spectrometer.
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Page 4 of 5

NH
N
2
CH
N
N
N
3
N
N
Ethanol/water
Base, reflux
N
N
O
CH
3
3a
2a
Scheme 1. Optimization for the synthesis of 1,2,3-triazolyl-2-aminopyrimidine hybrids (3a).
N
3
CHO
R
CH
N
3
R
N
K CO
2
3
N
N
N
N
Aq. NaOH
grinding, 4-7 min, r.t.
O
Ethanol,
reflux
H C
3
O
O
O
H C
3
1
2
NH
NaOH
H O or EtOH
2
.
H N
NH HCl
2
2
reflux, 30-40 min
R
a = H
b = 4-OMe
c = 2, 4-di-OMe
d = 4-Br
e = 3-Br
f = 4-Me
g = 2-OMe
h = 4-Cl
i = 4-F
j = 3-OMe
k = 2,4-di-Cl
l = thiophen-2-aldehyde
NH
2
N
N
N
N
N
CH
R
3
3
Scheme 2. Synthesis of 1,2,3-triazolyl-2-aminopyrimidine hybrids (3).
Table 1
Optimization for the synthesis of 1,2,3-triazolyl-2-aminopyrimidine hybrids (3a).
Entry Base
Time
6 h
6 h
8 h
8 h
6 h
6 h
30 min
40 min
Solvent
Ethanol
water
Ethanol
Water
Ethanol
Water
Ethanol
Water
Yielda
31
35
-
1
2
3
4
5
6
7
8
Et3N
Et3N
Pyridine
Pyridine
Na2CO3
Na2CO3
NaOH
NaOH
-
33
29
85
82
a Isolated yield
Table 2
Synthesis of 1,2,3-triazolyl-2-aminopyrimidine hybrids (3a-l)a in ethanol and water and their in vitro anti-bacterial activity against three human pathogens.
Minimum inhibitory concentration (MIC)
(µg/mL)
Ethanol
Water
Hybrids
(3a-l)
Entry
Time Yieldb Time Yieldb
S.aureus
P.aeruginosa K.pneumoniae
MTCC 3160 MTCC 2488
MTCC 3384
(min) (%) (min) (%)
1
2
3
4
5
6
7
8
30
30
30
30
30
30
30
30
30
30
30
30
85
83
78
63
62
81
73
83
79
75
72
83
40
40
40
40
40
40
40
40
40
40
40
40
82
87
82
65
61
82
75
81
74
78
79
85
NA
30
30
40
35
NA
40
NA
NA
35
NA
35
15
2
2
2
5
5
2
2
25
5
15
25
40
NA
25
35
25
2
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
25
30
2
35
2
10
5
10
10
NA
9
10
11
12
Tetracycline
DMSO
NA
NA
a Synthesized compounds were completely characterized by NMR (1D & 2D), IR and mass spectral techniques.
b Isolated yield.
Page 5 of 5