Synthesis and biological evaluation of novel 2,4,6-triazine derivatives as antimicrobial agents

Article abstract of DOI:10.1016/j.bmcl.2012.05.111

A series of 2,4,6-trisubstituted [1,3,5]triazines were synthesized and evaluated for their antimicrobial activity against two representative Gram-positive, Gram-negative bacteria and two fungi. Biological data revealed that among all the compounds screened, compounds 3f, 3g, 3h, 3i, 3m, 3o and 3p found to have promising antimicrobial activity against all the selected pathogenic bacteria and fungi. Out of the synthesized compounds seven analogues have shown MIC in the range of 6.25-12.5 μg/mL. These compounds were generally nontoxic and may prove useful as antimicrobial agents.

Full text of DOI:10.1016/j.bmcl.2012.05.111

Bioorganic & Medicinal Chemistry Letters 22 (2012) 5075–5077
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of novel 2,4,6-triazine derivatives
as antimicrobial agents
Sandip N. Gavade a, Vijay L. Markad b, Kisan M. Kodam b, Murlidhar S. Shingare c, Dhananjay V. Mane a,
⇑
a P.G. Department of Chemistry and Research Center, S.C.S. College, Omerga 413 606, India
b Biochemistry Division, Department of Chemistry, University of Pune, Pune 411 007, India
c Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431 004, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 2,4,6-trisubstituted [1,3,5]triazines were synthesized and evaluated for their antimicrobial
activity against two representative Gram-positive, Gram-negative bacteria and two fungi. Biological data
revealed that among all the compounds screened, compounds 3f, 3g, 3h, 3i, 3m, 3o and 3p found to have
promising antimicrobial activity against all the selected pathogenic bacteria and fungi. Out of the synthe-
Received 2 April 2012
Revised 16 May 2012
Accepted 30 May 2012
Available online 9 June 2012
sized compounds seven analogues have shown MIC in the range of 6.25–12.5
were generally nontoxic and may prove useful as antimicrobial agents.
lg/mL. These compounds
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Triazine derivatives
Antibacterial activity
Antifungal activity
MIC
The treatment of bacterial infections remains a challenging
therapeutic problem because of emerging infectious diseases and
the increasing number of multidrug-resistant microbial pathogens.
Despite the many antibiotics and chemotherapeutics available, the
emergence of old and new antibiotic-resistant bacterial strains in
the last decades leads to a substantial need for new classes of
anti-bacterial agents.1 The increasing incidence of infection caused
by the rapid development of bacterial resistance to most of the
known antibiotics is a serious health problem.2 While many factors
may be responsible for mutations in microbial genomes, it has
been widely demonstrated that the incorrect use of antibiotics
can greatly increase the development of resistant genotypes.3 As
multidrug-resistant bacterial strains proliferate, the necessity for
effective therapy has stimulated research into the design and syn-
thesis of novel antimicrobial molecules. The chemistry of [1,3,5]tri-
azine compounds has been studied intensively and is the subject of
many reviews.4 The triazine scaffold has provided the basis for the
design of biologically relevant molecules with broad biomedical
value as therapeutics. For example, triazine compounds possess
potent antiprotozoal,5 anticancer,6 antimalarial,7 and antiviral
activity.8 Also, it was reported that some of these compounds pos-
sess potent antimicrobial activity.9 These compounds have been
used in the treatment of depression,10 and hence received a consid-
erable therapeutic importance. These are valuable bases for estro-
gen receptor modulators11a and also used as bridging agents to
synthesize herbicides.11b Further substituted S-triazines have been
used as NLO materials, which have a wide range of applications in
optoelectronics and telecommunications.12 The starting material
for these compounds is cyanuric chloride. This is an inexpensive
commercially available reagent which makes its use more attrac-
tive. Increased interest in this scaffold lies in the different reactiv-
ities of the substituent chlorine atoms, which are controlled by
temperature.4 This allows sequential introduction of various sub-
stituents into the [1,3,5]triazine ring. In order to further expand
the scope of triazine derivatives as privileged medicinal scaffold,
we have been engaged in design, synthesis and antimicrobial activ-
ity evaluation of novel 2,4,6-trisubstituted [1,3,5]triazine deriva-
tives. We encouraged by recently reported antimicrobial activity
of 2-fluorophenyl-4,6-disubstituted [1,3,5]triazines13 and new S-
triazine based chalcones and their derivatives.14 Herein we dis-
close our results antibacterial and antifungal activity of novel
2,4,6-triamino [1,3,5]triazine derivatives.
Our synthetic strategy for the novel 2,4,6-trisubstituted [1,3,5]
triazine derivatives is illustrated in Scheme 1. The key intermediates
5-[(4,6-dichloro-1,3,5-triazin-2-yl)amino]pyridine-2-carbonitrile 1
was synthesized by 2,4,6-trichloro-1,3,5-triazine (cyanuric chlo-
ride) by reacting them with 5-amino 2-cyano pyridine in the pres-
ence of acetone at 0 °C—rt for 6 h in 78% yield. The trisubstituted
triazines (2a–2r) were synthesized by reaction of the 5-[(4,6-
dichloro-1,3,5-triazin-2-yl)amino]pyridine-2-carbonitrile (1) with
different nucleophiles (R, Fig. 1) in the presence of K2CO3 in DMF at
rt for 5 h in 63–86% yield. Trisubstituted triazine hydrochloride
(3a–3r)wasmadebyusing50%HClindioxaneatrtfor2 h. Thepurity
⇑
Corresponding author. Tel./fax: +91 240 2403134.
E-mail address: dr_dvmane@rediffmail.com (D.V. Mane).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.05.111

5076
S. N. Gavade et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5075–5077
Scheme 1. Synthesis of novel 2,4,6-triazine derivatives.
of the compounds was checked by TLC and HPLC. Spectral data
1H NMR,13C NMR and MS of the newly synthesized compounds
(3a–3r) was consistent with the proposed structures.
In order to search for the potent compound, the newly synthe-
sized compounds (3a–3r) were evaluated for their antibacterial
and antifungal activity against various Gram-positive, Gram-nega-
tive bacteria and fungal strains using agar well diffusion method.
The antimicrobial evaluation data is represented in Table 1. As
can be seen from our results, many compounds from the newly
synthesized series found to be potent antibacterial and antifungal
agents. Thus the compounds 3d, 3f, 3g, 3h, 3i, 3l, 3m, 3n, 3o and
3p (Table 1) exhibited comparable antibacterial and antifungal
activity than the standard Streptomycin and Nystatin, respectively,
against all the tested bacteria or fungi. Interestingly, the com-
pounds 3f, 3g, 3h, 3i, 3m, 3o and 3p exhibited potent to same anti-
bacterial and antifungal activity, respectively, as that of the
standard Streptomycin and Nystatin. The compounds 3f, 3g, 3h,
3m and 3o found to be potent among the series and even compa-
rable with standard Streptomycin as antibacterial agent against
some bacteria viz. Bacillus subtilis (MTCC 441), Staphylococcus aur-
eus (MTCC 96), Escherichia coli (MTCC 1650) and Pseudomonas aeru-
ginosa (MTCC 1688). Compounds 3f, 3g, 3i and 3o found to be good
antifungal agents and was comparable with standard Nystatin as
antifungal agent against some fungi viz. Aspergillus niger (MTCC
1781) and Candida albicans (MTCC 227). The remaining compounds
of this series were found to have moderate or low activity.
Among all the compounds tested, seven compounds showed
Figure 1. Different R substituents for compounds (3a–3r).
MIC in the range of 6.25–12.5
lg/mL whereas six compounds
Table 1
Antimicrobial activity of novel 2,4,6-triazine derivatives (MICa values are in
lg/mL)
Compd No.
Antibacterial activity
Antifungal activity
Gram-positive bacteria
Bacillus subtilis Staphylococcus aureus
Gram-negative bacteria
Escherichia coli
Pseudomonas aeruginosa
Aspergillus niger
Candida albicans
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
50 (12)
50 (10)
50 (12)
50 (12)
50 (12)
12.5 (12)
100 (12)
6.25 (12)
12.5 (12)
6.25 (12)
12.5 (12)
50 (12)
50 (12)
25 (14)
50 (12)
12.5 (12)
50 (12)
6.25 (12)
6.25 (12)
6.25 (10)
6.25 (12)
25 (14)
50 (10)
25 (12)
50 (10)
100 (14)
25 (14)
100 (14)
50 (12)
50 (14)
12.5 (14)
12.5 (14)
25 (12)
12.5 (14)
50 (14)
100 (14)
50 (12)
25 (14)
25 (12)
12.5 (12)
25 (12)
25 (12)
100 (14)
NTb
50 (14)
50 (10)
25 (14)
50 (10)
50 (12)
12.5 (14)
12.5 (12)
25 (12)
12.5 (14)
25 (12)
25 (14)
50 (14)
25 (14)
25 (14)
12.5 (12)
25 (12)
25 (12)
25 (14)
NT
50 (12)
12.5 (12)
100 (12)
6.25 (12)
6.25 (12)
6.25 (12)
6.25 (10)
25 (10)
50 (12)
12.5 (10)
6.25 (10)
25 (12)
6.25 (10)
12.5 (10)
25 (10)
12.5 (10)
100 (12)
6.25 (10)
6.25 (12)
12.5 (12)
12.5 (14)
25 (12)
50 (10)
25 (14)
6.25 (10)
12.5 (12)
6.25 (12)
12.5 (12)
50 (12)
25 (10)
50 (12)
50 (12)
25 (12)
12.5 (12)
6.25 (12)
12.5 (12)
6.25 (12)
6.25 (12)
25 (12)
12.5 (12)
6.25 (20)
NT
6.25 (12)
12.5 (14)
6.25 (14)
6.25 (14)
25 (14)
12.5 (12)
6.25 (22)
NT
3q
3r
25 (12)
6.25 (22)
NT
Streptomycin
Nystatin
6.25 (24)
NT
6.25 (20)
6.25 (20)
a
MIC values were evaluated at concentration range between 6.25 and 200 lg/ml.
NT: not tested. MIC (lg/mL) and zone of inhibition (mm) in parenthesis.
b

S. N. Gavade et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5075–5077
5077
showed a MIC of 12.5–50 lg/mL. The results showed a good struc-
Acknowledgments
ture–activity relationship. Results also shows the importance of
lipophilicity and basicity in the antibacterial and antifungal activ-
ity of the synthesized compounds (3a–r). Antibacterial activity of
1,3,5-triazine having R as N-methyl piperazine 3d showed a MIC
The authors acknowledge the financial support from UGC, [F. No.
39-774/2010 (SR)], New Delhi and are grateful to Principal of S.C.S.
College, Omerga for providing the necessary laboratory facilities.
of 12.5
acetyl 3k, benzoyl 3l and phenyl group 3m it showed a MIC of 50,
12.5 and 6.25 g/mL, respectively. Compound 3m has good activity
lg/mL whereas when the methyl group was replaced with
Supplementary data
l
as compare to 3d and 3k, it means that activity increases with in-
crease in lipophilicity and decreasing basicity of the compounds.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.05.111.
Morpholine substituted compound 3a showed a MIC of 50
whereas when morpholine was replaced with 4-(2-aminoethyl)
morpholine 3j MIC increased to 25 g/mL. When the morpholine
lg/mL
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