Synthesis and biological evaluation of dihydrotriazine derivatives as potential antibacterial agents

Article abstract of DOI:10.1016/j.cclet.2017.05.022

A series of 1,4-dihydro-1,3,5-triazine derivatives were designed and synthesized and their antibacterial and antifungal activities were evaluated. Most of the synthesized compounds showed potent inhibition of several Gram-positive bacterial strains (including multidrug-resistant clinical isolates) and Gram-negative bacterial strains, with minimum inhibitory concentrations (MICs) in the range of 2.1–181.2?μmol/L. Compounds 7a and 7c presented the most potent inhibitory activities against Gram-positive bacteria (e.g., Staphylococcus aureus 4220), Gram-negative bacteria (e.g., Escherichia coli 1924), and the fungus Candida albicans 7535, with MICs of 2.1 or 4.1?μmol/L. Especially, compound 7a was the most potent, with an MIC of 2.1?μmol/L against four multidrug-resistant, Gram-positive bacterial strains. The cytotoxic activity of the compound 7a, 7c and 7f was assessed in HepG2 cells, and the results suggest that 1,4-dihydro-1,3,5-triazine derivatives bearing a 6-benzyloxynaphthalen moiety are interesting scaffolds for the development of novel antibacterial agents.

Full text of DOI:10.1016/j.cclet.2017.05.022

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CCLET 4092 No. of Pages 6
Chinese Chemical Letters xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Synthesis and biological evaluation of dihydrotriazine derivatives as
potential antibacterial agents
Tian-Yi Zhanga,b,1, Chao Lia,1, Yu-Shun Tiana, Jia-Jun Lia, Liang-Peng Suna,
a,
Chang-Ji Zhenga, , Hu-Ri Piao
*
*
a
Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Yanbian University College of Pharmacy, Yanji
133000, China
Department of Pharmacy, Jilin Medical University, Jilin 132013, China
b
A R T I C L E I N F O
A B S T R A C T
Article history:
A series of 1,4-dihydro-1,3,5-triazine derivatives were designed and synthesized and their antibacterial
and antifungal activities were evaluated. Most of the synthesized compounds showed potent inhibition
of several Gram-positive bacterial strains (including multidrug-resistant clinical isolates) and Gram-
negative bacterial strains, with minimum inhibitory concentrations (MICs) in the range of 2.1–
Received 8 March 2017
Received in revised form 25 April 2017
Accepted 2 May 2017
Available online xxx
181.2
positive bacteria (e.g., Staphylococcus aureus 4220), Gram-negative bacteria (e.g., Escherichia coli 1924),
and the fungus Candida albicans 7535, with MICs of 2.1 or 4.1 mol/L. Especially, compound 7a was the
most potent, with an MIC of 2.1 mol/L against four multidrug-resistant, Gram-positive bacterial strains.
The cytotoxic activity of the compound 7a, 7c and 7f was assessed in HepG2 cells, and the results suggest
that 1,4-dihydro-1,3,5-triazine derivatives bearing a 6-benzyloxynaphthalen moiety are interesting
scaffolds for the development of novel antibacterial agents.
mmol/L. Compounds 7a and 7c presented the most potent inhibitory activities against Gram-
Keywords:
Antibacterial activitis
Antifungal activities
Cytotoxicity
Minimal inhibitory concentration
1,4-Dihydro-1,3,5-triazine
m
m
© 2017 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
1. Introduction
MRSA-related infections in the United States alone [2]. Therefore,
there is an urgent need for the development of new antibacterial
The management of bacterial infections has become increas-
ingly difficult with the emergence of antimicrobial resistance. In
particular, the ESKAPE pathogens (Enterococcus faecium, Staphylo-
coccus aureus, Klebsiella pneumoniae, Acinetobacter baumannii,
Pseudomonas aeruginosa, and Enterobacter species) are causing
significant problems worldwide [1]. Methicillin-resistant S. aureus
(MRSA) is a major pathogen causing both hospital- and communi-
ty-acquired infections. Among these organisms, MRSA alone
accounts for nearly one-half of the deaths attributed to antibiot-
ic-resistant infections. In 2013, the Centers for Disease Control and
Prevention reported that more than 11,000 people died from
agents with divergent and unique structures and mechanisms of
action that differ from those of existing antimicrobial agents [3].
Medicinal chemistry studies have shown that a 1,3,5-triazine
scaffold is an outstanding pharmacophore, and many molecules
with this scaffold have been reported as antibacterial agents. 1,2-
Dihydro-1,3,5-triazine (Baker triazines) compounds are by far the
best known, with several studies exploring their potential as
inhibitors of eukaryotic dihydrofolate reductase (DHFR), an
important enzyme in the de novo pathway of purine and thymidine
synthesis, and small molecules targeting this enzyme have
demonstrated utility as potential antibiotics [4,5]. Feng et al.
reported that the compound N2-methyl-6-(5-methylisoxazol-3-
yloxy)-N4-(4-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4-diamine
displayed an antimicrobial effect as high as 97.7% at a concentra-
* Corresponding authors.
E-mail addresses: zhengcj@ybu.edu.cn (C.-J. Zheng), piaohr@ybu.edu.cn
tion of 200 mg/mL [6]. Singga et al. found that triazine derivatives
inhibited some Gram-positive and Gram-negative bacteria by
inhibiting cell membrane growth [7].
(H.-R. Piao).
1
These authors contributed equally to this work.
http://dx.doi.org/10.1016/j.cclet.2017.05.022
1001-8417/© 2017 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: T.-Y. Zhang, et al., Synthesis and biological evaluation of dihydrotriazine derivatives as potential antibacterial
agents, Chin. Chem. Lett. (2017), http://dx.doi.org/10.1016/j.cclet.2017.05.022

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Fig. 1. Previously reported antibacterial compounds.
In our previous work, we found that several rhodanine
derivatives bearing chalcone [8], (2-oxo-2-phenylethoxy)benzyli-
dene [9], and (benzyloxy)benzylidene [10] moieties (Fig. 1)
showed moderate to strong activities against several Gram-
positive bacterial strains, including multidrug-resistant clinical
isolates. Unfortunately, compounds belonging to this series did not
show any bacteriostatic activity against Gram-negative bacteria. As
a part of our ongoing studies toward the development of novel
antibacterial agents, here we designed and synthesized a series of
1,4-dihydro-1,3,5-triazine derivatives using a hybrid strategy, in
which the rhodamine moiety was replaced by a dihydrogen
triazine scaffold. Thus, a series of 26 novel 1,4-dihydro-1,3,5-
triazine derivatives (Fig. 2) were synthesized and evaluated for
their antibacterial activities in vitro. The substituents on the phenyl
ring were changed simultaneously to investigate their contribution
to the biological activity.
2. Results and discussion
The in vitro antibacterial activities of the synthesized com-
pounds were evaluated using a 96-well microtiter plate and a serial
dilution method to obtain the minimum inhibitory concentrations
(MICs) for different strains (including multidrug-resistant clinical
isolates). Two Gram-positive strain (S. aureus RN 4220 and S.
Mutans KTCT 3289), five Gram-negative strains (Escherichia coli
KCTC 1924, E. coli CCARM 1356, P. aeruginosa 2742, P. aeruginosa
2004, and Salmonella enterica serovar Typhimurium 2421) and one
fungus (Candida albicans 7535) were used for the biological assay.
Gatifloxacin, moxifloxacin, norfloxacin, and oxacillin were used as
Fig. 2. Synthesized target compounds.
Please cite this article in press as: T.-Y. Zhang, et al., Synthesis and biological evaluation of dihydrotriazine derivatives as potential antibacterial
agents, Chin. Chem. Lett. (2017), http://dx.doi.org/10.1016/j.cclet.2017.05.022

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3
Table 1
Inhibitory activity (MIC,
m
mol/L) of compounds 6a, 7a–f, 10a–b, 11a–c, 12a–c, 13a–b, 14a–c, 15a–c and 16a–c against various bacteria.
Compound
R1
Gram-positive strains
Gram-negative strain
Fungus
C. albicans
7535h
S. aureus
S. Mutans
E. Coli
P. aeruginosa
S. typhimurium
4220a
3289b
1924c
1356d
2742e
2004f
2421g
6a
7a
7b
7c
7d
7e
7f
10a
10b
11a
11b
11c
12a
12b
12c
13a
13b
14a
14b
14c
15a
15b
15c
16a
16b
16c
Gatifloxacin
Moxifloxacin
Fluconazole
Itraconazole
H
72.2
2.1
4.5
2.2
18.5
4.7
38.5
67.9
>162.8
21.1
20
175.3
9.2
20
18.1
>161.9
33.8
10.2
22.4
19.9
10.2
89.6
39.9
82.7
181.2
37.1
0.7
>144.4
2.1
8.9
8.9
18.5
72.2
2.1
4.5
4.5
9.2
>144.4
8.3
35.6
35.6
147.7
37.3
154.1
>135.6
>162.8
>168.8
>160.3
>175.3
147.8
>160.3
>144.4
>161.9
>135.3
40.9
>179.2
79.8
81.8
>179.2
159.6
>165.3
>181.2
>148.5
42.6
>144.4
16.5
71.2
71.2
>147.7
74.6
>144.4
16.5
35.6
35.6
147.7
74.6
>144.4
8.3
35.6
35.6
147.7
74.6
154.1
>135.6
>162.8
>168.8
>160.3
>175.3
147.8
>160.3
>144.4
>161.9
>135.3
81.8
179.2
79.8
81.8
179.2
79.8
>165.3
>181.2
>148.5
1.3
72.2
4.1
8.9
4.5
9.2
2,4-(Cl)2
3-Cl
4-Cl
4-F
4-CH3
H
4-Br
H
4-CH3
4-Cl
H
2,4-(Cl)2
4-Cl
4-Br
H
4-Br
2,4-(Cl)2
4-Cl
4-Br
2,4-(Cl)2
4-Cl
4-Br
4-Cl
H
18.6
9.3
9.6
37.3
9.6
38.5
>135.6
>162.8
168.8
80.2
>175.3
36.9
80.2
72.2
>161.9
135.3
20.5
44.8
39.9
40.9
89.6
79.8
82.7
>181.2
148.5
0.7
>154.1
>135.6
>162.8
>168.8
>160.3
>175.3
>147.8
>160.3
>144.4
>161.9
>135.3
163.6
>179.2
>159.6
163.6
>179.2
>159.6
>165.3
>181.2
>148.5
2.7
154.1
>135.6
>162.8
>168.8
>160.3
>175.3
73.9
160.3
144.4
>161.9
>135.3
163.6
>179.2
>159.6
81.8
179.2
159.6
>165.3
>181.2
>148.5
5.3
5.0
n.d
n.d
135.6
>162.8
42.2
40.1
175.3
18.5
40.1
36.1
>161.9
33.8
2.6
22.4
10
5.1
44.8
19.9
41.3
181.2
74.2
5.3
135.6
>162.8
42.2
40.1
>175.3
18.5
40.1
36.1
>161.9
>135.3
20.5
44.8
39.9
20.5
89.6
39.9
165.3
>181.2
148.5
1.3
4-Br
0.6
n.d
n.d
0.6
n.d
n.d
5.0
n.d
n.d
318.9
n.d
n.d
2.5
n.d
n.d
1.2
n.d
n.d
1.2
3.3
0.09
n.d.: Not determined.
a
Staphylococcus aureus RN 4220 (S. aureus RN 4220 is a genotype of S. aureus. KCTC, Korean Collection for Type Cultures; CCARM, Culture Collection of Antimicrobial
Resistant Microbes).
b
Streptococcus mutans 3289.
Escherichia coliKCTC 1924.
Escherichia coli CCARM 1356.
Pseudomonas aeruginosa 2742.
Pseudomonas aeruginosa 2004.
Salmonella enterica serovar Typhimurium 2421.
Candida albicans 7535.
c
d
e
f
g
h
positive controls for antibacterial activity, and fluconazole and
itraconazole were used as positive controls for antifungal activity.
The in vitro antibacterial and antifungal activities of the
synthesized compounds are shown in Table 1. Most of the
synthesized compounds showed potent inhibitory activities
against the different bacteria and one fungus, with MICs ranging
potency of all the compounds synthesized, with an MIC of
4.1 mol/L, which was slightly lower than that of fluconazole
(MIC = 3.3 mol/L). Previously, we reported that rhodamine
m
m
derivatives bearing benzyloxy benzaldehyde or benzyloxy naph-
thaldehyde moieties did not show any activity against the Gram-
negative bacteria E. coli and P. aeruginosa [11], but dihydro-1,3,5-
triazine derivatives displayed moderate to high levels of inhibition
against these strains, indicating that the dihydro-1,3,5-triazine
scaffold is critical for drug potency. A comparison of the potency of
compounds 6a and 7a–f revealed that the introduction of an
additional ketone moiety reduced the antimicrobial activity. The
introduction of some halogen groups on the phenyl ring generally
increased the antimicrobial activity relative to that of the non-
substituted derivatives. Notably, the position of the Cl substituent
on the phenyl ring affected the potency, with activity in the order of
2,4-(Cl)2 > 4-Cl ꢀ 3-Cl. Isosteric replacement with a morpholine or
dimethylamine group at the N-position of the dihydro-1,3,5-
triazine ring generally did not affect the antimicrobial activity. It is
noteworthy that compounds bearing a 2,4-Cl2 substituted phenyl
ring showed excellent antimicrobial activities. Therefore, these
from 2.1 to 181.2
highest activity of all the compounds synthesized against S. aureus
4220, with an MIC of 2.1 mol/L. Against the Gram-negative E. coli
mmol/L. Compounds 7a and 7c exhibited the
m
1924, compounds 7a, 7b, 7c, 14a, and 15a were equipotent or more
potent than the positive controls gatifloxacin and moxifloxacin
(MIC = 5.0
compound 7a, with an MIC of 8.3
that of the positive control gatifloxacin (MIC = 42.6
potency of compounds 7b, 7c, 7e, and 14a, with an MIC of
35.6 mol/L against E. coli 1356, was 9-fold greater than that of the
positive control moxifloxacin (MIC = 318.9 mol/L). However, for
the P. aeruginosa 2742 and 2004 strains, only compound 7a
exhibited good activity, with an MIC of 16.5 mol/L. Against C.
albicans 7535, compounds 7a and 7c displayed the strongest
m
mol/L), with an MIC of 2.1
mol/L, was 5-fold greater than
mol/L). The
mmol/L. The potency of
m
m
m
m
m
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agents, Chin. Chem. Lett. (2017), http://dx.doi.org/10.1016/j.cclet.2017.05.022

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Table 2
Inhibitory activity (MIC,
b, 14a–c, 15a–c and 16a–c against clinical isolates of multidrug-resistant Gram-
positive strains.
most potent activity against the MRSA and QRSA strains, with an
MIC of 2.1 mol/L, making it equipotent or more potent than
gatifloxacin and norfloxacin (MICs of 8 and 4 g/mL against MRSA
mmol/L) of compounds 6a, 7a–f, 10a–b, 11a–c, 12a–c, 13a–
m
m
3167 and 3506, respectively). In general, against multidrug-
resistant strains, series 7 compounds were much more potent
than the compounds in the other series. Compounds 7a, 7b, 7d, and
14a exhibited 2 to 4-fold greater activities, with MICs of 2.1–
Compound
R1
MRSA
3167a
QRSA
3505c
3506b
3519d
6a
7a
7b
7c
H
72.2
2.1
2.2
2.2
4.6
144.4
2.1
4.5
4.5
9.2
144.4
2.1
8.9
8.9
18.6
72.2
2.1
4.5
8.9
4.6
2,4-(Cl)2
3-Cl
4-Cl
4-F
4.1
21.2
of oxacillin (MIC = 2.5
m
m
mol/L, than gatifloxacin and moxifloxacin (MICs = 10.0–
mol/L), and the activity of compound 7a was equal to that
mol/L).
m
7d
To see whether the antibacterial activity of the synthesized
compounds were selectively toxic, we evaluated the cytotoxicity of
compound 7a, 7c and 7f using a standard technique. As shown in
Table 3, compound 7f exhibited weaker activity than 7c against the
different bacteria, in spite of its slight greater cytotoxicity than 7c,
comparably indicating that the promising antibacterial activity of
these compounds may not be due to their cytotoxicity, but some
unknown mechanism of action.
To rationalize the observed antibacterial activity and under-
stand the possible mechanism of action of these compounds, a
libdocking investigation was undertaken. The crystal structure
data (S. aureus DHFR) were obtained from the protein data bank
(PDB ID: 3fra) [14,15]. Enzyme structures were checked for missing
atoms, bonds and contacts. Hydrogen atoms were added to the
enzyme structure. Water molecules and bound ligands were
manually deleted. Preferred coordination modes of 7a and 7f with
dihydrofolate reductase (DHFR) protein are presented in Fig. 3.
Fragment B of 7f is bound into the active site, in which the benzyl
group shows H-bond interaction with Val 31 and Ala 7. Fragment A
of 7a is bound into the active site where the morpholino group
shows H-bond interaction with Phe 92, Leu 5, and Val 31,
comparably indicated its more potent activity than that of 7f.
The preliminary docking results imply that compounds 7a and 7f
possibly display their antibacterial activity through the interaction
with DHFR protein by targeting residues of the active cavities of
DHFR.
7e
7f
10a
10b
11a
11b
11c
12a
12b
12c
13a
13b
14a
14b
14c
15a
4-CH3
H
4-Br
H
4-CH3
4-Cl
H
2,4-(Cl)2
4-Cl
4-Br
H
4-Br
2,4-(Cl)2
4-Cl
4-Br
2,4-(Cl)2
4-Cl
4-Br
4-Cl
H
4.7
9.6
4.7
9.3
19.3
9.3
9.6
19.3
>135.6
>162.8
42.2
80.2
>175.3
18.5
40.1
36.1
>161.9
67.6
20.5
89.6
79.8
40.9
179.2
10.0
41.3
67.9
>162.8
42.2
20.0
87.6
9.2
20.0
18.1
>161.9
33.8
10.2
22.4
10.0
5.1
44.8
19.9
82.7
>181.2
37.1
5.3
>135.6
>162.8
168.8
80.2
>175.3
18.5
80.2
72.2
>161.9
135.3
20.5
89.6
79.8
40.9
179.2
79.8
165.3
>181.2
148.5
21.2
10.0
>200.4
2.5
135.6
>162.8
42.2
40.1
>175.3
9.2
40.1
36.1
>161.9
67.6
5.1
44.8
39.9
20.4
89.6
39.9
82.7
>181.2
74.2
10.6
10.0
>200.4
2.5
15b
15c
16a
16b
>181.2
37.1
5.3
2.5
12.5
>159.4
16c
4-Br
Gatifloxacin
Moxifloxacin
Norfloxacin
Oxacillin
2.5
25.0
>159.4
a
Methicillin-resistant S. aureus CCARM 3167.
Methicillin-resistant S. aureus CCARM 3506.
Quinolone-resistant S. aureus CCARM 3505.
Quinolone-resistant S. aureus CCARM 3519.
b
c
d
3. Conclusions
Based on our previous work, we synthesized a series of 1,4-
dihydro-1,3,5-triazine derivatives and evaluated their antibacterial
activities against several Gram-positive and Gram-negative
bacteria, as well as a fungus (C. albicans). Some of these compounds
exhibited high inhibitory activities against the Gram-positive and
Gram-negative bacteria, including several multidrug-resistant
clinical isolates. Compound 7a showed the most potent antimi-
results provide further evidence that the 2,4-Cl2 substituted
benzene ring plays a critical role in the antimicrobial activity of
these compounds, which is consistent with the results obtained for
a previously reported series of rhodamine and aminoguanidine
derivatives [12,13].
As indicated in Table 2, the inhibitory activities of all the
synthesized compounds were tested against the clinical isolates of
several different multidrug-resistant, Gram-positive bacterial
strains (MRSA CCARM 3167 and 3506, and quinolone-resistant S.
aureus (QRSA) CCARM 3505 and 3519). Compound 7a exhibited the
crobial activity (MIC = 2.1 mmol/L) against selected MRSA and QRSA
strains. Preliminary docking study showed that these compounds
have a good interaction with the active cavities of DHFR, possibly
exhibit their potency via inhibiting DHFR. Further study examining
the mechanisms of action of these compounds is currently
underway in our laboratory.
Table 3
4. Experimental
Antibacterial activity and cytotoxicity for 7a, 7c and 7f.
The synthesis of the target compounds is presented in Scheme 1.
A series of intermediates (4, 5, 8, and 9) was obtained by reacting
hydroxybenzaldehyde or vanillin with the appropriate substituted
benzyl chlorides or 2-bromo-1-phenylethanones [16]. Then, the
intermediates were reacted with moroxydine hydrochloride or
metformin hydrochloride in acetic acid to generate the target
compounds. The structures of the synthesized compounds were
confirmed by 1H-NMR, 13C-NMR, and mass spectroscopy (see
Supporting information).
Test organisms
7a
7c
7f
MIC (
m
mol/L)
mol/L)
S. aureus 4220
MRSA 3167
HepG2b
2.1
2.1
34.3
2.2
2.2
46.7
38.5
9.6
51.1
a
IC50
(
m
aIC50 is the concentration required to inhibit the cell growth by 50%.
Data represent the average of three independent experiments running in triplicate.
Variation was generally between 5–10%.
bHuman hepatic cells.
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Fig. 3. Docking result of compound 7a and 7f. (A) Key residues in binding site surrounding 7a. (B) 2D molecular docking modeling of compound 7a with 3fra. (C) Key residues
in binding site surrounding 7f. (D) 2D molecular docking modeling of compound 7f with 3fra.
Scheme 1. Synthetic scheme for the synthesis of compounds 6a, 7a–f, 10 a–b,11a–c, 12a–c, 13a–b,14a–c, 15a–c and 16a–c. Reagents and conditions (a) K2CO3, DMF, 60 ꢁC (b)
AcOH, 120 ꢁC, 4–8 h.
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Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
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Please cite this article in press as: T.-Y. Zhang, et al., Synthesis and biological evaluation of dihydrotriazine derivatives as potential antibacterial
agents, Chin. Chem. Lett. (2017), http://dx.doi.org/10.1016/j.cclet.2017.05.022