Synthesis, Antimicrobial Activities, and Molecular Docking Studies of Dihydrotriazine Derivatives Bearing a Quinoline Moiety

Article abstract of DOI:10.1002/cbdv.201900056

In this article, three series of dihydrotriazine derivatives bearing a quinoline moiety (5a, 5b, 8a–8c, and 9a–9m) have been designed, synthesized, and evaluated as antibacterial agents. Compounds 8a–8c were found to be the most potent of all of the compounds tested with an MIC value of 1 μg/mL against several Gram-positive (S. aureus 4220 and MRSA CCARM 3506) and Gram-negative (E. coli 1924) strains of bacteria. In addition, 3-[4-amino-6-(phenethylamino)-2,5-dihydro-1,3,5-triazin-2-yl)-6-[(3-chlorobenzyl)oxy]quinolin-2-ol (8a) showed potent inhibitory activity (MIC=2 μg/mL) against Pseudomonas aeruginosa 2742, indicating that its antibacterial spectrum is similar to those of the positive controls gatifloxacin and moxifloxacin. Structure-activity relationships (SAR) analyses and docking studies implicated the dihydrotriazine group in increasing the antimicrobial potency of the quinoline compounds. In vitro enzyme study implied that compound 8a also displayed DHFR inhibition.

Full text of DOI:10.1002/cbdv.201900056

Title: Synthesis, antimicrobial activities, and molecular docking studies
of dihydrotriazine derivatives bearing a quinoline moiety
Authors: Xue-Qian Bai, Ying Chen, Zhe Liu, Lin-Hao Zhang, Tianyi
ZHANG, and Bo Feng
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To be cited as: Chem. Biodiversity 10.1002/cbdv.201900056
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10.1002/cbdv.201900056
Chemistry & Biodiversity
Synthesis, antimicrobial activities, and molecular docking
studies of dihydrotriazine derivatives bearing a quinoline moiety
a
a,
Xueqian Bai b,1, Ying Chen c,1, Zhe Liu , Linhao Zhang a,d, Tianyi Zhang *, and Bo
Feng a,*
a Department of Pharmacy, Jilin Medical University, Jilin, Jilin Province 132013, PR
China
b The affiliated hospital of Jilin Medical University, Jilin, Jilin Province 132013, PR,
China
c
Department of Cardiology and Nephrology, No.965 Hospital of PLA, Jilin, Jilin
Province 132011, PR, China
d
Department of pharmary, Yanbian University, Yanji, Jilin Province 133002, PR,
China
*Correspondence Author: Tel: + 86(432)64561064.
E-mail: tianyizhang@126.com.
*Correspondence Author: Tel: + 86(432)64560316.
E-mail: jyfengb@126.com.
1These authors contributed equally to this work.
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10.1002/cbdv.201900056
Chemistry & Biodiversity
In this paper, three series of dihydrotriazine derivatives bearing a quinoline
moiety (5a-b, 8a-c, and 9a-m) have been designed, synthesized, and evaluated as
antibacterial agents. Compound 8a, 8b and 8c were found to be the most potent of all
of the compounds tested, with an MIC value of 1 μg/mL against several
Gram-positive (S. aureus 4220 and MRSA CCARM 3506) and Gram-negative (E. coli
1924) strains of bacteria. In addition, compound 8a showed potent inhibitory activity
(MIC = 2 μg/mL) against Pseudomonas aeruginosa 2742, indicating that its
antibacterial spectrum is similar to those of the positive controls gatifloxacin and
moxifloxacin. Structure-activity relationships (SAR) analyses and docking studies
implicated the dihydrotriazine group in increasing the antimicrobial potency of the
quinoline compounds. In vitro enzyme study implied that compound 8a also displayed
DHFR inhibition.
Keywords: antibacterial agents • antifungal activities • quinoline • dihydrotriazine •
DHFR inhibition.
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10.1002/cbdv.201900056
Chemistry & Biodiversity
Introduction
A Gram-negative opportunistic pathogenic bacterium, Pseudomonas aeruginosa,
is an important causative agent of nosocomial infections[1,2] and is involved in several
acute and chronic infections. It is one of the major pathogens causing pneumonia.[3]
Moreover, during the past decades, P. aeruginosa strains resistant to nearly all
established antibiotics have emerged, necessitating alternative therapeutic options.[4,5]
Without effective antimicrobials for prevention and treatment of infections, medical
procedures such as organ transplantation, chemotherapy, diabetes management, and
routine surgery have a significantly higher risk of morbidity and mortality.[6] New
antibacterial agents that operate through unique mechanisms of action are of
significant importance to combat the emergence of antibiotic-resistant and tolerant
bacteria. Bacteria utilize multiple mechanisms to acquire, or gain, resistance to
antibiotics following drug exposure during treatment.[7] Recent studies have identified
dihydrogen triazine-containing compounds as inhibitors of dihydrofolate reductase
(DHFR), a ubiquitous enzyme that catalyses the conversion of 7,8-dihydrofolate to
5,6,7,8-tetrahydrofolate, which is involved in metabolic reactions such as purine and
thymidine nucleotide biosynthesis.[8,9] DHFR is required by all organisms to grow and
multiply; however, selective inhibitors of microbial enzymes have been utilized as
therapeutic agents.
A lot of compounds bearing a quinoline moiety have been reported in the
literature with a variety of different pharmacological activities, including
antimicrobial,[10-12] antimalarial,[13] and anticancer activities.[14] By the previous
investigations, we found that several rhodanine derivatives bearing a quinoline moiety
showed moderate to strong activities against several Gram-positive bacterial strains,
including multidrug-resistant clinical isolates, such as compound B (MIC = 1 μg/mL).
Unfortunately, compounds belonging to this series did not show any bacteriostatic
activity against Gram-negative bacteria.[15] We also reported the identification of a
series of 1,4-dihydro-1,3,5-triazine derivatives and evaluated their antibacterial
activities. Compound A was found to be the most potent of all of the compounds
tested, with an MIC value of 0.5 μg/mL against several Gram-positive (S. aureus
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10.1002/cbdv.201900056
Chemistry & Biodiversity
4220 and quinolone-resistant S. aureus CCARM 3505) and Gram-negative (E. coli
1924) strains of bacteria.[16] However, this compound was inactive against P.
aeruginosa 2742 and S. typhimurium 2421 (Fig. 1).
The concept of hybrid molecules has proved to be the most interesting topic in
medicinal chemistry, where two or more pharmacophores are linked covalently
resulting into one molecule.[17-19] Based on the above considerations, we designed and
synthesized a series of dihydrotriazine derivatives using a hybrid strategy, in which
the rhodanine moiety was replaced by a dihydrogen triazine scaffold. Thus, three
series of 18 novel dihydrotriazine derivatives (Fig. 2) were designed, synthesized and
evaluated for their antibacterial and antifungal activities in vitro. The substituents on
the hydrocarbon or alkyl phenyl ring were changed simultaneously to investigate their
contribution to the biological activity.
Figure 1. Chemical structures of some reported compounds
Figure 2. Designed target compounds
Results and discussion
Chemistry
The target compounds were synthesized as outlined in Scheme 1. Williamson
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10.1002/cbdv.201900056
Chemistry & Biodiversity
condensation reactions between 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (2) and a
variety of different substituted chloromethylbenzene or bromine alkane compounds (1
or 6) afforded the corresponding 6-substituted-3,4-dihydroquinolin-2(1H)-ones (3),
which were subsequently reacted under Vilsmeier-Haack conditions to give the
corresponding 6-substituted-2-chloroquinoline-3-carbaldehydes (4 or 7). Then, the
intermediates (4 or 7) were reacted with Phenformin hydrochloride or metformin
hydrochloride in acetic acid to generate the target compounds. The target compounds
were confirmed by 1H and 13C NMR and high-resolution mass spectrometry.
Scheme 1. Synthetic route for the compounds 5a-b, 8a-c and 9a-m.
Antibacterial activity
The compounds were screened against four Gram-positive strains (S. aureus
4220, QRSA CCARM 3505, MRSA CCARM 3506 and S.mutans 3289) and
Gram-negative strains (E. coli 1924, P. aeruginosa 2742 and S. typhimurium 2421),
as well as one fungus (C. albicans 7535), and the results are shown in Table 1. Most
of the synthesized compounds showed potent inhibitory activities against the different
bacteria tested in the current study with MICs ranging from 1 to 64 µg/mL. Almost all
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10.1002/cbdv.201900056
Chemistry & Biodiversity
of the compounds in series 8 exhibited potent antibacterial activity with MICs ranging
from 1 to 16 µg/mL, except for 8c against the S. typhinurium 2421 and QRSA
CCARM 3505 strain (MIC > 64 µg/mL). It is noteworthy that compound 8a showed
potent inhibitory activity (MIC = 2 μg/mL) against Pseudomonas aeruginosa 2742,
indicating that its antibacterial spectrum is similar to those of the positive controls
gatifloxacin and moxifloxacin. Compound 8b exhibited the greatest activities of all of
the compounds prepared in the current study with MIC values in the range of 1-16
µg/mL, making its potency comparable to those gatifloxacin and moxifloxacin.
Furthermore, in terms of its activity towards the fungus C. albicans 7535, compound
8b displayed the strongest activity of all of the compounds synthesized in the current
study with an MIC value of 2 µg/mL, which was lower than that of fluconazole. For
the S. typhinurium 2421, however, only compound 8b exhibited good activity with
MIC values of 16 µg/mL.
Based on the analysis of the activities of the synthesized compounds, the
following structure-activity relationships (SARs) were obtained. The inclusion of a
phenethyl group at the N-position of the dihydrotriazine ring, as exemplified by the
compounds in series 8 and 9, resulted in a significant difference in the activity, which
indicated that the substituent of the aromatic nucleus was critical to the activities of
these compounds. It is also noteworthy that compounds 8b and 9a, bearing a 2,4-di-Cl
substituted phenyl ring, showed excellent antimicrobial activities with MICs ranging
from 1 to 16 µg/mL and 8-32 µg/mL, respectively, against most of the bacteria strains
and the fungus tested in this study (except S. typhimurium 2421). Furthermore, the
position of the di-Cl substituent on the phenyl ring also affected the activity of the
compounds with an activity order of 2,4-di-Cl > 2,6-di-Cl, as exemplified by a
comparison of the results for the compounds 8b and 8c. These results therefore
provide further evidence to suggest that the 2,4-di-Cl substituted phenyl ring plays a
critical role in the activity of these compounds, which is consistent with the results
obtained for a previously reported series of rhodanine and dihydrotriazine
derivatives.[20,21]
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10.1002/cbdv.201900056
Chemistry & Biodiversity
Table 1. Antibacterial data as MIC[a] (μg/mL) for target compounds 5a-b, 8a-c and
9a-m.
Gram-positive strains
Fungus
Gram-negative strains
R1
R2
S. aureus
QRSA
3505[c]
MRSA S.mutans C. albicans
E.coli P. aeruginosa
S. typhinurium
4220[b]
3506[d]
3289[e]
7535[f] 1924[g]
2742[h]
2421[i]
5a
5b
－
－
NHMe2
NHMe2
32
8
>64
>64
32
16
64
32
64
32
32
16
64
>64
>64
>64
Phenylethan
amine
Phenylethan
amine
Phenylethan
amine
8a
8b
8c
3-Cl
1
1
1
16
4
1
1
1
2
1
2
4
2
4
1
1
1
2
4
64
16
2,4-di-Cl
2,6-di-Cl
>64
16
>64
9a
9b
9c
9d
9e
9f
2,4-di-Cl
2,6-di-Cl
2-Cl
NHMe2
NHMe2
NHMe2
NHMe2
NHMe2
NHMe2
NHMe2
NHMe2
NHMe2
NHMe2
NHMe2
8
64
8
16
32
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
8
32
16
64
8
8
16
64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
64
64
>64
64
>64
64
64
16
16
>64
64
64
32
64
32
>64
32
3-Cl
32
16
16
4-Cl
32
16
32
64
16
H
>64
>64
>64
32
>64
>64
64
>64
>64
>64
64
>64
>64
>64
64
>64
>64
64
9g
9h
9i
2-F
4-F
2-Br
32
32
9j
3-CH3
4-CH3
2-CN
64
64
64
64
64
9k
9l
64
32
64
64
64
NHMe2
NHMe2
>64
>64
>64
>64
>64
9m 4-NO2
Gatifloxacin
Moxifloxacin
Fluconazole
Trimethoprim
32
0.25
0.25
nd [j]
32
>64
8
4
nd
4
64
2
1
nd
4
>64
0.25
0.25
nd
>64
nd
nd
1
64
2
2
nd
4
>64
1
1
nd
32
>64
0.5
0.5
nd
0.5
2
2
[a]
MICs were determined by micro broth dilution method for microdilution plates. [b] S. aureus
4220. [c] QRSA 3505. [d] MRSA 3506. [e] S. mutans 3289. [f] Candida albicans 7535. [g] E. coli 1924.
[h] Pseudomonas aeruginosa 2742. [i] Salmonella typhimurium 2421. [j] nd: Not determined.
In vitro cytotoxic activity
Compound 8a was assessed on its cytotoxic effect against two human cell lines:
HCT116 and L02 to determine whether the compound 8a has inhibitory influence on
host cells. As shown in Table 2, the result indicated that the compound 8a showed no
appreciable cytotoxic activity (IC50 > 100 µmol/L against HCT116 and L02 cells),
suggesting that the promising starting point for further optimisation.
Table 2. Cytotoxicity activity (IC50[a] µmol/L) of compound 8a against HCT116 and
L02 cells.
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10.1002/cbdv.201900056
Chemistry & Biodiversity
Compound
In vitro cytotoxicity activity (IC50[a] µmol/L)
HCT116[b]
L02[c]
8a
> 100
> 100
[a] IC50 is defined as the concentration to inhibit the cell growth by 50%.
[b] Human colon cancer cells.
[c] Human normal hepatic cells.
Molecular docking
It has reported that dihydrotriazine and its derivatives could effectively interact
with dihydrofolate reductase (DHFR). The preferred coordination modes of 8a and 9a
with the S. aureus DHFR protein are presented in Fig. 3. The structure data were
obtained from the protein data bank (PDB ID: 3fra).[22-24] The output poses of the
ligands generated were analysed based on the LibDockScore function. The structures
of 8a and 9a were sketched in 2D and converted into 3D using the DS molecule editor
(Fig. 3B, E). Compound 8a is bound into the active site, in which the benzene ring
formed pi-pi T-shaped bond with Phe92. The thiazine N atom of 8a formed
conventional hydrogen bond with Ile14 and the quinolin ring of 8a formed
conventional hydrogen bond with the backbone of Gln19. The 3-Cl substituted phenyl
ring of 8a formed pi-alkyl bond with Arg44. Compound 9a is bound into the active
site where the thiazine N atom shows interaction with Gln19 and Ile14. Furthermore,
the enzyme surface model is shown in Figure 3C and 3F, which revealed that
compound 8a was well inserted into the active pocket of S. aureus DHFR,
comparably indicated its more potent activity than that of 9a. To summarise, our
docking results suggested that 8a, the compound with the most therapeutic potential,
strongly interacted with the critical active-site residues of DHFR.
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10.1002/cbdv.201900056
Chemistry & Biodiversity
Figure 3. (A) Three-dimensional conformation of compound 8a docked in DHFR
complex. (B) 2D molecular docking modeling of compound 8a with 3fra. (C)
Interaction of 8a with DHFR inside the binding pocket. (D) Three-dimensional
conformation of compound 9a docked in DHFR complex. (E) 2D molecular docking
modeling of compound 9a with 3fra. (F) Interaction of 9a with DHFR inside the
binding pocket.
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10.1002/cbdv.201900056
Chemistry & Biodiversity
Inhibition studies of compound 8a with DHFR
To verify the if compound 8a does indeed bind to and block the active site of
DHFR, we performed in vitro enzyme assays to test the inhibitory effect of compound
8a (MIC of 1 µg/mL) on DHFR activity (Figure 4). At concentrations of 50 µmol/L,
compound 8a decreased DHFR activity by 81% compared with the negative control.
These results confirm that compound 8a also displayed DHFR inhibition.
Figure 4. Inhibition of DHFR activities of compound 8a.
Conclusions
We have synthesized three series of dihydrotriazine derivatives containing a
quinoline moiety and evaluated their antibacterial and antifungal activities. The
results indicated that the majority of the target compounds exhibited moderate to good
levels of antibacterial activity against Gram-positive bacteria. In particular, all of the
compounds in series 8 exhibited good levels of antibacterial activities against
Gram-negative strains (E. coli 1924, P. aeruginosa 2742, S. typhinurium 2421) and
antifungal activity (C. albicans 7535). These results suggested that the dihydrotriazine
derivatives bearing a quinoline moiety, which plays a critical role in increasing the
antibacterial properties of the compounds. In vitro enzyme study implied that
compound 8a also displayed DHFR inhibition. These findings suggest that these
compounds are a good starting point for the rational development of novel
antibacterial agents.
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10.1002/cbdv.201900056
Chemistry & Biodiversity
Experimental section
All chemicals, reagents, and solvents were purchased from Aladdin (Shanghai,
China) or Macklin Reagent (Shanghai, China), and were used directly as purchased
1
without further purification. Chemical shifts in H NMR and 13C NMR spectra are
1
reported in parts per million (ppm) relative to tetramethylsilane (TMS). H and
13C-NMR spectra were performed on an AV-300 or AV-500 spectrometer (Bruker,
1
13
Zurich, Switzerland) operating at 300 MHz for H and 126 MHz for C and using
DMSO-d6 as solvent. High Resolution Mass Spectrometry was measured on a Thermo
Scientific LTQ Orbitrap XL spectrometer. Distilled water was self-prepared in our
laboratory.
General procedures for the synthesis of 5a-b, 8a-c, and 9a-m
Intermediates 4 and 7 were synthesized using the reported procedure.[15]
A
solution of intermediate compounds (1mmol) in glacial acetic acid (7mL), Metformin
hydrochloride or phenformin hydrochloride (1mmol) were added successively, and
the mixture was stirred at 120 ℃ for 4-6h. The solvent was removed under
diminished pressure, and the residue was purified by column chromatography using
20:1 dichloromethane/methanol to obtain target compounds.
3-(4-Amino-6-(dimethylamino)-2,5-dihydro-1,3,5-triazin-2-yl)-6-(pentyloxy)quin
olin-2-ol (5a):
White solid, Yield 40%; m.p. 129-131℃. 1H NMR (300 MHz, DMSO-d6) δ 12.12 (s,
1H, NH), 8.67 (s, 2H, NH2), 7.73 (s, 1H, Ar-H), 7.38-7.31 (m, 2H, Ar-H), 7.19 (dd, J
= 9.0, 2.7 Hz, 1H, Ar-H), 5.85 (s, 1H, CH), 3.99 (t, J = 6.5 Hz, 2H, CH2), 3.12 (s, 6H,
CH3), 1.77-1.69 (m, 2H, CH2), 1.06 (t, J = 7.0 Hz, 3H, CH3), 0.90 (t, J = 7.0 Hz, 4H,
CH2). 13C NMR (126 MHz, DMSO-d6) δ 160.69, 157.81, 156.43, 154.33, 135.04,
133.30, 131.23, 121.25, 116.98, 110.89, 68.41, 59.20, 56.47, 37.48 (2C), 28.83, 28.19,
22.35, 14.38. HRESI-MS m/z Anal. for C19H27N6O2: Calc. Mass 371.21900. Found
371.21942.
3-(4-Amino-6-(dimethylamino)-2,5-dihydro-1,3,5-triazin-2-yl)-6-(hexyloxy)quinol
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10.1002/cbdv.201900056
Chemistry & Biodiversity
in-2-ol (5b):
1
Yellow solid, Yield 40%; m.p. 64-66℃. H NMR (300 MHz, DMSO-d6) δ 12.15 (s,
1H, NH), 8.64 (s, 2H, NH2), 7.73 (s, 1H, Ar-H), 7.35 (dd, J = 13.5, 5.8 Hz, 2H, Ar-H),
7.19 (dd, J = 9.0, 2.7 Hz, 1H, Ar-H), 5.85 (s, 1H, CH), 3.99 (t, J = 6.5 Hz, 2H, CH2),
3.12 (s, 6H, CH3), 1.83-1.65 (m, 4H, CH2), 1.42 (t, J = 7.0 Hz, 3H, CH3), 0.88 (t, J =
7.0 Hz, 4H, CH2). 13C NMR (126 MHz, DMSO-d6) δ 157.67, 156.39, 154.36, 135.06,
131.17, 121.28, 119.52, 116.93, 110.90, 68.42, 59.15, 56.42, 48.15, 37.45 (2C), 31.45,
29.11, 25.66, 22.53, 14.35. HRESI-MS m/z Anal. for C20H29N6O2: Calc. Mass
385.23465. Found 385.23516.
3-(4-Amino-6-(phenethylamino)-2,5-dihydro-1,3,5-triazin-2-yl)-6-((3-chlorobenzy
l)oxy)quinolin-2-ol (8a):
1
White solid, Yield 48%; m.p. 110-112℃. H NMR (300 MHz, DMSO-d6) δ 7.66 (s,
1H), 7.51 (s, 1H, Ar-H), 7.45-7.37 (m, 4H, Ar-H), 7.35-7.31 (m, 2H, Ar-H), 7.28-7.15
(m, 5H, Ar-H), 5.84 (s, 1H, CH), 5.17 (s, 2H, CH2), 3.50 (t, J = 7.0 Hz, 2H, CH2),
3.14 (dd, J = 7.7, 6.1 Hz, 1H, NH), 2.80 (d, J = 6.5 Hz, 2H, CH2), 1.81 (s, 1H, NH).
13C NMR (126 MHz, DMSO-d6) δ 160.63, 158.24, 157.07, 153.84, 139.90, 139.21,
134.42, 133.65, 133.46, 131.46 , 130.72, 129.07, 128.69, 128.17, 127.64, 126.61,
126.46, 121.40, 119.37, 117.05, 111.42, 69.20, 58.87, 56.41, 41.73, 35.44, 18.70.
HRESI-MS m/z Anal. for C27H26ClN6O2: Calc. Mass 501.18003. Found 501.18036.
3-(4-Amino-6-(phenethylamino)-2,5-dihydro-1,3,5-triazin-2-yl)-6-((2,4-dichlorob
enzyl)oxy)quinolin-2-ol (8b):
White solid, Yield 48%; m.p. 165-167℃. 1H NMR (300 MHz, DMSO-d6) δ 12.32 (s,
1H, NH), 8.41 (s, 2H, NH2), 7.73-7.62 (m, 4H, Ar-H), 7.52-7.45 (m, 2H, Ar-H), 7.35
(d, J = 2.7 Hz, 1H, Ar-H), 7.22 (dd, J = 17.5, 7.6 Hz, 5H, Ar-H), 5.85 (s, 1H, CH),
5.20 (s, 2H, CH2), 3.50 (s, 2H, CH2), 3.17 (d, J = 3.8 Hz, 1H, NH), 2.79 (s, 2H, CH2).
13C NMR (126 MHz, DMSO-d6) δ 160.72, 158.36, 157.24, 153.70, 139.30, 134.59,
134.05, 133.89, 133.78, 131.81, 131.68, 129.41, 129.18, 128.77, 128.03, 126.69,
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10.1002/cbdv.201900056
Chemistry & Biodiversity
121.43, 119.43, 117.22, 111.55, 67.33, 59.02 , 56.49, 49.05, 41.92, 35.53, 19.03.
HRESI-MS m/z Anal. for C27H25Cl2N6O2: Calc. Mass 535.14106. Found 535.14160.
6-((2,6-Dichlorobenzyl)oxy)-3-(4-hydroxy-6-(phenethylamino)-2,5-dihydro-1,3,5-
triazin-2-yl)quinolin-2-ol (8c):
White solid, Yield 55%; m.p. 234-236℃. 1H NMR (300 MHz, DMSO-d6) δ 12.17 (s,
1H, NH), 8.49 (s, 2H, NH2), 7.72 (s, 1H, NH2), 7.54 (ddd, J = 17.1, 8.8, 1.8 Hz, 4H,
Ar-H), 7.29 (ddd, J = 23.7, 18.4, 9.7 Hz, 7H, Ar-H), 5.86 (s, 1H, CH), 5.29 (s, 2H,
CH2), 4.05 (s, 2H, CH2), 2.80 (s, 2H, CH2). 13C NMR (126 MHz, DMSO-d6) δ 160.73,
158.37, 157.23, 154.18, 139.30, 136.53, 134.54, 133.83, 132.15, 132.02, 131.68,
129.29, 129.18, 128.77, 126.69, 121.43, 119.42, 117.21, 111.41, 66.03, 58.98, 56.49,
41.91, 35.53, 19.03. HRESI-MS m/z Anal. for C27H25Cl2N6O2: Calc. Mass 535.14106.
Found 535.14148.
3-(4-Amino-6-(dimethylamino)-2,5-dihydro-1,3,5-triazin-2-yl)-6-((2,4-dichlorobe
nzyl)oxy)quinolin-2-ol (9a):
White solid, Yield 42%; m.p. 212-214℃. 1H NMR (300 MHz, DMSO-d6) δ 12.15 (s,
1H, NH), 8.75 (s, 1H, NH2), 8.42 (s, 1H, NH2), 7.77 (s, 1H, Ar-H), 7.71 (d, J = 2.0 Hz,
1H, Ar-H), 7.66 (d, J = 8.3 Hz, 1H, Ar-H), 7.56-7.48 (m, 2H, Ar-H), 7.35 (dd, J = 10.5,
13
5.7 Hz, 2H, Ar-H), 5.76 (s, 1H, CH), 5.19 (s, 2H, CH2), 3.12 (s, 6H, CH3). C NMR
(126 MHz, DMSO-d6) δ 160.72, 157.72, 156.42, 153.67, 135.01, 134.06, 133.89,
131.83, 131.38, 129.41, 128.05, 121.37, 119.50, 117.12, 111.71, 67.31, 59.20, 56.48,
55.39, 37.48, 19.03. HRESI-MS m/z Anal. for C21H21Cl2N6O2: Calc. Mass 459.10976.
Found 459.11075.
3-(4-Amino-6-(dimethylamino)-2,5-dihydro-1,3,5-triazin-2-yl)-6-((2,6-dichlorobe
nzyl)oxy)quinolin-2-ol (9b):
White solid, Yield 42%; m.p. 286-290℃. 1H NMR (300 MHz, DMSO-d6) δ 12.17 (s,
1H, NH), 8.82 (s, 1H, NH2), 8.45 (s, 1H, NH2), 7.76 (s, 1H, Ar-H), 7.64-7.56 (m, 3H,
Ar-H), 7.52-7.47 (m, 1H, Ar-H), 7.36 (d, J = 9.0 Hz, 1H, Ar-H), 7.29 (dd, J = 9.0, 2.5
Hz, 1H, Ar-H), 5.87 (s, 1H, CH), 5.28 (s, 2H, CH2), 3.15 (s, 6H, CH3). 13C NMR (126
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10.1002/cbdv.201900056
Chemistry & Biodiversity
MHz, DMSO-d6) δ 160.74, 157.74, 156.43, 154.11, 136.52, 134.95, 133.86, 132.16,
132.00, 131.39, 129.29, 121.39, 119.47, 117.13, 111.53, 65.99, 59.15, 56.47, 49.04,
37.49, 19.03. HRESI-MS m/z Anal. for C21H21Cl2N6O2: Calc. Mass 459.10976. Found
459.11066.
3-(4-Amino-6-(dimethylamino)-2,5-dihydro-1,3,5-triazin-2-yl)-6-((2-chlorobenzyl)
oxy)quinolin-2-ol (9c):
White solid, Yield 46%; m.p. 252-254℃. 1H NMR (300 MHz, DMSO-d6) δ 12.16 (s,
1H, NH), 8.81 (s, 1H, NH2), 8.45 (s, 1H, NH2), 7.77 (s, 1H, Ar-H), 7.66-7.62 (m, 1H,
Ar-H), 7.57-7.51 (m, 2H, Ar-H), 7.43-7.39 (m, 2H, Ar-H), 7.37-7.31 (m, 2H, Ar-H),
5.86 (s, 1H, CH), 5.20 (s, 2H, CH2), 3.13 (s, 6H, CH3). 13C NMR (126 MHz,
DMSO-d6) δ 160.72, 157.75, 156.42, 153.84, 135.04, 134.64, 133.74, 133.14, 131.36,
130.67, 129.88, 121.38, 119.51, 117.11, 111.59, 67.89, 59.19, 56.47, 49.04, 37.49,
19.02. HRESI-MS m/z Anal. for C21H22ClN6O2: Calc. Mass 425.14873. Found
425.14960.
3-(4-Amino-6-(dimethylamino)-2,5-dihydro-1,3,5-triazin-2-yl)-6-((3-chlorobenzyl)
oxy)quinolin-2-ol (9d):
White solid, Yield 46%; m.p. 169-171℃. 1H NMR (500 MHz, DMSO-d6) δ 12.15 (d,
J = 5.9 Hz, 1H, NH), 8.85 (d, J = 30.3 Hz, 1H, NH2), 8.48 (d, J = 16.5 Hz, 1H, NH2),
7.73 (s, 1H, Ar-H), 7.54 (s, 1H, Ar-H), 7.50 (d, J = 2.6 Hz, 1H, Ar-H), 7.45-7.35 (m,
4H, Ar-H), 7.31 (dd, J = 8.9, 2.2 Hz, 1H, Ar-H), 5.88-5.84 (m, 1H, CH), 5.17 (s, 2H,
13
CH2), 3.12 (s, 6H, CH3). C NMR (126 MHz, DMSO-d6) δ 160.70, 157.73, 156.42,
153.74, 139.94, 134.97, 133.63, 131.34, 130.87, 128.29, 127.80, 126.68, 121.36,
119.47, 117.06, 111.72, 69.26, 59.21, 56.48, 37.47, 19.03. HRESI-MS m/z Anal. for
C21H22ClN6O2: Calc. Mass 425.14873. Found 425.14819.
3-(4-Amino-6-(dimethylamino)-2,5-dihydro-1,3,5-triazin-2-yl)-6-((4-chlorobenzyl)
oxy)quinolin-2-ol (9e):
White solid, Yield 44%; m.p. 188-190℃. 1H NMR (300 MHz, DMSO-d6) δ 12.14 (s,
1H, NH), 8.79 (d, J = 3.3 Hz, 1H, NH2), 8.45 (s, 1H, NH2), 7.73 (s, 1H, Ar-H), 7.48 (d,
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10.1002/cbdv.201900056
Chemistry & Biodiversity
J = 2.8 Hz, 5H, Ar-H), 7.38-7.28 (m, 2H, Ar-H), 5.86 (s, 1H, CH), 5.15 (s, 2H, CH2),
3.14 (s, 6H, CH3). 13C NMR (126 MHz, DMSO-d6) δ 160.69, 157.75, 156.41, 153.79,
136.40, 134.98, 133.62, 132.94, 131.32, 130.00, 128.93, 121.39, 119.47, 117.05,
111.71, 69.36, 59.20, 56.48, 55.39, 37.47, 19.02. HRESI-MS m/z Anal. for
C21H22ClN6O2: Calc. Mass 425.14873. Found 425.14877.
3-(4-Amino-6-(dimethylamino)-2,5-dihydro-1,3,5-triazin-2-yl)-6-(benzyloxy)quin
olin-2-ol (9f):
Yellow solid, Yield 55%; m.p. 212-214℃. 1H NMR (300 MHz, DMSO-d6) δ 12.14 (s,
1H, NH), 8.83 (s, 1H, NH2), 8.47 (s, 1H, NH2), 7.74 (s, 1H, Ar-H), 7.45 (ddd, J = 15.8,
12.0, 5.0 Hz, 6H, Ar-H), 7.35-7.26 (m, 2H, Ar-H), 5.76 (s, 1H, CH), 5.14 (s, 2H, CH2),
3.12 (s, 6H, CH3). 13C NMR (126 MHz, DMSO-d6) δ 160.69, 157.77, 156.42, 153.99,
137.33, 135.01, 133.55, 131.29, 128.92, 128.37, 128.21, 121.42, 119.48, 117.03,
111.59, 70.21, 59.20, 56.47, 55.40, 37.49, 19.03. HRESI-MS m/z Anal. for
C21H23N6O2: Calc. Mass 391.18770. Found 391.18710.
3-(4-Amino-6-(dimethylamino)-2,5-dihydro-1,3,5-triazin-2-yl)-6-((2-fluorobenzyl)
oxy)quinolin-2-ol (9g):
Yellow solid, Yield 44%; m.p. 265-267℃. 1H NMR (300 MHz, DMSO-d6) δ 12.16 (s,
1H, NH), 8.85 (s, 1H, NH2), 8.47 (s, 1H, NH2), 7.76 (s, 1H, Ar-H), 7.58 (d, J = 6.9 Hz,
2H, Ar-H), 7.44 (d, J = 8.0 Hz, 1H, Ar-H), 7.37 (d, J = 9.0 Hz, 1H, Ar-H), 7.31 (d, J =
2.6 Hz, 1H, Ar-H), 7.27 (s, 1H, Ar-H), 7.25 (s, 1H, Ar-H), 5.86 (s, 1H, CH), 5.18 (s,
2H, CH2), 3.13 (s, 6H, CH3). 13C NMR (126 MHz, DMSO-d6) δ 160.71, 157.75,
156.42, 153.82, 135.01, 133.70, 131.33, 131.11, 131.08, 130.94, 130.88, 121.40,
119.49, 117.07, 111.62, 64.55, 59.20, 56.48, 49.04, 37.49, 19.02. HRESI-MS m/z
Anal. for C21H22FN6O2: Calc. Mass 409.17828. Found 409.17871.
3-(4-Amino-6-(dimethylamino)-2,5-dihydro-1,3,5-triazin-2-yl)-6-((4-fluorobenzyl)
oxy)quinolin-2-ol (9h):
Yellow solid, Yield 52%; m.p. 199-201℃. 1H NMR (300 MHz, DMSO-d6) δ 12.14 (s,
1H, NH), 8.70 (s, 2H, NH2), 7.73 (s, 1H, Ar-H), 7.55-7.49 (m, 3H, Ar-H), 7.35-7.28
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10.1002/cbdv.201900056
Chemistry & Biodiversity
(m, 2H, Ar-H), 7.23 (t, J = 8.7 Hz, 2H, Ar-H), 5.85 (s, 1H, CH), 5.12 (s, 2H, CH2),
3.11 (s, 6H, CH3). 13C NMR (126 MHz, DMSO-d6) δ 160.73, 157.82, 156.49, 153.88,
135.03, 133.58, 131.43, 130.51, 130.44, 121.41, 119.50, 117.03, 115.83, 115.66,
111.62, 69.50, 59.32, 56.48, 55.39, 37.45, 19.02. HRESI-MS m/z Anal. for
C21H22FN6O2: Calc. Mass 409.17828. Found 409.17862.
3-(4-Amino-6-(dimethylamino)-2,5-dihydro-1,3,5-triazin-2-yl)-6-((2-bromobenzyl)
oxy)quinolin-2-ol (9i):
1
Yellow solid, Yield 42%; m.p. 284-286℃. H NMR (300 MHz, DMSO-d6) δ 7.78 (s,
1H, Ar-H), 7.69 (d, J = 7.9 Hz, 1H, Ar-H), 7.62 (d, J = 7.6 Hz, 1H, Ar-H), 7.55 (s, 1H,
Ar-H), 7.43 (d, J = 7.4 Hz, 1H, Ar-H), 7.37-7.29 (m, 3H, Ar-H), 5.86 (s, 1H, CH),
5.16 (s, 2H, CH2), 3.12 (s, 6H, CH3). 13C NMR (126 MHz, DMSO-d6) δ 160.62,
157.58, 156.34, 153.87, 136.21, 135.06, 133.13, 130.83, 130.69, 128.40, 123.41,
121.40, 119.48, 117.05, 111.59, 70.11, 59.15, 56.49, 56.37, 37.44, 18.96. HRESI-MS
m/z Anal. for C21H22BrN6O2: Calc. Mass 469.09821. Found 469.09894.
3-(4-Amino-6-(dimethylamino)-2,5-dihydro-1,3,5-triazin-2-yl)-6-((3-methylbenzy
l)oxy)quinolin-2-ol (9j):
Yellow solid, Yield 52%; m.p. 154-156℃. 1H NMR (300 MHz, DMSO-d6) δ 12.43 (s,
1H, NH), 8.62 (s, 2H, NH2), 7.74 (s, 1H, Ar-H), 7.49 (d, J = 2.4 Hz, 1H, Ar-H), 7.29
(dd, J = 12.1, 7.6 Hz, 5H, Ar-H), 7.15 (d, J = 7.2 Hz, 1H, Ar-H), 5.85 (s, 1H, CH),
5.10 (s, 2H, CH2), 3.11 (s, 6H, CH3), 2.32 (s, 3H, CH3). 13C NMR (126 MHz,
DMSO-d6) δ 160.71, 157.77, 156.49, 154.05, 138.09, 137.23, 135.06, 133.47, 131.38,
129.01, 128.80, 125.30, 121.40, 119.50, 116.99, 111.54, 70.24, 59.33, 56.48, 37.43,
21.46, 19.01. HRESI-MS m/z Anal. for C22H25N6O2: Calc. Mass 405.20335. Found
405.20380.
3-(4-Amino-6-(dimethylamino)-2,5-dihydro-1,3,5-triazin-2-yl)-6-((4-methylbenzy
l)oxy)quinolin-2-ol (9k):
Yellow solid, Yield 48%; m.p. 159-161℃. 1H NMR (300 MHz, DMSO-d6) δ 12.12 (s,
1H, NH), 8.74 (s, 1H, NH2), 8.41 (s, 1H, NH2), 7.73 (s, 1H, Ar-H), 7.50 (d, J = 2.4 Hz,
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10.1002/cbdv.201900056
Chemistry & Biodiversity
1H, Ar-H), 7.38-7.31 (m, 3H, Ar-H), 7.27 (dd, J = 9.0, 2.5 Hz, 1H, Ar-H), 7.21 (d, J =
8.0 Hz, 2H, Ar-H), 5.86 (s, 1H, CH), 5.09 (s, 2H, CH2), 3.12 (s, 6H, CH3), 2.31 (s, 3H,
CH3). 13C NMR (126 MHz, DMSO-d6) δ 160.70, 157.71, 156.42, 154.03, 137.63,
135.01, 134.27, 133.49, 131.24, 129.47, 128.31, 121.48, 119.48, 116.99, 111.63,
70.13, 59.23, 56.48, 55.39, 37.47, 21.25, 19.03. HRESI-MS m/z Anal. for C22H25N6O2:
Calc. Mass 405.20335. Found 405.20364.
2-(((3-(4-Amino-6-(dimethylamino)-2,5-dihydro-1,3,5-triazin-2-yl)-2-hydroxyqui
nolin-6-yl)oxy)methyl)benzonitrile (9l):
White solid, Yield 48%; m.p. 260-262℃. 1H NMR (300 MHz, DMSO-d6) δ 7.90 (d, J
= 7.8 Hz, 1H, Ar-H), 7.79-7.73 (m, 3H, Ar-H), 7.58 (dd, J = 9.7, 5.8 Hz, 2H, Ar-H),
13
7.39-7.28 (m, 2H, Ar-H), 5.87 (s, 1H, CH), 5.28 (s, 2H, CH2), 3.11 (s, 6H, CH3). C
NMR (126 MHz, DMSO-d6) δ 160.78, 157.76, 156.53, 153.72, 140.30, 135.04,
133.96, 133.85, 133.82, 131.56, 130.19, 129.69, 121.31, 119.51, 117.71, 117.11,
111.83, 68.58, 59.40, 56.48, 37.43, 19.03. HRESI-MS m/z Anal. for C22H22N7O2: Calc.
Mass 416.18295. Found 416.18335.
3-(4-Amino-6-(dimethylamino)-2,5-dihydro-1,3,5-triazin-2-yl)-6-((4-nitrobenzyl)o
xy)quinolin-2-ol (9m):
Yellow solid, Yield 52%; m.p. 220-222℃. 1H NMR (300 MHz, DMSO-d6) δ 12.13 (s,
1H, NH), 8.57 (s, 2H, NH2), 8.27 (d, J = 8.8 Hz, 2H, Ar-H), 7.74 (d, J = 9.0 Hz, 3H,
Ar-H), 7.51 (s, 1H, Ar-H), 7.34 (d, J = 2.5 Hz, 2H, Ar-H), 5.85 (s, 1H, CH), 5.33 (s,
2H, CH2), 3.11 (s, 6H, CH3). 13C NMR (126 MHz, DMSO-d6) δ 160.72, 157.77,
156.46, 153.56, 147.52, 145.28, 134.95, 133.76, 131.49, 128.73, 124.11, 121.31,
119.49, 117.13, 111.79, 68.99, 59.26, 56.48, 49.05, 37.45, 19.02. HRESI-MS m/z
Anal. for C21H22N7O4: Calc. Mass 436.17278. Found 436.17273.
In vitro inhibition of bacterial and fungal growth
Determination of minimal inhibitory concentrations (MIC) was performed as
described previously.[16] Testing was performed by the standard broth microdilution
method with trimethoprim, moxifloxacin and gatifloxacin. All stock solutions of the
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10.1002/cbdv.201900056
Chemistry & Biodiversity
compounds were dissolved in DMSO. A two-fold serial dilution technique was used
to obtain final concentrations of 64-0.25 μg/mL.
Molecular modeling
All docking runs were carried out using Discovery Studio v17.1.0.16143. The
crystal structure data (S. aureus DHFR) were obtained from the protein data bank
(PDB ID: 3fra). The water molecules and heavy atom in protein were removed and
the protein was prepared by adding hydrogen and correcting incomplete residues
using Clean Protein tool of DS, then the protein was refined with CHARMm.
Inhibition of DHFR activities in vitro
Solid-phase antibody was prepared by coating the microtiter plate wells with
purified human dihydrofolate reductase (DHFR) antibody. Determination of DHFR
activities was performed as described previously.[16] All experiments were performed
in triplicates and results were presented as the average of three independent
measurements.
Acknowledgment This research was supported by the National Natural Science
Foundation of China (Grant numbers 81773692); The Department of Education of
Jilin Province (No. JJKH20191070KJ); The Health Department of Jilin Province
(2018ZC034) and the Doctoral Foundation of Jilin Medical University (No.
JYBS2018007).
Author Contribution Statement
T. Y. Zhang and B. Feng designed the experiments, performed the separation
experiments and structural characterization, wrote the article. X. Q. Bai performed the
bioactivity assay and docking study. Y. Chen provided the guidance and revised the
manuscript. Z. Liu and L. H. Zhao performed the synthesis of compounds.
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10.1002/cbdv.201900056
Chemistry & Biodiversity
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