Novel triazole derivatives containing different ester skeleton: Design, synthesis, biological evaluation and molecular docking

Article abstract of DOI:10.1248/cpb.c19-00624

Invasive fungal disease constitutes a growing health problem and development of novel antifungal drugs with high potency and selectivity are in an urgent need. In this study, a novel series of triazole derivatives containing different ester skeleton were designed and synthesized. Microdilution broth method was used to investigate antifungal activity. Significant inhibitory activity of compounds 5c, 5d, 5e, 5f, 5m and 5n was evaluated against the Candida albicans (I), Candida albicans clinical isolate (II), Candida glabrata clinical isolate (I), and Candida glabrata (II) with minimum inhibitory concentrations (MIC₈₀) values ranging from 2 to 16μg/mL. Notably, compounds 5e and 5n showed the best inhibition against Candida albicans (II), Candida glabrata (I), and Candida glabrata (II) at the concentrations of 2 and 8μg/mL, respectively. Molecular docking study revealed that the target compounds interacted with CYP51 mainly through hydrophobic and van der Waals interactions. The results indicated that these novel triazole derivatives could serve as promising leads for development of antifungal agents.

Full text of DOI:10.1248/cpb.c19-00624

Chemical and Pharmaceutical Bulletin Advance Publication by J-STAGE
DOI:10.1248/cpb.c19-00624
Advance Publication
November 8, 2019
Chem. Pharm. Bull.
Regular Article
Novel triazole derivatives containing different ester skeleton: Design,
synthesis, biological evaluation and molecular docking
Xiaoyan Han,a Shumin Wang,a Na Zhang,a Liwen Ren,c Xiaoyang Sun,d Yali Song,,b
Jinhua Wang,*,c and Bin Xiao*,a,c
aLaboratory of Clinical Pharmacy, Ordos School of Clinical Medicine, Inner Mongolia
Medical University, Inner Mongolia Ordos 017000, China: bKey Laboratory of
Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences,
c
Hebei University, Hebei Baoding 071002, China: Beijing Key Laboratory of Drug Target
Identification, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking
d
Union Medical College, Beijing 100050, China: and National drug clinical trial institution
of Cangzhou Central Hospital, CangZhou 061000, China.
* Corresponding Authors:
Jinhua Wang, E-mail: wjh@imm.ac.cn
Bin Xiao, E-mail: michael-bin@163.com
Ⓒ 2019 The Pharmaceutical Society of Japan

Abstract
Invasive fungal disease constitutes a growing health problem and development of novel
antifungal drugs with high potency and selectivity are in an urgent need. In this study, a novel
series of triazole derivatives containing different ester skeleton were designed and
synthesized. Microdilution broth method was used to investigate antifungal activity.
Significant inhibitory activity of compounds 5c, 5d, 5e, 5f, 5m and 5n was evaluated against
the Candida albicans (I), Candida albicans clinical isolate (II), Candida glabrata clinical
isolate (I), and Candida glabrata (II) with MIC80 values ranging from 2 μg/mL to 16 μg/mL.
Notably, compounds 5e and 5n showed the best inhibition against Candida albicans (II),
Candida glabrata (I), and Candida glabrata (II) at the concentrations of 2 μg/mL and 8
μg/mL, respectively. Molecular docking study revealed that the target compounds interacted
with CYP51 mainly through hydrophobic and Van der Waals interactions. The results
indicated that these novel triazole derivatives could serve as promising leads for development
of antifungal agents.
Key words: Triazole; Synthesis; Antifungal activity; Structure-activity relationship;
Molecular docking
Chemical and Pharmaceutical Bulletin Advance Publication

1. Introduction
Global morbidity due to life-threatening fungal infections has dramatically increased in
recent decades, particularly among individuals suffering from cancer, autoimmune diseases,
organ transplants or AIDS.1-3) Clinically, Aspergillus fumigatus (mortality rate: 50-90%),
Cryptococcus neoformans (mortality rate: 20-70%), and Candida albicans (mortality rate:
20-40%) are the major pathogenic agents for systemic fungal infections.4) Numerous
antifungal drugs including polyenes (e.g., amphotericin B), fluorinated pyrimidines
(e.g., 5-fluorocytosine), azoles (e.g., fluconazole), and echinocandins (e.g., caspofungin)
(Fig. 1) are available for the treatment of invasive fungal infections.5) For their high
therapeutic index, broad spectrum activities and superior safety profile, the azole antifungals
are considered as first-line therapy in current clinic. However, some of them still suffer from
serious drug resistance issues, there is a real need for developing novel antifungal triazoles
with improved profiles.6,7
Fig. 1. Chemical structures of representative antifungal agents
Azole antifungal agents competitively inhibit the lanosterol 14α-demethylase (CYP51),
which catalyzes the oxidative removal of the 14α-methyl group of lanosterol to give
△14,15-desaturated intermediates in ergosterol biosynthesis. This selective inhibition of
CYP51 would result in depletion of ergosterol and accumulation of lanosterol, thereby
inhibiting the growth and proliferation of fungi.8,9) Moreover, CYP51 has been regarded by
many researchers as a target for molecular docking and widely applied in the rational design
of antifungal compounds.10-15)
Studies showed that16) the antifungal triazoles featured a core structure composed of a
triazole, a halophenyl ring, while differing in the side chains. The development of triazole
drugs is primarily driven through structure optimization especially of the side chains as well
as SAR study. Itraconazole (Fig. 2) is the triazole antifungal drug available in the market and
widely used for candidiasis. The long side chain of itraconnazole containing four linearly
linked cyclic rings might attribute to its low solubility and erratic bioavailability, which drove
the research to design novel agents with medium side chains.17) Therefore, replacing the long
side chain in the itraconazole structure with different ester moieties containing aryl rings and
halogenated alkyl chain might result in novel triazole antifungal drugs. Furthermore,
molecular docking study indicated that the triazole bound to the heme iron of CYP51, and the
Chemical and Pharmaceutical Bulletin Advance Publication

halophenyl ring could locate into the hydrophobic pocket.18) We hypothesized that the ester
moieties might accommodate in the deep cavity of CYP51, as well as providing in
hydrophobic pockets of the biological targets which contribute to improve the potency,
stability and specificity of the binding site. In addition, the ester groups were to be introduced
in the target compounds because they could be further removed to reduce molecular weight.
The halogen as a strong electron-withdrawing group could affect the charge distribution and
hydrophobility of drug molecules and the time of drug action. Thus, the halogenated alkyl
chain was to be introduced to leave large space for further optimization.
The above mentioned promoted us to design and synthesize a series of
1-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethyl derivatives containing a triazole ring, a
dichlorophenyl group, and ester groups in the side chain. In our design, the structure of
itraconazole was altered as a platform and different ester groups were insert into the side
chain to find out whether these groups were necessary for the antifungal activity (Fig. 2).
Fig. 2. Design of compounds 5a-5q
2. Results and Discussion
2.1. Chemistry
1-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethyl derivatives (5a-5q) were synthesized
in four steps as illustrated in Chart 1. At first, 1,3-dichlorobenzene (1.0 equiv), chloroacetyl
chloride (ClCH2COCl) (1.2 equiv) and anhydrous aluminum chloride (AlCl3) (1.0 equiv) in
an anhydrous dichloromethane (DCM) solution were heated at reflux for 4 h to obtain
compound 2 in 80% yield.19) Secondly, intermediate 3 was prepared by condensation of
compound 2 (1.0 equiv) with triazole (1.5 equiv) in the presence of potassium carbonate
(K2CO3) (1.0 equiv) and acetonitrile (CH3CN) for 8 h at reflux. Intermediates 3 was obtained
in the yield of 39%. Thirdly, intermediate 3 (1.0 equiv) and sodium borohydride (NaBH4)
(2.0 equiv) in an anhydrous ethanol-tetrahydrofuran (THF) solution were reacted at room
temperature for 4 h to obtain compound 4 in 80% yield. Finally, compound 4 (1.0 equiv) and
various acid (1.5 equiv) were reacted in the presence of N,N'-dicyclohexylcarbodiimide
Chemical and Pharmaceutical Bulletin Advance Publication

(DCC) (1.3 equiv), 4-dimethylaminopyridine (DMAP) (1.3 equiv) and anhydrous
dichloromethane for overnight at reflux to give final compounds 5a-5q in 70%-89% yield.
The reaction was monitored by TLC, and the reaction mixture was purified by column
chromatography.
Chart 1. Synthetic route of compounds 5a-5q. Reagents and conditions: (i) ClCH2COCl,
AlCl3, Anhydrous CH2Cl2, reflux, 4 h, 80% yield; (ii) Triazole, K2CO3, CH3CN, reflux, 8 h,
39% yield; (iii) NaBH4, Ethanol-THF, r.t., 4 h, 80% yield; (iiii) DCC, DMAP, Anhydrous
CH2Cl2, reflux, overnight, 70-89% yield.
The structures of all compounds were shown in Table 1. All the compounds were
elucidated by 1H NMR, 13C NMR and HRMS.
Table 1. Structure, yield, reaction time and melting point of compounds 5a-5q
Chemical and Pharmaceutical Bulletin Advance Publication

No.
R
Time (h)
13
Yield (%)
75
m.p.(℃)
85-87
5a
12
13
14
13
12
14
13
13
12
13
13
14
14
13
13
14
8
70
83
80
81
78
85
79
89
87
87
82
80
86
78
83
80
39
91-93
80-82
5b
5c
5d
5e
5f
85-87
62-64
64-65
64-66
5g
5h
5i
66-67
126-128
85-86
5j
167-168
90-91
5k
5l
177-179
141-142
129-130
175-177
84-85
5m
5n
5o
5p
5q
3
Cl
------
113-114
2.2. Biological activity
The antifungal activity of the compounds 5a-5q against nine human pathogenic fungi was
evaluated according to the protocols of the National Committee for Clinical Laboratory
Standards. Fluconazole (FCZ), Amphotericin B (Amp B) and Itraconazole (ITZ) were used as
positive control drugs. The broth microdilution method was used to determine the minimum
Chemical and Pharmaceutical Bulletin Advance Publication

inhibitory concentrations (MIC80) of the synthesized compounds.20)
As shown in Table 2, most of the compounds showed weak antifungal activity against C.
par., A. fum., C. kru. and C. tro., while there was a good antifungal activity against C. alb., C.
gla. and C. neo.. Several compounds, such as compounds 5c, 5d, 5e, 5f, 5m and 5n exhibited
superior or comparable antifungal activity to FCZ with MIC80 values in the range of 2-16
μg/mL, particularly for C. alb.(I)、C. alb.(II)、C. gla.(I), and C. gla.(II). Among them,
compounds 5e and 5n showed the most potent activity against four important fungal
pathogens (MIC80 = 2-8 μg/mL). Compound 5c (inhibition of C. alb. (Ⅱ)) could be achieved
at 2 μg/mL and compounds 5d and 5f (inhibition of C. alb. (Ⅱ)) could be achieved at
4 μg/mL. Compound 5m (inhibition of C. gla. (Ⅰ) and C. gla. (Ⅱ)) could be achieved at
8 μg/mL. These above-mentioned compounds exhibited superior activity to FCZ.
Interestingly, compound 5p (MIC80 = 2 μg/mL) was highly active against C. alb.(I), which
was more active than FCZ (MIC80 = 8 μg/mL).
In contrast, the target compounds generally showed improved activity against C. neo.,
whereas they were less potent against C. par.. For example, the inhibitory activity of
compounds 5c, 5d, 5e, 5f and 5g (MIC80 = 32 μg/mL) against C. neo. were comparable to
that of FCZ (MIC80 = 32 μg/mL). For C. kru., most compounds showed weak activity except
compound 5n (MIC80 = 32 μg/mL), which was more potent than FCZ (MIC80 = 64 μg/mL).
However, all the compounds were inactive against A. fum. and C. tro..
As seen from the Table 2, compound 3 and intermediate 4 showed weak antifungal
activity as compared to the compounds 5a-5q. The introduction of different ester groups on
the intermediate 4 resulted in a better improvement of the antifungal activity.
Chemical and Pharmaceutical Bulletin Advance Publication

Table 2. In vitro antifungal activity of the target compounds 5a-5qa
MIC80 (μg/mL)
Compd
.
C. alb. C. alb. C. kru. C. par. C. gla. C. gla. C. neo. A. fum. C. tro.
(Ⅰ)
64
64
8
8
4
(Ⅱ)
16
16
2
4
2
(Ⅰ)
128
128
16
16
8
16
32
64
128
(Ⅱ)
128
128
16
16
8
16
32
32
128
128
128
64
128
128
128
>128 64
>128 64
>128 128
>128 128
>128 128
>128 128
>128 64
64
64
32
64
128
128
128
128
32
32
32
32
32
64
128
128
128
128
128
128
128
128
128
64
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
32
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
3
128
128
64
128
128
128
128
128
128
128
64
128
128
128
128
128
8
4
32
64
64
128
16
128
8
2
128
2
16
16
32
64
32
64
8
>128 128
32
128
8
8
128
128
128
8
2
32
64
128
8
64
32
64
32
32
8
128
128
64
128
32
128
64
128
16
2
>128 16
>128 128
128
32
16
8
>128 64
64
128
16
2
>128 128
128
64
1
16
16
0.5
<1
64
32
8
64
128
4
4
FCZ
ITZ
Amp B
0.25
<1
0.25
<1
1
<1
<1
<1
2
1
2
aAbbreviations: C. alb.(I), Candida albicans (ATCC 90028); C. alb.(II), Candida albicans
clinical isolate (1802274); C. kru., Candida krusei (ATCC 6528); C. par., Candida
parapsilosis clinical isolate (18022019); C. gla.(I), Candida glabrata clinical isolate
(1802183); C. gla.(II), Candida glabrata (ATCC 15126); C. neo., Cryptococcus neoformans
(ATCC 34877); A. fum., Aspergillus fumigatus clinical isolate (2423); C. tro., Candida
tropicalis clinical isolate (1802372); FCZ: Fluconazole; ITZ: Itraconazole; Amp B:
Amphotericin B.
2.3. Structure activity relationships study
On the basis of the antifungal activity, preliminary structure-activity relationships (SARs)
were obtained. Firstly, compared with the compounds 3 and 4, the introduction of different
acids on the 1-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one scaffold (5a-5q)
resulted in a better improvement of the antifungal activity, suggesting that the interactions of
the aliphatic and aromatic groups with CYP51 were important for its binding affinity.
Secondly, for the compounds 5a-5h, the length of halogenated alkyl side chain on ester
group was essential to their antifungal activities. The data suggested that the optimal chain
Chemical and Pharmaceutical Bulletin Advance Publication

lengths for maximal antifungal activity were C4 and C5 (5c, 5d, 5e, 5f), and the general trend
for activity versus chain length was C5 > C4 > C6 > C3. Among the compounds 5c, 5d, 5e, 5f,
chloro substituted alkyl side chain on ester group (5c, 5e) was more active than the bromo
substituted (5d, 5f) against C. alb., C. gla. and C. neo.
Thirdly, for the compounds 5i-5q, electron-withdrawing groups (halogens, such as -F, -Cl
and -Br) on benzene ring, enhanced the inhibitory activity against C. alb., C. gla. and C. neo..
On the contrary, electron-donating groups (such as -CH3), decreased the inhibitory activity.
Therefore, to some extent, we could predict that electron-withdrawing group could affect the
charge distribution and hydrophobility of drug molecules to improve the biological activity of
compounds. Moreover, 4-substitutions on benzene ring (5m, 5n and 5p) were more favorable
than the 3-substitutions (5l, 5o and 5q). Among the compounds 5m, 5n, 5p, 4-fluoro
substitution (5n) was more active than the 4-chloro substitution (5m). However, 4-bromo
substitution (5p) had little effect on the antifungal activity as compared to the compounds 5n
and 5m. These results gave us a clear conclusion that the halogen substituents on benzene
ring gave rise to different antifungal activity depending on the halogen position and type.
Finally, the replacement of the halogenated alkyl ester side chains (5a-5h) by phenyl
groups (5i-5q) resulted in a decrease in antifungal activity. These results clearly indicated the
importance that halogen substituents have on the antifungal activity of this class of triazole
derivatives.
2.4. Molecular docking
In order to rationalize the antifungal activity and provide more straightforward information
about ligand-enzyme interactions for further rational drug design, molecular docking was
performed for itraconazole (ITZ), compounds 5e and 5q. The crystal structure of CYP5121)
(PDB ID: 5EQB) bound with its active ligand ITZ was served as a useful template for
generating proposed binding modes. The docking results were showed in Fig. 3 and Table 3.
The overall conformation of the ITZ in the active site of CYP51 was shown in Fig. 3A.
The docking method was quite accurate to predict the real interaction of ligands and CYP51,
where the re-docking experiment gave a RMSD value of 1.9844 Å. Moreover, the triazole
group of the ITZ made a coordination bond with the heme iron and showed carbon hydrogen
bond interaction with Gly314. The 2,4-dichlorophenyl group could be put into the
hydrophobic pocket formed by Ile139, Met313 and Phe236. In addition, the long tail of ITZ
lied within a hydrophobic pocket and formed Van der Waals interactions with the surrounding
residues, such as Leu383, Ser382, Ala69 and Phe384. The phenyl group of side chain could
form π-π interaction with Phe241 and the piperazine ring of side chain had carbon hydrogen
bonds with residues of Ser508 and Met509.
More insights revealed that compound 5e might bind with the active site cavity of CYP51
(Fig. 3B). The -CDOCKER ENERGY value of it, which was 21.4974 kcal/mol, was higher
than the natural ligand ITZ (14.2919 kcal/mol). It indicated that compound 5e might exert
better antifungal activity than ITZ. The triazole ring made a coordination bond with the heme
iron and formed hydrogen bond interaction with Tyr126. The 2,4-dichlorophenyl group could
show π-π interactions with Leu380 and Phe236. Further, the ester side chain was interacting
with Met509, Leu383, Phe384, Phe241 and Ser382 through Van der Waals force.
Compared with compound 5e, compound 5q showed weaker antifungal activity. The
Chemical and Pharmaceutical Bulletin Advance Publication

calculated -CDOCKER ENERGY value was 3.6624 kcal/mol. The -CDOCKER
INTERACTION ENERGY value of it, which was 38.1424 kcal/mol, was lower than the
compound 5e (45.1817 kcal/mol). As shown in Fig. 3C, the triazole ring showed π-π
interaction with His381 and the ester side chain was interacting with Phe384, Tyr126 and
Leu383 through Van der Waals force. Compound 5q showed weaker interactions with the key
amino acid residues of the CYP51 binding pocket than compound 5e. Thus, the molecular
modeling studies suggested that compound 5e might act as an antifungal agent by occupying
the CYP51 binding pocket and showing favorable interactions with the key amino acid
residues.
A
B
Chemical and Pharmaceutical Bulletin Advance Publication

C
Fig. 3. The binding modes of ITZ (A), 5e (B), and 5q (C) in the active site of CYP51 The
heme is shown in blue (Upper) and molecules ITZ, 5e and 5q are shown in purple-red
(Lower).
Table 3. Ligand-CYP51 interactions of the target compounds 5a-5q
LIGANDS
-CDOCKER ENERGYa -CDOCKER INTERACTION
(kcal/mol)
14.2919
27.1352
21.4974
21.6036
25.7246
23.5840
19.3272
15.9591
9.7196
ENERGYb (kcal/mol)
80.1265
48.3584
45.1817
44.9928
43.1719
40.9958
40.8749
40.5997
40.5280
40.0338
39.9109
39.7354
39.5278
39.4440
38.6478
38.1424
38.0478
37.5572
32.2895
Itraconazole
5h
5e
5f
5g
5c
5d
5m
5p
5a
5l
18.0549
4.0308
5k
5j
17.2615
11.9170
20.2553
14.1954
3.6624
11.6228
12.2871
6.8256
5b
5n
5q
5o
5i
3
a -CDOCKER ENERGY: The higher the value of -CDOCKER ENERGY, the more stable the
conformation.
Chemical and Pharmaceutical Bulletin Advance Publication

b
-CDOCKER INTERACTION ENERGY: The higher the CDOCKER INTERACTION
ENERGY value represents more stable ligand binding.
3. Conclusions
A novel series of triazole derivatives containing different ester skeleton were synthesized
and evaluated as antifungal agents. Compounds 5e and 5n showed the best antifungal activity
in vitro, which (inhibition of Candida albicans (II) and Candida glabrata (I), (II)) could be
achieved at the concentrations of 2 μg/mL and 8 μg/mL, respectively. In addition, compounds
5c, 5d, 5f and 5m displayed the remarkable in vitro inhibitory activity against Candida
albicans and Candida glabrata strains, which was superior or comparable to that of the
reference drug fluconazole. However, all the compounds also showed weak inhibition to
other fungi which were Candida parapsilosis, Aspergillus fumigatus, Candida krusei and
Candida tropicalis. Moreover, molecular docking was performed to position compounds 5e
and 5q into the CYP51 active site to determine the potential binding mode. In conclusion,
these preliminary results are promising and some of these compounds may be potential
candidates as antifungal agents.
Experimental
General chemistry methods, synthesis procedures, spectral data, biological assays, molecular
docking are given in Supplementary information.
Acknowledgments
We gratefully acknowledge The Independent Scientific Research Project Program of Ordos
Central Hospital (EY2017002) for financial support; The Joint Project of Science and
Technology
Million
Engineering
of
Inner
Mongolia
Medical
University
(YKD2017KJBW(LH)023); The Natural Science Foundation of Hebei Province
(B2018201269).
Conflict of Interest
The authors declare no conflict of interest.
Supplementary Materials
The online version of this article contains supplementary materials.
Chemical and Pharmaceutical Bulletin Advance Publication

References and notes
1) Groll A. H., Lumb J., Future Microbiol, 7, 179-184(2012).
2) Vandeputte P., Ferrari S., Coste A. T., Int. J. Microbiol., 2012, 1-24 (2012).
3) Crunkhorn S., Nat. Rev. Drug Discov., 15, 604-604 (2016).
4) Han X. Y., Zhong Y. F., Li S. B., Liang G. C., Zhou G., Wang X. K., Chen B. H., Song Y.
L., Chem. Pharm. Bull., 64, 1411-1416 (2016).
5) Kathiravan M. K., Salake A. B., Chothe A. S., Dudhe P. B., Watode R. P., Mukta M. S.,
Gadhwe S., Bioorg. Med. Chem., 20, 5678-5698 (2012).
6) Chai X. Y., Zhang J., Cao Y. B., Zou Y., Wu Q. Y., Zhang D. Z., Jiang Y. Y., Sun Q. Y.,
Eur. J. Med. Chem., 46, 3167-3176 (2011).
7) Zhang Y. Y., Mi J. L., Zhou C. H., Zhou X. D., Eur. J. Med. Chem., 46, 4391-4402
(2011).
8) Zou Y., Zhao Q. J., Liao J., Hu H. G., Yu S. C., Chai X. Y., Xu M. J., Wu Q. Y., Bioorg.
Med. Chem. Lett., 22, 2959-2962 (2012).
9) Jiang Y. W., Zhang J., Cao Y. B., Chai X. Y., Zou Y., Wu Q. Y., Zhang D. Z., Jiang Y. Y.,
Sun Q. Y., Bioorg. Med. Chem. Lett., 21, 4471-4475 (2011).
10) Yu S. C., Chai X. Y., Wang Y. W., Cao Y. B., Zhang J., Wu Q. Y., Zhang D. Z., Jiang Y. Y.,
Yan T. H., Sun Q. Y., Drug Des. Dev. Ther., 8, 383-390 (2014).
11) Xu K. H., Huang L., Xu Z., Wang Y. W., Bai G. J., Wu Q. Y., Wang X. Y., Yu S. C., Jiang
Y. Y., Drug Des. Dev. Ther., 9, 1459-1467 (2015).
12) Chai X. Y., Yu S. C., Jiang Y. W., Zou Y., Wu Q. Y., Zhang D. Z., Jiang Y. Y., Cao Y. B.,
Sun, Q. Y., Archives. Pharmacal. Res., 35, 1895-1901 (2012).
13) Wang Y. W., Xu K. H., Bai G. J., Huang L., Wu Q. Y., Pan W. H., Yu S. C., Mol. (Basel,
Switzerland), 19, 11333-11340 (2014).
14) Yu S. C., Wang N., Chai X. Y., Wang B. G., Cui H., Zhao Q. J., Zou Y., Sun Q. Y., Meng
Q. G., Wu Q. Y., Archives. Pharmacal. Res., 36, 1215-1222 (2013).
15) Xie F., Ni T. J. H., Zhao J., Pang L., Li R., Cai Z., Ding Z. C., Wang T., Yu S. C., Jin Y. S.,
Zhang D. Z., Jiang Y. Y., Bioorg. Med. Chem. Lett., 27, 2171-2173 (2017).
16) Choi J. Y., Roush W. R., Curr. Top. Med. Chem., 17, 30-39(2017).
17) Andes D., Curr. Med. Res. Opin., 29, 13-18 (2013).
18) Hargrove T. Y., Wawrzak Z., Lamb D. C., Guengerich F. P., Lepesheva G. I., J. Biol.
Chem., 290, 23916-23934 (2015).
19) Jiang Z. G., Gu J. L., Wang C., Wang S. Z., Liu N., Jiang Y., Dong G. Q., Wang Y., Liu Y.,
Yao J. Z., Miao Z. Y., Zhang W. N., Sheng C. Q., Eur. J. Med. Chem., 82, 490-497
(2014).
20) Cao X. F., Xu Y. Y., Cao Y. B., Wang R. L., Zhou R., Chu W. J., Yang Y. S., Eur. J. Med.
Chem., 102, 471-476 (2015).
21) Monk B. C., Tomasiak T. M., Keniya M. V., Huschmann F. U., Tyndall J. D. A.,
O'Connell J. D., Cannon R. D., Mcdonald J. G., Rodriguez A., Finer-Moore J. S., Stroud
R. M., Proc. Natl. Acad. Sci. U. S. A., 111, 3865-3870(2014).
Chemical and Pharmaceutical Bulletin Advance Publication