5-(4-Hydroxyphenyl)-3H-1,2-dithiole-3-thione-based fibrates as potential hypolipidemic and hepatoprotective agents

Article abstract of DOI:10.1016/j.bmcl.2018.10.003

Hypolipidemic effects of the newly synthesized 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione-based fibrates were evaluated in Triton WR-1339 and high-fat diet (HFD)-induced hyperlipidemic mice. Preliminary screening of all the synthesized compounds was don

Full text of DOI:10.1016/j.bmcl.2018.10.003

Accepted Manuscript
5
-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione-Based Fibrates as Potential Hy-
polipidemic and Hepatoprotective Agents
Zi-Zhang Chen, Yun-Dong Xie, Li-Hua Shao, Qiu-Tang Wang, Yan-Hong Xu,
Xiao-Li Bian
PII:
S0960-894X(18)30783-2
https://doi.org/10.1016/j.bmcl.2018.10.003
BMCL 26062
DOI:
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
21 June 2018
12 September 2018
1 October 2018
Please cite this article as: Chen, Z-Z., Xie, Y-D., Shao, L-H., Wang, Q-T., Xu, Y-H., Bian, X-L., 5-(4-
hydroxyphenyl)-3H-1,2-dithiole-3-thione-Based Fibrates as Potential Hypolipidemic and Hepatoprotective Agents,
Bioorganic & Medicinal Chemistry Letters (2018), doi: https://doi.org/10.1016/j.bmcl.2018.10.003
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5
-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione-Based
Fibrates
as
Potential Hypolipidemic and Hepatoprotective Agents
a
a,b
a
a
a
Zi-Zhang Chen , Yun-Dong Xie , Li-Hua Shao , Qiu-Tang Wang , Yan-Hong Xu ,
a
Xiao-Li Bian *
a
College of Pharmacy, Xi’an Jiaotong University, No.76 Yanta West Road, Xi’an, Shaanxi Province 710061,
People’s Republic of China
b
Department of Medicine, Tibet University of Nationalities, No.6 Wenhui East Road, Xianyang, Shaanxi Province 712082,
People’s Republic of China
Corresponding author: Xiao-li Bian
E-mail: bianxl@mail.xjtu.edu.cn
ABSTRACT
Hypolipidemic effects of the newly synthesized 5-(4-hydroxyphenyl)-3H-1,
2
-dithiole-3-thione-based fibrates were evaluated in Triton WR-1339 and high-fat diet
(
HFD)-induced hyperlipidemic mice. Preliminary screening of all the synthesized
compounds was done by using an acute model (Triton WR-1339 model), in which
compound 6 shown more significant antidyslipidemic activity than fenofibrate (FF).
The compound 6 was also found to reduce serum triglyceride (TG), total cholesterol
(
TC) and low density lipoprotein cholesterin (LDL) in HFD-induced hyperlipidemic
mice. Moreover, compound 6 displayed hepatoprotective effect, a significant
amelioration in hepatic indices (AST and ALT) toxicity was observed and the
1

histological examination showed that compound 6 inhibited the development of
hepatic lipid accumulation and ameliorated the damage in hepatic and pancreatic
tissues compared to model mice. Additional effects such as the potent antioxidant and
anti-inflammatory action confirmed and reinforced the efficacy of compound 6 as a
new agent of dual-effect hypolipidemic and hepatoprotective activities.
Keywords: Fibrates; Hypolipidemic; Hepatoprotection
Abbreviations: AI, atherosclerosis index; ADT, 5-(4-methoxyphenyl)-3H-1,2-dithiole
-
3-thione; ADT-OH, 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione; ALT, alanine
1
3
13
aminotransferase. AST, aspartate transaminase; C-NMR, C-nuclear magnetic
resonance; DMF, N,N-dimethylformamide; ESI-MS, electrospray ionization mass
spectrometry; FF, fenofibrate; GSH-PX, glutathione peroxidase; HDL, high density
1
1
lipoprotein; H-NMR, H-nuclear magnetic resonance; IL-6, interleukin-6; LDL, low
density lipoprotein; MDA, malondialdehyde; PPAR-α, peroxisomeproliferator
activated receptor-α; SOD, superoxide dismutase; TC, total cholesterol; TG,
triglyceride; TNF-α, tumor necrosis factor-α.
Hyperlipidemia is a disease which the lipid content of the blood disorder
significantly, and these lipids include total cholesterol (TC), cholesterol esters,
1
, 2
triglycerides(TG), phospholipids(PL) and low density lipoprotein(LDL) and others.
Besides, hyperlipidemia is a major cause of atherosclerosis which can lead to the
2

related cardiovascular diseases such as coronary heart disease, myocardial infarction
disease and ischemic cerebrovascular disease. The primary dyslipidemia associated
with atherosclerosis is characterized by elevated triglycerides, reduced high density
lipoproteins (HDL) levels, and higher LDL composition. Therefore, the amelioration
of hyperlipidemia, especially higher TG, has great significance on prevention and
3
, 4
treatment of cardiovascular and cerebrovascular diseases.
Fibrates have been extensively applied for the past several decades in the
treatment of combined dyslipidaemia, but they require high doses to exhibit
significant efficacy and are also associated with primary transaminase elevation,
especially applied when in combination with a statin. Recently, the fibrates class of
lipid-lowering drugs such as clofibrate, fenofibrate, gemfibrozil and beclobrate (Fig.1)
are selective activators of alpha-isotype of the receptors peroxisomeproliferator
activated receptor-α (PPAR-α), phenoxy acetic acid as the pharmacophore has been
used in the synthesis of fibrate hypolipidemic agents, which was attached with various
types of heterocycles such as thiazole, oxazole, indole, benzisoxazole and
5
-7
morpholine. Although the fibrate agents have potently hypolipidemic activity, the
main side effect of these drugs is liver damage. Therefore, a more effective agent
having both hypolipidemic activity and liver protective properties is in great demand.
In the design of new drugs, the development of hybrid molecules by means of
the combination of different pharmacophores may lead to compounds with interesting
biological profiles. 5-(4-methoxyphenyl)-3H-1,2-dithiol-3-thione (ADT, Fig.1) was
8
-10
one of the most extensively studied hepatoprotective drugs,
which also exhibited
3

antioxidant, anti-inflammatory and antineoplastic activities. ADT had been marketed
as a hepatoprotective drug, and it was always functionalized with other
pharmacophores to synthesize ester-bound ADT-OH derivatives to improve the
efficacy of compounds, such as hepatoprotective, antioxidant and anti-inflammatory
11-13
activities.
In view of these, according to the structure-activity relationship of
1
4, 15
fibrates class of lipid-lowering drugs,
the phenol-hydroxyl group of ADT-OH
was introduced into the structure of aliphatic ester via ether linkages to synthesize the
derivatives as fibrate analogs (Fig.1). We expected that the target compounds not only
exhibited significantly hypolipidemic activity, but also showed obviously
hepatoprotective activity.
Figure 1. Designing of ADT-OH-fibrate hybrids based on ADT and fibrate scaffolds
4

showing lipid lowering and hepatoprotective activities.
In this study, we presented the synthesis of ADT-OH pharmacophore containing
fibrate class derivatives. The 5-(4-methoxyphenyl)-3H-1,2-dithiole-3-thione (ADT)
was used as starting material for the synthesis of final derivatives as outlined in
Scheme 1. ADT was demethylated by using pyridine hydrochloride to give
5
-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT-OH). ADT-OH and different
monobromo-ester (1a-1g) undergo nucleophilic reaction to obtain ADT fibrate
1
6, 17
1
13
derivatives.
Compounds 1-7 were identified by H NMR, C NMR and ESI-MS
and the structure of compounds 1-7 showed in Scheme 1.
Scheme 1. 5-(4-hydroxyphenyl)-3H-1,2-dithiol-3-thione(ADT) derivatives. Reagents
and conditions:(a) pyridine hydrochloride, reflux, 0.5h, 220℃; (b)K
2
CO , KI, DMF,
3
reflux, 6h, 80℃.
Firstly, the hypolipidemic effects of the compounds 1-7 was evaluated in
1
8
hyperlipidemic mice induced by Triton WR-1339. The male mice (20±2g) were
divided into 11 groups, and compounds 1-7 were given respectively by oral
administration except normal and model groups for 7 days. On the 6th day, except the
normal group, the other group mice were injected Triton WR-1339 by the tail vein to
induce hyperlipemia. After 24 hours, the blood of mice was withdrawn and TG, TC
5

and MDA levels of serum were measured. The results of hypolipidemic activity
indicated that the test compounds exhibited antihyperlipidemic activity at the dose of
1
3 mg/kg. All of the target compounds and FF were found able to reduce serum TG
while ADT did not display this effect at this dose. Moreover, compounds 5, 6 and 7
could also reduce serum TC while FF and ADT did not show cholesterol-lowering
activity at the same dose. (Fig.2). Meanwhile, compounds 1-7 and fenofibrate
decreased serum MDA levels. (Fig.3)
Figure 2. Triglyceride and total cholesterol serum levels of Triton WR-1339 induced
#
#
*
**
hyperlipidemic mice, mean±SEM, n=8, P＜0.01 vs Normal group; P＜0.05, P＜
0
.01 vs Model group; △△P＜0.01 vs FF group. The dosage of the test compounds and
FF was 13 mg/kg.
Figure 3. Serum MDA levels of Triton WR-1339 induced hyperlipidemic mice,
#
#
*
**
mean±SEM, n=8, P＜0.01 vs Normal group; P＜0.05, P＜0.01 vs Model group.
6

The dosage of the test compounds and FF was 13 mg/kg.
Among of these compounds, the hypolipidemic activity of the compound 6 was
the best than other target compounds and the standard drug FF. Summarizing the
structure-hypolipidemic activity relationship of these compounds, we had come to
some conclusions, compared with ADT, we found that all these compounds were
analogs of phenoxy alkanes acid which was very important for antihyperlipidemic
activity. Substitution on phenolic hydroxyl of compounds with different carbon chain
lengths had varying effects on hypolipidemic activity in reducing TG and TC. The
length of substituted carbon chain has great influence on lipid lowering activity. It is
good for reducing TG, especially TC, if the number of carbon of substituted carbon
chain is three or more. Compound 6 that has four carbons was better than compound 4
1
2
that did not has carbon. The substituted groups (R and R ) also have great influence
on lipid lowering activity. Small substituents (methyl) were better for lipid-lowering
than large ones (ethyl). Lipid lowering activity was best when no substituents were
available. The hypolipidemic activity of compound 3 substituted with methyl was
increased compared with other substituted compounds 1 and 2. Summarizing the
structure-antioxidant activity relationship of these compounds, we also had come to
some conclusions. The longer the carbon chain, the better the antioxidant activity.
Compound 7 that has five carbons was the best than other compounds. The substituted
1
2
groups (R and R ) have great influence on antioxidant activity. Small substituents
(
methyl) were better for antioxidant than large ones (ethyl). Antioxidant activity was
7

best when no substituents were available. The structure-activity relationship of lipid
lowering and antioxidant of these new compounds are similar.
With these promising activities in hand, chronic lipid lowering activity study on
compound 6 was performed on HFD-induced hyperlipidemic mice for 60 days by oral
2
, 5
administration to further evaluate the hypolipidemic and antioxidant activities.
Male mice (20±2 g) were used for the evaluation of activities. FF (13 mg/kg)
was selected as standard drug. Normal diet was available to normal group for 60 days
and vehicle (10 ml/kg) was administered for last 30 days. HFD was available to the
other groups (Model, compound 6 and FF) for 60 days and vehicle (10 ml/kg), test
compounds (13 mg/kg) and standard drug (13 mg/kg) were administered respectively
for last 30 days. On the last day, the blood and livers of mice were withdrawn and
total lipid profiles (TC, TG, LDL and HDL), antioxidant index (SOD, MDA and
GSH-PX) were determined. Moreover, hepatic biochemical indexes (AST and ALT)
and hepatic histopathology were also researched.
The results indicated that compound 6 exhibited antihyperlipidemic and
antioxidant activities at the dose of 13 mg/kg. The compound 6 was able to decrease
serum TG by 29.4% and TC by 12.5% while FF reduced serum TG by 19.0% and TC
by 1.6% (Fig.4). The compound 6 exhibited the significant activity of lowering TC (P
＜
0.05) as compared with the standard drug FF (P >0.05). The atherosclerosis index
of compound 6 group was significantly decreased (40.1%) compared with model
group. The previously studies showed that the decreased AI was beneficial to prevent
the occurrence and development of atherosclerosis and the complication of
8

cardiovascular and cerebrovascular diseases (Fig.5). Therefore, the compound 6
showed more extensive effects on antihyperlipedemia compared to that of FF.
Figure 4. Percent reduction of total lipid profiles of the HFD-induced hyperlipidemic
#
##
*
**
mice. mean±SEM, n=10, P＜0.01, P＜0.01 vs Normal group; P＜0.05, P＜0.01
vs Model group. The dosage of compound 6 and FF was 13 mg/kg.
Figure 5. Atherosclerosis index of the HFD-induced hyperlipidemic mice.
#
*
**
mean±SEM, n=10, P＜0.05 vs Normal group; P＜0.05, P＜0.01 vs Model group.
The dosage of compound 6 and FF was 13 mg/kg.
In addition, as shown in Fig.6, compared with the model group, the SOD and
GSH-PX activities were significantly increased, MDA level, an index of lipid
peroxidation, was obviously decreased (p<0.05). As we know, hyperlipidemia could
9

lead to oxidative stress, therefore, enhancing the antioxidant activity of the body can
improve the oxidative stress condition of hyperlipemia. As shown in Fig.7, compound
6
significantly reduced the levels of TNF-α and IL-6 to show inhibitory activities on
1
9-21
pro-inflammatory cytokine synthesis in hyperlipidemic mice.
The results showed
that compound 6 could significantly suppress expressions of the productions of IL-6
and TNF-α. Furthermore, in vivo evaluation results indicated that compound 6 could
inhibit the inflammatory response to exhibit the anti-inflammatory activity.
Figure 6. Percent reduction of serum SOD, MDA, and GSH-PX levels of the
#
##
HFD-induced hyperlipidemic mice. mean±SEM, n=10, P＜0.01, P＜0.01 vs
*
Normal group; P＜0.05 vs Model group. The dosage of compound 6 and FF was 13
mg/kg.
Figure 7. Percent reduction of serum TNF-α and IL-6 levels of the HFD-induced
10

#
#
hyperlipidemic mice were measured by ELISA. mean±SEM, n=8, P＜0.01 vs
*
**
Normal group; P＜0.05, P＜0.01vs Model group. The dosage of compound 6 and
FF was 13 mg/kg.
To evaluation the hepatic function of mice, serum AST and ALT levels which
were always analyzed as indications were measured. As shown in Fig.8, the levels of
AST were significantly elevated in the model group, while the levels of AST had no
significant difference compared to the normal group. As expected, the compound 6
significantly decreased AST and ALT levels by 31.5% and 8.2% compared to model
group, however, the levels of ALT in four groups did not show the significance
compared with each other.
Figure 8. Percent reduction of serum AST and ALT levels of the HFD-induced
#
#
*
**
hyperlipidemic mice. mean±SEM, n=8, P＜0.01 vs Normal group; P＜0.05, P＜
0
.01vs Model group. The dosage of compound 6 and FF was 13 mg/kg.
Furthermore, the hepatoprotective effect was found by histopathological examine.
As exhibited in Fig.9, the pathology slice of liver tissue oil-red O stain showed that
the liver cells were compactly arranged and no lipid droplets were seen in the liver
cytoplasm in normal mice. On the contrary, we found a lot of diffuse red lipid droplets
11

in mice liver of model group, but the red lipid droplets in hepatocytes were
significantly decreased in compound 6 and FF group mice. The findings indicated that
compound 6 inhibited lipid accumulation in the liver of hyperlipidemic mice. As
exhibited in Fig.10, compared with normal group, the liver cells of model group had
abnormal morphology, the nucleus got bigger, accompanied by haemorrhagic and
infiltrated by inflammation cells. However, the improvement of tissue hemorrhage
symptom and the decreased inflammatory cell infiltration were observed in the liver
of compound 6 group mice.
The results of liver histomorphology (Fig.9 and
Fig.10) confirmed that compound 6 effectively alleviated the liver injury caused by
hyperlipidemia.
Figure 9. Histopathological studies of liver in mice (oil-red O stain 100×). (a) Normal
group mouse liver; (b) Model group mouse liver; (c) Compound 6 group mouse liver;
(
d) FF group mouse liver. The dosage of compound 6 and FF was 13 mg/kg.
Figure 10. Histopathological studies of liver in mice (H&E 100×). (a) Normal group
mouse liver; (b) Model group mouse liver; (c) Compound 6 group mouse liver; (d) FF
group mouse liver. The dosage of compound 6 and FF was 13 mg/kg.
12

Atherosclerosis, a complex disease process, was connected with hyperlipidemia
especially hypertriglyceride. The treatments of hypertriglyceride played an important
role in attenuating vascular complications and fibrate agents had been the main
selection for therapeutic intervention. Moreover, it had been reported that ADT
showed marked hypolipidemic activity decreasing lipid of serum, after structural
modification, the lipid-lowering activity was enhanced and better than ADT. ADT
was hydrogen sulfide donor, which can release hydrogen sulfide to exert antioxidant
and other activity. Hydrogen sulfide release may help improve blood lipids. The target
compounds were all analogs of fibrate agents, which may exhibit the activities of
PPAR-α agonists. It also confirmed that phenoxy alkanes acid was essential for the
lipid-lowering activity of fibrate agents. Therefore, both of them may contribute to
ameliorate dyslipidemia.
Moreover,
the
compounds
all
have
the
structure
of
5
-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione which was considered to be the
pharmacophore of hepatoprotective activity. For example, they were able to inhibit
the cyclooxygenase isoenzymes and suppress the NF-κB activation to exhibit
antioxidant and anti-inflammatory activities. Therefore, we hypothesized that two
pharmacophore of test compounds synergistically suppress the progress of
hyperlipidemia with antioxidant and anti-inflammatory activities and prevent the liver
cells from damage and lipid accumulation in hyperlipemia mice.
In conclusion, a novel series of ADT-based fibrates was synthesized and
evaluated for their antihyperlipidemic and hepatoprotective potentials in two
13

experimentally hyperlipidemic mice models. Compound 6 emerged as a promising
agent for both dyslipidemia and liver protection as the compound significantly
modulated blood serum lipids and ameliorated liver damage without affecting the
feeding pattern of the mice. Additional researches such as the potent antioxidant and
anti-inflammatory action confirmed and reinforced the effective of compound 6 as a
new agent with multifunctional effects such as hypolipidemia, hepatoprotection,
antioxidation and anti-inflammation. The strongly moderately and efficiently balanced
activities of compound 6 seem to be a good candidate for the development of a new
type of multifunctional hypolipidemic drug.
Acknowledgements
This work was supported by the National Natural Science Foundation of China
(
Grant No. 21172177).
Supplementary data
Supplementary data associated with this article can be found in supplement
material.
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17

Highlights
1
2
. Design of 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione derivatives with a
significantly hypolipidemic activity.
. Study indicated that tested compound also showed hepatoprotective activity in
hyperlipidaemia.
3
. The tested compound displayed potent antioxidant and anti-inflammatory
activities
18