Synthesis, α-glucosidase inhibition, and molecular docking studies of novel N-substituted hydrazide derivatives of atranorin as antidiabetic agents

Article abstract of DOI:10.1016/j.bmcl.2020.127359

A series of novel N-substituted hydrazide derivatives were synthesized by reacting atranorin, a compound with a natural depside structure (1), with a range of hydrazines. The natural product and 12 new analogues (2–13) were investigated for inhibition of α-glucosidase. The N-substituted hydrazide derivatives showed more potent inhibition than the original. The experimental results were confirmed by docking analysis. This study suggests that these compounds are promising molecules for diabetes therapy. Molecular dynamics simulations were carried out with compound 2 demonstrating the best docking model using Gromac during simulation up to 20 ns to explore the stability of the complex ligand-protein. Furthermore, the activity of all synthetic compounds 2–13 against a normal cell line HEK293, used for assessing their cytotoxicity, was evaluated.

Full text of DOI:10.1016/j.bmcl.2020.127359

Journal Pre-proofs
Synthesis, α-glucosidase inhibition, and molecular docking studies of novel
N-substituted hydrazide derivatives of atranorin as antidiabetic agents
Thuc-Huy Duong, Asshaima Paramita Devi, Nguyen-Minh-An Tran, Hoang-
Vinh-Truong Phan, Ngoc-Vinh Huynh, Jirapast Sichaem, Hoai-Duc Tran,
Mahboob Alam, Thi-Phuong Nguyen, Huu-Hung Nguyen, Warinthorn
Chavasiri, Tien-Cong Nguyen
PII:
S0960-894X(20)30470-4
DOI:
Reference:
https://doi.org/10.1016/j.bmcl.2020.127359
BMCL 127359
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
1 March 2020
25 May 2020
17 June 2020
Please cite this article as: Duong, T-H., Paramita Devi, A., Tran, N-M., Phan, H-V., Huynh, N-V., Sichaem, J.,
Tran, H-D., Alam, M., Nguyen, T-P., Nguyen, H-H., Chavasiri, W., Nguyen, T-C., Synthesis, α-glucosidase
inhibition, and molecular docking studies of novel N-substituted hydrazide derivatives of atranorin as antidiabetic
agents, Bioorganic & Medicinal Chemistry Letters (2020), doi: https://doi.org/10.1016/j.bmcl.2020.127359
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Synthesis, α-glucosidase inhibition, and molecular docking studies of novel N-
substituted hydrazide derivatives of atranorin as antidiabetic agents
a,b
c
d
Thuc-Huy Duong , Asshaima Paramita Devi , Nguyen-Minh-An Tran , Hoang-Vinh-Truong
e
f
g,
d
h
Phan , Ngoc-Vinh Huynh , Jirapast Sichaem *, Hoai-Duc Tran , Mahboob Alam , Thi-
i
k
c
e,
Phuong Nguyen , Huu-Hung Nguyen , Warinthorn Chavasiri , Tien-Cong Nguyen *
aDepartment for Management of Science and Technology Development, Ton Duc Thang University,
Ho Chi Minh City, Vietnam; duongthuchuy@tdtu.edu.vn
bFaculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam
cCenter of Excellence in Natural Products Chemistry, Department of Chemistry, Faculty of Science,
Chulalongkorn University, Pathumwan, Bangkok 10330, Thailand
dIndustrial University of Ho Chi Minh City, Ho Chi Minh City, Vietnam
eDepartment of Chemistry, Ho Chi Minh City University of Education, 280 An Duong Vuong Street,
District 5, 748342 Ho Chi Minh City, Vietnam
fDepartment of Organic Chemistry, VNUHCM - University of Science, Ho Chi Minh City, Vietnam.
gResearch Unit in Natural Products Chemistry and Bioactivities, Faculty of Science and
Technology, Thammasat University Lampang Campus, Lampang 52190, Thailand
hDivision of Chemistry and Biotechnology, Dongguk University, 123 Dongdae-ro, Gyeongju 780-
7
14, Republic of Korea
iNTT Hi-Tech Institute, Nguyen Tat Thanh University, 300A Nguyen Tat Thanh, District 4, Ho Chi
Minh City, Vietnam
kFaculty of Environment and Biotechnology, Van Lang University, 45 Nguyen Khac Nhu, District 1,
Ho Chi Minh City, Vietnam
*
Corresponding authors;
Dr. Jirapast Sichaem. Research Unit in Natural Products Chemistry and Bioactivities, Faculty of
Science and Technology, Thammasat University Lampang Campus, Lampang 52190, Thailand.
Email: jirapast@tu.ac.th
Dr. Tien-Cong Nguyen. Department of Chemistry, Ho Chi Minh City University of Education, 280
An Duong Vuong Street, District 5, 748342 Ho Chi Minh City, Vietnam.
Email: congnt@hcmup.edu.vn
1

Abstract
A series of novel N-substituted hydrazide derivatives were synthesized by reacting atranorin,
a compound with a natural depside structure (1), with a range of hydrazines. The natural product
and 12 new analogues (2-13) were investigated for inhibition of α-glucosidase. The N-substituted
hydrazide derivatives showed more potent inhibition than the original. The experimental results
were confirmed by docking analysis. This study suggests that these compounds are promising
molecules for diabetes therapy. Molecular dynamics simulations were carried out with compound 2
demonstrating the best docking model using Gromac during simulation up to 20 ns to explore the
stability of the complex ligand-protein. Furthermore, the activity of all synthetic compounds 2-13
against a normal cell line HEK293, used for assessing their cytotoxicity, was evaluated.
Key words: Parmotrema tsavoense; atranorin; N-substituted hydrazide derivatives; α-glucosidase
inhibition; cytotoxicity
Type 2 diabetes mellitus (T2DM) affects a large population worldwide. It is a serious and
common chronic disease resulting from a complex inheritance-environment interaction along with
other risk factors such as obesity and sedentary lifestyle. There are several classes of antidiabetic
drugs to treat this disease include insulin, metformin, thiazolinediones, sulfonylureas, DPPIV
inhibitors, and α-glucosidase inhibitors. However, it is difficult to effectively treat T2DM by single
treatment option in the long term. Therefore, there is a significant unmet medical need for the
development of new, long term safety and highly effective antidiabetic therapies with novel and
multiple mode of action. 1
α-Glucosidase is the enzyme that catalyzes the breakage of the α-1,4-glycosidic bonds of
polysaccharides with concomitant conversion into glucose.2 α-Glucosidase inhibitors are
therapeutic agents that can reduce the level of glucose in type 2 diabetes (T2DM) by preventing the
hydrolysis of glucose by α-glucosidase, a carbohydrate metabolizing enzyme. Acarbose is an
antidiabetic drug used to treat T2DM that causes various side effects including abdominal
discomfort, diarrhea, bloating, pain, and flatulence. Previous studies have shown that α-glucosidase
3
can be related to diseases such as cancer and viral infections. Therefore, α-glucosidase is an
attractive target for developing drugs to treat T2DM and several α-glucosidase inhibitors are already
in the market or in clinical trial.
2

Atranorin, a biologically active lichen metabolite, exhibits a wide range of biological
activities, being antimicrobial, antiviral, anti-inflammatory, analgesic, and cytotoxic at levels from
moderate to high.4-6 Interestingly, it is able to inhibit enzymes involved in human diseases,
including tyrosinase, glucosidase, acetylcholinesterase, and xanthine oxidase.7-12 Atranorin is
present in large amounts in the Parmotrema lichens.7,13 The preparation of atranorin derivatives is
receiving wide attraction. Vu and co-workers (2015) modified the aldehyde group at C-3 to yield
two derivatives that were more active against the hepatitis C virus (HCV) than the parent
compound.13 Mallavadhani and co-workers (2018) prepared five analogs of atranorin by
etherification, reduction, and nucleophilic addition. These compounds were evaluated for
1
4
cytotoxicity to multiple cancer cell lines and were more active than atranorin itself. However, few
atranorin derivatives have been synthesized. We report the preparation and structural elucidation of
N-substituted hydrazide derivatives of atranorin. Evaluation of their α-glucosidase inhibition as well
as a molecular docking analysis and studies on the inhibitory mode of these synthetic compounds
were explored. In addition, the docked complexes were refined and validated using molecular
dynamics simulations to map the interactions between the protein ligand.
Atranorin (1) was purified from the lichens P. tsavoense and P. praesorediosum.15-18 Having
1
in hand, N-subtituted hydrazine reagents (N2-N13) were prepared (Scheme 1) following
previously reported procedures.17-22 Nucleophilic addition between 1 and N2-N13 was conducted in
o
ethanol/acetic acid at 50 C to yield novel derivatives 2-13, at yield from 50-90% (Scheme 2). The
chemical structures of the synthetic compounds were identified from the 1D-and 2D-NMR and
HRESIMS spectra. The aldehyde proton signal at δ 10.36 in 1 was replaced by a singlet methine at
H
δH 8.57-8.95 in 2-13. This was assignable to an imine group. Likewise, the aldehyde group at δC
1
93.8 of atranorin was replaced by the imine group at δ 144.9-147.4 The structural analysis was
C
confirmed by HMBC correlations and mass spectroscopic data.
3

O
O
O
b
OH
a
c
OCH3
NHNH2
O
N2: 50.4%
N3: 48.0%
O
H
H
NH2
OH
b
N
N
OC H
NHNH2
2
5
H C
3
H C
3
H C
3
O
O
N4: R = 2-CH , 39.4%
N5
: R = 3-CH , 44.2%
N6: R = 4-CH , 45.1%
N7: R = 4-Br, 54.2 %
3
O
O
c
b
3
OC H
NHNH2
O
2
5
3
R
R
R
O
N11: 2-i-Pr-5-CH , 42.8%
3
O
b
O
OH
c
OC H
2
5
NHNH2
N8: 46.3%
N9 57.0%
CHO
OC H
NHNH2
O
2
5
d
b
O
O
O
OH
S
N
S
N
S
N
c
b
S
O
S
O
SH
N10: 55.7%
OC H
NHNH2
2
5
O
O
O
O
I
I
OH
OH
a
a
OCH3
OH
e
OCH3
OH
b
NHNH2
OH
N12: 57.0%
O
O
O
Cl
Cl
Cl
b
N13
: 47.2%
OH
OH
OCH3
OH
NHNH2
OH
Scheme 1. Pathway to preparation of hydrazides N2-N13. a: CH OH/H SO , refluxed, 8 h;
3
2
4
b: N H 80%/Ethanol, refluxed, 6 h; c: ClCH CO C H /K CO , acetone, refluxed, 24 h; d:
2
4
2
2
2
5
2
3
o
ClCH CO C H /K CO , DMF, 80-90 C, 3 h; e: KI/ CH OH, NaClO, 12 h. Overall yield.
2
2
2
5
2
3
3
4

O
O
O
OCH3
OH
O
OCH3
OH
RCONHNH2
N2-N13
O
O
EtOH- AcOH
HO
OH
HO
OH
+
5
0oC, 2 h
N
H
O
H
1
2-13
R
NH
O
Br
R =
O
O
O
N
O
H
3
4
5
6
7
2
I
Cl
O
S
S
N
O
O
OH
12
OH
13
8
9
10
11
Scheme 2. Pathway to preparation of hydrazides N2-N13.
The α-glucosidase inhibition of 1 and all the newly synthetic compounds 2-13 was evaluated
2
3
according to the literature protocol. Acarbose, an α-glucosidase inhibitor used to treat T2DM, was
chosen as a positive control for activity comparison. The results of our activity study were compiled
in Table 1. As can be seen from the data in Table 1, all synthetic compounds showed potency with
IC50 values from 6.67 to 54.71 µM. The relationship between the structure and activity was
investigated. All products were more active than both the starting material (1) and a positive
control, acarbose (IC 200 µM of 1 and 93.6 µM of acarbose). Compound 2 was the most active,
5
0
indicating the important role played by the benzyl group of hydrazide N2. The order of potency
reflected the R substituent: phenyl group (12 and 13) > arylamino (3) > aryloxy (4-9). The
substituents on the R group also affected potency. The chlorine atom in 13 conferred more potency
than the iodine atom in 12. Among the aryloxy groups, the electron-donating methyl group in 4-6
decreased potency while the electron-withdraw bromo group in 8 increased it. Interestingly, the
sulfur-containing compound 10 showed good activity, with IC value of 9.12 µM (compared to the
5
0
similar scaffolds 8 and 9). In addition, all synthetic compounds 2-13 exhibited just weak or no
cytotoxicity toward HEK293 cell line (Table 2).
5

Table 1. α-Glucosidase inhibitory activity of compounds 1-13.
a
a
No.
1
IC50 (M)
No.
8
IC50 (M)
>100
18.86±0.70
2
3
4
5
6
7
6.67±0.60
31.47±0.87
53.33±1.38
40.56±1.18
54.71±0.76
17.31±0.56
9
39.66±0.85
9.12±0.45
28.15±1.55
41.17±1.27
9.91±0.36
10
11
12
13
b
Acabose 93.6±0.49
a
Values are the mean ± SD. All experiments were performed at least three times.
Reference compound.
b
Table 2. Cytotoxicity of synthetic compounds 2-13 against HEK293 cell line.
a
a
No.
2
3
4
5
IC50 (M)
No.
9
10
11
12
13
IC50 (M)
>100
>100
>100
>100
>100
84.4 ± 4.4
70.1 ± 1.7
>100
94.1 ± 8.3
63.2 ± 13.3
6
7
b
>100
Doxorucibin 7.92 ± 0.07
8
52.7 ± 2.3
a
Values are the mean ± SD. All experiments were performed at least three times.
Reference compound
b
In order to gain some structural insight into the inhibitory mechanisms for the α-glucosidase
inhibitors, the binding modes in the active site were investigated. Figures 1-9 illustrates the
molecular interactions of 2 and 13 with α-glucosidase. The IC value of 2 was 2.4 times the
5
0
inhibition constant, while the free energy of binding was also negative, indicating that 2 had good
inhibitory activity again enzyme 3TOP. Ligand (2) docked well to 3TOP because the free energy
of binding was more negative. The IC value was also close to the estimated value. The stable
5
0
conformation (2) formed 5 hydrogen bonds with target-receptors. These were stable hydrogen
atoms in the following decreasing order :(2):H-A:GLN1109:OE1, 1.86 Å > A:LYS1088:HZ3-
:
(2):O, 2.00 Å > :(2):H-B:GLU1095:OE1, 2.01 Å > B:LYS1088:HZ2-:(2):O, 2.07 Å >
A:ARG1097:HH11- :(2):O, 2.45 Å. See Table S3 and Figure 4. The hydrogen atoms in 2, A:
LYS1088, A:LYS1088, B:LYS1088, and A:ARG1097 donated, whereas those ligand (2) and the
receptor accepted. The hydrogen bond :(2):H-A:GLN1109:OE1, with bond length of 1.86 Å linked
6

to receptor, 3 TOP compared with that of bond length of 1.61 Å B:ARG1097:HH11-:(10):O
suggesting that hydrogen bond B:ARG1097:HH11-:(10):O was more stable than :(2):H-
A:GLN1109:OE1. As shown in Figure 5, other interactions were pi-cation, pi-anion between
residual amino acids, LYS A: 1088, GLU A: 1095, alkyl interactions between ILE A:1104, ARG
1
097, and methyl groups of aromatic (2). The ligand map also exposed secondary interactions as
hydrogen bonds-LYS 1088, ARG 1097, GLU 1095, and GLN 1109, steric- LYS 1088, ARG 1097,
GLU 1095, GLN 1109, and THR 1101, with overlaps (Figure 6). The best conformation (13) linked
to docking poses on 3TOP, forming three hydrogen bonds (Table S3 and Figure 7). The most stable
hydrogen bond was :(13):H-B:GLU1095:OE2, with a bond length of 1.86 Å: The hydrogen bond
strengths ranked :(13):H-B:GLU1095:OE2, 1.86 Å > A:ARG1097:HH11-:(13):O, 2.05 Å > :(1):H-
A:GLU1095:OE1, 2.13 Å. The donor atoms were hydrogen on A: ARG1097 and on 13, while
accepters were on receptor or conformation (13). The residual amino acids were highly
hydrophilic: B:GLU1095, A:ARG1097, and A:GLU1095. The different interactions forming
between residual amino acids of receptor-3TOP and the optimal conformation (13) as shown in
Figure 8 as pi-cation between LYS B: 1088 and aromatic ring, alkyl, ILE B: 1104 with methyl
group, pi alkyl from ILE B: 1104, ILE A: 1104 to aromatic ring, and unfavorable acceptor-acceptor
from GLU A: 1095 to the nitrogen atom of azomethin (CH=N). In Figure 9, the ligand map shows
hydrogen bonds between ARG1097, GLU1095, and docking poses, and steric interactions between
ASP1107, ILE1104, Gly1102, GLU1095, LYS1088, and 13.
Figure 1. Binding of structure (10) with active sites of 3TOP. Hydrogen bonds between
residual amino acids of 3TOP and conformation (10).
7

Figure 2. Interactions between receptor (3TOP) and stable conformation (10) as a 2D
diagram.
Figure 3. Ligand map showing secondary interactions to be hydrogen bonds, electrostatic,
steric, and overlaps between (10) and docking poses of 3TOP at 4 Å.
Figure 4. Binding of structure (2) with active sites of 3TOP. Hydrogen bonds between
residual amino acids of 3TOP and conformation (2).
8

Figure 5. Interactions between receptor (3TOP) and the stable conformation (2) as a 2D
diagram.
Figure 6. Ligand map showing secondary interactions to be hydrogen bonds, electrostatic,
steric, and overlaps between (2) and docking poses of 3TOP at 4 Å.
9

Figure 7. Binding of structure (13) with active sites of 3TOP. Hydrogen bonds between
residual amino acids of 3TOP and conformation (13).
Figure 8. Interactions between receptor (3TOP) and stable conformation (2) as a 2D
diagram.
1
0

Figure 9. Ligand map showing secondary interactions to be hydrogen bonds, electrostatic,
steric, and overlaps between (13) and docking poses of 3TOP at 4Å.
Based on docking results, molecular dynamics (MD) simulation was performed on the
selected lowest energy and best docking complex (compound 2). Using Gromacs, we performed
time-based MD simulation at 20 ns to test the durability and overall stability of the docked
complexes. The residual deviations in the complexes were calculated using the RMSD graph
produced by Xmgrace software. Figure 10 showed the residual deviation of the ligand docked into
the receptor. The upward trend was observed in the best docked posing model with different RMSD
values of 0.5-1.0 nm at 0.25 ns, followed by a downward trend of 1.0-0.75 nm at 7.5 ns, after then
RMSD values in equilibrium (starting) from 7.5 to 20 ns during the simulation period. Observation
from MD simulation, stable nature of compound 2 interacted complex throughout MD trajectories
thereby increasing the efficiency of the docking result. The H-bond resulted in the simulation of
molecular dynamics showed that, in most frames, two hydrogen bonds were found between ligand
and protein structure (Figure 10B). Coulomb and Lennard-Jones (LJ) interaction potentials between
the ligand (compound 2) and the protein in the course of the simulation were considered short range
types of energies obtained from MD simulation trajectory files (Figure S61a). LJ-SR is normal non-
bonded interactions within the short-range cutoff (Figure S61a, red). Overall, the LJ-SR energy
values ranged between −100 to −150 kJ/mol and were fairly stable. On the other hand, short-range
coulomb energy values (Coul-SR) are used to know the equilibrium of the during the simulation
run. Coul-SR 's energy values (Figure S61a, black) are highly fluctuated at system initialization and
1
1

indicate the system stability, but LJ-SR energies was considered rationally as binding predictors.24
Graphs of Gromacs energy according to various parameters such as Coulomb-SR & Lennard-Jones-
SR interactions, density, potential, pressure, and temperature were presented in supplementary
information. The values of the parameters mentioned above were within system equilibrium limits.
The parameter explications were given separately in the Figure S61 legends.
Figure 10. Analysis of the protein backbone associated with ligand (2) structure during
simulation (A) RMSD plot; (B) Hbond distribution plot vs time.
In conclusion, we here report the synthesis of a series of novel N-substituted hydrazide
derivatives through nucleophilic additions between 1 and N-subtituted hydrazine reagents. The
synthesized N-substituted hydrazide derivative 2 showed the most powerful inhibition of yeast α-
glucosidase (IC 6.67ꢀμM). The potent inhibition of 2 was elaborated by molecular docking
5
0
studies, in which its binding profile towards key residual amino acids in the α-glucosidase’s active
site. The simulation of the molecular dynamics was performed for compound 2 and emphasized
both the affinity and stability of the ligand with the protein during contacting in the 20 ns time
period. Therefore, synthetic compound 2 should hold a great potential as a leading compound for
the treatment of T2DM.
Acknowledgements
This research is funded by the Foundation for Science and Technology Development of Ton
Duc Thang University (FOSTECT), website: http:// fostect. tdt. edu. vn, under Grant
FOSTECT.2018.04. Equipment support from Thammasat University Research Unit in Natural
Products Chemistry and Bioactivities, Thammasat University, is gratefully acknowledged.
1
2

Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https:// doi.org/…………….
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Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
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