Synthesis of novel (R)-4-fluorophenyl-1H-1,2,3-triazoles: A new class of α-glucosidase inhibitors

Article abstract of DOI:10.1016/j.bioorg.2019.103182

Diabetes is a non-communicable disease, which occurs either due to the lack of insulin or the inability of the human body to recognize it. The recent data indicates an increase in the trend of people diagnosed with Type 2 diabetes mellitus (T2DM). α-Glucosidase inhibitors are known to reduce the impact of carbohydrates on blood glucose level and prevent the digestion of carbohydrates. α-glucosidase inhibitors hold great potential for the treatment of T2DM. In search of better α-glucosidase inhibitors, a series of novel (R)-4-fluorophenyl-1H-1,2,3-triazole derivatives were synthesized (6 and 8a-n) and evaluated for their α-glucosidase inhibitory activity in vitro. All new compounds were characterized by ¹H NMR, ¹³C NMR, ¹⁹F NMR, ESI-MS, and where applicable by single crystal X-ray diffraction (8 m). A preliminary structure-activity relationship suggested that the presence of 1H-1,2,3-triazole ring in (R)-4-fluorophenyl-1H-1,2,3-triazole derivatives has remarkable contribution in the overall activity. Molecular docking studies were carried out to investigate the binding mode of compounds within the active site of the α-glucosidase enzyme. Docking results are in complete agreement with the experimental finding. This study unravelled a new class of triazole derivatives with α-glucosidase inhibitory activity.

Full text of DOI:10.1016/j.bioorg.2019.103182

Journal Pre-Proof
Synthesis of novel (R)-4-fluorophenyl-1H-1,2,3-triazoles: A new class of α-
glucosidase inhibitors
Satya Kumar Avula, Ajmal Khan, Sobia Ahsan Halim, Zahra Al-Abri,
Muhammad U. Anwar, Ahmed Al-Rawahi, Rene Csuk, Ahmed Al-Harrasi
PII:
S0045-2068(19)30452-3
DOI:
https://doi.org/10.1016/j.bioorg.2019.103182
YBIOO 103182
Reference:
Bioorganic Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
22 March 2019
4 July 2019
1 August 2019
Please cite this article as: S. Kumar Avula, A. Khan, S. Ahsan Halim, Z. Al-Abri, M.U. Anwar, A. Al-Rawahi, R.
Csuk, A. Al-Harrasi, Synthesis of novel (R)-4-fluorophenyl-1H-1,2,3-triazoles: A new class of α-glucosidase
inhibitors, Bioorganic Chemistry (2019), doi: https://doi.org/10.1016/j.bioorg.2019.103182
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JOURNAL PRE-PROOF
Synthesis of novel (R)-4-fluorophenyl-1H-1,2,3-triazoles: A new class of α-
glucosidase inhibitors
Satya Kumar Avulaa, Ajmal Khana, Sobia Ahsan Halima, Zahra Al-Abria, Muhammad U.
Anwara, Ahmed Al-Rawahia, Rene Csukb, Ahmed Al-Harrasia*
aNatural and Medical Sciences Research Center, University of Nizwa, P.O. Box 33, Postal Code
616, Birkat Al Mauz, Nizwa, Sultanate of Oman (phone: +968 25446328; e-mails:
aharrasi@unizwa.edu.om)
bOrganic Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 2, d-06120,
Halle (Saale), Germany
*Corresponding author (A. Al-Harrasi)
aNatural and Medical Sciences Research Center, University of Nizwa, P.O. Box 33, Postal Code
616, Birkat Al Mauz, Nizwa, Sultanate of Oman (phone: +968 25446328; e-mails:
aharrasi@unizwa.edu.om)
1

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Abstract: Diabetes is a non-communicable disease, which occurs either due to the lack of
insulin or the inability of the human body to recognize it. The recent data indicates an
increase in the trend of people diagnosed with Type 2 diabetes mellitus (T2DM). α-
Glucosidase inhibitors are known to reduce the impact of carbohydrates on blood glucose
level and prevent the digestion of carbohydrates. α-glucosidase inhibitors hold great potential
for the treatment of T2DM. In search of better α-glucosidase inhibitors, a series of novel (R)-
4-fluorophenyl-1H-1,2,3-triazole derivatives were synthesized (6 and 8a-n) and evaluated for
their α-glucosidase inhibitory activity in vitro. All new compounds were characterized by 1H
NMR, 13C NMR, 19F NMR, ESI-MS, and where applicable by single crystal X-ray diffraction
(8m). A preliminary structure-activity relationship suggested that the presence of 1H-1,2,3-
triazole ring in (R)-4-fluorophenyl-1H-1,2,3-triazole derivatives has remarkable contribution
in the overall activity. Molecular docking studies were carried out to investigate the binding
mode of compounds within the active site of the α-glucosidase enzyme. Docking results are
in complete agreement with the experimental finding. This study unravelled a new class of
triazole derivatives with α-glucosidase inhibitory activity.
Keywords: Synthesis, (R)-4-fluorophenyl-1H-1,2,3-triazoles, X-ray crystallography, α-
Glucosidase inhibitor, Molecular docking studies.
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1. Introduction
Nitrogen containing heterocyclic compounds play a vital role in the pharmaceuticals and
agrochemicals [1].
N
N
N
N
N
N
H
H
1H-1,2,3-triazole
1H-1,2,4-triazole
Among the heterocyclic systems in organic chemistry, 1,2,3-triazoles hold great importance
due to their broad spectrum of applications in pharmaceuticals, biochemical, medicinal and
material sciences [2]. Their chemistry underwent a substantial growth over the past decades
[3,4]. 1H-1,2,3-triazole containing compounds were reported to exhibit a large range of
biological activities such as antimicrobial activity against gram positive bacteria [5], anti-
HIV [6,7], antiviral [8], antiallergic [9], antifungal [10,11], anticonvulsant [12] and anti-
nociceptive activity [13]. Moreover, these derivatives were also utilized as intermediates for
the synthesis of antibiotics [14,15], fungicides [16], insecticide [17] and, plant growth
regulators [18]. They are widely used in industrial applications such as photo stabilizers,
dyes, photographic materials, corrosion inhibition (of copper and copper alloys), and
agrochemicals [19]. The fluorine containing 1,2,3-triazole derivatives could be a subject of
special interest. Incorporation of fluorine atom is known to significantly influence the
physical and chemico-biological properties of the organic molecules [20,21]. Due to this,
great efforts have been exerted to develop new synthetic methodologies toward fluorine-
containing moieties in particular fluorinated heterocycles. In contrast, a limited number of
fluoro-substituted 1,2,3-triazoles have been reported [22,23]. Rufinamide is commercially
available drug which contain 1H-1,2,3-triazole (Fig. 1). It blocks calcium channels, a severe
form of childhood epilepsy and it has been approved for the treatment of Lennox-Gastaut
syndrome [24].
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F
NH2
H
O
N
S
N
N
NH2
O
N
F
HO
S
O
CO2H
N
N
NH
Rufinamide
Cefatrizine
F
F
R1
CF3
N
O
O
N
N
N
N
N
CF3
R1
F
F
II
Regioisomer ( )
I
Regioisomer ( )
Fig. 1. Chemical Structures of some bioactive 1H-1,2,3-triazole derivatives
α-Glucosidase is a potential drug target for type 2 Diabetes mellitus (T2DM) [25, 26], which
is one of the most common and serious metabolic diseases characterized by high blood-
glucose levels [27]. T2DM is mainly treated by the inhibition of carbohydrate hydrolysing
enzymes which in turn suppress the postprandial hyperglycemia by reducing the absorption
of gut glucose [28]. Thus, the inhibition of α-glucosidase to control elevated glucose levels in
blood is a popular choice [29]. α-Glucosidase inhibitors (AGIs) including acarbose, miglitol
and voglibose, are associated with side effect like flatulence, diarrhea and abdominal
discomfort and have low efficacy with high IC50 values [30]. Recent studies have
demonstrated that 1,2,3-triazole ring containing heterocycles are superior α-glucosidase
inhibitors (Fig. 2) [31].
R
O
N
N
NH
N
N
N
OH
OCH3
N
CN
N
N
S
O
O2N
N
N
N
N
O O
F
(R)
N
N
OMe
Cl
F
N
O
CN
N
N
NH
N
N
N
N
N
N
CH3
F
F
R
This work
Me
Fig. 2. Chemical Structures of some 1H-1,2,3-triazole derivatives as potential α-glucosidase inhibitors.
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Our recent report in this series suggest its potential α-glucosidase inhibitory activity [32]. In
continuation to our previous findings [32,33], we herein report the synthesis and in vitro anti-
α-glucosidase activity of a new series of fluorine containing (R)-4-fluorophenyl-1H-1,2,3-
triazole derivatives. Furthermore, structural-activity relationship as well as molecular
docking results are thoroughly discussed.
2. Results and discussion
2.1. Chemistry
2.2. Synthesis of (R)-4-fluorophenyl-1H-1,2,3-triazole bromide (6)
The key intermediate (R)-4-fluorophenyl-1H-1,2,3-triazole bromide
6
was
synthesized using a convenient five-step procedure starting from the commercially available
1
(S)-ethyl lactate 1 via modified chiron approach as shown in Scheme 1 [32]. The H NMR
spectrum of compound 6 showed a doublet at δ 1.31 which is attributed to methyl protons of
–CH–O–Ph and a singlet peak at δ 3.74, which is assigned to methoxy protons on phenyl
ring. A doublet of doublet (δ = 4.54) and a multiplet (δ = 4.64) signals correspond to the –
CH–O– and –CH2–N–, respectively. The seven aromatic protons appeared in the region of δ
7.76-6.68 ppm, while a singlet appeared at δ 8.02 for triazole proton (–CH–N3). The structure
of compound 6 was confirmed by 2D NMR experiments (HMBC, HSQC, COSY and
NOESY) as well. The high-resolution mass spectrometric (HRMS) data at 406.0567 (M+H)
further supports the reported structure.
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O
EtO
OMe
HO
OMe
O
O
O
a
b
EtO
OH
(S)-Ethyl Lactate ( )
Br
Br
2
1
3
c
TsO
OMe
N3
OMe
N
OMe
F
O
O
N
O
d
e
N
Br
Br
Br
6
4
5
o
Scheme 1. Reagents and conditions: (a) 4-bromo-2-methoxyphenol, PPh3, DIAD, dry THF, 0 C to room
temperature, 3 h, 86%; (b) DIBAL-H, dry DCM, 0 oC to room temperature, 3 h, 90%; (c) TsCl, Et3N, dry DCM,
o
o
DMAP, 0 C to room temperature, 5 h, 95%; (d) NaN3, DMF, 70 C, 3 h, 78%; (e) 1-ethynyl-4-fluorobenzene,
CuI, Et3N, CH3CN, room temperature, 3 h, 79%.
2.3. Synthesis of (R)-4-fluorophenyl-1H-1,2,3-triazole derivatives (8a-n)
The final step was functionalization of the aryl bromide moiety by Suzuki-Miyaura reaction
[34,35] of (R)-4-fluorophenyl-1H-1,2,3-triazole bromide 6 with different arylboronic acids
7a-n (1.5 equiv) afforded the (R)-4-fluorophenyl-1H-1,2,3-triazole derivatives 8a-n in 69-
86% yields (Scheme 2, Table 1). Both electron-poor and electron-rich arylboronic acids were
successfully employed. The reactions were clean and the best yields were obtained in 1, 4-
dioxane at 120 oC using Pd (PPh3)4 (5 mol %) as a catalyst and K2CO3 (3.0 equiv) as a base.
OMe
N
N
OMe
N
N
F
F
i
O
O
N
N
Ar-B(OH)2
Ar
Br
7a-n
(
)
8a-n
6
(Target comounds)
Scheme 2. Synthesis of Target compounds (8a-n). Reagents and conditions: (i) 6 (1.0 equiv), 7a-n (1.5 equiv),
Pd (PPh3)4 (5 mol %), K2CO3 (3.0 equiv), 1, 4-dioxane, 120 oC, 8 h.
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Table 1: Synthesis of (R)-4-fluorophenyl-1H-1,2,3-triazole derivatives (8a-n).
Reagents (7)
Compounds (8)
Ar1
Yield of 10 (%)a
a
b
c
a
b
c
Ph
76
73
69
85
82
79
84
80
77
82
86
79
82
78
4-MeC6H4
4-MeOC6H4
4-NO2C6H4
4-ClC6H4
d
e
d
e
f
f
4-NCC6H4
4-FC6H4
g
h
i
g
h
i
3,5-(F3C)2C6H3
4-CHOC6H4
2,6-(F)2C6H3
2,3,4-(F)3C6H2
2-C10H7
j
j
k
l
k
l
m
n
m
n
4-AcC6H4
2-C8H5S
aYields refer to pure isolated products.
The chemical structures of the (R)-4-fluorophenyl-1H-1,2,3-triazole derivatives (8a-n, target
compounds) were confirmed by spectroscopic techniques (1H NMR, 13C NMR, 19F NMR, IR
and HRMS). Single crystals of 8m were grown from slow evaporation CH2Cl2 solution. The
structure of compound 8m was unambiguously confirmed by X-ray crystal structure analysis
(Fig. 3).
Fig. 3. Crystal structure of compound 8m
Biological activity
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Screening of all compounds suggested significant inhibition of α-glucosidase by all
compounds with IC50 values in range of 17.9±0.4 - 193.7±0.42 μM (Table-2), when
compared to the standard drug acarbose (IC50 = 942 ± 0.74 μM). Incorporation of
unsubstituted phenyl ring at Ar position, decreased the activity of 1H-1,2,3-triazole
derivatives observed in compound 8a (IC50 = 193.7±0.42 μM). On the other hand, addition of
a methyl group on this phenyl is responsible to activate the ring, as a result activity was
increased as seen in compound 8b (IC50 = 84.2±2.6 μM). The activity of this series was
further enhanced by adding a stronger electron donating group as observed in compound 8c
having methoxy group which resulted in IC50 value of 66.8±1.2 μM. A similar trend was
observed for compounds 8d-8j. The activity of this series was further improved when more
functionalities were introduced (compounds 8k-8n). The detailed structure-activity
relationship was explained in the molecular docking studies.
Table 2: α-Glucosidase inhibitory activities, molecular docking scores and molecular
interactions of compounds 8a-8n
Compounds
8a
IC50 ± SEM (μM) Docking Score
Interactions (Å)
O11---Wat1174 (1.77)
O48---Wat1056 (2.05)
N25---Asn241 (2.67)
O11---Wat1174 (1.71)
O47---Wat1056 (1.92)
O48---His111 (2.81)
O11---Wat1174 (1.77)
O48---Wat1056 (1.88)
N25---Asn241 (2.81)
O11---Wat1174 (1.80)
F53---Arg439 (2.74)
Triazole ring---His 279 (π-π)
O54---His111 (1.83)
O11---Wat1174 (1.79)
O48---Wat1056 (2.34)
O11---Wat1174 (1.78)
N25---Asn241 (3.12)
F53---Arg212 (3.10)
F55---His348 (2.47)
193.7±0.42
-4.39
8b
8c
84.2±2.6
66.8±1.2
-4.44
-4.86
8d
8e
59.5±1.1
48.6±0.8
-4.90
-5.73
8f
8g
8h
43.7±0.8
37.6±0.45
40.18±0.6
-5.91
-6.36
-6.27
8i
8j
57±3.4
-5.67
-5.74
44.3±0.6
8k
21.7±0.8
-7.18
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8l
17.9±0.4
-7.41
-6.48
O11---Wat1174 (1.65)
N25---Asn241 (2.45)
O52---Wat1026 (2.35)
Triazole-ring---His279 (π-π)
N25---Asn241 (2.66)
S38---Wat1102 (2.17)
S38---Asp349 (3.21)
N25---Asn241 (2.63)
O15---Glu304 (2.68)
O17---Pro309 (2.82)
N37--- Glu304 (3.54)
O64---Wat1102 (2.73)
O79---Glu276 (2.54)
O81---Asp349 (2.84)
O44---Wat1174 (2.70)
O81---Arg212 (3.07)
O83--- His348 (3.33)
O83---Wat1026 (2.92)
O87--- His111 (2.81)
N37--- Glu304 (3.54)
8m
29.5±0.26
23.9±1.1
8n
-6.89
-3.90
Acarbose (Standard)
942 ± 0.74
SEM= Standrad error mean
Molecular molding and docking analysis
For docking, homology modelling was conducted to predict the three dimensional (3D)
structure of Saccharomyces cerevisiae. α-Glucosidase enzyme, and its properties were
evaluated to check the quality of the model. The protein is composed of total 579 residues.
The Ramachandran plot showed that 444 (86.7%), 63 (12.3%), 3 (0.6%), and two (0.4%)
residues lied in the most favored, additional allowed, generously allowed, and disallowed
regions, respectively. However, two residues (Ala278 and Thr566), which are displayed in
disallowed region are not a part of active site region. ERRAT showed 93.52 quality factor
and Verify3D depicted that 95.5% residues showed average 3D-1D score of 0.7. The model
is of good quality. The active site residues were predicted by superimposing the closest
homologue (72% identity) i.e. S. cerevisiae. Isomaltase enzyme in complex with isomaltose
(PDB code: 3AXH) which suggests that Asp214 and Glu276 of S. cerevisiae α-glucosidase
act as nucleophile and proton donor, respectively. While Asp349 act as a transition state
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stabilizer for substrate molecule. The catalytic site is composed of Asp214, Glu276, and
Asp349. While several residues including Asp68, Tyr71, Val108, His111, Phe157, Phe158,
Phe177, Gln181, Arg212, Thr215, Leu218, Glu276, Ala278, Phe300, Arg312, His348,
Asp349, Gln350, Asp408, Arg439, Arg443 surround the catalytic site. Moreover some water
molecules including Wat1021, Wat1026, Wat1056, Wat1058, Wat1061, Wat1087, Wat1102,
Wat1122, Wat1174, and Wat1228 plays crucial role in the binding of the substrate molecule.
The entrance of the active site is composed of Phe231, His239, Asn241, His279, Glu304, and
Arg312. Phe231, and His239 act as a gate keeper residues that opens when ligand comes
inside the gorge. The overall topology of the model is presented in Figure 4.
Figure 4: (a) The three-dimensional structure of protein model. (b). The active site is
highlighted in box. Residues are depicted in pink stick, while protein is shown in gold helix.
(c). Interactions of substrate molecule (isomaltose) with the active site residues and water
molecules is shown. Substrate moiety is depicted in yellow stick, the catalytic residues are
shown in green sticks, and hydrogen bonds are shown in black lines.
Structure-activity relationship
All the compounds (8a-8n) along with the standard compound (acarbose) were docked into
the active site of S. cerevisiae α-Glucosidase. All the compounds adopted similar orientation,
fluorophenyl substituted triazole moiety interacts at the entrance of the active site, while the
substituted biphenyl moiety is oriented towards the catalytic residues. The triazole moiety of
the most active compound 8l forms hydrogen bond with the side chain carboxamide nitrogen
of Asn241, while phenyl oxygen accepts hydrogen bond from the surrounding water
molecule (Wat1174). The docking results show that water molecules in the active site are
important in stabilizing the protein ligand interactions. Moreover the side chains of His111,
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Phe177 and Tyr71 provides π-π interactions to the naphthalene ring of the compound.
Compounds 8k, 8n, and 8m displayed activities in range of 21-29μM. The docked view of
these compounds demonstrated that the electronegative group at biphenyl ring is responsible
for the binding of these compound with the side chains of Arg212, His348, Asp349, and
His279. These residues are lied at the base of the gorge, thus these interactions stabilize the
compounds in the active site. In addition, substitution of the bulky groups at this position is
responsible for the decreased activity of the compound. For instance, compounds 8g, 8h, 8f,
8j and 8e exhibited activities in range of 37-48μM. These compounds may either loss water
mediated bridging or bonding with the side chain of Asn241, as a result their activities are
reduced. Compounds 8i, 8d, 8c, and 8b depicted activities in range of 59-84μM. The
aldehydic oxygen of compound 8i mediates hydrogen bonding with the side chain of His111,
however this compound does not bind with the water molecules or Asn241. Similarly, nitrite
oxygen of compound 8d forms hydrogen bond with the side chain of His111. The methoxy
oxygen of compound 8c interacts with water molecules but do not interact with Asn241, or
His111. The binding mode of compound 8b suggests that this compound interacts with the
Asn241, while it doesn’t mediate any interactions with the water molecule or the residues lied
at the base of active site. The least active compound (8a) does not interact with Asn241,
instead it’s triazole moiety is tilted more towards Arg312, however triazole moiety does not
form bond with Arg312. Methoxy oxygen and biphenyl substituted oxygen may interact with
the water molecules. The docking results revealed an important role of Asn241, it’s side
chain carboxamide group acts as a hydrogen bond donor to the triazole nitrogen of active
compounds. Moreover, two water molecules Wat1056, and Wat1174 plays crucial role in
protein-ligand bridging. Water molecule 1056 forms bidentate interaction with the side chain
guanidinium moiety of Arg312, thus this water molecule bridges the ligand with the side
chain of Arg312. Water molecule 1174 does not interact with the surrounding residues,
however it has interactions with the ligands. Compounds 8m and 8n interact with water
molecules 1026 and 1102, respectively. Wat1026 bridges ligand 8m with the side chain of
Asp68, while 1102 bridges 8n with the side chain of the catalytic residue Glu276, thus these
water mediated bridging helps to stabilize the interactions of ligands with in the active site.
The interaction of each ligand and their docking scores are tabulated in Table 2. The docking
results are in complete agreement with the experimental findings and the docking score
correlates well with the inhibitory potency of compounds. The docked poses of all the
compounds are shown in Figure 5.
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Figure 5: (a). The binding orientation of Compounds 8a-8n in the active site of S. cerevisiae
α-glucosidase (b). The docked view of most active compound 8l is presented. Compounds is
shown in purple sticks, active side residues are shown in green sticks, while hydrogen bonds
are depicted in pink lines.
3. Conclusions
In summary, a series of (R)-4-fluorophenyl-1H-1,2,3-triazole derivatives (8a-8n) were
designed, synthesized and evaluated as novel α-glucosidase inhibitors. Therefore, a fluoro
group was the most favourable substituent on the phenyl ring and 1,2,3-triazole ring in (R)-4-
fluorophenyl-1H-1,2,3-triazole derivatives are responsible for the anti-α-glucosidase activity.
Further studies on the structural optimization of these derivatives are still underway in our
laboratory.
4. Experimental Section
4.1. General
All experiments were carried out in dry reaction vessels under dry nitrogen atmosphere. All
reagents were purchased from Sigma-Aldrich chemical company, Germany. Solvents were
purified and dried by standard procedures before use in experiments. The spectra were
recorded with the following instruments; IR: PerkineElmer RX FT-IR spectrophotometer; IR
wave numbers (ν) are given in cm−1. HR-ESI-MS: Agilent Technologies, 6530 Accurate
Mass. The 1H- and 13C-NMR spectra were recorded on 600 MHz and 150 MHz spectrometers
using the solvent peak as internal reference (CDCl3, δ H: 7.26; δ C: 77.0). The 19F-NMR
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spectra was recorded on 564 MHz spectrometer. Data were reported in the following order:
chemical shift (δ) in ppm; multiplicities are indicated: m = multiplet; q = quadrate, dd =
doublet of doublet, t = triplet, d = doublet, s = singlet; coupling constants (J) are in hertz
(Hz). HPLC technique was performed with variable wavelength detector. Column
chromatography was carried out by using silica gel of the selected particle size of 100-200
mesh. All reactions were monitored by Thin-Layer-Chromatography (TLC) using silica gel
F254. Visualization was accomplished with UV-light and I2 stain. Solvents for the catalytic
reaction were technical grade and dried by standard procedures. Solvents for column
chromatography (EtOAc, n-hexane) were technical grade and distilled prior to use. Organic
extracts were dried over anhydrous Na2SO4). For X-ray measurements, single crystal of 8m
was mounted on a MiTeGen loop with grease and examined on a Bruker D8 Venture APEX
diffractometer equipped with Photon 100 CCD area detector at 296 (2) K using graphite-
monochromated Mo-Kα radiation (λ = 0.71073Å). Data was collected using the APEX-II
software [36], integrated using SAINT [37], and corrected for absorption using a multi-scan
approach (SADABS) [38]. The structure was solved using intrinsic phasing (SHELXT) [39].
Final cell constants were determined from full least squares refinement of all observed
reflections. All non-H atoms were located in subsequent difference maps and refined
anisotropically with SHELXL-97 [40], using full least squares refinement against F2. H-
atoms were added at calculated positions and refined with a riding model. The structure has
been deposited with the CCDC (CSD deposition numbers 1903648).
4.2. General procedure for preparation of (R)-4-fluorophenyl-1H-1,2,3-triazole bromide (6).
The key intermediate (R)-4-fluorophenyl-1H-1,2,3-triazole bromide 6 was prepared
according to literature method [25].
4.3. General Suzuki–Miyaura reaction procedure for cross-coupled product 8a-n.
1,4-dioxane (5 mL per 1 mmol) solution of 6 (1.0 equiv), K3CO3 (3.0 equiv per cross-
coupling step), Pd (PPh3)4 (5 mol), and arylboronic acid 7a-n (1.5 equiv per cross coupling
°
°
step) was stirred at 120 C for 8 h. After cooling to 20 C, H2O was added. The organic and
the aqueous layers were separated, and the latter was extracted with CH2Cl2 (15 × 3 mL). The
combined organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was
concentrated in vacuo. The residue was purified by column chromatography (EtOAc/Hexane
9:1) to give a pure cross-coupled product 8a-n.
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(R)-4-(4-fluorophenyl)-1-(2-((3-methoxy-[1,1'-biphenyl]-4-yl)oxy)propyl)-1H-1,2,3-triazole
1
(8a):Colorless liquid; Yield = 76%; IR (liquid): 1494, 1216, 771, 743, 669 cm-1; H NMR
(600 MHz, CDCl3): δ 8.11 (1H, s), 7.77 (2H, dd, J = 6.0, 5.4 Hz), 7.49 (2H, d, J = 7.8 Hz),
7.39 (2H, t, J = 7.2 Hz), 7.30 (1H, t, J = 7.2 Hz), 7.07 (4H, dd, J = 8.4, 11.4 Hz), 6.88 (1H,
d, J = 8.4 Hz), 4.72 (2H, m), 4.58 (1H, dd, J = 7.2 Hz), 3.84 (3H, s), 1.37 (3H, d, J = 6.6
13
Hz); C NMR (150 MHz, CDCl3): δ 163.4, 161.7,150.8, 146.7, 145.6, 140.7, 136.6, 128.7,
127.3, 127.1, 127.0, 126.9, 121.3, 119.6, 118.0, 115.8, 115.7, 111.3, 75.1, 55.7, 55.0, 17.3;
19F NMR (564 MHz, CDCl3): δ -113.89; HRMS (ESI+): Found (M+H+): 404.2002
C24H23FN3O2 required 404.2004.
(R)-4-(4-fluorophenyl)-1-(2-((3-methoxy-4'-methyl-[1,1'-biphenyl]-4-yl)oxy)propyl)-1H-
1,2,3-triazole (8b): Colorless liquid; Yield = 73%; IR (liquid): 1498, 1215, 750, 667 cm-1;
1H NMR (600 MHz, CDCl3): δ 8.11 (1H, s), 7.77 (2H, dd, J = 5.4, 6.0 Hz), 7.39 (2H, d, J =
7.8 Hz), 7.21 (2H, t, J = 7.8 Hz), 7.08 (2H, t, J = 8.4 Hz), 7.04 (2H, t, J = 9.0 Hz), 6.86 (1H,
d, J = 7.8 Hz), 4.71 (2H, m), 4.58 (1H, dd, J = 7.8 Hz), 3.83 (3H, s), 2.36 (3H, s), 1.36 (3H,
13
d, J = 6.0 Hz); C NMR (150 MHz, CDCl3): δ 163.3, 161.7, 150.8, 146.7, 145.4, 137.8,
136.9, 136.6, 129.4, 127.3, 127.1, 126.7, 121.3, 119.3, 118.0, 115.8, 115.7, 111.1, 75.2,
55.7, 55.0, 21.0, 17.3; 19F NMR (564 MHz, CDCl3): δ -113.92; HRMS (ESI+): Found
(M+H+): 418.2189 C25H25FN3O2 required 418.2186.
(R)-1-(2-((3,4'-dimethoxy-[1,1'-biphenyl]-4-yl)oxy)propyl)-4-(4-fluorophenyl)-1H-1,2,3-
triazole (8c): Yellow amorphous solid; Yield = 69%; IR (solid): 1497, 1237, 1215, 770, 744,
666 cm-1; 1H NMR (600 MHz, CDCl3): δ 8.11 (1H, s), 7.77 (2H, dd, J = 5.4 Hz), 7.42 (2H,
d, J = 9.0 Hz), 7.08 (2H, t, J = 8.4 Hz), 7.00 (2H, dd, J = 4.8, 1.8 Hz), 6.93 (2H, d, J = 8.4
Hz), 6.85 (1H, d, J = 7.8 Hz), 4.73 (2H, m), 4.57 (1H, dd, J = 7.2, 7.8 Hz), 3.83 (3H, s), 3.82
(3H, s), 1.36 (3H, d, J = 6.6 Hz); 13C NMR (150 MHz, CDCl3): δ 163.4, 161.7,159.0, 150.8,
146.7, 145.1, 136.3, 133.3, 127.9, 127.3, 121.3, 119.1, 118.2, 115.8, 115.6, 114.2, 111.0,
19
75.2, 55.7, 55.3, 55.0, 17.3; F NMR (564 MHz, CDCl3): δ -113.90; HRMS (ESI+): Found
(M+H+): 434.1925 C25H25FN3O3 required 434.1927.
(R)-4-(4-fluorophenyl)-1-(2-((3-methoxy-4'-nitro-[1,1'-biphenyl]-4-yl)oxy)propyl)-1H-1,2,3-
triazole (8d): Yellow liquid; Yield = 85%; IR (liquid): 1597, 1496, 1345, 1217, 844, 772,
1
748, 668 cm-1; H NMR (600 MHz, CDCl3): δ 8.24 (2H, d, J = 9.0 Hz), 8.08 (1H, s), 7.77
(2H, dd, J = 6.0, 5.4 Hz), 7.62 (2H, d, J = 8.4 Hz), 7.09 (4H, m), 6.91 (1H, d, J = 8.4 Hz),
13
4.74 (2H, m), 4.60 (1H, dd, J = 7.2 Hz), 3.87 (3H, s), 1.39 (3H, d, J = 6.6 Hz); C NMR
14

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(150 MHz, CDCl3): δ 163.4, 161.8,150.9, 147.0, 146.8, 146.7, 133.6, 127.4, 127.3, 126.8,
124.1, 121.3, 120.1, 117.5, 115.9, 115.7, 111.2, 75.0, 55.9, 55.0, 17.3; 19F NMR (564 MHz,
CDCl3): δ -113.52; HRMS (ESI+): Found (M+H+): 449.1811 C24H22FN4O4 required
449.1813.
(R)-1-(2-((4'-chloro-3-methoxy-[1,1'-biphenyl]-4-yl)oxy)propyl)-4-(4-fluorophenyl)-1H-
1,2,3-triazole (8e): White solid; Yield = 82%; IR (solid): 1215, 770, 743, 668 cm-1; 1H NMR
(600 MHz, CDCl3): δ 8.10 (1H, s), 7.77 (2H, dd, J = 5.4 Hz), 7.41 (2H, d, J = 7.8 Hz), 7.35
(2H, d, J = 8.4 Hz), 7.08 (2H, t, J = 9.0 Hz), 7.00 (2H, t, J = 1.2 Hz), 6.87 (1H, d, J = 8.4
13
Hz), 4.72 (2H, m), 4.58 (1H, dd, J = 7.2 Hz), 3.84 (3H, s), 1.37 (3H, d, J = 6.6 Hz); C
NMR (150 MHz, CDCl3): δ 163.4, 161.7, 150.8, 146.7, 145.9, 139.1, 135.2, 133.2, 128.8,
128.1, 127.3, 121.3, 119.4, 117.9, 115.8, 115.7, 111.0, 75.1, 55.8, 55.0, 17.3; 19F NMR (564
MHz, CDCl3): δ -113.81; HRMS (ESI+): Found (M+H+): 438.1292 C24H22ClFN3O2 required
438.1290.
(R)-4'-((1-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)propan-2-yl)oxy)-3'-methoxy-[1,1'-
biphenyl]-4-carbonitrile (8f): Pale yellow amorphous solid; Yield = 79%; IR (solid): 2225,
1496, 1215, 771, 744, 667 cm-1; 1H NMR (600 MHz, CDCl3): δ 8.07 (1H, s), 7.76 (2H, dd, J
= 6.0, 5.4 Hz), 7.66 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 8.4 Hz), 7.06 (4H, m), 6.89 (1H, d,
J = 8.4 Hz), 4.72 (2H, m), 4.58 (1H, dd, J = 7.2 Hz), 3.85 (3H, s), 1.38 (3H, d, J = 6.0 Hz);
13C NMR (150 MHz, CDCl3): δ 163.4, 161.7, 151.0, 146.8, 145.1, 134.1, 132.5, 127.4,
19
127.3, 121.2, 119.9, 118.8, 117.7, 115.8, 115.7, 111.21, 110.7, 75.0, 55.9, 55.0, 17.3; F
NMR (564 MHz, CDCl3): δ -113.70; HRMS (ESI+): Found (M+H+): 429.1992 C25H22FN4O2
required 429.1995.
(R)-1-(2-((4'-fluoro-3-methoxy-[1,1'-biphenyl]-4-yl)oxy)propyl)-4-(4-fluorophenyl)-1H-
1,2,3-triazole (8g): White solid; Yield = 84%; IR (solid): 1497, 1215, 771, 743, 668 cm-1; 1H
NMR (600 MHz, CDCl3): δ 8.10 (1H, s), 7.77 (2H, dd, J = 5.4 Hz), 7.43 (2H, dd, J = 5.4
Hz), 7.07 (4H, m), 6.99 (2H, d, J = 7.8 Hz), 6.86 (1H, d, J = 7.8 Hz), 4.71 (2H, m), 4.58
(1H, dd, J = 7.2 Hz), 3.84 (3H, s), 1.37 (3H, d, J = 6.0 Hz); 13C NMR (150 MHz, CDCl3): δ
163.4, 163.1, 161.7, 161.5, 150.8, 146.7, 145.6, 136.8, 135.6, 128.4, 127.3, 121.3, 119.4,
118.0, 115.8, 115.7, 115.6, 115.5, 111.1, 75.1, 55.8, 55.0, 17.3; 19F NMR (564 MHz,
CDCl3): δ -113.82, -115.83; HRMS (ESI+): Found (M+H+): 422.1940 C24H22F2N3O2
required 422.1938.
15

JOURNAL PRE-PROOF
(R)-4-(4-fluorophenyl)-1-(2-((3-methoxy-3',5'-bis(trifluoromethyl)-[1,1'-biphenyl]-4-
yl)oxy)propyl)-1H-1,2,3-triazole (8h): White amorphous solid; Yield = 80%; IR (solid):
1
1496, 1327, 1265, 1166, 1219, 772 cm-1; H NMR (600 MHz, CDCl3): δ 8.07 (1H, s), 7.88
(2H, s), 7.79 (1H, s), 7.77 (2H, d, J = 5.4 Hz), 7.06 (3H, m), 7.02 (1H, s), 6.91 (1H, d, J =
7.8 Hz), 4.75 (2H, m), 4.59 (1H, dd, J = 7.2 Hz), 3.88 (3H, s), 1.39 (3H, d, J = 6.6 Hz); 13C
NMR (150 MHz, CDCl3): δ 163.4, 161.8, 151.1, 147.0, 146.8, 142.8, 133.2, 132.0, 127.3,
127.2, 126.9, 124.2, 122.4, 121.2, 120.6, 120.0, 117.8, 115.8, 115.7, 111.2, 75.1, 56.0, 55.4,
17.2; 19F NMR (564 MHz, CDCl3): δ -62.81, -113.89; HRMS (ESI+): Found (M+H+):
540.1691 C26H21F7N3O2 required 540.1693.
(R)-4'-((1-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)propan-2-yl)oxy)-3'-methoxy-[1,1'-
biphenyl]-4-carbaldehyde (8i): White amorphous solid; Yield = 77%; IR (solid): 1710,
1497, 1214, 743, 669 cm-1; 1H NMR (600 MHz, CDCl3): δ 10.01 (1H, s), 8.10 (1H, s), 7.89
(2H, d, J = 7.8 Hz), 7.77 (2H, dd, J = 5.4 Hz), 7.64 (2H, d, J = 7.8 Hz), 7.09 (4H, m), 6.90
(1H, d, J = 7.8 Hz), 4.75 (2H, m), 4.59 (1H, dd, J = 7.2 Hz), 3.87 (3H, s), 1.39 (3H, d, J =
13
6.0 Hz); C NMR (150 MHz, CDCl3): δ 191.81, 163.4, 161.8, 150.9, 146.7, 146.6, 135.0,
134.7, 130.2, 127.4, 127.3, 126.8, 121.3, 120.0, 117.6, 115.8, 115.7, 111.2, 75.0, 55.9, 55.0,
17.3; 19F NMR (564 MHz, CDCl3): δ -113.54; HRMS (ESI+): Found (M+H+): 432.1761
C25H23FN3O3 required 432.1763.
(R)-1-(2-((2',6'-difluoro-3-methoxy-[1,1'-biphenyl]-4-yl)oxy)propyl)-4-(4-fluorophenyl)-1H-
1,2,3-triazole (8j): Colorless liquid; Yield = 82%; IR (liquid): 1498, 1215, 754, 666 cm-1; 1H
NMR (600 MHz, CDCl3): δ 8.13 (1H, s), 7.78 (2H, dd, J = 5.4 Hz), 7.24 (1H, t, J = 7.2 Hz),
7.09 (2H, t, J = 8.4 Hz), 6.95 (4H, m), 6.89 (1H, d, J = 8.4 Hz), 4.73 (2H, m), 4.59 (1H, dd,
13
J = 7.2 Hz), 3.80 (3H, s), 1.38 (3H, d, J = 6.0 Hz); C NMR (150 MHz, CDCl3): δ 163.5,
161.8, 160.9, 159.2, 150.2, 146.5, 146.0, 128.8, 128.7, 127.5, 127.4, 123.1, 121.5, 117.1,
115.9, 115.7, 114.4, 111.7, 111.6, 111.5, 74.8, 55.8, 55.1, 17.3; 19F NMR (564 MHz,
CDCl3): δ -113.72, -114.33; HRMS (ESI+): Found (M+H+): 440.1896 C24H21F3N3O2
required 440.1893.
(R)-4-(4-fluorophenyl)-1-(2-((2',3',4'-trifluoro-3-methoxy-[1,1'-biphenyl]-4-yl)oxy)propyl)-
1H-1,2,3-triazole (8k): Colorless liquid; Yield = 86%; IR (liquid): 1499, 1215, 1068, 745,
669 cm-1; 1H NMR (600 MHz, CDCl3): δ 8.09 (1H, s), 7.77 (2H, dd, J = 5.4 Hz), 7.08 (2H, t,
16

JOURNAL PRE-PROOF
J = 8.4 Hz) 7.09 (3H, m), 6.95 (1H, d, J = 9.0 Hz), 6.88 (1H, d, J = 7.8 Hz), 4.73 (2H, m),
4.58 (1H, dd, J = 6.6, 7.2 Hz), 3.82 (3H, s), 1.38 (3H, d, J = 6.0 Hz); 13C NMR (150 MHz,
CDCl3): δ 163.4, 161.7, 150.5, 146.8, 146.2, 128.8, 127.3, 127.0, 123.6, 123.5, 121.4, 121.3,
117.4, 115.8, 115.7, 112.9, 112.1, 112.0, 75.0, 55.8, 55.0, 17.3; 19F NMR (564 MHz,
CDCl3): δ -113.79, -135.73, -138.72, -159.92; HRMS (ESI+): Found (M+H+): 458.1725
C24H20F4N3O2 required 458.1723.
(R)-4-(4-fluorophenyl)-1-(2-(2-methoxy-4-(naphthalen-2-yl)phenoxy)propyl)-1H-1,2,3-
triazole (8l): Pale brown amorphous solid; Yield = 79%; IR (solid): 1496, 1214, 743, 669
cm-1; 1H NMR (600 MHz, CDCl3): δ 8.14 (1H, s), 7.93 (1H, s), 7.85 (3H, m), 7.79 (2H, dd,
J = 5.4 Hz), 7.64 (1H, d, J = 8.4 Hz), 7.46 (2H, m), 7.18 (2H, d, J = 9.0 Hz), 7.09 (2H, t, J =
9.0 Hz), 6.92 (1H, d, J = 7.8 Hz), 4.73 (2H, m), 4.60 (1H, dd, J = 7.2, 6.6 Hz), 3.89 (3H, s),
1.39 (3H, d, J = 6.0 Hz); 13C NMR (150 MHz, CDCl3): δ 163.4, 161.8, 150.9, 145.7, 138.0,
136.5, 133.6, 132.5, 128.4, 128.0, 127.6, 127.4, 127.3, 126.9, 126.3, 125.9, 125.4, 125.3,
121.4, 119.9, 118.0, 115.8, 115.7, 111.4, 75.1, 55.8, 55.1, 17.3; 19F NMR (564 MHz,
CDCl3): δ -113.74; HRMS (ESI+): Found (M+H+): 454.2133 C28H25FN3O2 required
454.2136.
(R)-1-(4'-((1-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)propan-2-yl)oxy)-3'-methoxy-[1,1'-
biphenyl]-4-yl)ethanone (8m): White solid; Yield = 82%; IR (solid): 1679, 1497, 1215, 841,
1
752, 670 cm-1; H NMR (600 MHz, CDCl3): δ 8.09 (1H, s), 7.98 (2H, d, J = 8.4 Hz), 7.77
(2H, d, J = 5.4 Hz), 7.58 (2H, d, J = 8.4 Hz), 7.09 (4H, m), 6.89 (1H, d, J = 7.8 Hz), 4.73
(2H, m), 4.59 (1H, dd, J = 7.2 Hz), 3.86 (3H, s), 2.60 (3H, s), 1.38 (3H, d, J = 6.0 Hz); 13C
NMR (150 MHz, CDCl3): δ 197.6, 163.4, 161.7, 150.9, 146.4, 145.2, 135.7, 134.9, 128.9,
127.3, 126.9, 121.3, 119.9, 117.7, 115.8, 115.7, 111.2, 75.1, 55.8, 55.0, 26.6, 17.3; 19F NMR
(564 MHz, CDCl3): δ -113.77; HRMS (ESI+): Found (M+H+): 446.1645 C26H25FN3O3
required 446.1647.
(R)-1-(2-(4-(benzo[b]thiophen-2-yl)-2-methoxyphenoxy)propyl)-4-(4-fluorophenyl)-1H-
1,2,3-triazole (8n): White amorphous solid; Yield = 78%; IR (solid): 1498, 1215, 1143,
1036, 747, 669 cm-1; 1H NMR (600 MHz, CDCl3): δ 8.10 (1H, s), 7.78 (3H, m), 7.72 (1H, d,
J = 7.8 Hz), 7.40 (1H, s), 7.32 (1H, t, J = 7.2 Hz), 7.28 (1H, t, J = 7.8 Hz), 7.18 (2H, m),
7.09 (2H, t, J = 8.4 Hz), 6.86 (1H, d, J = 8.4 Hz), 4.73 (2H, m), 4.58 (1H, dd, J = 7.2 Hz),
3.87 (3H, s), 1.37 (3H, d, J = 6.6 Hz); 13C NMR (150 MHz, CDCl3): δ 163.4, 161.8, 150.9,
17

JOURNAL PRE-PROOF
146.7, 146.4, 143.7, 140.6, 139.3,129.6, 127.4, 127.3, 126.9, 124.5, 124.2, 123.4, 122.1,
121.3, 119.3, 119.0, 117.9, 115.8, 115.7, 110.6, 75.1, 55.8, 55.0, 17.2; 19F NMR (564 MHz,
CDCl3): δ -113.74; HRMS (ESI+): Found (M+H+): 460.1686 C26H23FN3O2S required
460.1684.
In vitro α-glucosidase inhibition assay
α-Glucosidase inhibitory activity was evaluated by using 0.1 M phosphate buffer (pH 6.8) at
37 ˚C [32]. The enzyme (0.2 U/mL) in phosphate buffered saline was incubated with various
°
concentrations of test compounds at 37 C for 15 min. The substrate, p-nitrophenyl-α-D-
glucopyranoside (0.7 mM, final) was then added and the change in absorbance at 400 nm was
monitored for 30 min using a spectrophotometer (Spectra max M2, Molecular Devices, CA,
USA). Test compound was replaced with DMSO-d6 (7.5% final) in the control. Acarbose was
used as the standard inhibitor. The percent inhibition was calculated by using the following
formula:
% Inhibition = 100-(OD test well/OD control) ×100
Molecular Modelling and Docking Studies
Docking was carried out using Molecular Operating Environment [41]. The 3D- structures of
ligands were constructed on MOE, and wash module was used to add hydrogen and partial
charges on ligands. Ligands were minimized with AMBER12:EHT force field until the
gradient was reached to 0.1kcal/mol/A2. For docking, homology modeling of S. cerevisiae α-
glucosidase
enzyme
(UniprotKB
accession
number
P53341)
(https://www.uniprot.org/uniprot/P53341) was performed on SwissModel server
(https://swissmodel.expasy.org/) by using 3A47 and 3AXH as templates. The stereochemical
and geometrical properties of generated models were evaluated by Procheck [42], ERRAT
(http://servicesn.mbi.ucla.edu/ERRAT/)
and
verify3D
(http://servicesn.mbi.ucla.edu/Verify3D/). The best model was selected for further study.
Hydrogen and partial charges were added on Protein file by Protonate3D command and
minimize the structure with AMBER12:EHT force field. Water molecules in the active site,
were included in protein during docking. Docking was carried out with Alpha Triangle
placement method and London dG scoring function [41].
Conflict of interest
18

JOURNAL PRE-PROOF
All authors confirm that this article content has no conflict of interest.
Acknowledgement
The authors would like to thank the University of Nizwa for the generous support of this
project. We thank analytical and technical staff for assistance.
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 A novel series of (R)-4-fluorophenyl-1H-1,2,3-triazole derivatives (8a-n) were
synthesized.
 The structures were confirmed by 1H NMR, 13C NMR, 19F NMR, ESI-MS, and single
crystal X-ray diffraction.
 All compounds displayed significant α-glucosidase inhibition with IC50 values of 17.9
- 193.7 µM.
 Molecular docking studies were performed to establish their structure-activity
relationship and binding interaction at atomic level.
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