Synthesis and biological evaluation of novel quinazoline-triazole hybrid compounds with potential use in Alzheimer's disease

Article abstract of DOI:10.1016/j.bmcl.2020.127404

A library of twelve quinazoline-triazole hybrid compounds were designed, synthesized and evaluated as a novel class of acetylcholinesterase inhibitors to treat Alzheimer's disease (AD). The biological assay results demonstrated the ability of several hybrid compounds to inhibit AChE enzyme (IC₅₀ range = 0.2–83.9 μM). To understand the high potential activity of these compounds, molecular docking simulations were performed to get better insights into the mechanism of binding of quinazoline-triazole hybrid compounds. As expected, compounds 8a and 9a-b bind to both catalytic anionic site (CAS) and peripheral anionic site (PAS) in the active site of AChE enzyme, which implicates that these compounds could act as dual binding site inhibitors. These compounds were not cytotoxic and they also displayed appropriated physicochemical as well as pharmacokinetic profile to be developed as novel anti-AD drug candidates.

Full text of DOI:10.1016/j.bmcl.2020.127404

Journal Pre-proofs
Synthesis and biological evaluation of novel quinazoline-triazole hybrid com‐
pounds with potential use in Alzheimer’s disease
Giang Le-Nhat-Thuy, Nga Nguyen Thi, Hai Pham-The, Tuyet Anh Dang Thi,
Huong Nguyen Thi, Thu Ha Nguyen Thi, Sa Nguyen Hoang, Tuyen Van
Nguyen
PII:
S0960-894X(20)30515-1
DOI:
Reference:
https://doi.org/10.1016/j.bmcl.2020.127404
BMCL 127404
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
27 May 2020
3 July 2020
7 July 2020
Please cite this article as: Le-Nhat-Thuy, G., Nguyen Thi, N., Pham-The, H., Anh Dang Thi, T., Nguyen Thi, H.,
Ha Nguyen Thi, T., Nguyen Hoang, S., Van Nguyen, T., Synthesis and biological evaluation of novel
quinazoline-triazole hybrid compounds with potential use in Alzheimer’s disease, Bioorganic & Medicinal
Chemistry Letters (2020), doi: https://doi.org/10.1016/j.bmcl.2020.127404
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Synthesis and biological evaluation of novel quinazoline-triazole hybrid
compounds with potential use in Alzheimer’s disease
Giang Le-Nhat-Thuya,b*, Nga Nguyen Thib,c, Hai Pham-Thed, Tuyet Anh Dang Thia,b, Huong
Nguyen Thid, Thu Ha Nguyen Thia, Sa Nguyen Hoange, Tuyen Van Nguyena,b*
aInstitute of Chemistry, Vietnam Academy of Science and Technology (VAST), 18 Hoang Quoc Viet, Cau Giay, Hanoi,
Vietnam
bGraduate University of Science and Technology, VAST, 18 Hoang Quoc Viet, Cau Giay, Hanoi, Vietnam
cHanoi Medicinal College, 35 Doan Thi Diem, Dong Da, Hanoi, Vietnam
dHanoi University of Pharmacy, 13-15 Le Thanh Tong, Hoan Kiem, Hanoi, Vietnam
eUniversity of Khanh Hoa, 1 Nguyen Chanh, Nhatrang, Khanhhoa, Vietnam
* Corresponding author. Tel.: +84 917683979.
E-mail addressess: ngvtuyen@hotmail.com (T. V. Nguyen), lenhatthuygiang@yahoo.com (G. Le-Nhat-Thuy)
ABSTRACT
A library of twelve quinazoline-triazole hybrid compounds were designed, synthesized
and evaluated as a novel class of acetylcholinesterase inhibitors to treat Alzheimer’s disease
(AD). The biological assay results demonstrated the ability of several hybrid compounds to
inhibit AChE enzyme (IC50 range = 0.2-83.9 µM). To understand the high potential activity of
these compounds, molecular docking simulations were performed to get better insights into
the mechanism of binding of quinazoline-triazole hybrid compounds. As expected,
compounds 8a and 9a-b bind to both catalytic anionic site (CAS) and peripheral anionic site
(PAS) in the active site of AChE enzyme, which implicates that these compounds could act as
dual binding site inhibitors. These compounds were not cytotoxic and they also displayed
appropriated physicochemical as well as pharmacokinetic profile to be developed as novel
anti-AD drug candidates.
Keywords: Azheimer’s disease, acetylcholinesterase inhibitor, click chemistry,
quinazoline, triazole, hybridization
Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder and one of the
most common forms of dementia in the elderly. AD causes a progressive damage on the
central nervous system, including memory loss, decline in language, cognitive dysfunction
and behavioral disorders.1-3 A wide ranges of factors have been considered as the main causes
of AD, including formation of toxic amyloid beta (Aβ) protein in the brain,4 tau protein
hyperphosphorylation and aggregation,5 biometals dysfunction (ions; copper, iron, and
zinc),6,7 alteration of calcium homeostasis, inflammation and oxidative stress due to
generation of reactive oxygen species (ROS),8 and deficits in the cholinergic transmission.9
The complexity and heterogeneous etiology of AD play an important role in new drug
development to avoid the progress of this disease. Nowadays, most of theurapeutic treatments
for AD has focused on the inhibition of acetylcholinesterase (AChE) to increase the level of
acetylcholine (ACh) in cholinergic synaptic clefts.10 Acetylcholinesterase (AChE) has
catalytic anionic site (CAS) and peripheral anionic site (PAS) which are selectively accepting
ACh.11,12 AChE can be inhibited by AChE inhibitors (AChEI) through the interaction of the
1

inhibitor and amino acid residues in the CS (competitive inhibitors) and PAS (non-
competitive inhibitors). To date, only four cholinesterase inhibitors (AChEIs) including
tacrine,13 donepezil,14 rivastigmine,15 and galantamine16 were approved for commercial use in
the treatment of AD. However, tacrine was removed from the pharmaceutical market owing
to severe adverse effects associated with hepatotoxicity.17 Therefore, new safer cholinesterase
inhibitors with minimal adverse effects and/or multi-target activity are urgently needed.
mheNtloitfbe-istrroaionrcgyyneconalftei-ucsroifaxrnrla-teamniknedemwiynsbogysertnkrtueshdc,ettuicral
Nitrogen-containing heterocycles are key structural units in natural and synthetic
bioactive agents. In the library of six-membered heterocyclic frameworks, quinazolines
represent a privileged structure which has been widely utilized to design therapeutic drugs
due to their diversity of the biological and pharmacological activities such as anti-cancer, anti-
microbial etc.18,19 Quinazoline derivatives have also attracted lots of attention as anti-AD
agents.3,20-25 They have been found as a crucial scaffold for the optimal AChEI activity
interacting with the CAS and PS of AChE.22 Recently, the study reported by Rao P. et al. has
evidently hightlighted cholinesterase activities of 2,4-disubstituted quinazolines containing
various primary amine groups at position C4 of quinazoline framework.24 Apart from
quinazolines, triazole-containing derivatives have been also considered as versatile anti-AChE
agents.2,26-28 The triazole moiety plays a crucial role for improving the AChE inhibitory
activity. Study by Shaprless et al. demonstrated that 1,2,3-triazole-linked tacrine and
phenanthridinium derivatives possessed remarkable AChEI activity by incorporation of 1,2,3-
triazole ring.26 Moreover, the conjugation of 1,2,3-triazole moiety with different heterocyclic
systems such as chromenones,27,28 quinolines,29,30 isoxazoles,31 or piperidines32 indicated their
potencies in the design and synthesis of novel anti-Alzheimer agents.
OMe
MeO
O
NH
HN
N
N
F
N
N
N
Me
F
N
N
N
H
Me
Me
AChE inhibitor (IC50 = 2.1 M) [24]
IC50 (AChEI) = 1.2 M
IC50 (BChEI) = 0.38 M [23]
Me
N
Me
O
N
N
N
N
N
N
N
N
H
N
N
N
O
O
O
AChE inhibitor (IC50 = 1.8 M) [28]
Cl
AChE inhibitor (75%, IC50 = 4.89 M)
BChE inhibitor (90%, IC50 = 3.61 M) [30]
NO2
Me
N
N
N
N
N
N
N
Ar
N
HN
N
N
HN
N
N
N
Ar
Ar
O
O
O
N
N
N
N
9
8
10
AChE inhibitor
Fig. 1. Design of compounds 8-10
2

In the light of the potential AChE inhibitory of quinazolines and 1,2,3-triazole ring
mentioned above, herein we designed and synthesized a series of quinazoline-triazole hybrid
compounds with the aim of obtaining new leads in AChE inhibitors. It was demonstrated that
the success of the dual-binding CAS and PAS sites strategy is evidence by the large increase
in AChE inhibitory potency of dimers or hybrids compared to the parent compounds from
which they have been designed.33 Therefore, the hybridization of anti-AD potential
quinazoline and triazole scaffolds led to the reasonable synthesis of the targeted compounds
8-10 (Fig. 1). Moreover, the introduction of a triazole moiety in the targeted molecules could
facilitate H-bond interactions between the backbone and the catalytic aspartate, and provide
suitable linkage for the attachment of a wide range of hetero/aromatic pendant groups. Hence,
in the present work, several 4,6-disubstituted quinazolines containing propynyloxyl group at
C6 position were synthesized, followed hybridization with different azide derivatives to give
the targeted quinazoline-triazole hybrid compounds. The obtained compounds were then
evaluated for their AChE inhibitory to investigate their potential use for treating AD.
HO
CHO
O
CHO
O
OH
(a)
(b)
N
NO2
NO2
NO2
1
2
3
N
N
N
O
O
O
(d)
(e)
(c)
Me
N
N
Me
NO2
NH2
5
6
4
NR1R2
N
N
N
NR1R2
Ar
O
O
(g)
(f)
N
N
N
N
7a-c
8-10
Me
N
NR1R2 =
H
N
;
;
N
N
NO2
H
Ar = 2-NO2C6H5, 3-NO2C6H5, 4-NO2C6H5, 3-CN-4-CF3C6H4
Scheme 1: Preparation of anilinoquinazoline–substituted triazole hybrid compounds 8-10. (a) propargyl
bromide, Cs2CO3, acetonitrile, rt, 12 h, 97%; (b) NH2OH.HCl, NaOH, MeOH, H2O, rt, 30 min, 95%; (c) Ac2O,
reflux, 8 h, 85%; (d) Na2S2O4, H2O, 50-65oC, 4 h, 85%; (e) DMF-DMA, acetic acid, toluene, reflux, 4 h, 80%;
(f) amine, acetic acid, toluene, 60oC-110oC, 4 h, 63-70%; (g) azide, DIPEA, CuI, THF, rt, 1-2 days, 65-91%.
The synthetic route to targeted hybrid compounds 8-10 is represented in Scheme 1. First,
the starting material 2-nitro-5hydroxybenzaldehyde 1 reacted with propargyl bromide in basic
conditions to give 2-nitro-5-(prop-2-yn-1-yloxy)benzaldehyde 2, which was converted to
aldoxime 3 by treatment with hydroxyamine. Aldoxime 3 was next subjected to
intramolecular dehydration with anhydride acetic to afford the benzonitrile 4. Reduction of
the nitro group of compound 4 using sodium dithionite in acidic solution gave the
corresponding amine 5. The latter was treated with DMF-DMA to furnish the formamidine
intermediate 6, which was then subjected to cyclization with different amine to afford the 6-
(prop-2-yn-1-yloxy)quinazolin-4-amines 7a-c in moderate yields. In the final step, the
hybridization of quinazolines 7a-c with various arylazide derivatives was accomplished using
catalyst CuI in the presence of DIPEA in THF at room temperature to afford quinazoline-
triazole hybrid compounds 8-10 in 60-91% yields. The chemical structures of synthesized
3

compounds 7a-c, 8-10 were determined by IR, NMR and MS spectra. In the 1H NMR spectra
of compounds 8-10 a single peak corresponding to triazolyl proton was observed in the
downfield (8.80-9.40 ppm). While proton NH of compounds 8a-d appeared as singlet peak at
9.94-9.96 ppm, and those of compounds 9a-d resonanced as triplet peak at 8.64-8.66 ppm.
In the second section of this work, the anti-AChE and anticancer activities of the
synthezied compounds were evaluated. In vitro anti-AChE activity of quinazolines 7a-c and
1,2,3-triazole-quinazoline hybrid compounds 8-10 was conducted based on modified
Ellman’s method34,35 (Table 1). All data were presented as mean ± SEM of three independent
experiments. The synthesized compounds 7-10 can be generally divided into three catagories
based on the different amine moiety connected to C-4 position of quinazoline scaffold, 3-
nitrophenylamine (7a, 8a-d), benzylamine (7b, 9a-d), and N-methylpiperazyl groups (7c,
10a-d).
Substituation by different amine group on the C-4 position of quinazoline skeleton
affected the AChE inhibition differently. Compound 7b having benzylamine group displayed
moderate activity (IC50 = 47.73 µM), whereas compound 7c having N-methylpiperazyl group
showed lower activity (IC50 = 83.90 µM), and compound 7a having 3-nitrophenylamine
group was not active toward AChE with IC50 > 200 µM. These results agreed with the work
of Mohamed T. that the benzylamines at C-4 position of quinazoline framework has
significant effect on AChEI activity.24 It was hypothesized that the presence of benzylamine
would enhance the C-4 group’s flexibility and allow for more favorable binding within the
ChE enzyme.
The coupling of substituted 1,2,3-triazolyl groups with targeted quinazolines 7a-c at the
C-6 side chain was found to differently affect the AChEI activity of the resulting hybrid
compounds 8-10. Some of them exhibited potent inhibitory activity against AChE with IC50
values ranging from microlar concentrations. As can be seen in Table 1, the best AChEI
activity was obtained by compound 9a (IC50 = 0.23 µM) in comparison to donepezil as the
reference drug (IC50 = 0.12 µM). This compound 9a possessed benzylamine moiety
connected to C-4 position of quinazoline framework and 2-nitrophenyl connected to 1,2,3-
triazole ring. Changing nitro group to meta-position led to a brief reduction of AChEI activity
of compound 9b with IC50 = 1.10 µM, however, compound 9c having nitro group at para-
position lost AChEI activity (IC50 > 200 µM).
The introduction of N-methylpiperazyl moiety instead of benzylamine led to different
results. Generally, N-methylpiperazyl derivatives 10a-b depicted lower activity than
compounds 9a-b (IC50 = 37.38 and 15.79 µM, respectively) and inversely 3-
nitrophenyltriazole derivative 10b was more active than 2-nitrophenyltriazole 10a by two
times. Compound 10c showed no activity as compound 9c, demonstrating that compounds
containing 4-nitrophenyl linked to 1,2,3-triazole ring deteriorated inhibitory activity toward
AChE. Besides that, a series of compounds 8a-d possessing 3-nitrophenylamine moiety
except 8a showed no activity. However, compound 8a showed potential AChEI activity with
IC50 = 2.06 µM. These results indicated that the nature of amine groups linked to C-4 position
of quinazoline scaffold played an important role in inducing anti-AChE activity of their
hybrid compounds.
On the other hand, the AChEI activity of the synthesized hybrid compounds was also
completely influenced by the electronic properties of substituents on the aromatic ring
connected to 1,2,3-triazole. It seems that nitro group on the aryl ring connected to 1,2,3-
triazole induced better anti-AChE activity compared that with 3-trifluoromethyl-4-nitrile
4

group. In fact, the replacement of nitrophenyl moiety by 3-nitrile-4-trifluoromethylphenyl led
to a significant reduction of anti-AChE activity in compounds 8d, 9d and 10d. The low
inhibitory activity of these compounds suggests a lack flexibility caused by substituted fused
aromatic moieties.
To conclude, comparing the most potent hybrid compounds 8a-b, 9a-b and 10a-b with
separate quinazoline compounds 7a-c on AChEI activity revealed that the valuable
hybridization of merging 1,2,3-triazole and quinazoline into single hybrid compounds.
Table 1
Anti-acetylcholinesterase activity of synthesized compounds 7-10
Entry
NR1R2
Ar
Compound IC50 (AChE), µM
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
-
7a
8a
8b
8c
8d
7b
9a
9b
9c
9d
7c
10a
10b
10c
10d
> 200
2.06 ± 0.19
> 200
> 200
> 200
47.73 ± 0.81
0.23 ± 0.15
1.10 ± 0.27
> 200
2-NO2C6H5
3-NO2C6H5
4-NO2C6H5
3-CN-4-CF3C6H4
-
2-NO2C6H5
3-NO2C6H5
4-NO2C6H5
3-CN-4-CF3C6H4
-
2-NO2C6H5
3-NO2C6H5
4-NO2C6H5
3-CN-4-CF3C6H4
Donepezil
N
NO2
H
H
N
> 200
83.90 ± 1.06
37.38 ± 2.01
15.79 ± 0.18
> 200
> 200
0.12 ± 0.36
N
N
With the aim to evaluate the cytotoxic effects on human cancer cell lines, the most potent
compounds 7b, 7c, 8a, 9a, 9b, 10a and 10b were evaluated for their cytotoxicity against KB-
CCL-17 (epidermoid carcinoma cancer), HepG2-HB-8065 (hepatoma carcinoma cancer) and
SK-Lu-1 (non-small lung cancer) cancer cell lines through MTT assay (Table 2). Ellipticine
were used as positive controls. As it is clear in Table 2, they showed no significant cytotoxic
effect against these cancer cell lines.
Table 2
Cytotoxicity of the compounds 7b, 7c, 8a, 9a, 9b, 10a and 10b against selected human
cancer cell lines
Entry
Compound
IC50 (KB), µM
IC50 (HepG2), µM
IC50 (Lu), µM
1
2
3
4
5
6
7
8
7b
7c
8a
9a
9b
59.72 ± 2.30
> 200
> 200
42.69 ± 3.40
> 200
> 200
> 200
1.10 ± 0.05
> 200
> 200
> 200
> 200
> 200
> 200
> 200
> 200
> 200
> 200
1.30 ± 0.04
> 200
94.08 ± 1.35
142.5 ± 1.07
> 200
10a
10b
Ellipticine
0.85 ± 0.04
In this study, quinazoline-triazole hybrid analogues have been designed and synthesized.
Some of them showed good inhibitory activities against AChE enzyme, such as 8a, 9a, 9b,
10a and 10b. To better decipher the structure-activity relationships, the molecular docking
simulations were performed using ICM-Pro Molsoft 3.8-7 to investigate the interactions
between AChE enzyme and these compounds.36 To do so, the crystal structure of recombinant
human AChE in complex with Donepezil was retrieved from RCSB Protein Data bank (PDB
ID: 4EY7).37 Docking protocol was similar to those published previously. We firstly validated
5

the method by redocking co-crystal ligand into the active site of AChE, taking into account
the root-mean square deviation (r.m.s.d.) and interaction paterns.38
As revealed from Fig. 2A, AChE has a deep and narrow gorge lined with aromatic amino
acids, e.g. Tyr72, Tyr124, Trp286, Tyr341… which are important for the binding and
orientation of inhibitors on their way from the PAS (peripheral anionic site) to the choline
binding site (also named catalytic anionic site).39 On the other site is the acyl binding pocket
composed by Phe295 and Phe338, which could play a key role in the selective inhibition of
AChE. The ligand, after being stabilized in the acyl and oxyanion hole, could interact with the
catalytic triad of three residues Ser203, Glu334, and His447, those are important for the
hydrolysis of acetylcholine.37 From the Fig. 2B, the co-crystallized ligand and the redocked
donepezil were highly overlapped with r.m.s.d. of 0.22Å and the docking score was -25.28
kCal/mol. All the interactions were highly conserved, including H-bonds between the 5,6-
dimethoxy-1-indanone moiety of the drug and Phe295 as well as multiple π–π interactions
with the residues at the PAS region and the choline binding site. The results obtained are
similar to those previously published,38 suggesting the validity of the docking method.
Figure 2. (A) Active site gorges of human AChE (chain A, PDB ID: 4EY7) and (B)
superimposition of co-crystal (green) and redocked (yellow) Donepezil inside the active site
of AChE.
Applying the docking method perviously validated, five derivatives were docked into the
active site of human AChE. From 8a to 10b, there can be revealed some difference of binding
modes (see Fig. 3). Compounds 8a, 9a, and 9b showed strong interactions against Trp86
aromatic side chain of the choline binding region, meanwhile compounds 10a and 10b lacked
of that stacking interactions. Compared to 9a and 9b, piperazyl moieties in 10a and 10b could
favourably bind to the residues at PAS through stacking interactions with Trp286. In addition,
the quinazoline systems appeared to be impotant for 8a, 10a and 10b as they bound to Trp286
by multiple π–π interactions and H-bonds with Phe295 and/or Ser293 which is similar to
donepezil. On the other hands, H-bonding played a significant role on the stabilization of 9a
and 9b as they strongly interacted with Ser293 and Arg296 of the PAS site through the
pyrimidine ring of quinazoline. All the compounds showed similar π–π interactions between
triazoles towards Tyr341 and nitro-benzene rings with Tyr337. The docking scores estimated
by ICM package for 8a, 9a, and 9b ranked from -24.71 to -26.07 kCal/mol which are similar
to that calculated for donepezil. Meanwhile docking scores of 10a and 10b were only -16.83
6

and -17.02 kCal/mol, suggesting a lower affinity of these compounds towards AChE
compared to donepezil.
Figure 3. Conformations of the docked compounds 8a, 9a-b, and 10a-b in the active site of
human AChE.
Today early drug-likeness profiling has become pivotal in the drug discovery process.40
We therefore decided to predict several physicochemical and pharmacokinetic properties of
the AChE bioactive compounds 8a, 9a, 9b, 10a and 10b using suitable approaches. The main
results were shown in Table 3.
Table 3. Predicted pharmacokinetic properties of synthesized compounds
Caco-2
Solubility3
(mg/ml)
BBB5
P-gp6
Cytochrome
P4507
Cpd. Ro51 Tox. Rule2
permeability
class4
distribution substrate
8a
9a
1
0
0
1
1
Low
Moderate
Moderate
Low
1.97e-3
2.27e-03
2.25e-03
2.26e-02
2.24e-02
High
High
Moderate
Moderate
High
No
No
No
No
No
1A2, 3A4
2C9, 2C19, 3A4
2C9, 2C19, 3A4
2C9, 3A4
Moderate
Moderate
High
9b
10a
10b
Low
High
High
2C9, 3A4
1Number of Lipinski’s Rule of Five violations41; 2in vivo toxicological rule of Hughes et al42; 3intrinsic solubility
at 25°C calculated by ESOL equation of Delaney43; 4Caco-2 cell permeability classification using 3Prule44: High
5
class if Papp ≥ 16×106cm/s, Moderate class if 0.7×10-6 ≤ Papp < 16×10-6cm/s; Blood-Brain Barrier distribution
6
classes based on Castillo-Garit et al45; P-glycoprotein efflux inhibition state identified via online server
http://pgp.biozyne.com/46; 7metabolisms via CYP enzymes identified via admetSAR 1.0 approach.47
We first computed physicochemical properties involved into the Lipinski’s rule of five
(Ro5) and the toxicological rule proposed by Hughes et al. using Volsurf 1.0.4+
software.41,42,48 The results showed that 8a, 10a and 10b had > 10 H-bond acceptors in the
structures with logP < 3 and PSA > 75Å2 which could be translated into one violation of Ro5
7

and low toxicological profile.41,42 At the same time 9a and 9b fulfilled the Ro5 and show
high-logP/high-PSA profiles. The aqueous solubility of the chemicals was predicted to be
quite low (< 0.1 mg/ml) excepting 10a and 10b.48 In addition, all compounds were predicted
as moderate-to-high permeants across Caco-2 monolayer, a model of gastrointestinal
membrane, according to the 3PRule developed by Pham-The et al.44 Taking into consideration
of the permeability and solubility classes, 8a, 10a and 10b could be predicted as high
intestinal absorption (fraction absorbed higher than 85%) meanwhile 9a and 9b could have
varied absorption extents (30-85%).49 According to the classification trees proposed by
Castillo-Garit et al,45 all compounds showed moderate-to-high blood-brain barrier
distributions which are desirable to be developed as anti-AD agents. At last, the possible first
pass metabolisms via P-glycoprotein (P-gp), an efflux membrane transporter, and multiple
Cytochrome P450 enzymes were predicted by using cheminformatics approaches.46,47
According to the support vector machine model proposed by Levatic et al.,46 all compounds
were predicted as non-substrates of P-gp. Nevertheless, the predictions of admetSAR webtool
showed that the synthesized compounds are sensible to the enzymes such as CYP1A2, 2C9,
2C19 and 3A4.47
In summary, a series of quinazoline–triazole hybrid compounds were designed,
synthesized and evaluated for their anti-AChE activity. Most of the synthesized compounds
showed moderate to good AChEI activity and among them, compound N-benzyl-6-((1-(2-
nitrophenyl)-1H-1,2,3-triazol-4-yl)methoxy)quinazolin-4-amine (9a) was found to be the
most potent inhibitor with IC50 = 0.23 µM. Premilinary investigation of the structure-activity
relationships (SARs) of these synthezied compounds 7-10 revealed that the nature of the
amine linked to C4 of quinazoline scaffold and the aryl group which connected to the triazole
influenced the anti-AChE activity remarkably. Our molecular docking study revealed that
compounds 8a and 9a-b bind to both catalytic anionic site (CAS) and peripheral anionic site
(PAS) in the active site of AChE enzyme, which implicates that these compounds could act as
dual binding site inhibitors. Furthermore, compounds 8a, 9a-b and 10a-b were not cytotoxic
and they also displayed appropriated physicochemical as well as pharmacokinetic profile to
be developed as novel anti-AD drug candidates. Considering these overall results, this study
demonstrates how our strategy enable the discovery of novel promising and privileged
structures. Finally, the results indicate that these new compounds could be considered as a
new lead for further optimization.
Acknowledgement
The authors are indebted to the Institute of Chemistry (Vietnam Academy of Science &
Technology) Grant number: VHH.2020.2.06 and Vietnamese National Foundation for Sciene
and Technology Development (NAFOSTED) Grant number: 104.01-2017.27 for financial
support.
A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at
https://doi.org/10.1016/j.bmcl.2020.
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GRAPHICAL ABSTRACT
Synthesis and biological evaluation of novel quinazoline-triazole hybrid compounds with potential
use in Alzheimer’s disease
Best potent AChE inhibitory agents
NO2
N
N
N
N
N
N
N
HN
N
N
HN
N
HN
N
N
O
O
O
N
N
N
NO2
NO2
O2N
9b
Compound
8a
9a
Compound
Compound
IC50 (AChE) 1.10  0.27 M
IC50 (AChE) 2.06  0.19 M
IC50 (AChE) 0.23  0.15 M
Synthesis and biological evaluation of novel quinazoline-triazole hybrid compounds with potential
use in Alzheimer’s disease
Giang Le-Nhat-Thuya,b*, Nga Nguyen Thib,c, Hai Pham-Thed, Tuyet Anh Dang Thia,b, Huong
Nguyen Thid, Thu Ha Nguyen Thia, Sa Nguyen Hoange, Tuyen Van Nguyena,b*
aInstitute of Chemistry, Vietnam Academy of Science and Technology (VAST), 18 Hoang Quoc Viet, Cau Giay, Hanoi, Vietnam
bGraduate University of Science and Technology, VAST, 18 Hoang Quoc Viet, Cau Giay, Hanoi, Vietnam
cHanoi Medicinal College, 35 Doan Thi Diem, Dong Da, Hanoi, Vietnam
10

dHanoi University of Pharmacy, 13-15 Le Thanh Tong, Hoan Kiem, Hanoi, Vietnam
eUniversity of Khanh Hoa, 1 Nguyen Chanh, Nhatrang, Khanhhoa, Vietnam
* Corresponding author. Tel.: +84 917683979.
E-mail addressess: ngvtuyen@hotmail.com (T. V. Nguyen), lenhatthuygiang@yahoo.com (G. Le-Nhat-Thuy)
 Twelve new quinazoline-triazole hybrid compounds were designed and
synthesized.
 Their acetylcholinesterase inhibitory activity was evaluated.
 Compound 9a was found to be the most promising anti-AChE agent with IC50 =
0.23 µM.

Molecular modeling suggested a selective inhibition of hit compounds 8a, 9a,
and 9b bind to both catalytic (CAS) and peripheral site (PS) in the active site of AChE.
11