Synthesis and antiplasmodial evaluation of 1H-1,2,3-triazole grafted 4-aminoquinoline-benzoxaborole hybrids and benzoxaborole analogues

Article abstract of DOI:10.1016/j.bioorg.2021.104733

A library of 1H-1,2,3-triazole-tethered 4-aminoquinoline-benzoxaborole hybrids as well as aryl substituted benzoxaborole analogues was synthesized and screened for their anti-plasmodial efficacy against both chloroquine-susceptibility 3D7 and chloroquine-

Full text of DOI:10.1016/j.bioorg.2021.104733

Bioorganic Chemistry 109 (2021) 104733
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
Synthesis and antiplasmodial evaluation of 1H-1,2,3-triazole grafted
4
-aminoquinoline-benzoxaborole hybrids and benzoxaborole analogues
a
b
a
,
*
b
c,d,e
Anu Saini , Sumit Kumar , Raghu Raj , Shefali Chowdhary , Mathieu Gendrot
,
c,
d
,
e,
f
c
,
d
,
e
,
f
c,
d,
e,
f
b,*
Joel Mosnier
, Isabelle Fonta
, Bruno Pradines
, Vipan Kumar
a
Department of Chemistry, DAV College, Amritsar, India
b
c
d
e
f
Department of Chemistry, Guru Nanak Dev University, Amritsar, India
Unit ´e Parasitologie et Entomologie, D ´e partement Microbiologie et Maladies Infectieuses, Institut de Recherche Biom ´e dicale des Arm ´e es, Marseille, France
Aix Marseille Univ, IRD, SSA, AP-HM, VITROME, Marseille, France
IHU M ´e diterran ´e e Infection, Marseille, France
Centre National de R ´e f ´e rence du Paludisme, Marseille, France
A R T I C L E I N F O
A B S T R A C T
Keywords:
A library of 1H-1,2,3-triazole-tethered 4-aminoquinoline-benzoxaborole hybrids as well as aryl substituted
benzoxaborole analogues was synthesized and screened for their anti-plasmodial efficacy against both
chloroquine-susceptibility 3D7 and chloroquine-resistant W2 strains of P. falciparum. The inclusion of quinoline
core among the synthesized analogues resulted in substantial enhancement of anti-plasmodial activities. Further,
the spacer of a flexible alkyl chain is marginally preferred over piperazyl-ethyl in inhibiting growth of
P. falciparum. The most potent 4-aminoquinoline-benzoxaborole conjugate with ethyl as spacer exhibited IC50
4
-Aminoquinoline
Benzoxaborole
H-1,2,3-Triazole
1
Suzuki-miyaura reaction
Anti-plasmodial activity
Cytotoxicity
values of 4.15 and 3.78 M against 3D7 CQ-susceptible and W2 CQ-resistant strains of P. falciparum with lower
μ
cross resistance with Chloroquine. There was no difference in anti-plasmodial activities between the CQ-
susceptible 3D7 and CQ-resistant W2 strains of P. falciparum for the benzoxaborole derivatives lacking a quin-
oline core.
1
. Introduction
Malaria remains major health issue worldwide due to the lack of an
resistance along with adverse effects such as hepatotoxicity and agran-
ulocytosis associated with this therapy has hampered the efforts to
eradicate this disease [4–7].
effective vaccine and widespread resistance to the currently available
drugs. Globally, ~228 million cases and 405,000 deaths occurred from
malaria in 2018. Among these, 272,000 (67%) were children aged under
the age of 5 years while 11 million pregnancies could have been exposed
to malaria infection. The most virulent species of malarial protozoa,
Plasmodium falciparum is responsible for 99.7% of malaria cases in the
African region in 2018 [1]. Chloroquine (CQ) was an inexpensive and
effective antimalarial drug used to combat the disease for decades and
was considered as the Gold Standard. The emergence and spread of
resistance to CQ and to the most antimalarial drugs used in mono-
therapy have paved the way for the development of new anti-malarial
regimens [2,3]. World Health Organization (WHO) has currently rec-
ommended the combination of artemisinin and quinoline based drugs,
popularly known as Artemisinin-based Combination Therapy (ACT) for
treatment of falciparum malaria. However, the appearance of drug-
Structural re-engineering of 4-aminoquinolines along with its amal-
gamation with known bioactive pharmacophores, known as 4-amino-
quinoline hybridization has emerged as one of the imperative
strategies for accessing new frameworks with good anti-plasmodial ac-
tivities and low incidence of resistance [8,9]. Numerous 4-aminoquino-
line conjugates such as artemisinin-quinine, trioxaferroquines,
clotrimazole-quinoline, 4-aminoquinoline-phthalimide (I), 4-aminoqui-
noline-naphthalimide (II), 4-aminoquinoline-pyrimidine (III), 4-amino-
quinoline-purine (IV) (Fig. 1) etc. have revealed the success of this
strategy by reversing the compound specific CQ-resistance [10–14].
Benzoxaborole has emerged as an important heterocycle for molec-
ular recognition and biotechnology with varied therapeutic applica-
tions. The diverse potential of benzoxaborole was well exemplified by
recent upsurge in its scientific literature including antifungal, antibac-
terial, antiviral, anti-inflammatory, anticancer and anti-parasitic
*
Corresponding authors.
E-mail addresses: raghusharma4@gmail.com (R. Raj), vipan_org@yahoo.com (V. Kumar).
https://doi.org/10.1016/j.bioorg.2021.104733
Received 12 September 2020; Received in revised form 1 February 2021; Accepted 4 February 2021
Available online 16 February 2021
0
045-2068/© 2021 Elsevier Inc. All rights reserved.

A. Saini et al.
Bioorganic Chemistry 109 (2021) 104733
activities [15,16]. The rationalization of literature revealed the recent
emergence of benzoxaborole core as a promising motif with a potential
to treat multi-drug resistant malaria. In one of such series, the com-
pounds (V and VI) displayed in vivo efficacy against P. berghei infection
with ED90 ranging from 7.4 to 16.2 mg/kg. The promising compounds
exhibited a novel mechanism of action including the inhibition of
P. falciparum LeuRS [17]. Another series of 7-methyl benzoxaborole
pyrazine carboxamide was optimized to afford VII which has demon-
strated longer half-life, higher bioavailability, and excellent in vivo ef-
ficacy against P. Berghei [18]. Peptidyl boronic acids have been
identified as selective anti-plasmodium proteasome inhibitors with ef-
ficacy on both artemisinin-sensitive and -resistant parasites with one of
the scaffold VIII being 56 folds more active than HepG2 [19].
triazole-tethered benzyl-benzoxaboroles using benzyl-bromide 6 as the
precursor (Scheme 2).
The synthesis of 4-aminoquinoline-benzoxaborole conjugates were
synthesized via an initial treatment of 4,7-dichloroquinoline 11 with
◦
sodium azide at 60 C to afford precursor 12. The reaction of 12 with O-
propargylated bromobenzaldehyde in presence of CuSO
ascorbate afforded 13. Suzuki-miyaura borylation of 13 with Pin
the presence of Pd(dppf)Cl generated the corresponding boronic ester
4
and sodium
2 2
B
in
2
14. The reduction of aldehydic group of 14 with sodium borohydride
followed by acidification led to the formation of corresponding 4-amino-
quinoline-benzoxaborole conjugates 15 (Scheme 3).
For the synthesis of 4-aminoquinoline-benzoxaborole conjugates
having alkyl chain lengths between the two pharmacophores 19, the
approach was initiated by reacting 4,7-dichloroquinoline with ethanol/
propanol amine in presence of triethylamine followed by their mesyla-
Considering the novel anti-malarial targets of boron-containing
benzoxaborole, it is considered worthwhile to explore the synthesis of
their 7-chloroquinoline-based hybrids which could possibly act as a dual
function anti-plasmodials. Thus in continuation of our endeavour for
identifying new anti-plasmodials [20], the present communication de-
scribes the synthesis of a series of 1H-1,2,3-triazole linked phenyl/
naphthyl/benzyl substituted benzoxaboroles having varied alkyl chain
lengths for assaying their anti-plasmodial activities against both CQ-
susceptible3D7 and CQ-resistant W2 strains of P. falciparum. The aryl
core was then replaced with 4-aminoquinoiline, either directly linked to
triazole core or through alkyl chains so as to determine its influence on
the anti-plasmodial efficacy. 1H-1,2,3-triazole core was introduced as a
linker because of its well established ability to participate in non-
covalent interactions which can improve the pharmacokinetic proper-
ties along with binding with molecular targets [21].
3
tion and subsequent reaction with NaN to afford click chemistry pre-
cursor 16. Cu-promoted click chemistry between O-propargylated
bromobenzaldehyde and 16 led to the synthesis of 17 which upon re-
2 2 2
action with Pin B in presence of Pd(dppf)Cl and KOAc as base led to
the formation of the corresponding boronic ester 18. Sodium borohy-
dride promoted reduction and subsequent acidification yielded 4-ami-
noquinoline-benzoxaborole conjugates 19 with alkyl chains as spacer,
as depicted in Scheme 4.
Scheme 5 illustrated the methodology for the preparation of 4-ami-
noquinoline-benzoxaborole conjugate 24 linked via piperazinyl-ethyl
core. Thus, the treatment of 11 with 2-piperazin-1-yl-ethanol gave 20
which upon a sequence of mesylation, azidation and click-chemistry
with O-propargylated bromobenzaldehyde yielded 22. Boronylation of
2
2 with subsequent aldehydic reduction and acidification generated the
2
. Result and discussion
corresponding conjugate 24.
The spectral features of conjugates were assigned on the basis of
spectral data and analytical evidence. For example, the conjugate 19b,
exhibits a molecular ion peak [M+1] and [M+3] at 450.1413 and
452.1417 in its High Resolution Mass Spectrum (HRMS). In PMR spec-
trum, conjugate showed the presence of a singlet at δ 2.37 due to the
presence of methyl group, two singlet at δ 4.57 and 5.18 due to presence
of two methylene, and characteristic singlet at δ 8.22 corresponding to a
triazole proton. Further, 13C NMR spectrum exhibits appearances of
characteristic signal at δ 157.9 due to carbonyl carbon along with the
required number of carbons confirmed the assigned structure.
2
.1. Synthetic chemistry
The first set of target scaffolds viz. 1H-1,2,3-triazole linked phenyl/
naphthyl-benzoxaboroles was prepared by an initial base-promoted
alkylation of phenol/1-naphthol 1 with varied di-bromoalkanes with
subsequent treatment with sodium azide to yield O-alkylazido phenol/
naphthol2. Cu-promoted azide-alkyne cycloaddition between 2 and O-
propargylated-2-bromobenzaldehyde afforded the corresponding 1H-
1
,2,3-triazole tethered adduct3 in excellent yields. Catalytic bornylation
of 3 with (pinacolato)boronin the presence of Pd(dppf)Cl as catalyst
gave 4. Sodium borohydride-promoted reduction of aldehydic group in
followed by acidification resulted in the formation of desired 1H-1,2,3-
2
2
.2. In vitro anti-plasmodial activity
4
triazole linked phenyl/naphthyl-benzoxaboroles 5 (Scheme 1).
Similar sequence of synthetic steps, as described above, were
employed to afford the second set of target scaffolds viz.1H-1,2,3-
The synthesized compounds were assayed for their anti-plasmodial
potential against CQ-susceptibile 3D7 and CQ-resistant W2 strain of
P. falciparum. A careful examination of Table 1 revealed that although
Fig. 1. Structures of few quinoline and benzoxaborole based antimalarials.
2

A. Saini et al.
Bioorganic Chemistry 109 (2021) 104733
Scheme 1. Synthesis of 1H-1,2,3-triazole linked phenyl/naphthyl-benzoxaboroles 5.
Scheme 2. Synthesis of 1H-1,2,3-triazole-tethered benzyl-benzoxaboroles 10.
Scheme 3. Synthesis of 4-aminoquinoline-benzoxaborole conjugates 15.
the synthesized compounds were not as active as the standard drug CQ,
the compounds exhibited IC50s in low micromolar range against both the
tested strains and exhibited interesting Structure-Activity Relationship
(SAR). Among the triazole-tethered precursors with phenyl-core 3a–d,
the compounds showed decent anti-plasmodial activities with IC50s
ranging from 5.55 to 7.46 and 4.83–7.56
μM against 3D7 and W2 strains,
3

A. Saini et al.
Bioorganic Chemistry 109 (2021) 104733
Scheme 4. Synthesis of 4-aminoquinoline-benzoxaborole conjugates 19 with spacers.
Scheme 5. Synthesis of 4-aminoquinoline-benzoxaborole conjugate 24 linked via piperazinyl-ethyl core.
respectively. The conversion of 3 to corresponding boronate esters or
precursor 22 confirming the favourable influence of flexible chains on
quinoline-core while the corresponding oxaborole 24 displayed mod-
erate activities against both the strains. A graphical representation of the
SAR of the synthesized compounds is depicted in Fig. 2. All synthesized
compounds displayed reduced cross-resistance with chloroquine, with a
resistance index (RI) factor, according to CQ susceptibility, in the range
0.64–1.30 as compared to 19.79 for standard drug, CQ. The most potent
oxaboroles did not improve the anti-plasmodial profiles as evident by
4
a–d and 5a–d. The replacement of phenyl ring with naphthyl-core also
had a little influence on the anti-plasmodial activities, especially in case
of aldehydic precursors’ 3e–h and the corresponding boronate esters’
4
e–h. Slight improvement in anti-plasmodial activities, however has
been observed in case of 1H-1,2,3-triazole-linked naphthyl-oxaboroles
with the most potent compound among them, exhibiting IC50s of 4.94
conjugate 19a showed IC50 values of 4.15 and 3.78 M against CQ-
μ
and 4.17
μ
M against 3D7 and W2-strains, respectively. The replacement
susceptibility (3D7) and CQ-resistant (W2) strain of P. falciparum with
RI of 0.91 and thus considered to have a little cross-resistance with CQ
[22]. Three of the most promising hybrids 19a, 19b and 24 were eval-
uated for their cytotoxicity against mammalian Vero kidney cell lines
and the results are enlisted in Table 2. The hybrids were non-cytotoxic
against Vero cells and exhibited selective indices SI in the range of
16.94–26.45.
The feeding of malarial parasites on hemoglobin for acquiring
nutrition results in the release of huge amount of free heme which is
itself toxic to the parasite’s survival. The parasire has evolved a mech-
anism to detoxify the free heme by its conversion to a non-toxic insol-
uble material called hemozoin [23]. 4-Aminoquinolines are known to
of naphthyl with benzyl-core did not show any improvement in anti-
plasmodial activities. Similar profiling of 4-aminoquinoline based pre-
cursor 13, the corresponding boronate ester 14 and oxaborole 15
explicated an interesting SAR with activities improving considerably
from the aldehydic precursor to oxaborole as evident by comparing 13
[
(IC50 = 6.19 (3D7) and 7.39
μM (W2)] with 15 [(IC50 = 4.87 (3D7) and
5
.22 M (W2)]. Introducing alkyl chain length as spacer between the
μ
two pharmacophores substantially improved the anti-plasmodial activ-
ities with more influence being observed among 4-aminoquinoline-ben-
zoxaboroles (19a–b) than the corresponding precursors (17a–b). The
inclusion of a piperazyl-ethyl as spacer reduced the activities in the
4

A. Saini et al.
Bioorganic Chemistry 109 (2021) 104733
Table 1
hemin in 40% DMSO/water shows a band at 401 nm corresponding to
monomeric heme, and a decrease in the intensity of this band after
adding a drug is an indicator of drug-heme interactions. The titrations of
Antiplasmodial activities of synthesized compounds.
a
b
c
Compound
n
3D7 (CQ-S) IC50
(
μM)
W2 (CQ-R) IC50
(
μM)
RI
1
9a with monomeric heme in aqueous DMSO solutions at pH 7.4 (0.02
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
a
b
c
d
e
f
2
3
4
5
2
3
4
5
2
3
4
5
2
3
4
5
2
3
4
5
2
3
4
5
–
–
–
–
–
–
1
2
1
2
1
2
–
–
–
7.44
7.46
5.55
7.42
5.68
6.03
6.59
6.12
ND
7.65
4.83
5.17
6.80
5.44
7.28
7.61
5.77
ND
1.02
0.64
0.93
0.91
0.95
1.20
1.15
0.94
ND
M HEPES buffer, physiological pH, Fig. 3) and pH 5.6 (0.02 M MES
buffer, parasites’ DV, Fig. 4), respectively, showed a significant decrease
in the intensity of the band representing monomeric heme. By analyzing
the titration curves using HypSpec, a nonlinear least-square fitting
program, the binding of compound 19a with heme was determined via
log K values at both tested pH conditions and the results are included in
Table 3. To compare the values with those of the standard drug, CQ, the
UV–vis experiment was conducted with CQ and monomeric heme under
identical conditions. As evident, the binding of 19a with heme was
comparable to CQ at both physiological and acidic pH.
g
h
a
b
c
d
e
f
6.45
ND
6.60
ND
1.02
ND
6.05
ND
6.98
ND
1.15
ND
ND
ND
ND
In conclusion, a series of 1H-1,2,3-triazole-tethered benzoxaborole-
derivatives as well as 4-aminoquinoline-benzoxaborole conjugates
were synthesized and evaluated for their anti-plasmodial activities
against both CQ-sensitive as well as resistant strains of P. falciparum.
SAR studies indicated the improvement in anti-plasmodial activities on
replacing the aryl ring with quinoline core with a marginal preference of
flexible alkyl chain as linker over piperazinering. Hybrids 19a, 19b and
g
h
a
b
c
d
e
f
5.63
ND
7.19
ND
1.27
ND
5.66
5.02
5.24
6.40
4.94
ND
5.18
4.56
6.80
6.39
4.17
ND
0.91
0.90
1.29
0.99
0.84
ND
2
4 with ethyl, propyl and piperazyl-ethyl as spacer along with 4-amino-
g
h
5.00
5.00
5.20
5.59
5.18
6.19
6.49
4.87
4.30
6.29
7.37
5.18
4.15
4.13
8.34
ND
4.27
5.37
6.77
7.74
5.22
7.39
6.19
5.22
5.07
7.09
6.23
4.64
3.78
3.91
8.26
ND
0.85
1.07
1.30
1.38
1.00
1.19
0.95
1.07
1.17
1.12
0.84
0.89
0.91
0.94
0.99
ND
quinoline core and oxaborole ring proved to be most promising among
the series exhibiting IC50s of 3.78, 3.91 and 4.86
respectively.
μM on W2 strain,
0
3
3
. Experimental section
4
5
1H NMR spectra were recorded in deuterochloroform (CDCl
DMSO‑d with Jeol 300 (300 MHz), Jeol 400 (400 MHz) and Bruker 500
500 MHz) spectrometer using TMS as an internal standard. Chemical
7a
7b
8a
8b
9a
9b
2
3
) and
6
(
shift values are expressed as parts per million downfield from TMS and J
values are in hertz. Splitting patterns are indicated as s: singlet, d:
doublet, t: triplet, m: multiplet, dd: double doublet, ddd: doublet of a
3
13
doublet of a doublet, and br: broad peak. C NMR spectra were recor-
4
5.31
0.024
4.86
0.475
0.91
19.79
ded on a Bruker 400 (100 MHz) and Bruker 500 (125 MHz) spectrometer
CQ
3 6
in deuterochloroform (CDCl ) and dimethylsulfoxide (DMSO‑d ) using
a
CQ-S: Chloroquinesusceptible strain.
CQ-R: Chloroquine resistant strain.
TMS as internal standard. High resolution mass spectra were recorded
on a Bruker-micrOTOF-Q II spectrometer.
b
c
Resistance index (RI): IC50(W2)/IC50(3D7) according to chloroquine
susceptibility.
exert their anti-plasmodial activities via inhibiting heme to hemozoin
conversion through formation of a complex between the porphyrin ring
of free heme and quinoline core. CQ complexation with heme in aqueous
medium therefore can be identified by changes in the UV–vis spectrum
of aqueous hematin [24].
Table 2
Cytotoxic activities of 19a, 19b and 24 on Vero cells.
Compounds
IC50
(μ
M) Vero Kidney Cell line
IC50
(μ
M) (W2 strain)
SI
Thus, in order to decipher the primary mode of action of the syn-
thesized hybrids, we conducted UV–vis spectrophotometry studies of the
most potent compound, 19a, with monomeric heme. A solution of
1
9a
>100
>100
3.78
3.91
4.86
26.45
25.57
16.94
19b
24
82.36
Fig. 2. General structure of lead compound and target hybrid compounds.
5

A. Saini et al.
Bioorganic Chemistry 109 (2021) 104733
Fig. 3. Titration of monomeric heme (12
μ
M) at pH 7.4 (0.02 M HEPES buffer in aqueous DMSO solution) with increasing concentration of 19a (0–18
μ
M) in 0.02 M
HEPES buffer in aqueous DMSO solution and linear dependence of absorption at 401 nm on heme-19a complex concentration.
Fig. 4. Titration of monomeric heme (12
μ
M) at pH 5.6 (0.02 M MES buffer in aqueous DMSO solution) with increasing concentration of 19a (0–16
μ
M) in 0.02 M
MES buffer in aqueous DMSO solution and linear dependence of absorption at 401 nm on heme-19a complex concentration.
7
.28 (d, J = 3.0 Hz, 1H, ArH), 7.30 (d, J = 8.0 Hz, 1H, ArH), 7.50–7.56
13
Table 3
(
m, 2H, ArH), 7.65 (s, 1H, triazole-H), 10.30 (s, 1H,
–
CHO); C NMR
): δ ppm = 29.8, 47.2, 62.2, 63.8, 114.2, 114.4,
18.3, 121.2, 123.2, 123.5, 129.6, 134.0, 134.7, 143.0, 157.9, 158.3,
91.6. HRMS Calculated for C19 18BrN
Binding constant (log K) for 19a and CQ with monomeric heme.
(
125 MHz, DMSO‑d
6
Entry
pH 5.6
MES Buffer)
pH 7.4
1
1
(
(HEPES Buffer)
H
3
O
3
[M+1] 416.0532 and [M+3]
1
9a
6.81
5.18
6.89
5.10
418.0532 found 416.0541 and 418.0524; Anal. Calcd. (%) for: C, 54.82;
H, 4.36; N, 10.09; Found: C, 54.95; H, 4.46; N, 10.01.
CQ
3
.1.2. 2-bromo-5-((1-(4-phenoxybutyl)-1H-1,2,3-triazol-4-yl)methoxy)
benzaldehyde (3b)
White Solid; Yield: 88%; H NMR (500 MHz, CDCl
H, CH CH ), 3.96–3.99 (m, 2H,
), 2.02–2.09 (m, 2H,
), 4.51–4.54 (m, 2H, ), 5.25 (s, 2H, ),
.88–6.90 (d, J = 8.0 Hz, 2H, ArH), 6.96 (t, J = 7.5 Hz, 1H, ArH), 7.20
dd, J = 3.0, 8.5 Hz, 1H, ArH), 7.29 (d, J = 3.0 Hz, 1H, ArH), 7.32 (d, J =
.0 Hz, 1H, ArH), 7.46–7.51 (m, 2H, ArH), 7.62 (s, 1H, triazole H), 9.9
s, 1H,
CHO); 13C NMR (125 MHz, DMSO‑d
): δ ppm = 26.0, 27.1,
1.9, 63.0, 65.4, 114.0, 114.3, 118.4, 120.9, 122.8, 123.5, 129.1, 134.0,
34.5, 143.3, 158.1, 158.9, 191.2. HRMS Calculated for C20 20BrN
3
.1. General procedure for the synthesis of precursors 3/8/13/17/22
To the stirred solution of azide based precursors 2/7/12/16/21 (1
1
3
): δ 1.81–1.87 (m,
2
–
6
2
–
– –
2
–
mmol) and O-propargylated-2-bromobenzaldehyde (1 mmol) inEtOH:
O (90:10) mixture, was added CuSO O (0.055 mmol) and sodium
N
–
CH2
–
–
O
–
CH2
O
– – –
CH2
H
2
4
⋅5H
2
ascorbate (0.143 mmol). The reaction mixture was stirred at room
(
temperature for 7–8 h and progress of reaction was monitored via TLC.
After the usual workup in CHCl and H O, organic layers were collected,
3 2
8
–
(
–
6
combined, and dried over anhydrous sodium sulphate and evaporated to
give crude product which was further purified through column
chromatography.
6
1
H
3 3
O
[
M+1] 430.0688 and [M+3] 432.0688 found 430.0674 and 432.0679;
Anal. Calcd. (%) for: C, 55.83; H, 4.69; N, 9.77; Found: C, 55.91; H, 4.80;
N, 9.94.
3
.1.1. 2-bromo-5-((1-(3-phenoxypropyl)-1H-1,2,3-triazol-4-yl)methoxy)
benzaldehyde (3a)
White Solid; Yield: 90%; H NMR (500 MHz, CDCl
H, CH CH ), 4.61–4.64 (m, 2H,
), 3.96–3.98 (m, 2H,
CH2 ), 5.22 (s, 2H,
CH2–), 6.87–6.88 (d, J = 8.0 Hz, 2H,
ArH), 6.98 (t, J = 7.5 Hz, 1H, ArH), 7.11 (dd, J = 3.0, 8.5 Hz, 1H, ArH),
1
3
): δ 2.41–2.44 (m,
3
.1.3. 2-bromo-5-((1-(5-phenoxypentyl)-1H-1,2,3-triazol-4-yl)methoxy)
benzaldehyde (3c)
White Solid; Yield: 86%; H NMR (500 MHz, CDCl
2
–
–
–
2
–
–
–
N
– –
2
O
O
– –
1
3
): δ 1.52–1.58 (m,
6

A. Saini et al.
Bioorganic Chemistry 109 (2021) 104733
2
H,
.95–3.98 (m, 2H,
CH
H, ArH), 7.14 (dd, J = 3.0, 8.5 Hz, 1H, ArH), 7.28–7.31 (m, 2H, ArH),
.53–7.57 (m, 2H, ArH), 7.63 (s, 1H, triazole H), 10.2 (s, 1H, CHO);
): δ ppm = 23.2, 28.6, 29.9, 50.3, 62.3,
7.1, 114.2, 114.4, 118.4, 120.7, 122.7, 123.3, 129.4, 134.0, 134.7,
43.0, 157.9, 158.8, 191.6. HRMS Calculated for C21 22BrN
[M+1]
44.0845 and [M+3] 446.0845 found 444.0837 and 446.0856; Anal.
–
CH
2
–
), 1.82–1.87 (m, 2H,
CH
), 4.40–4.44 (m, 2H,
), 6.88 (d, J = 8.0 Hz,2H, ArH), 6.95 (t, J = 7.5 Hz,
–
CH
2
–
), 1.98–2.06 (m, 2H,
–
2
CH
2
–
),
7.63 (s, 1H, triazole
–
H), 7.77 (d, J = 8.0 Hz, 1H, ArH), 8.09 (d, J = 6.5
6
Hz, 1H, ArH); 10.06 (s, 1H, ): δ
–
CHO); 13C NMR (125 MHz, DMSO‑d
3
N
– –
–
–
2
–
O
–
CH
–
), 5.24
(
s, 2H,
–
O
–
2
ppm = 23.2, 28.6, 29.9, 48.1, 62.2, 67.9, 104.7, 114.2, 114.9, 120.2,
1
7
121.1, 122.5, 123.2, 124.3, 125.4, 125.6, 126.3, 127.0, 128.5, 130.0,
–
–
3 3
137.0, 142.0, 155.6, 159.0, 191.3. HRMS Calculated for C25H24BrN O
1
3
C NMR (125 MHz, DMSO‑d
6
[M+1] 494.1001 and [M+3] 496.1001 found 494.1012 and 496.1009;
Anal. Calcd. (%) for: C, 60.74; H, 4.89; N, 8.50; Found: C, 60.61; H, 4.97;
N, 8.66.
6
1
4
H
3 3
O
Calcd. (%) for: C, 56.77; H, 4.99; N, 9.46; Found: C, 56.88; H, 4.91; N,
3.1.8. 2-bromo-5-((1-(6-(naphthalene-1-yloxy)hexyl)-1H-1,2,3-triazol-4-
9
.33.
yl)methoxy)benzaldehyde (3 h)
1
White Solid; Yield: 87%; H NMR (300 MHz, CDCl
3
): δ 1.25–1.28 (m,
), 1.81–1.85 (m, 2H, CH ),
), 3.99–4.02 (m, 2H, CH ), 4.45–4.48
), 5.14 (s, 2H, CH
), 6.67 (d, J = 7.8 Hz, 1H,
ArH), 6.91 (dd, J = 3.0, 8.7 Hz, 1H, ArH), 7.23 (t, J = 8.1 Hz, 1H, ArH),
7.35–7.40 (m, 5H, ArH), 7.64 (s, 1H, triazole H), 7.77 (d, J = 8.1 Hz,
1H, ArH), 8.06 (d, J = 6.6 Hz, 1H, ArH); 10.11 (s, 1H,
(125 MHz, DMSO‑d
3
.1.4. 2-bromo-5-((1-(6-phenoxyhexyl)-1H-1,2,3-triazol-4-yl)methoxy)
2H,
2.05–2.08 (m, 2H,
(m, 2H, CH
–
CH
2
–
), 1.48–1.53 (m, 2H,
–
CH
2
–
– –
2
benzaldehyde (3d)
White Solid; Yield: 83%; H NMR (500 MHz, CDCl
H, CH CH ), 1.81–1.88 (m, 2H,
), 1.51–1.58 (m, 2H,
.06–2.10 (m, 2H, CH ), 4.02–4.05 (m, 2H, CH ), 4.54–4.57
CH ), 5.26 (s, 2H, CH
), 6.84–6.87 (m, 2H,
ArH), 7.00 (t, J = 7.5 Hz, 1H, ArH), 7.15 (dd, J = 3.0, 8.5 Hz, 1H, ArH),
–
CH
2
–
–
N
– –
2
1
3
): δ 1.24–1.29 (m,
CH ),
–
O
–
–
2
–
O
– –
2
2
2
–
2
–
–
2
–
– –
2
–
2
–
–
2
N
–
–
–
–
2
2
1
3
(
m, 2H,
–
O
–
–
–
O
–
–
CHO); C NMR
6
): δ ppm = 25.6, 27.1, 28.6, 29.8, 47.8, 62.0, 68.0,
7
.25 (d, J = 3.0 Hz, 1H, ArH), 7.35 (d, J = 8.0 Hz, 1H, ArH), 7.45–7.49
m, 2H, ArH), 7.56 (s, 1H, triazole H), 10.3 (s, 1H,
CHO); 13C NMR
125 MHz, DMSO‑d
): δ ppm = 25.5, 27.2, 28.5, 29.9, 50.1, 62.2, 68.0,
14.1, 114.5, 118.3, 121.2, 123.1, 123.5, 129.2, 134.2, 134.6, 143.0,
57.9, 158.6, 191.0. HRMS Calculated for C22 24BrN
[M+1]
58.1001 and [M+3] 460.1001 found 458.1009 and 460.1015; Anal.
104.8, 114.2, 114.8, 120.3, 121.0, 122.3, 123.6, 124.6, 125.4, 125.7,
126.2, 127.4, 128.3, 130.2, 137.2, 141.5, 155.4, 159.1, 191.0. HRMS
(
(
–
–
6
Calculated for C26
H
26BrN
3
O
3
[M+1] 508.1158 and [M+3] 510.1158
1
1
4
found 508.1150 and 510.1170; Anal. Calcd. (%) for: C, 61.42; H, 5.15;
N, 8.27; Found: C, 61.50; H, 5.26; N, 8.44.
H
3 3
O
Calcd. (%) for: C, 57.65; H, 5.28; N, 9.17; Found: C, 57.73; H, 5.11; N,
3.1.9. 5-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)-2-bromobenzaldehyde
9
.09.
(8)
1
White Solid; Yield: 93%; H NMR (500 MHz, CDCl
3
): δ 5.22 (s, 2H,
), 6.90–6.94 (m,2H, ArH),
7.22–7.27 (m, 2H, ArH), 7.42–7.45 (m, 3H, ArH), 7.65 (s, 1H, tri-
3
.1.5. 2-bromo-5-((1-(3-(naphthalen-1-yloxy)propyl)-1H-1,2,3-triazol-4-
2 2
N CH ), 5.42 (s, 2H, O CH
– – – – – –
yl)methoxy)benzaldehyde (3e)
1
13
White Solid; Yield: 90%; H NMR (300 MHz, CDCl
3
): δ 2.43–2.49 (m,
azole
(125 MHz, DMSO‑d
128.8, 129.2, 131.0, 134.5, 143.1, 145.2, 155.9, 159.8, 191.0. HRMS
Calculated for C17 14BrN
–
H), 7.75 (d, J = 8.0 Hz, 1H, ArH), 10.0 (s, 1H,
–
CHO); C NMR
2
–
6
7
1
H,
–
–
CH
CH2
.94 (dd, J = 3.0, 8.7 Hz, 1H, ArH), 7.24 (t, J = 8.1 Hz, 1H, ArH),
.34–7.41 (m,5H, ArH), 7.52 (s, 1H, triazole H), 7.71 (d, J = 8.1 Hz,
H, ArH), 8.12 (d, J = 6.6 Hz, 1H, ArH); 10.17 (s, 1H,
CHO); 13C NMR
2
–
–
), 4.00–4.04 (m, 2H,
–
N
–
CH
2
–
), 4.58–4.63 (m, 2H,
6
): δ ppm = 55.5, 70.1, 107.2, 114.8, 122.1, 128.3,
O
), 5.06 (s, 2H,
O
– –
CH2–), 6.63 (d, J = 7.8 Hz, 1H, ArH),
H
3
O
2
[M+1] 372.0269 and [M+3] 373.0269
–
found 372.0282 and 373.0259; Anal. Calcd. (%) for: C, 54.86; H, 3.79;
N, 11.29; Found: C, 54.71; H, 3.91; N, 11.46.
–
(
125 MHz, DMSO‑d
6
): δ ppm = 28.5, 48.0, 62.4, 68.0, 105.2, 114.1,
1
1
14.9, 120.0, 121.4, 122.1, 123.1, 124.4, 125.3, 125.6, 126.1, 127.2,
28.6, 130.1, 137.1, 141.2, 155.9, 159.4, 191.2. HRMS Calculated for
3.1.10. 2-bromo-5-((1-(7-chloroquinolin-4-yl)-1H-1,2,3-triazol-4-yl)
methoxy)benzaldehyde (13)
C
23
H
20BrN
3
O
3
[M+1] 466.0688 and [M+3] 468.0688 found 466.0672
White Solid; Yield: 92%; 1H NMR (300 MHz, DMSO‑d
6
): δ 5.25 (s,
), 6.60 (d, J = 5.1 Hz, 1H, ArH), 7.18 (dd, J = 2.7, 8.7
NH-exchangeable with D
O + 3ArH),
and 468.0697; Anal. Calcd. (%) for: C, 59.24; H, 4.32; N, 9.01; Found: C,
2H,
O CH
2
– – –
5
9.33; H, 4.40; N, 9.15.
Hz, 1H, ArH), 7.44–7.49 (m, 4H,
–
2
7
.82 (d, J = 3.0 Hz, 1H, ArH), 8.13 (d, J = 8.7 Hz, 1H, ArH), 8.31 (s, 1H,
13
3
.1.6. 2-bromo-5-((1-(4-(naphthalen-1-yloxy)butyl)-1H-1,2,3-triazol-4-
triazole
–
H), 8.34 (d, J = 5.1 Hz, 1H, ArH), 10.00 (s, 1H,
): δ ppm = 62.0,80.4, 113.1, 113.5, 118.1,
120.9, 125.5, 127.0, 128.5, 129.1, 131.0, 135.4, 141.1, 142.2, 144.7,
4 2
150.0, 152.7, 158.1, 190.0. HRMS Calculated for C19 12BrClN O
–
CHO);
C
yl)methoxy)benzaldehyde (3f)
NMR (100 MHz, DMSO‑d
6
1
White Solid; Yield: 88%; H NMR (300 MHz, CDCl
3
): δ 1.80–1.86 (m,
2
–
H,
–
CH
2
–
–
), 2.10–2.15 (m, 2H,
), 4.60–4.64 (m, 2H,
), 6.61 (d, J = 7.8 Hz, 1H, ArH), 6.96 (dd, J = 2.7, 8.7 Hz,
–
CH
2
–
–
), 4.20–4.24 (m, 2H,
H
N
O
–
CH2
–
O
CH2 ), 5.15 (s, 2H,
–
[M+1] 442.9832 and [M+3] 444.9832 found 442.9841 and 444.9821;
Anal. Calcd. (%) for: C, 51.43; H, 2.73; N, 12.63; Found: C, 51.54; H,
2.59; N, 12.73.
–
–
CH2
–
1
H, ArH), 7.23 (t, J = 8.1 Hz, 1H, ArH), 7.32–7.38 (m,5H, ArH), 7.55 (s,
H, triazole
H), 7.69 (d, J = 8.1 Hz, 1H, ArH), 8.01 (d, J = 6.6 Hz, 1H,
CHO); 13C NMR (125 MHz, DMSO‑d
): δ ppm =
6.2, 27.3, 47.8, 62.5, 67.6, 104.8, 113.8, 114.8, 120.1, 121.6, 122.0,
23.4, 124.3, 125.4, 125.6, 126.0, 127.5, 128.5,130.0, 136.9, 141.6,
55.4, 159.3, 191.1. HRMS Calculated for C24 22BrN
[M+1]
80.0845 and [M+3] 482.0845 found 480.0853 and 480.0858; Anal.
1
–
ArH); 10.20 (s, 1H,
–
6
3.1.11. 2-bromo-5-((1-(2-((7-chloroquinolin-4-yl)amino)ethyl)-1H-1,2,3-
2
1
1
4
triazol-4-yl)methoxy)benzaldehyde (17a)
1
White Solid; Yield: 89%; H NMR (400 MHz, DMSO‑d
6
): δ 3.36–3.38
), 5.18 (s, 2H,
), 6.51 (d, J = 5.2 Hz, 1H, ArH), 7.29 (dd, J = 2.8, 8.0 Hz,1H,
ArH), 7.41–7.48 (m, 4H, NH-exchangeable with D O + 3ArH), 7.76
(d, J = 3.2 Hz, 1H, ArH), 8.11 (d, J = 8.8 Hz, 1H, ArH), 8.25 (s, 1H,
H
3
O
3
(m, 2H,
– –
CH
2 2
N CH ), 4.63–4.65 (m, 2H, N CH
– – – – – –
–
O
2
Calcd. (%) for: C, 60.01; H, 4.62; N, 8.75; Found: C, 59.92; H, 4.75; N,
–
2
8
.86.
1
3
triazole
–
H), 8.36 (d, J = 5.2 Hz, 1H, ArH), 9.93 (s, 1H,
–
CHO);
C
3
.1.7. 2-bromo-5-((1-(5-(naphthalen-1-yloxy)pentyl)-1H-1,2,3-triazol-4-
NMR (100 MHz, DMSO‑d
6
): δ ppm = 42.8, 48.4, 61.7,99.3, 112.8, 113.6,
yl)methoxy)benzaldehyde (3 g)
117.6, 120.8, 125.8, 127.3, 128.6, 129.5, 131.0, 135.8, 140.8, 142.3,
144.3, 149.8, 152.8, 157.8, 190.5. HRMS Calculated for
1
White Solid; Yield: 91%; H NMR (500 MHz, CDCl
–
3
): δ 1.52–1.57 (m,
CH ),
), 5.16
), 6.71 (d, J = 8.0 Hz, 1H, ArH), 6.89 (dd, J = 3.0, 9.0
Hz, 1H, ArH), 7.29 (t, J = 8.0 Hz, 1H, ArH), 7.40–7.48 (m, 5H, ArH),
2
H,
.10–4.13 (m, 2H,
– –
CH
CH
2
–
), 1.77–1.84 (m, 2H,
–
CH
–
2
), 2.05–2.11 (m, 2H,
–
2
2
–
C
21
H17BrClN
5
O
2
[M+1] 486.0254 and [M+3] 488.0254 found
4
N
– –
CH
2
–
), 4.55–4.59 (m, 2H,
–
O
–
CH
–
486.0244 and 486.0269; Anal. Calcd. (%) for: C, 51.82; H, 3.52; N,
14.39; Found: C, 51.71; H, 3.66; N, 14.27.
(
s, 2H,
–
O
2
7

A. Saini et al.
Bioorganic Chemistry 109 (2021) 104733
3
1
.1.12. 2-bromo-5-((1-(3-((7-chloroquinolin-4-yl)amino)propyl)-1H-
478.2435 found 478.2448; Anal.Calcd. (%) for: C, 65.42; H, 6.76; N,
8.80; Found: C, 65.30; H, 6.69; N, 8.91.
,2,3-triazol-4-yl)methoxy)benzaldehyde (17b)
1
White Solid; Yield: 85%; H NMR (300 MHz, DMSO‑d
6
): δ 1.91–2.00
), 4.60–4.63 (m, 2H,
), 6.58 (d, J = 4.8 Hz, 1H, ArH),
.30 (dd, J = 2.7, 9.0 Hz, 1H, ArH), 7.38–7.48 (m, 4H, NH-
exchangeable with D
O + 3ArH), 7.76 (d, J = 3.0 Hz, 1H, ArH), 8.14 (d,
J = 9.0 Hz, 1H, ArH), 8.23 (s, 1H, triazole H), 8.37 (d, J = 4.8 Hz, 1H,
ArH), 9.89 (s, 1H,
CHO); 13C NMR (100 MHz, DMSO‑d
): δ ppm =
8.9, 42.7, 48.6, 62.0,99.5, 113.0, 113.6, 118.3, 121.0, 125.6, 127.2,
28.6, 129.4, 130.9, 135.5, 141.3, 142.4, 144.6, 150.2, 153.0, 157.9,
91.1. HRMS Calculated for C22 19BrClN
[M+1] 500.0411 and
(
m, 2H,
–
CH
2
–
), 3.32–3.36 (m, 2H,
N
– –
CH
–
2
3.2.3. ((1-(5-phenoxypentyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(4,4,5,5-
–
7
N
–
CH2
–
), 5.11 (s, 2H,
–
O
–
CH
–
tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (4c)
2
1
–
Yellow waxy Solid; Yield: 71%; H NMR (500 MHz, CDCl
): δ 1.33 (s,
), 1.83–1.89 (m, 2H,
), 4.09–4.12 (m, 2H, CH ),
), 5.23 (s, 2H, CH
), 6.82 (d, J =
8.0 Hz,2H, ArH), 6.95–6.99 (m, 2H, ArH), 7.26–7.35 (m, 3H, ArH), 7.60
(s, 1H, triazole CHO);
H), 8.19 (d, J = 8.0 Hz, 1H, ArH), 9.93 (s, 1H,
C NMR (125 MHz, DMSO‑d
): δ ppm = 22.6, 23.5, 28.5, 29.6, 50.1,
62.8, 69.0, 92.1, 113.6, 114.2, 120.3, 121.1, 128.1, 129.6, 132.0, 133.9,
137.3, 143.1, 158.9, 160.0, 191.2. HRMS Calculated for C27 34BN
M+1] 492.2592 found 492.2584; Anal.Calcd. (%) for: C, 66.00; H,
6.97; N, 8.55; Found: C, 65.14; H, 7.07; N, 8.72.
3
12H, 4 ×
CH
), 2.14–2.19 (m, 2H,
4.52–4.55 (m, 2H, CH
–
CH
3
), 1.55–1.64 (m, 2H,
CH
2
– –
2
–
–
–
2
–
CH
–
–
N
– –
2
2
–
–
O
–
–
O
– – –
6
2
2
2
1
1
–
–
1
3
H
5
O
2
6
[
M+3] 502.0411 found 500.0401 and 502.0403; Anal. Calcd. (%) for: C,
5
2.77; H, 3.82; N, 13.99; Found: C, 52.87; H, 3.66; N, 13.90.
H
3 5
O
[
3
1
.1.13. 2-bromo-5-((1-(2-(4-(7-chloroquinolin-4-yl)piperazin-1-yl)ethyl)-
H-1,2,3-triazol-4-yl)methoxy)benzaldehyde (22)
White Solid; Yield: 85%; 1H NMR (300 MHz, DMSO‑d
): δ 3.12 (s,
), 4.17–4.28 (m, 4H,
), 6.65 (d, J = 5.1 Hz, 1H,
3.2.4. 5-((1-(6-phenoxyhexyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-
6
4
2
H, 2 ×
–
N
–
CH
2
–
), 3.74 (s, 4H, 2 ×
–
N
–
–
CH
2
–
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (4d)
1
×
–
N
–
CH
2
–
), 5.15 (s, 2H,
–
O
–
CH
2
Yellow waxy Solid; Yield: 75%; H NMR (500 MHz, CDCl
3
): δ 1.20 (s,
), 1.60–1.68 (m, 2H,
), 2.02–2.10 (m, 2H, CH ),
), 4.55–4.58 (m, 2H, CH ), 5.26
), 6.77 (d, J = 8.0 Hz, 2H, ArH), 6.90–6.95 (m, 2H,
ArH), 7.24–7.33 (m, 3H, ArH),7.62 (s, 1H, triazole H), 8.13 (d, J = 8.0
Hz, 1H, ArH), 10.00 (s, 1H, ): δ
CHO); 13C NMR (125 MHz, DMSO‑d
ArH), 7.22 (dd, J = 2.4, 8.7 Hz,1H, ArH), 7.32–7.42 (m, 3H, ArH), 7.60
d, J = 2.4 Hz, 1H, ArH), 8.04 (d, J = 9.0 Hz, 1H, ArH), 8.32 (s, 1H,
triazole
H), 8.40 (d, J = 5.1 Hz, 1H, ArH), 10.01 (s, 1H,
CHO); 13
NMR (100 MHz, DMSO‑d
): δ ppm = 49.0, 50.8, 52.7, 57.1, 70.2, 106.4,
12.7, 113.3, 119.2, 121.3, 125.1, 127.0, 128.9, 130.1, 132.2, 135.4,
42.0, 142.6, 145.3, 150.0, 152.8, 158.4, 190.6. HRMS Calculated for
24ClBrN
12H, 4 ×
CH
), 1.81–1.88 (m, 2H,
4.05–4.08 (m, 2H, CH
(s, 2H, CH
–
CH
3
), 1.25–1.32 (m, 2H,
CH
2
– –
(
–
2
–
–
–
CH
–
2
– –
2
2
–
–
C
–
N
–
–
O
– –
2
–
O
– –
6
2
1
1
–
–
6
C
25
H
6
O
2
[M+1] 555.0833 and [M+3] 557.0833 found
ppm = 23.2, 25.0, 27.3, 28.8, 29.7, 51.0, 63.1, 69.5, 92.5, 113.8, 114.5,
5
1
55.0849 and 557.0842; Anal. Calcd. (%) for: C, 54.02; H, 4.35; N,
5.12; Found: C, 54.11; H, 4.50; N, 15.04.
120.6, 121.2, 128.0, 129.4, 132.1, 134.0, 137.3, 142.7, 158.8, 160.2,
190.9. HRMS Calculated for C28
06.2763; Anal.Calcd. (%) for: C, 66.54; H, 7.18; N, 8.31; Found: C,
66.60; H, 7.10; N, 8.18.
H
3
36BN O
5
[M+1] 506.2748 found
5
3
.2. General procedure for the synthesis of compounds 4/9/14/18/23
Nitrogen was bubbled through the solution of 3/8/13/17/22(1
3.2.5. 5-((1-(3-(naphthalen-1-yloxy)propyl)-1H-1,2,3-triazol-4-yl)
methoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde
mmol) in 1,4-dioxane for 15 min.. Potassium acetate (3 mmol), Pd(dppf)
Cl
2
(0.1 mmol) and bis(pinacolato)diboron (1.5 mmol) were added and
(4e)
◦
1
the reaction mixture was allowed to stir for 16–20 h at 100 C under N
2
.
Yellow waxy Solid; Yield: 79%; H NMR (500 MHz, CDCl
3
): δ 1.25 (s,
), 4.00–4.04 (m, 2H,
), 5.23 (s, 2H,
), 6.71 (d, J = 8.0 Hz, 1H, ArH), 6.90 (d, J = 2.0 Hz, 1H,
H), 7.79 (d, J = 6.0
12H, 4 ×
–
CH ), 2.32–2.37 (m, 2H,
– –
3
CH2
The reaction monitored by TLC and reaction mixture was evaporated
under reduced pressure to dryness. The residue was purified via column
chromatography using 60–120 silica gel to afford desired product as
yellow waxy solid.
–
N
–
CH
–
), 4.52–4.55 (m, 2H,
–
O
–
CH2
–
2
–
O
– –
CH2
ArH), 7.29–7.45 (m, 6H, ArH), 7.60 (s, 1H, triazole
Hz, 1H, ArH), 8.20 (d, J = 8.5 Hz, 1H, ArH); 9.78 (s, 1H,
NMR (125 MHz, DMSO‑d
–
1
3
–
CHO);
C
3
.2.1. 5-((1-(3-phenoxypropyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-
6
): δ ppm = 22.7, 28.6, 48.9, 62.5, 69.0, 92.8,
(
4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (4a)
106.0, 114.4, 120.0, 121.3, 123.2, 125.3, 125.9, 126.4, 127.5, 128.3,
131.0, 132.1, 133.9, 134.6, 137.1, 142.3, 155.0, 159.7, 191.3. HRMS
1
Yellow waxy Solid; Yield: 78%; H NMR (500 MHz, CDCl
CH CH ), 3.98–4.02 (m, 2H,
), 2.43–2.48 (m, 2H,
), 4.51–4.54 (m, 2H, CH2 ), 5.24 (s, 2H,
), 6.80 (d, J = 8.0 Hz, 2H, ArH), 6.90 (t, J = 7.5 Hz, 1H,
3
): δ 1.29 (s,
1
2H, 4 ×
–
3
–
–
2
Calculated for C29
H
32BN
3
O
5
[M+1] 514.2435 found 514.2448; Anal.
–
–
N
–
CH
–
–
O
–
–
Calcd. (%) for: C, 67.85; H, 6.28; N, 8.18; Found: C, 67.96; H, 6.45; N,
8.31.
2
O
CH2
– –
ArH), 6.95 (d, J = 2.5 Hz, 1H, ArH), 7.28–7.39 (m, 3H, ArH),7.63 (s, 1H,
triazole
H), 8.12 (d, J = 8.0 Hz, 1H, ArH), 9.88 (s, 1H,
CHO); 13
NMR (125 MHz, DMSO‑d
): δ ppm = 22.8, 29.6, 51.0, 63.0, 69.2, 92.5,
13.7, 114.4, 120.0, 121.1, 128.4, 129.5, 132.0, 134.5, 137.6, 142.8,
58.7, 159.8, 191.4. HRMS Calculated for 30BN
–
–
C
3.2.6. 5-((1-(4-(naphthalen-1-yloxy)butyl)-1H-1,2,3-triazol-4-yl)
methoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde
6
1
1
4
9
(4f)
1
C
25
H
3
O
5
[M+1]
Yellow waxy Solid; Yield: 74%; H NMR (500 MHz, CDCl
3
): δ 1.22 (s,
), 2.12–2.18 (m, 2H,
), 4.48–4.51 (m, 2H,
), 6.78 (d, J = 8.0 Hz, 1H, ArH),
6.95 (d, J = 2.0 Hz, 1H, ArH), 7.31–7.47 (m, 6H, ArH), 7.66 (s, 1H,
H), 7.82 (d, J = 6.0 Hz, 1H, ArH), 8.12 (d, J = 8.0 Hz, 1H,
12H, 4 ×
CH
), 4.06–4.09 (m, 2H,
– – –
CH2 ), 5.19 (s, 2H, O CH2
CH ), 1.82–1.88 (m, 2H,
– – –
3
CH2
64.2279 found 464.2268; Anal. Calcd. (%) for: C, 64.81; H, 6.53; N,
.07; Found: C, 64.73; H, 6.39; N, 8.95.
–
–
2
N
– – –
CH2
–
O
–
–
3
.2.2. 5-((1-(4-phenoxybutyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-
triazole
–
(
4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (4b)
1
13
ArH); 9.91 (s, 1H,
–
CHO); C NMR (125 MHz, DMSO‑d ): δ ppm =
6
Yellow waxy Solid; Yield: 80%; H NMR (500 MHz, CDCl
2H, 4 × CH ), 1.78–1.84 (m, 2H, CH ), 2.07–2.14 (m, 2H,
CH CH2 ), 4.46–4.49 (m, 2H,
), 4.01–4.04 (m, 2H,
CH2 ), 5.18 (s, 2H, CH2
), 6.76 (d, J = 8.0 Hz, 2H, ArH),
.92–6.97 (m, 2H, ArH), 7.25–7.35 (m, 3H, ArH), 7.66 (s, 1H, tri-
azole
H), 8.11 (d, J = 8.0 Hz, 1H, ArH), 9.80 (s, 1H,
CHO); 13C NMR
125 MHz, DMSO‑d
): δ ppm = 23.0, 26.2, 27.0, 50.8, 62.9, 69.4, 92.3,
13.9, 114.5, 120.3, 121.0, 128.2, 129.5, 132.1, 134.3, 137.5, 143.0,
58.6, 160.2, 191.0. HRMS Calculated for 32BN
[M+1]
3
): δ 1.27 (s,
1
–
3
–
–
2
23.1, 26.3, 27.4,50.0, 62.6, 68.8, 92.7, 106.4, 114.2, 120.1, 121.4,
123.0, 125.2, 125.5, 126.6, 127.4, 128.3, 131.1, 132.3, 134.3, 134.9,
137.0, 142.3, 155.1, 159.6, 191.0. HRMS Calculated for C30H34BN O
–
–
N
– – –
2
–
O
–
–
O
– – –
3
5
6
[M+1] 528.2592 found 528.2582; Anal.Calcd. (%) for: C, 68.32; H,
–
–
6.50; N, 7.97; Found: C, 68.50; H, 6.41; N, 8.09.
(
6
1
1
C
26
H
3 5
O
8

A. Saini et al.
Bioorganic Chemistry 109 (2021) 104733
3
.2.7. 5-((1-(5-(naphthalen-1-yloxy)pentyl)-1H-1,2,3-triazol-4-yl)
exchangeable with D
2
O + 3ArH), 7.84 (d, J = 3.0 Hz, 1H, ArH), 8.09 (d,
methoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde
J = 8.7 Hz, 1H, ArH), 8.33 (s, 1H, triazole H), 8.41 (d, J = 5.1 Hz, 1H,
–
(
4 g)
Yellow waxy Solid; Yield: 70%; H NMR (500 MHz, CDCl
2H, 4 × CH ), 1.60–1.61 (m, 2H, CH -), 2.00–2.09 (m, 4H, 2 ×
CH CH2 ), 4.42–4.45 (m, 2H,
), 4.13–4.16 (m, 2H,
CH2 ), 5.25 (s, 2H, CH2
), 6.80 (d, J = 8.0 Hz, 1H, ArH),
.89 (d, J = 1.5 Hz, 1H, ArH), 7.36–7.48 (m, 6H, ArH), 7.62 (s, 1H,
triazole
H), 7.80 (d, J = 6.0 Hz, 1H, ArH), 8.23 (d, J = 8.5 Hz, 1H,
ArH); 9.98 (s, 1H,
NMR (125 MHz, DMSO‑d
ArH), 9.90 (s, 1H,
–
CHO); 13C NMR (100 MHz, DMSO‑d
6
): δ ppm =
1
3
): δ 1.27 (s,
25.4, 42.8, 48.4, 61.8, 92.2, 99.4, 114.6, 117.9, 122.0, 123.1, 124.4,
1
–
3
–
2
–
124.9, 125.9, 128.2, 130.7, 134.1, 138.2, 142.4, 149.2, 150.1, 152.0,
–
–
–
N
–
158.6. HRMS Calculated for C27H29BClN O4 [M+1] 534.2001 and
2
5
–
O
–
–
–
O
–
–
[M+3] 536.2001 found 534.2015 and 536.2018; Anal. Calcd. (%) for: C,
6
60.75; H, 5.48; N, 13.12; Found: C, 60.67; H, 5.35; N, 13.26.
–
CHO); 13C NMR (125 MHz, DMSO‑d
): δ ppm =
13
C
3.2.12. 5-((1-(3-((7-chloroquinolin-4-yl)amino)propyl)-1H-1,2,3-triazol-
4-yl)methoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)
–
6
6
): δ ppm = 22.6, 23.5, 28.7, 29.8,50.2, 62.3,
6
1
1
5
6
9.2, 93.4, 106.5, 114.2, 120.5, 121.6, 123.1, 125.2, 125.8, 126.3,
benzaldehyde (18b)
1
27.4, 128.1, 131.1, 132.3, 133.9, 134.5, 137.2, 142.0, 154.8, 159.9,
Yellow waxy Solid; Yield: 74%; H NMR (400 MHz, DMSO‑d
6
): δ 1.28
), 4.62–4.66 (m, 2H,
), 6.61 (d, J = 5.2 Hz, 1H, ArH),
7.24 (dd, J = 2.8, 8.8 Hz,1H, ArH), 7.39–7.46 (m, 4H, NH-
exchangeable with D
O + 3ArH), 7.89 (d, J = 2.8 Hz, 1H, ArH), 8.13 (d,
J = 8.8 Hz, 1H, ArH), 8.25 (s, 1H, triazole H), 8.44 (d, J = 5.2 Hz, 1H,
ArH), 9.97 (s, 1H,
CHO); 13C NMR (100 MHz, DMSO‑d
90.7.HRMS Calculated for C31
H
36BN
3
O
5
[M+1] 542.2748 found
(s, 12H, 4 ×
CH
–
CH
3
), 3.40–3.45 (m, 2H,
CH
N CH
2
– – –
42.2762; Anal.Calcd. (%) for: C, 68.77; H, 6.70; N, 7.76; Found: C,
8.61; H, 6.59; N, 7.90.
–
N
–
2
–
), 5.22 (s, 2H,
–
O
– –
2
–
2
3
.2.8. 5-((1-(6-(naphthalen-1-yloxy)hexyl)-1H-1,2,3-triazol-4-yl)
–
methoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde
–
6
): δ ppm =
(
4 h)
Yellow waxy Solid; Yield: 72%; H NMR (500 MHz, CDCl
2H, 4 × CH ), 1.52–1.60 (m, 2H, CH ), 1.84–1.89 (m, 2H,
CH CH ), 4.10–4.13 (m, 2H, CH ),
), 2.10–2.16 (m, 2H,
.55–4.58 (m, 2H, CH ), 5.25 (s, 2H, CH ), 6.75 (d, J =
.0 Hz, 1H, ArH), 6.93 (d, J = 2.0 Hz, 1H, ArH), 7.35–7.49 (m, 6H, ArH),
.61 (s, 1H, triazole
H), 7.83 (d, J = 6.0 Hz, 1H, ArH), 8.22 (d, J = 8.5
CHO); 13C NMR (125 MHz, DMSO‑d
): δ
25.4, 28.6, 43.1, 48.7, 62.0, 92.0, 98.9, 114.4, 117.8, 121.9, 123.1,
1
3
): δ 1.22 (s,
124.5, 125.2, 125.6, 128.1, 131.3, 134.2, 138.0, 142.8, 149.1, 150.4,
1
–
4
8
7
–
3
–
2
–
152.5, 158.8. HRMS Calculated for C28
H
5
31BClN O
4
[M+1] 548.2158
–
–
–
–
–
N
–
–
and [M+3] 550.2158 found 548.2172 and 550.2151; Anal. Calcd. (%)
2
2
2
–
O
–
–
O
–
–
for: C, 61.39; H, 5.70; N, 12.78; Found: C, 61.30; H, 5.51; N, 12.62.
2
2
–
3.2.13. 2-bromo-5-((1-(2-(4-(7-chloroquinolin-4-yl)piperazin-1-yl)ethyl)-
Hz, 1H, ArH); 9.99 (s, 1H,
–
6
1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde (23)
1
ppm = 23.1, 25.2, 27.6, 29.0, 30.1,51.0, 63.0, 68.7, 93.2, 106.3, 114.2,
Yellow waxy Solid; Yield: 65%; H NMR (300 MHz, DMSO‑d
6
): δ 3.10
), 4.10–4.18 (m,
), 6.66 (d, J = 5.1 Hz, 1H,
1
1
20.1, 121.4, 123.1, 125.2, 125.6, 126.3, 127.6, 128.2, 131.2, 132.2,
33.8, 134.6, 137.0, 142.5, 155.4, 160.3, 191.5. HRMS Calculated for
(s, 4H, 2 ×
4H, 2 ×
–
N
–
2
CH
–
2
), 3.75 (s, 4H, 2 ×
N CH
2
– – –
2
–
N
–
CH
–
), 5.19 (s, 2H,
–
O
–
CH
–
C
32
H
38BN
3
O
5
[M+1] 556.2905 found 556.2915; Anal.Calcd. (%) for: C,
ArH), 7.31 (dd, J = 2.7, 8.7 Hz,1H, ArH), 7.38–7.47 (m, 3H, ArH), 7.68
6
9.19; H, 6.90; N, 7.56; Found: C, 69.30; H, 6.99; N, 7.38.
(d, J = 2.4 Hz, 1H, ArH), 8.10 (d, J = 9.0 Hz, 1H, ArH), 8.28 (s, 1H,
1
3
triazole
–
H), 8.42 (d, J = 5.1 Hz, 1H, ArH), 10.12 (s, 1H,
–
CHO);
C
3
.2.9. 5-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)-2-(4,4,5,5-
NMR (100 MHz, DMSO‑d
6
): δ ppm = 25.1, 48.6, 51.1, 52.9, 57.0, 68.9,
tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (9)
92.1, 99.0, 114.5, 119.3, 123.9, 124.1, 124.5, 125.2, 125.9, 128.1,
131.0, 134.5, 137.7, 142.0, 148.6, 149.9, 152.1, 159.2, 191.3. HRMS
1
Yellow waxy Solid; Yield: 69%; H NMR (500 MHz, CDCl
3
): δ 1.24 (s,
CH ),
.90 (d, J = 8.0 Hz, 2H, ArH), 7.27–7.33 (m, 3H, ArH), 7.45–7.50 (m,
H, ArH), 7.65 (s, 1H, triazole
H), 7.85 (d, J = 8.0 Hz, 1H, ArH), 10.2
CHO); 13C NMR (125 MHz, DMSO‑d
): δ ppm = 23.3, 55.0,
0.0, 92.0, 114.5, 120.7, 122.2, 125.9, 127.8, 128.4, 129.4, 131.6,
34.2, 139.0, 143.7, 161.2, 191.6. HRMS Calculated for C23 26BN
1
6
2
2H, 4 ×
–
CH
3
), 5.25 (s, 2H,
–
N
–
CH
–
), 5.50 (s, 2H,
2
–
O
–
2
–
Calculated for C31
H36ClBN
6
O
4
[M+1] 603.2580 and [M+3] 605.2580
found 603.2567 and 605.2571; Anal. Calcd. (%) for: C, 61.76; H, 6.02;
N, 13.94; Found: C, 61.85; H, 6.18; N, 14.13.
–
(
s, 1H,
–
6
7
1
3.3. General procedure for the synthesis of compounds 5/10/15/19/24
H
3 4
O
[
M+1] 420.2016 found 420.2007; Anal.Calcd. (%) for: C, 65.89; H,
To the stirred solution of 4/9/14/18/23 (1 mmol) in methanol, add
6
.25; N, 10.02; Found: C, 65.70; H, 6.13; N, 10.19.
slowly NaBH
4
powder (1 mmol) at 0–10 ◦C. The reaction mixture was
stirredfor1 h at rt. Then, reduce the volume of reaction mixture at low
3
.2.10. 5-((1-(7-chloroquinolin-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)-2-
temperature under reduced pressure to one-third of methanol. The
◦
(
4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (14)
resulting mixture was further cooled to 0 C and acidified with diluted
1
Yellow waxy Solid; Yield: 72%; H NMR (500 MHz, DMSO‑d
6
): δ 1.21
HCl up to pH 3. Add 2-two-fold cold water to the acidified reaction
(
s, 12H, 4 ×
–
CH
3
), 5.30 (s, 2H,
–
–
O CH
2
–
), 7.20–23 (m, 2H, ArH),
2
mixture. The white precipitate was collected, wash firstly with H O and
7
9
.77 (dd, J = 2.5, 8.5 Hz, 1H, ArH), 7.88–7.92 (m, 2H, ArH), 8.09 (d, J =
then with MeOH/water mixture, and finally dried to give pure product.
.0 Hz, 1H, ArH), 8.23 (d, J = 2.5 Hz, 1H, ArH), 8.88 (s, 1H, tri-
azole
–
H), 9.11 (d, J = 5.0 Hz, 1H, ArH), 10.2 (s, 1H,
CHO); 13C NMR
–
3.3.1. 5-((1-(3-phenoxypropyl)-1H-1,2,3-triazol-4-yl)methoxy)benzo[c]
(
125 MHz, DMSO‑d
6
): δ ppm = 25.2, 68.8, 91.5, 99.4, 114.6, 117.9,
22.0, 123.1, 124.4, 124.9, 125.7, 128.0, 130.9, 134.0, 138.1, 142.7,
49.4, 150.2, 152.4, 159.0. HRMS Calculated for C25 24BClN
[1,2]oxaborol-1(3H)-ol (5a)
1
1
1
White Solid; Yield: 68%; H NMR (500 MHz, CDCl
3
): δ 2.42–2.45 (m,
), 4.61–4.63 (m, 2H,
), 5.27 (s, 2H, CH ), 5.34
OH exchangeable with D
O), 6.87–6.89 (m, 2H, ArH),
6.95–6.98 (m, 3H, ArH), 7.28–7.31(m, 2H, ArH), 7.64–7.66 (m, 2H,
ArH); 13C NMR (125 MHz, DMSO‑d
): δ ppm = 29.8, 49.8, 62.3, 67.0,
70.3, 106.8, 114.2, 115.0, 120.9, 122.4, 129.6, 132.0, 138.7, 142.6,
144.1, 158.3, 160.8. HRMS Calculated for 20BN
H
4
O
4
2H,
–
CH
CH
(s, 1H,
2
–
–
), 3.97–3.98 (m, 2H,
N CH
2
– – –
[
M+1] 491.1579 and [M+3] 493.1579 found 491.1590 and 493.1571;
–
O
–
2
), 5.00 (s, 2H, CH
–
O
–
–
2
–
O
– –
2
Anal. Calcd. (%) for: C, 61.19; H, 4.93; N, 11.42; Found: C, 61.33; H,
–
2
4
.90; N, 11.52.
6
3
.2.11. 5-((1-(2-((7-chloroquinolin-4-yl)amino)ethyl)-1H-1,2,3-triazol-4-
yl)methoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde
18a)
Yellow waxy Solid; Yield: 69%; H NMR (300 MHz, DMSO‑d
s, 12H, 4 × CH ), 3.34–3.37 (m, 2H, CH ), 4.60–4.63 (m, 2H,
CH ), 5.20 (s, 2H, CH
), 6.54 (d, J = 5.1 Hz, 1H, ArH),
.29 (dd, J = 2.7, 8.4 Hz,1H, ArH), 7.36–7.42 (m, 4H, NH-
C
19
H
3
O
4
[M+1]
(
366.1547 found 366.1531; Anal.Calcd. (%) for: C, 62.49; H, 5.52; N,
11.51; Found: C, 62.35; H, 5.61; N, 11.40.
1
6
): δ 1.24
(
–
7
–
3
–
N
– –
2
N
–
–
2
O
– – –
2
–
9

A. Saini et al.
Bioorganic Chemistry 109 (2021) 104733
3
.3.2. 5-((1-(4-phenoxybutyl)-1H-1,2,3-triazol-4-yl)methoxy)benzo[c]
121.5, 123.3, 125.3, 125.4, 125.9, 126.4, 127.8, 129.3, 134.4, 142.7,
[
1,2]oxaborol-1(3H)-ol (5b)
144.6, 154.3, 159.0. HRMS Calculated for
C
24
H
24BN
3
O
4
[M+1]
White Solid; Yield: 70%; 1H NMR (500 MHz, CDCl
): δ 1.87–1.93
430.1860 found 430.1849; Anal.Calcd. (%) for: C, 67.15; H, 5.64; N,
9.79; Found: C, 67.03; H, 5.50; N, 9.95.
3
(
–
5
m,2H,
CH2
.24 (s, 2H,
.90–6.93 (m, 2H, ArH), 7.01–7.05 (m, 3H, ArH), 7.24–7.29 (m, 2H,
–
CH
), 4.51–4.54 (m, 2H,
CH ), 5.39 (s, 1H,
2
–
), 2.10–2.15 (m, 2H,
CH2
OH exchangeable with D
–
CH
2
–
), 4.04–4.07 (m, 2H,
CH ),
O),
N
–
–
–
O
–
–
),5.02 (s, 2H,
O
– – –
2
O
– –
–
2
–
3.3.7. 5-((1-(5-(naphthalen-1-yloxy)pentyl)-1H-1,2,3-triazol-4-yl)
2
6
methoxy)benzo[c][1,2]oxaborol-1(3H)-ol (5 g)
1
3
1
ArH), 7.63–7.67 (m, 2H, ArH); C NMR (125 MHz, DMSO‑d
2
1
6
): δ ppm =
6.4, 27.3, 50.0, 62.0, 67.4, 70.1, 106.7, 114.1, 115.2, 120.8, 122.2,
29.3, 132.1, 138.8, 142.5, 144.2, 158.6, 160.9. HRMS Calculated for
22BN
White Solid; Yield: 60%; H NMR (500 MHz, CDCl
3
): δ 1.50–1.56 (m,
), 2.01–2.07 (m, 2H, CH ),
), 4.42–4.45 (m, 2H, CH ), 5.02
), 5.21(s, 2H, CH ), 5.32 (s, 1H, OH
exchangeable with D
O), 6.81–6.85 (m, 2H, ArH), 6.94–6.99 (m, 3H,
ArH), 7.23–7.29 (m, 4H, ArH), 7.62–7.64 (m, 2H, ArH); C NMR (125
MHz, DMSO‑d
2H,
3.96–3.99 (m, 2H,
(s, 2H, CH
–
CH
2
–
), 1.84–1.89 (m, 2H,
–
CH
2
–
– –
2
2
–
N
–
CH
–
–
O
– –
2
C
20
H
3
O
4
[M+1] 380.1703 found 380.1710; Anal.Calcd. (%) for: C,
–
O
–
2
–
–
O
–
2
–
–
6
3.35; H, 5.85; N, 11.08; Found: C, 63.45; H, 5.71; N, 11.20.
2
1
3
3
.3.3. 5-((1-(5-phenoxypentyl)-1H-1,2,3-triazol-4-yl)methoxy)benzo[c]
6
): δ ppm = 23.1, 28.9, 29.6,48.5, 61.9, 65.0, 67.0, 104.6,
[
1,2]oxaborol-1(3H)-ol (5c)
113.0, 113.8, 119.6, 120.3, 121.6, 123.8, 125.4, 125.6, 126.0, 126.5,
127.5, 129.1, 134.6, 142.4, 145.0, 154.0, 159.1. HRMS Calculated for
1
White Solid; Yield: 63%; H NMR (500 MHz, CDCl
H, CH CH ), 2.02–2.09 (m, 2H,
), 1.88–1.95 (m, 2H,
.05–4.08 (m, 2H, CH ), 4.51–4.54 (m, 2H, CH
CH ), 5.27 (s, 2H, CH ), 5.35 (s, 1H,
exchangeable with D
O), 6.88–6.91 (m, 2H, ArH), 6.99–7.03 (m, 3H,
ArH), 7.26–7.32(m, 2H, ArH), 7.60–7.64 (m, 2H, ArH); C NMR (125
MHz, DMSO‑d
3
): δ 1.55–1.59 (m,
CH ),
), 5.06
OH
2
4
–
2
–
–
2
–
–
2
2
–
C
25
H
26BN
3
O
4
[M+1] 444.2016 found 444.2019; Anal.Calcd. (%) for: C,
–
N
–
–
–
O
–
–
67.73; H, 5.91; N, 9.48; Found: C, 67.84; H, 5.83; N, 9.64.
2
(
s, 2H,
O
– –
2
–
O
– –
–
2
–
2
3.3.8. 5-((1-(6-(naphthalen-1-yloxy)hexyl)-1H-1,2,3-triazol-4-yl)
1
3
methoxy)benzo[c][1,2]oxaborol-1(3H)-ol (5 h)
1
6
): δ ppm = 23.2, 28.6, 29.9, 50.3, 62.1, 67.1, 70.8, 106.6,
14.4, 115.1, 120.7, 122.5, 129.4, 131.8, 139.2, 142.7, 143.9, 158.8,
61.0. HRMS Calculated for C21 24BN
White Solid; Yield: 61%; H NMR (500 MHz, CDCl
3
): δ 1.22–1.27 (m,
1
1
3
6
2H,
2.11–2.017 (m, 2H,
4.41–4.43 (m, 2H,
CH ), 5.30 (s, 1H,
.5 Hz, 1H, ArH), 6.92–7.00 (m, 2H, ArH), 7.23 (t, J = 8.0 Hz, 1H, ArH),
7.35 (t, J = 8.0 Hz, 1H, ArH), 7.49 (d, J = 8.5 Hz,1H, ArH), 7.52–7.55
(m, 2H, ArH), 7.67 (s, 1H, triazole
H), 7.80 (d, J = 7.0 Hz, 1H, ArH),
–
CH
2
–
), 1.52–1.58 (m, 2H,
CH
), 3.95–3.98 (m, 2H,
CH ), 5.01 (s, 2H, CH
OH exchangeable with D
–
CH
2
–
), 1.89–1.95 (m, 2H,
–
CH
2
–
2
),
H
3
O
4
[M+1] 394.1860 found
–
–
2
–
–
N
–
CH
–
),
94.1845; Anal.Calcd. (%) for: C, 64.14; H, 6.15; N, 10.69; Found: C,
4.01; H, 6.06; N, 10.60.
–
O
2
–
–
–
O
–
2
–
), 5.22 (s, 2H,
–
O
–
–
2
O), 6.70 (d, J =
2
7
3
.3.4. 5-((1-(6-phenoxyhexyl)-1H-1,2,3-triazol-4-yl)methoxy)benzo[c]
[
1,2]oxaborol-1(3H)-ol (5d)
–
13
1
White Solid; Yield: 65%; H NMR (500 MHz, CDCl
H, CH CH ), 1.83–1.89 (m, 2H,
), 1.58–1.65 (m, 2H,
.03–2.08 (m, 2H, CH ), 3.97–4.00 (m, 2H, CH ), 4.42–4.45
CH ), 5.05 (s, 2H, ), 5.26 (s, 2H,
), 5.34 (s, 1H,
OH exchangeable with D O), 6.85–6.89 (m,
H, ArH), 6.94–6.98 (m, 3H, ArH), 7.29–7.93(m, 2H, ArH), 7.58–7.62
m, 2H, ArH); 13C NMR (125 MHz, DMSO‑d
3
): δ 1.22–1.28 (m,
8.13 (d, J = 7.0 Hz, 1H, ArH); C NMR (125 MHz, DMSO‑d ): δ ppm =
6
2
2
–
2
–
–
–
2
–
CH ),
2
–
25.8, 27.3, 28.8, 29.7, 48.6, 61.8, 65.9, 68.0, 104.4, 113.2, 113.9, 119.8,
120.9, 121.3, 123.6, 125.1, 125.4, 125.6, 126.9, 127.7, 129.5, 134.3,
–
2
–
–
N
– –
–
2
2
(
–
2
m, 2H,
CH2
–
–
O
–
–
O
– –
CH
2
142.8, 145.2, 153.9, 159.0. HRMS Calculated for C26
H
28BN
3
O
4
[M+1]
O
–
–
2
458.2173 found 458.2160; Anal.Calcd. (%) for: C, 68.28; H, 6.17; N,
9.19; Found: C, 68.36; H, 6.07; N, 9.30.
(
6
): δ ppm = 25.8, 27.4, 28.9,
2
1
9.6, 49.9, 62.2, 67.0, 70.2, 106.4, 114.5, 115.0, 120.9, 122.0, 129.2,
32.0, 138.7, 142.3, 143.8, 158.9, 161.0. HRMS Calculated for
3.3.9. 5-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)benzo[c][1,2]
oxaborol-1(3H)-ol (10)
1
C
22
H
26BN
3
O
4
[M+1] 408.2016 found 408.2024; Anal.Calcd. (%) for: C,
White Solid; Yield: 72%; H NMR (500 MHz, CDCl
3
): δ 5.04 (s, 2H,
O), 5.25 (s, 2H,
), 6.94–6.98 (m,2H, ArH),
6
4.88; H, 6.43; N, 10.32; Found: C, 64.78; H, 6.29; N, 10.41.
–
N
–
CH
2
–
), 5.21 (s, 1H,
–
OH exchangeable with D
2
–
O
–
CH2
–
), 5.55 (s, 2H,
–
O
–
CH2
–
3
.3.5. 5-((1-(3-(naphthalen-1-yloxy)propyl)-1H-1,2,3-triazol-4-yl)
7.28–7.30 (m, 2H, ArH), 7.38–7.40 (m, 3H, ArH), 7.55 (s, 1H, tri-
13
methoxy)benzo[c][1,2]oxaborol-1(3H)-ol (5e)
azole
–
H), 7.65 (d, J = 8.0 Hz, 1H, ArH); C NMR (125 MHz, DMSO‑d
6
):
1
White Solid; Yield: 65%; H NMR (500 MHz, CDCl
3
): δ 2.54–2.58 (m,
),4.66 (s, 2H,
), 5.04 (s, 1H, OH
), 6.76 (d, J = 7.5 Hz,
H, ArH), 6.86–7.00 (m, 2H, ArH), 7.24 (t, J = 8.0 Hz, 1H, ArH), 7.36 (t,
J = 8.0 Hz, 1H, ArH), 7.47 (d, J = 8.5 Hz,1H, ArH), 7.50–7.53 (m, 2H,
ArH), 7.62 (s, 1H, triazole
H), 7.83 (d, J = 7.0 Hz, 1H, ArH), 8.23 (d, J
7.0 Hz, 1H, ArH); 13C NMR (125 MHz, DMSO‑d
δ ppm = 54.3, 62.1, 70.9, 106.6, 115.1, 122.6, 128.1, 128.8, 129.1,
131.7, 134.3, 142.7, 144.3, 156.4, 161.0. HRMS Calculated for
C17H16BN O [M+1] 322.1285 found 322.1272; Anal.Calcd. (%) for: C,
2
H,
CH2
exchangeable with D
–
CH
2
–
), 4.14–4.17 (m, 2H,
), 4.69–4.72 (m, 2H,
O), 5.19 (s, 2H,
N CH
2
– – –
–
–
O
–
–
O
–
CH2
–
–
3
3
–
O
–
CH
–
63.58; H, 5.02; N, 13.08; Found: C, 63.65; H, 4.86; N, 13.19.
2
2
1
3.3.10. 5-((1-(7-chloroquinolin-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)
–
benzo[c][1,2]oxaborol-1(3H)-ol (15)
1
=
6
): δ ppm = 29.9, 47.4,
White Solid; Yield: 75%; H NMR (500 MHz, DMSO‑d
6
): δ 4.16 (ddd,
), 5.06 (t, J = 5.5 Hz, 1H, OH
CH ), 7.02 (m, 2H, ArH),
6
1
1
4
6
1.9, 64.1, 65.0, 104.7, 113.1, 113.9, 119.6, 120.7, 121.6, 123.2,
25.40, 125.44, 125.8, 126.5, 127.6, 129.6, 134.5, 142.7, 144.2, 153.9,
J = 5.0, 14.0, 19.0 Hz, 2H,
–
O
–
CH
2
–
–
–
exchangeable with D O), 5.37 (s, 2H,
2
O
– –
2
58.4. HRMS Calculated for C23
H22BN
3
O
4
[M+1] 416.1703 found
7.27 (d, J = 2.0 Hz, 1H, ArH), 7.80 (dd, J = 2.0, 9.0 Hz, 1H, ArH), 7.90
16.1714; Anal.Calcd. (%) for: C, 66.53; H, 5.34; N, 10.12; Found: C,
6.60; H, 5.22; N, 10.05.
(d, J = 5.0 Hz, 1H, ArH), 8.03 (d, J = 9.0 Hz, 1H, ArH), 8.30 (d, J = 3.0
Hz, 1H, ArH), 9.00 (s, 1H, triazole
–
H), 9.17 (d, J = 5.0 Hz, 1H, ArH);
1
3
C NMR (100 MHz, DMSO‑d
117.6, 120.8, 125.8, 127.3, 128.6, 129.5, 131.0,135.8, 140.8, 142.3,
144.3, 149.8, 152.8, 157.8. HRMS Calculated for C19 14BClN
6
): δ ppm = 61.1, 61.3, 79.6, 112.8, 113.6,
3
.3.6. 5-((1-(4-(naphthalen-1-yloxy)butyl)-1H-1,2,3-triazol-4-gyl)
methoxy)benzo[c][1,2]oxaborol-1(3H)-ol (5f)
H
4
O
3
[M+1]
1
White Solid; Yield: 67%; H NMR (500 MHz, CDCl
3
): δ 1.77–1.84 (m,
393.0847 and [M+3] 395.0847 found 393.0839 and 395.0858; Anal.
Calcd. (%) for: C, 58.13; H, 3.59; N, 14.27; Found: C, 58.03; H, 3.73; N,
14.18.
2
–
5
H,
–
CH
CH2
.24 (s, 2H,
.84–6.89 (m, 2H, ArH), 6.91–6.98 (m, 3H, ArH), 7.24–7.28 (m, 4H,
2
–
–
), 2.08–2.17 (m, 2H,
), 4.43–4.47 (m, 2H,
CH ), 5.36 (s, 1H,
–
CH
CH2 ), 5.02 (s, 2H,
OH exchangeable with D
–
2
), 3.95–3.98 (m, 2H,
CH2 ),
O),
N
–
O
– –
–
O
– – –
–
–
O
–
–
2
2
6
3.3.11. 5-((1-(2-((7-chloroquinolin-4-yl)amino)ethyl)-1H-1,2,3-triazol-4-
1
3
ArH), 7.62–7.64 (m, 2H, ArH); C NMR (125 MHz, DMSO‑d
2
6
): δ ppm =
yl)methoxy)benzo[c][1,2]oxaborol-1(3H)-ol (19a)
1
6.3, 27.6, 49.1, 61.5, 65.1, 66.4, 105.0, 112.9, 113.6, 119.5, 120.5,
White Solid; Yield: 73%; H NMR (300 MHz, DMSO‑d
6
): δ 3.80–3.82
1
0

A. Saini et al.
Bioorganic Chemistry 109 (2021) 104733
(
–
m, 2H,
CH2
with D
O), 6.57 (d, J = 5.4 Hz, 1H,ArH), 6.86 (d, J = 7.5 Hz,1H, ArH),
.19 (s, 1H, ArH), 7.33 (br s, 1H, NH-exchangeable with D O),
.40–7.57 (m, 2H, ArH), 7.82 (s, 1H, ArH), 8.19 (d, J = 8.7 Hz, 1H, ArH),
–
N
–
CH
2
–
), 4.44 (s, 2H,
–
O
–
CH
2
–
), 4.66–4.69 (m, 2H,
10000 nM (final concentration of 0.5% of DMSO).Stock solution of
chloroquine diphosphate (Sigma, Saint Louis, MO, USA) was prepared in
water and then diluted in RPMI in order to have 11 final concentrations
ranging from 5 nM to 3200 nM. Chloroquine was used for P. falciparum
activity comparison. For the in vitro assay, 25 µl of each concentration of
benzoxaborole derivatives or chloroquine were aliquoted with 200 µl of
parasitized red blood cells (final parasitemia, 0.1%; final haematocrit,
N
–
–
), 5.11 (s, 2H,
–
O
CH2
– –
), 5.31 (s, 1H,
–
OH exchangeable
2
7
7
8
–
2
1
3
.26 (s, 1H, triazole
): δ ppm = 42.9, 48.3, 61.8, 63.1, 99.4, 114.6, 117.9,
22.0, 123.1, 124.4, 124.9, 125.7, 128.0, 130.9, 134.0, 138.1, 142.7,
49.4, 150.2, 152.4, 159.0. HRMS Calculated for C21 19BClN
–
H), 8.40 (d, J = 5.2 Hz, 1H, ArH); C NMR (100
MHz, DMSO‑d
6
◦
1
1
1.5%) into 96-well plates. The plates were incubated for 72 hr at 37 Cin
H
5
O
3
2 2 2
controlled atmospheric conditions 5% CO , 10% O and 75% N .After
[
M+1] 436.1269 and [M+3] 438.1269 found 436.1278 and 438.1282;
thawing the plates, 50 µl of PBS 1x were added to haemolysed cultures
and were homogenized by vortexing the plates. A volume of 50 µl of
supernatant was added with 50 µl of lysis buffer containing SYBR Green I
Anal. Calcd. (%) for: C, 57.89; H, 4.40; N, 16.08; Found: C, 57.75; H,
4
.31; N, 15.97.
(
final concentration 20x) (ThermoFisher Scientific, Paisley, UK) in flat
3
4
.3.12. 5-((1-(3-((7-chloroquinolin-4-yl)amino)propyl)-1H-1,2,3-triazol-
bottom black plate (ThermoFisher Scientific, Kamstrupvej, Denmark) in
a dark room. The plate was incubated at room temperature in the dark
for 24 h. The fluorescence is read at 485 nm and 530 nm (excitation and
emission wavelength bands, respectively) using a fluorescent plate
reader (Tecan Infinite F200, Lyon, France).
-yl)methoxy)benzo[c][1,2] oxaborol-1(3H)-ol (19b)
1
White Solid; Yield: 68%; H NMR (300 MHz, DMSO‑d
6
): δ 1.94–2.02
), 4.57 (s, 2H,
), 5.18 (s, 2H,
OH exchangeable with D O), 6.52 (d, J =
(
m, 2H,
–
CH
), 4.65–4.67 (m, 2H,
), 5.22 (s, 1H,
–
2
), 3.39–3.42 (m, 2H,
–
N
– –
CH
2
–
–
O
–
CH2
–
N CH2
– – –
O
–
CH2
–
–
2
The concentration at which the drugs were able to inhibit 50% of
parasite growth (IC50) was calculated with the inhibitory sigmoid Emax
model, with estimation of the IC50 through non-linear regression using a
standard function of the R software (IC Estimator version 1.2). The
antiplasmodial in vitro assay was performed five times for each product.
The IC50 values represented the mean value calculated from five
experiments.
4
.8 Hz, 1H,ArH), 6.89 (dd, J = 2.4, 9.0 Hz,1H, ArH), 7.11 (d, J = 2.4
Hz,1H, ArH), 7.37–7.45 (m, 3H,
7
–
NH-exchangeable with D
2
O + 2ArH),
.85 (d, J = 2.7 Hz, 1H, ArH), 8.14 (d, J = 9.0 Hz, 1H, ArH), 8.22 (s, 1H,
13
triazole
–
H), 8.33 (d, J = 4.8 Hz, 1H, ArH); C NMR (100 MHz,
DMSO‑d
6
): δ ppm = 28.6, 42.1, 48.9, 61.3, 62.1,99.5, 112.8, 113.5,
1
1
17.9, 120.6, 125.9, 127.4, 128.3, 129.6, 131.1, 135.8, 140.9, 142.5,
5 3
44.6, 149.9, 152.7, 157.9. HRMS Calculated for C22H21BClN O
[
M+1] 450.1426 and [M+3] 452.1426 found 450.1413 and 452.1417;
3.4.2. Cytotoxicity assay
Anal. Calcd. (%) for: C, 58.76; H, 4.71; N, 15.57; Found: C, 58.85; H,
Vero kidney epithelial cells (ATCC® CCL-81™) were cultured in
RPMI 1640 cell culture medium (Life technologies) supplemented with
4
.87; N, 15.40.
◦
1
0% foetal calf serum and incubated at 37 C with 5% CO2. Once the
3
1
.3.13. 5-((1-(2-(4-(7-chloroquinolin-4-yl)piperazin-1-yl)ethyl)-1H-
desired confluency was achieved, cells were detached from the flask
surface using trypsin and centrifuged at 220 × g for 5 min at room
temperature to pellet cells. The cell pellet was resuspended in 1 mL of
culture medium and enumerated using a Malassez counting chamber.
,2,3-triazol-4-yl)methoxy)benzo[c][1,2]oxaborol-1(3H)-ol (24)
1
White Solid; Yield: 58%; H NMR (400 MHz, DMSO‑d
6
): δ 3.20 (s,
); 4.22–4.31 (m, 4H,
), 5.21 (s, 2H, CH ),
O), 6.55 (d, J = 5.4 Hz, 1H,
4
2
5
H, 2 ×
N
– –
CH ); 3.71 (s, 4H, 2 ×
), 4.95 (s, 2H,
OH exchangeable with D
–
2
N CH
2
– – –
4
×
–
N
–
CH
2
–
– –
O CH
2
–
–
O
–
2
–
Cell density was adjusted to approximately 2 × 10 cells/well in 96-well
◦
.30 (s, 1H,
–
2
plates and left to adhere overnight at 37 C and 5% CO
2
. To determine
ArH), 7.28 (dd, J = 2.4, 9.0 Hz,1H, ArH), 7.38–7.47 (m, 3H, ArH), 7.80
cytotoxicity of synthetic compounds, serial dilutions were performed
(
d, J = 2.4 Hz, 1H, ArH), 8.01 (d, J = 9.0 Hz, 1H, ArH), 8.28 (s, 1H,
ranging from 100
μ
g to 3.1 g/mL. Cell cultures were placed back in the
μ
1
3
◦
triazole
–
6
H), 8.35 (d, J = 5.1 Hz, 1H, ArH); C NMR (100 MHz,
): δ ppm = 49.2, 51.2, 52.6, 57.2, 69.9, 106.5, 112.9, 113.6,
incubator at 37 C and 5% CO
2
for 24 h. After incubation, 10% (vol/vol)
◦
DMSO‑d
resazurin was added to each well and left to incubate at 37 C and 5%
1
1
18.4, 121.0, 125.5, 127.0, 128.2, 130.1, 132.0, 135.3, 141.5, 142.9,
2
CO prior to data acquisition using a fluorescent plate reader (excitation
45.0, 150.7, 152.8, 158.6. HRMS Calculated for C25
H26BClN
6
O
3
540 nm, emission 590 nm). DMSO was included as a negative control,
while 20% SDS was included as a positive control at the pre-designated
concentrations. Data was analysed using Graphpad Prism 5 (Graphphad
software). The half maximal inhibitory concentration (IC50) was calcu-
lated using a non-linear regression dose response curve. Selectivity
Index (SI) was calculated as a function of the IC50/MIC [12].
[
M+1] 505.1848 and [M+3] 507.1848 found 505.1860 and 507.1839;
Anal. Calcd. (%) for: C, 59.49; H, 5.19; N, 16.65; Found: C, 59.32; H,
5
3
3
.31; N, 16.55.
.4. Biological evaluation
.4.1. In vitro antiplasmodial assay
Declaration of Competing Interest
The two P. falciparum strains, the chloroquine-susceptible 3D7 (iso-
lated in West Africa; obtained from MR4, VA, USA), and the
chloroquine-resistant strain W2 (isolated in Indochina; obtained from
MR4, VA, USA), were maintained in culture in RPMI 1640 (Invitrogen,
Paisley, UK), supplemented with 10% human serum (Abcys S.A. Paris,
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.
France) and buffered with 25 mM HEPES and 25 mM NaHCO
3
. Parasites
Acknowledgment
were grown in A-positive human blood (EtablissementFrançais du Sang,
Marseille, France) under controlled atmospheric conditions that con-
Financial assistance from SERB (Science and Engineering Research
Board) under Start-Up Research grant Scheme No. YSS/2015/000879/
CS (RR) is gratefully acknowledged.
◦
sisted of 10% O , 5% CO and 85% N at 37 C with a humidity of 95%.
2 2 2
The two P. falciparums trains 3D7 and W2, were synchronized twice with
sorbitol before use [25]. The clonality of these strains was verified both
in our laboratory and in an independent laboratory from the Worldwide
Antimalarial Resistance Network (WWARN) by PCR genotyping of the
polymorphic genetic markers msp1 and msp2 and microsatellite loci
Appendix A. Supplementary material
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bioorg.2021.104733.
[
26,27].
The compounds were re-suspended and then diluted RPMI- DMSO
% (v/v) to obtain 11 final concentrations ranging from 0.78 nM to
5
1
1

A. Saini et al.
Bioorganic Chemistry 109 (2021) 104733
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