Microwave assisted regioselective synthesis of quinoline appended triazoles as potent anti-tubercular and antifungal agents via copper (I) catalyzed cycloaddition

Article abstract of DOI:10.1016/j.bmcl.2021.127984

Quinolin-3-yl-methyl-1,2,3-triazolyl-1,2,4-triazol-3(4H)-ones 8j-v were synthesized by click chemistry as an ultimate tactic where [3 + 2] cycloaddition of azides with terminal alkynes has been evolved. Herein, we are inclined to divulge the implication and prevalence of CuSO₄·5H₂O and THF/water promoted [3 + 2] cycloaddition reactions. The foremost supremacy of this method are transitory reaction times, facile workup, excellent yields (88–92%) with exorbitant purity and regioselective single product formation both under conventional and microwave method. Docking studies illustrated strong binding interactions with enzyme InhA-D148G (PDB ID: 4DQU) by means of high C-score values. The anti-tubercular and antifungal screening of synthesized compounds proclaimed promising activity. The in vitro and in silico studies imply that these triazoles appended quinolines may acquire the ideal structural prerequisites for auxiliary expansion of novel therapeutic agents.

Full text of DOI:10.1016/j.bmcl.2021.127984

Bioorg. Med. Chem. Lett. 41 (2021) 127984
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Microwave assisted regioselective synthesis of quinoline appended triazoles
as potent anti-tubercular and antifungal agents via copper (I)
catalyzed cycloaddition
,
Aravind R. Nesaragia, Ravindra R. Kamblea *, Praveen K. Bayannavara, Saba Kauser J. Shaikha,
Swati R. Hoolageria, Barnabas Kodasia, Shrinivas D. Joshib, Vijay M. Kumbarc
a Department of Studies in Chemistry, Karnatak University Dharwad 580003, India
b Novel Drug Design and Discovery Laboratory, Department of Pharmaceutical Chemistry, S.E.T.’s College of Pharmacy, Dharwad 580002, India
c Central Research Laboratory, Maratha Mandal’s NGH Institute of Dental Sciences and Research Centre, Belagavi 590010, India
A R T I C L E I N F O
A B S T R A C T
Keywords:
Quinolin-3-yl-methyl-1,2,3-triazolyl-1,2,4-triazol-3(4H)-ones 8j-v were synthesized by click chemistry as an ul-
timate tactic where [3 + 2] cycloaddition of azides with terminal alkynes has been evolved. Herein, we are
inclined to divulge the implication and prevalence of CuSO4⋅5H2O and THF/water promoted [3 + 2] cycload-
dition reactions. The foremost supremacy of this method are transitory reaction times, facile workup, excellent
yields (88–92%) with exorbitant purity and regioselective single product formation both under conventional and
microwave method. Docking studies illustrated strong binding interactions with enzyme InhA-D148G (PDB ID:
4DQU) by means of high C-score values. The anti-tubercular and antifungal screening of synthesized compounds
proclaimed promising activity. The in vitro and in silico studies imply that these triazoles appended quinolines
may acquire the ideal structural prerequisites for auxiliary expansion of novel therapeutic agents.
Anti-tubercular agents
Antifungal agents
Click chemistry
Molecular docking
1,2,4-Triazole,1,2,3-triazole
Quinoline
Tuberculosis (TB) is a treatable contagious lung disease caused by
Mycobacterium tuberculosis (MTB), regardless of the accessibility of
productive drugs, the disease causes tremendous number of deaths and
remains the supreme cause of global deaths due to infectious diseases.1
According to WHO 2020 report, an estimated ten million people con-
tracted TB and around 1.2 million people died, including 0.208 million
cases co-infected with HIV.2 The prolonged treatment generally results
in contravention of the treatment and therefore cause multidrug resis-
tance tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis
(XDR-TB) which are highly life threatening, extremely extortionate and
complex to treat. The ever-increasing number of MDR-TB cases has
caused immense concern as they contribute to an enhancement in deaths
from TB and are habitually correlated with HIV infection. The existence
of MDR-TB reflects a frailty in TB control, but this weakness can be
treated with extended chemotherapy. With an extended treatment
period, however, patients face an increased risk of toxicity and the
treatment costs became several times higher than the typical treatment
of TB.11 This has created new challenges for the impediment, treatment
and control of TB. Even with the availability of effective anti-TB drugs
such as isoniazid and rifampicin, there is severe problem egress as MTB
developed resistance against the first-line as well as the second-line
drugs.3 Therefore, there is an immense necessity to develop contempo-
rary inhibitors that reduce the complexity and duration of the current
therapeutic treatment as well as beneficially treat MDR and XDR
tuberculosis.
Amidst innumerable N-heterocycles, quinolines and 1,2,3-triazoles
are two essential classes of small heterocyclic molecules which have a
wide range of chemotherapeutic demands. Quinolines and their analogs
represent a fundamental class of organic molecules that have attracted
significant attention from synthetic as well as medicinal chemists due to
their existence in various natural products, displaying a broad range of
physiological activities.4 It is appealing to note that quinoline moiety is
the core substructure in recently approved anti-TB drug, bedaquiline
(TMC207), a diarylquinoline-based molecule.5 Furthermore, some de-
rivatives of an antimalarial drug mefloquine possess impressive anti-
bacterial as well as anti-tubercular activity.6 The quinoline-based
antibiotics, ciprofloxacin and moxifloxacin also show promising anti-
tubercular activity and are recommended by WHO as second-line anti-
TB drugs.
The modern research in drug discovery has intended at introducing
* Corresponding author.
E-mail address: ravichem@kud.ac.in (R.R. Kamble).
https://doi.org/10.1016/j.bmcl.2021.127984
Received 22 December 2020; Received in revised form 9 March 2021; Accepted 16 March 2021
Available online 22 March 2021
0960-894X/© 2021 Elsevier Ltd. All rights reserved.

A.R. Nesaragi et al.
Bioorganic & Medicinal Chemistry Letters 41 (2021) 127984
Fig. 1. 1,2,3-Triazoles and 1,2,4-Triazoles possessing anti-tubercular and antifungal activity.
the 1,2,3-triazole moiety as a connecting link between two or more
pharmacophore. 1,2,3-Triazoles have gained much attention, as their
fascinating physical and biological properties as well as their magnifi-
cent stability render them promising drug core structures. The 1,3-
dipolar cycloaddition reaction of a 1,3-dipole to a dipolarophile (i.e.
an acetylene or an alkyne) for the synthesis of five-membered hetero-
cycles is a well-known transformation in synthetic organic chemistry.7
The Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction has
successfully fulfilled the requirement of “click chemistry” as prescribed
by Sharpless and within a few years has become a premier component of
synthetic organic chemistry.8 Sharpless9 and Meldal10 have reported the
dramatic rate enhancement (up to 107 times) and enhanced regiose-
lectivity of the Huisgen 1,3- dipolar cycloaddition reaction of an organic
azide and terminal acetylene to afford the 1,4-disubstituted-1,2,3-tria-
zole in presence of Cu(I) catalyst.
novel precursor for the synthesis of diverse biologically functional het-
erocycles viz., pyrazoles, 1,3,4-oxadiazoles, phenyl indazoles, pyrazo-
lines, and tetrazines via 1,3-dipolar cycloaddition and addition
elimination reactions.19
Microwave irradiation has been used efficiently to escalate diverse
chemical reactions. Often, a few minutes of microwave irradiation are
adequate for reactions that conventionally require several hours for
accomplishment. The attributes of Microwave Assisted Organic Syn-
thesis (MAOS) is the fabulous acceleration perceived in numerous re-
actions with consequences that cannot be reproduced by conventional
heating. Due to the certainty that it is more eco-friendly, Microwave
synthesis is deemed as
a significant approach towards green
chemistry.20
To designate the complications of escalating resistance, grievous side
effects of a few anti-TB drugs, prolonged treatment, incompatibility of
anti-retroviral therapies for contemporary TB regimen, research activ-
ities to build up novel anti-TB agents with intense efficacy have become
a hasty priority. Numerous studies targeting the mycobacterial cell wall
and predominantly the biosynthesis of mycolic acid have been publi-
cized. InhA also known as Enoy Acyl Carrier Protein Reductase (Mtb ENR)
is a vital enzyme of mycolic acid biosynthesis pathway. In the synthesis
of type II fatty acids which are essential for the formation of the
mycobacterial cell wall, this pathway is implicated and is therefore
considered to be a good target. The major advantage of this target is that
it is present in the mycobacterium but is missing in human. Furthermore,
InhA has been acknowledged as the molecular target of the fron-
tline anti-tubercular drugs isoniazid and ethionamide (ETA).21
In recent times, 1,2,3-triazoles have been a vital class of compounds
because of their wide range of biological applications together with anti-
tubercular,11 antibacterial, anti-allergic, anti-HIV,12 anti-fungal,13
α
-glycosidase inhibitor14 and anti-tubercular15 activities. Baltas and co-
workers16 reported the 1,4-disubstituted 1,2,3-triazole derivatives (I
and II) (Fig. 1) exhibiting good inhibitory activities against MTB H37Rv.
In a similar way, benzimidazole clubbed 1,2,3-triazoles with fluorine
(III) series of H37Rv strain inhibitors have been reported.17 The 1,2,3-
triazole based compounds (IV) are active against various pathogenic
and opportunistic Mycobacteria including M.avium and MTB.18 Recently,
a 1,2,3-triazole based isoniazid derivative (V) has shown to possess anti-
tubercular activity against MTB H37Rv. The well known antifungal
drugs TAK-456 (VI) and fluconazole (VII) are also compiled of triazole
entity as well (Fig. 1).
In connection with the expansion of new active molecules against
MTB, a small focused array of 1,2,3-triazole integrated molecules have
been competently equipped by click chemistry. We were persuaded to
design green and novel quinolinyl-1,2,3-triazolyl-1,2,4-triazol-3(4H)-
ones 8j-v from biologically active starting materials in minimal steps
with favorable overall yield. Herein, we are inclined towards reporting
the most expedient synthesis of 1,4-disubstituted-1,2,3-triazoles both
Considerable attention is attracted by 1,2,4-triazoles which are
among pharmacologically vital heterocyclic compounds due to their
captivating biological activities. Hence, for a more direct path, we
choose to prepare 1,2,4-triazole using N-arylsydnone which belongs to
mesoionic class of compounds. N-Arylsydnone act as functional and
2

A.R. Nesaragi et al.
Bioorganic & Medicinal Chemistry Letters 41 (2021) 127984
Scheme 1. Synthesis of acetylenic dipolarophile 4a-b.
Scheme 2. Synthesis of quinolinyl-1,2,3-triazolyl-1,2,4-triazol-3(4H)-one 8j-v.
conventionally as well as microwave irradiation and their anti-
tubercular, antifungal activity and molecular docking study.
Table 1
Optimization of reaction conditions for the compound 8j.
Entry
CuSO4⋅H2O (mol%)
Solvent
Time (h)
Yield (%)
Results and discussion
1
0
DMF
24
18
14
24
15
12
4
0
2
2
DMF
24
32
0
The current study explores the most commodious green approach for
the synthesis of regioselective quinolinyl-1,2,3-triazolyl-1,2,4-triazol-3
(4H)-one 8j-v with excellent yields and purity in shorter duration
(Scheme 2). 2-Chloro-6/7/8-substituted-quinoline-3-carbaldehyde 6c-i
was synthesized by Vilsmeier-Haack reaction which further was reduced
using NaBH4 to the corresponding alcohol which later gave 3-(bromo-
methyl)-2-chloro-6/7/8-substituted quinoline when treated with phos-
phorous tribromide in DCM. The corresponding dipolar azide 7c-i was
obtained by treating 3-(bromomethyl)-2-chloro-6/7/8-substituted
quinoline with sodium azide in aqueous acetone at room temperature.
This was accompanied by azide-alkyne cycloaddition of the acetylenic
dipolarophiles 4a-b (Scheme 1) and 3-azidomethyl quinolines 7c-i, for
3
2
DMSO
4
5
t-butanol
5
10
10
10
15
15
15
15
15
15
20
20
t-butanol:H2O (1:1)
t-butanol:H2O (1:2)
THF:H2O (1:1)
THF:H2O (2:1)
THF:H2O (1:2)
THF:H2O (1:1)
t-butanol:H2O (1:2)
PEG-400
65
63
65
70
68
80
68
70
63
80
72
6
7
8
4
9
3
10
11
12
13
14
15
1
7
8
t-butanol:H2O (2:1)
THF:H2O (1:1)
PEG-400
7
1
5
3

A.R. Nesaragi et al.
Bioorganic & Medicinal Chemistry Letters 41 (2021) 127984
reaction in diverse catalyst ratios and solvent systems such as dimethyl
sulfoxide (DMSO) (Table 1, entry 3), THF/H2O (2:1) (Table 1, entry 8),
THF/H2O (1:2) (Table 1, entry 9), t-butanol/Water (1:1) (Table 1, entry
5), t-butanol/water (1:2) (Table 1, entry 6, 11), t-butanol/water (2:1)
(Table 1, entry 13), PEG-400 (Table 1, entry 12, 15). Earlier divulged
reaction conditions with various solvents, resulted in the product with
moderate yields by means of prolonged time. The use of only 15 mol%
CuSO4⋅5H2O is generous to thrust the reaction to progress further and
elevated quantities of the catalyst did not enhance the yields to any
eminent expanse (Table 1, entry 14). This composition of catalyst and
the solvent were used for the synthesis of title compounds under mi-
crowave irradiation method which exerted the enhanced yields
(88–92%) instantaneously (3–5 min). At this precise moment, we
comprehend the significance and the preponderance of CuSO4⋅5H2O and
THF/water promoted [3+2] cycloaddition reactions.
Table 2
Synthesized compounds (8j-v) and their yields.
Products
8j-v
Ar
R
Conventional
Microwave
Time
(h)
Yield
Time
Yield
(%)
(%)
(min)
8j
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
H
4
5
6
4
5
4
5
80
75
79
75
74
79
80
3
3
3
5
3
3
4
92
90
91
88
89
90
88
8k
8l
6-Br
6-Cl
7-Cl
6-CH3
8-CH3
7-
8m
8n
8o
8p
OCH3
H
8q
8r
8s
8t
4-H3CO-
C6H4
6
4
5
6
4
5
80
81
78
77
79
80
5
4
3
5
4
4
91
88
92
91
90
90
4-H3CO-
C6H4
6-Br
Taking into account the aforesaid provisions, an array of structurally
conflicting novel quinolinyl-1,2,3-triazolyl-1,2,4-triazol-3(4H)-one de-
rivatives 8j-v were synthesized in adequate yields (88–92%) and rep-
resented in Table 2.
4-H3CO-
C6H4
6-Cl
4-H3CO-
C6H4
7-Cl
8u
8v
4-H3CO-
C6H4
6-CH3
8-CH3
Surflex-Dock was used to probe the featured intermolecular in-
teractions amid the ligand and the target protein. Docking studies
4-H3CO-
C6H4
furnish
a fair idea related to drug-receptor interactions. Three-
dimensional structure information on the target protein was captured
from the PDB entry 4DQU. Processing of the protein comprised the
deletion of the ligand and the solvent molecules as well as the inclusion
of hydrogen atoms. In order to rationalize the biological results of our
compounds, molecular docking studies with the enoyl acyl carrier pro-
tein reductase (InhA) of M. tuberculosis were performed. This objective is
present only in the mycobacterium and acknowledged as the molecular
target of the frontline anti-tubercular drugs. All the inhibitors were
docked into the active site of enzyme InhA-D148G (PDB ID: 4DQU) as
portrayed in Fig. 2. The inferred binding energies of the compounds are
tabularized in Table 3. The compound 8n makes two hydrogen bonding
interactions at the vital site of the enzyme (PDB ID: 4DQU) as portrayed
in the Fig. 3A-B, bonding interaction raised from 2nd nitrogen atom of
triazole ring with hydrogen of ILE21 (-N——H-ILE21, 2.12 Å) and ox-
ygen atom of carbonyl group present on the 3rd position of triazole ring
which we have optimized the reaction conditions with miscellaneous
catalytic amount of CuSO4⋅5H2O in various solvents as cited in Table 1.
For the optimization of the yields, miscellaneous prerequisite con-
ditions have been implemented for the emergence of final compounds
(Table 1). The presence of CuSO4⋅5H2O was evident as no product for-
mation was discerned in its deprivation (Table 1, entry 1). An additional
array of reaction mixture was enabled to stir at customary room tem-
perature within the occupancy of sodium ascorbate and CuSO4⋅5H2O in
DMF and the reaction was accomplished with poor yield (Table 1, entry
2). No product emergence was noticed, when dry t-butanol was used as
the solvent (Table 1, entry 4). Evidently, an overabundance of water was
fruitful to this method. Moreover, the reason could be that it is going to
advance the emulsification of 4a-b in this reaction system. It was dis-
cerned eventually that the reaction proceeded more proficiently when
the reaction was carried out in the existence of CuSO4⋅5H2O (15 mmol)
in THF:H2O in 1:1 ratio at room temperature provoking outstanding
yield of the cycloaddition product. On that account, kneading use of
these optimal reaction conditions, product 8j was secluded with 80% of
yield (Table 1, entry 10). Ultimately, we explored indistinguishable
–
crafts a bonding interaction with hydrogen of ILE194 (-C O——H-
–
ILE194, 1.99 Å). The remaining docking portrays are provided in elec-
tronic supplementary information. As emphasized in the Fig. 4A–C, the
compound 8r makes two hydrogen bonding interactions at the active
site of the enzyme (PDB ID: 4DQU), bonding interaction raised from 2nd
nitrogen atom of triazole ring with hydrogen of ILE21 (-N——H-ILE21,
Fig. 2. Binding mode of all the compounds at the active site of the enzyme InhA-D148G (PDB ID: 4DQU).
4

A.R. Nesaragi et al.
Bioorganic & Medicinal Chemistry Letters 41 (2021) 127984
Table 3
Surflex docking score (kcal/mol) of the title compounds 8j-v on enzyme (PDB ID: 4DQU).
Entry No.
C Scorea
Crash Scoreb
Polar Scorec
D Scored
PMF Scoree
G Scoref
Chem Scoreg
Amino acid involved inH-bond
4DQU_ligand
7.75
6.58
6.65
5.47
5.37
7.77
6.49
7.91
7.57
6.69
6.29
5.33
8.98
8.64
3.58
ꢀ 1.15
ꢀ 1.41
ꢀ 1.03
ꢀ 1.10
ꢀ 2.41
ꢀ 0.68
ꢀ 0.72
ꢀ 1.10
ꢀ 2.84
ꢀ 1.04
ꢀ 1.40
ꢀ 2.95
ꢀ 3.19
ꢀ 3.63
ꢀ 0.87
5.90
0.87
0.01
1.88
0.21
2.47
1.18
1.41
0.96
1.64
1.15
1.53
1.01
0.98
4.25
ꢀ 1259.86
ꢀ 123.135
ꢀ 144.864
ꢀ 131.442
ꢀ 128.149
ꢀ 131.123
ꢀ 114.824
ꢀ 135.707
ꢀ 165.417
ꢀ 120.606
ꢀ 141.606
ꢀ 125.070
ꢀ 161.357
ꢀ 162.859
ꢀ 50.863
ꢀ 86.99
ꢀ 2.577
5.896
ꢀ 334.65
ꢀ 20.41
–
8j
ꢀ 241.755
ꢀ 255.643
ꢀ 207.341
ꢀ 269.945
ꢀ 218.531
ꢀ 214.792
ꢀ 251.691
ꢀ 312.274
ꢀ 220.268
ꢀ 242.446
ꢀ 291.639
ꢀ 329.923
ꢀ 348.613
ꢀ 100.434
ꢀ 31.308
ꢀ 29.712
ꢀ 30.912
ꢀ 25.338
ꢀ 34.241
ꢀ 28.891
ꢀ 35.334
ꢀ 39.375
ꢀ 25.655
ꢀ 30.594
ꢀ 36.366
ꢀ 36.240
ꢀ 37.191
ꢀ 18.170
ILE21
8k
–
8l
ꢀ 24.804
ꢀ 11.300
ꢀ 13.083
2.852
GLY96
8m
8n
GLY96
ILE21, ILE194
THR196
THR196, TYR158
GLY14
8o
8p
ꢀ 31.539
ꢀ 27.279
5.097
8q
8r
ILE21, ILE194
ILE194
8s
ꢀ 25.267
ꢀ 70.960
ꢀ 16.595
ꢀ 25.550
ꢀ 1.345
8t
ARG43, PHE41
GLY14, ASP42
ASP42, GLY14
–
8u
8v
Isoniazid
a
CScore (Consensus Score) integrates a number of popular scoring functions for ranking the affinity of ligands bound to the active site of a receptor and reports the
output of total score.
b
Crash-score revealing the inappropriate penetration into the binding site. Crash scores close to 0 are favorable. Negative numbers indicate penetration.
c
Polar score indicating the contribution of the polar interactions to the total score. The polar score may be useful for excluding docking results that make no
hydrogen bonds.
d
D-score for charge and van der Waals interactions between the protein and the ligand.
e
PMF-score indicating the Helmholtz free energies of interactions for protein–ligand atom pairs (Potential of Mean Force, PMF).
f
g
G-score showing energy of hydrogen bonding in the complex (i.e., ligand–protein).
Chem-score points for H-bonding, lipophilic contact, and rotational entropy, along with an intercept term.
Fig. 3. Binding interaction of compound 8n at the active site of the enzyme InhA-D148G (PDB: 4DQU).
2.45 Å) and oxygen atom of methoxy group present on the phenyl ring
makes a bonding interaction with hydrogen of ILE194 (-O——H-ILE194,
2.08 Å). As portrayed in Fig. 5(A–C), the 4DQU_ligand manifested nine
H-bonding interactions (Amino acids; SER20, ILE21, THR196, ILE194,
GLY96, ILE95, LYS165, VAL165, ASP64). Standard Isoniazid has shown
six bonding interactions at the active site of the enzyme (PDB ID: 4DQU)
(Amino acids; ALA22, SER20, ILE21, GLY14, SER94, LYS165). Inter-
estingly, most of the newly synthesized compounds have shown same
interactions with the amino acids GLY14, ASP42, THR196, ILE21,
ILE194, GLY96 as that of 4DQU_ligand and isoniazid. Hence, from these
studies, we can corroborate the experimental findings, which suggest
that the title compounds act by inhibiting the InhA enzyme. The docked
view of isoniazid has been represented in Fig. 6(A–C). Fig. 7(A and B)
personifies the hydrophobic and hydrophilic amino acids encompassing
to the studied compounds 8n and 8r.
four compounds 8n, 8p, 8u and 8v have higher C-score values than the
4DQU_ligand. The synthesized compounds bind to the enzyme in
equivalent manner as that of 4DQU_ligand. Thus, the compounds un-
veiled the resemblance in the genesis of H-bond with the standard drug
isoniazid and 4DQU_ligand especially with respect to the residues ILE21
and ILE194 amino acid residues.
In vitro anti-tubercular activity
The synthesized compounds were screened for their anti-tubercular
efficacy against M. tuberculosis H37Rv (ATCC-27294) using the stan-
dard Microplate Alamar Blue Assay (MABA) with standard drug isoni-
azid. The results were compared with ciprofloxacin and pyrazinamide.
All the compounds were tested against M. tuberculosis H37Rv at diverse
concentrations ranging from 0.20 µg/ml to100 µg/ml. The MIC of the
tested compounds divulged in Table 4, revealed that most of the newly
synthesized compounds proclaimed lower MIC values ranging from
1.60 µg/ml to 25 µg/ml against M. tuberculosis H37Rv strain.
The comparative molecular docking study of synthesized compounds
and 4DQU_ligand emphasizes that the synthesized compounds man-
ifested high C-score value. 4DQU_ligand Cscore value is 7.75 whereas
5

A.R. Nesaragi et al.
Bioorganic & Medicinal Chemistry Letters 41 (2021) 127984
Fig. 4. Interaction of compound 8r at the vital site of the enzyme PDB: 4DQU.
Fig. 5. Interacting sort of compound 4DQU_ligand at the vital site of the enzyme PDB: 4DQU.
6

A.R. Nesaragi et al.
Bioorganic & Medicinal Chemistry Letters 41 (2021) 127984
Fig. 6. Docked view of Isoniazid at the active spot of the enzyme PDB: 4DQU.
Fig. 7. A) Hydrophobic amino acids surrounded to compounds 8n (green colour) and 8r (cyan colour). B) Hydrophilic amino acids surrounded to compounds 8n
and 8r.
The results manifested that compounds 8n (methyl at C6 position of
the quinoline), 8o (methyl at C7 position of the quinoline), 8p (methoxy
at C6 position of the quinoline), 8s (chloro at C6 position of the quino-
line, 4-methoxy phenyl substitution at C1 position of the 1,2,4-triazole),
8t (chloro at C7 position of the quinoline, 4-methoxy phenyl substitution
at C1 position of the 1,2,4-triazole), 8u (methyl at C6 position of the
quinoline, 4-methoxy substitution at C1 position of the 1,2,4-triazole),
8v (methyl at C7 position of the quinoline, 4-methoxy at C1 position of
the 1,2,4-triazole) exhibited excellent activity with MICs ranging from
activity with MIC of 6.25–25 μg/ml. The results also divulged that
activating groups on quinoline and the phenyl ring attached to 1,2,4-tri-
azole were perceived to enhance the anti-tubercular activity (viz., 8n,
8o, 8p, 8s, 8t, 8u and 8v) with MICs 1.60–3.25 μg/ml.
The cytotoxicity studies were executed using MTT assay and
imparted as IC50 (Table 4) for HEK293 (Normal human kidney cell line).
The proportions between cytotoxicity and tubercular assessments
facilitated the persistence of selectivity index (SI). According to Tuber-
culosis Antimicrobial Acquisition and Coordinating Facility (TAACF), new
drugs must have a selective index equal or superior than 10, with MIC
1.60 to 3.12 µg/ml in comparison with isoniazid having MIC of 1.60
μg/
ml. Compounds 8j, 8k, 8l, 8m, 8q and 8r illustrated good to moderate
lower than 6.25 μg/ml and low cytotoxicity for further screening. In this
7

A.R. Nesaragi et al.
Bioorganic & Medicinal Chemistry Letters 41 (2021) 127984
synthesized compounds are proven to be better as compared with the
marketed drug fluconazole. The compounds (8j-v) exhibited excellent
activity against
Table 4
In vitro anti-tubercular assessment of MIC (μg/ml) of title compounds 8j-v.
Entry
Ar
R
MIC(µg/
IC50(µg/
SI
A. niger with MIC values ranging from 0.20 to 6.25 µg/ml, C. albicans
with MIC values ranging from 0.20 to 6.25 µg/ml, A. flavus with MIC
values ranging from 0.20 to 12.50 µg/ml and A. fumigatus with MIC
values ranging from 3.12 to 50 µg/ml in comparison with fluconazole.
ml)
ml)
8j
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
H
25
655.30
1652.0
458.60
869.30
477.50
728.80
1008.0
26.21
8k
8l
6-Br
6-Cl
7-Cl
6-CH3
8-CH3
7-
25
66.08
36.68
12.5
25
8m
8n
8o
8p
34.77
3.12
1.60
1.60
153.04
233.58
630.00
In silico ADME prophecy
OCH3
H
The measure of drug success is not only its superior productiveness
but also an adequate ADME (absorption, distribution, metabolism, and
excretion) portrait. Herein, we have computed molecular weight (MW),
logarithm of partition coefficient (miLog P), number of hydrogen bond
acceptors (n-ON), number of hydrogen bonds donors (n-OHNH), topo-
logical polar surface area (TPSA), number of rotatable bonds (n-ROTB),
and Lipinski’s rule of five22 using Molinspiration online property
calculation toolkit.23 Absorption (% ABS) was calculated by: % ABS =
109 – (0.345 TPSA).24 Drug-likeness model score (a collective property
of physico-chemical properties, pharmacokinetics, and pharmacody-
namics of a compound is represented by a numerical value) was figured
by MolSoft software.25
8q
8r
8s
8t
4-H3CO-
C6H4
12.5
6.25
3.12
3.12
1.60
1.60
958.40
332.70
1062.0
1465.0
615.20
585.60
76.67
53.23
4-H3CO-
C6H4
6-Br
4-H3CO-
C6H4
6-Cl
340.38
469.55
384.50
366.00
4-H3CO-
C6H4
7-Cl
8u
8v
4-H3CO-
C6H4
6-CH3
8-CH3
4-H3CO-
C6H4
Isoniazid
–
–
–
–
1.60
3.12
6.25
–
–
–
–
–
–
Ciprofloxacin
Pyrazinamide
–
The computational study of compounds 8j-v was performed to
predict pharmacokinetic parameters, bioactivity and drug likeliness
properties and is tabulated in Tables 5 and 6. The computational
study reveals that compounds displayed a good % ABS (% absorption)
ranging from 77.02 to 80.21%. Furthermore, all the synthesized
compounds 8j-v obeyed the Lipinski’s rule of five (miLog P ≤ 5). A
molecule likely to be developed as an orally active drug aspirant
should not be evidence for more than one violation of the following
four criteria: miLog P (octanol–water partition coefficient) ≤ 5, mo-
lecular weight ≤500, number of hydrogen bond acceptors ≤10 and
number of hydrogen bond donors ≤5.26 The probability of a molecule
to be potent will be greater for higher value of drug likeliness model
score. Without exception all these compounds emerged having good
potential for ultimate development as oral agents as they have obeyed
the benchmark for orally active drugs.
–
In summary, a simple, efficient and green synthesis of novel quino-
linyl-1,2,3-triazolyl-1,2,4-triazol-3(4H)-ones (8j-v) have been flour-
ished. All the molecules were synthesized in modest to excessive yields
under placid conditions. Both THF/water and CuSO4⋅5H2O are afford-
able and eco-friendly. The study revealed prominence of CuSO4⋅5H2O
We comprehend the significance and the preponderance of CuSO4.5H2O
and THF/water promoted [3+2] cycloaddition reactions.
The newly synthesized compounds were screened for anti-
tubercular and antifungal assay. The anti-TB results manifested that
compounds 8n, 8o, 8p, 8s, 8t, 8u and 8v with MICs 1.60–3.25 μg/ml
revealed excellent activity in comparison with the marketed drugs
isoniazid (MIC 1.60 g/ml) ciprofloxacin (MIC 3.12 g/ml) and pyr-
azinamide (MIC 6.25 g/ml). The compounds (8j-v) exhibited admi-
μ
μ
μ
Fig. 8. In vitro antifungal results of the compounds 8j-v.
rable antifungal activity against A. niger with MIC values ranging
from 0.20 to 6.25 µg/ml, C. albicans with MIC values ranging from
0.20 to 6.25 µg/ml, A. flavus with MIC values ranging from 0.20 to
12.50 µg/ml and A. fumigatus with MIC values ranging from 3.12 to
50 µg/ml in comparison with fluconazole. The in vitro and in silico
studies imply that these triazoles appended quinolines may acquire
the ideal structural prerequisites for auxiliary expansion of novel
therapeutic agents.
regard the compounds displayed acceptable safety and therapeutic
index symbolized by their SI ranging from 26.21 to 630.
In vitro antifungal activity
The in vitro antifungal activity of the title compounds (8j-v) were
tested against four different pathogenic fungal species viz., A. niger, C.
albicans, A. flavus and A. fumigatus. Fluconazole the clinical antifungal
drug was used as a reference. MICs (Minimum Inhibitory Concentrations
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
in μg/ml) are summarized in Fig. 8.
The antifungal results revealed that all the compounds have
exhibited excellent activity against the tested fungal strains. The
8

A.R. Nesaragi et al.
Bioorganic & Medicinal Chemistry Letters 41 (2021) 127984
Table 5
Pharmacokinetic parameters of the compounds 8j-v.
Entry
MW
miLogP
TPSA
n Atoms
n ON
n OHNH
n Violation
n rotb
% ABS
8j
417.86
496.76
452.31
452.31
431.89
431.89
447.89
447.89
526.78
482.33
482.33
461.91
461.91
2.74
3.53
3.40
3.40
3.17
3.14
2.77
2.80
3.58
3.45
3.45
3.22
3.20
83.44
83.44
83.44
83.44
83.44
83.44
92.67
92.67
92.67
92.67
92.67
92.67
92.67
30
31
31
31
31
31
32
32
33
33
33
33
33
8
8
8
8
8
8
9
9
9
9
9
9
9
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
0
0
0
0
5
5
5
5
5
5
6
6
6
6
6
6
6
80.21
80.21
80.21
80.21
80.21
80.21
77.02
77.02
77.02
77.02
77.02
77.02
77.02
8k
8l
8m
8n
8o
8p
8q
8r
8s
8t
8u
8v
MW: Molecular weight, miLog P: Logarithm of partition coefficient, TPSA: Topological polar surface area, n-ON Acceptors: Number of hydrogen bond acceptors, n-
OHNH donors: Number of hydrogen bonds donors, n-ROTB: Number of rotatable bonds, % ABS: Percentage absorption.
Table 6
Bioactivity and druglikeliness scores of compounds 8j-v.
Entry
GPCR ligand
Ion channel modulator
Kinase inhibitor
Nuclear receptor ligand
Protease inhibitor
Enzyme inhibitor
Drug likeliness
8j
0.28
0.17
0.27
0.28
0.23
0.24
0.23
0.23
0.12
0.21
0.23
0.18
0.19
ꢀ 0.05
ꢀ 0.14
ꢀ 0.06
ꢀ 0.03
ꢀ 0.12
ꢀ 0.15
ꢀ 0.11
ꢀ 0.11
ꢀ 0.20
ꢀ 0.12
ꢀ 0.08
ꢀ 0.17
ꢀ 0.19
ꢀ 0.01
ꢀ 0.05
ꢀ 0.02
ꢀ 0.03
ꢀ 0.06
ꢀ 0.05
ꢀ 0.01
ꢀ 0.04
ꢀ 0.08
ꢀ 0.06
ꢀ 0.06
ꢀ 0.08
ꢀ 0.08
ꢀ 0.25
ꢀ 0.37
ꢀ 0.26
ꢀ 0.26
ꢀ 0.27
ꢀ 0.24
ꢀ 0.23
ꢀ 0.25
ꢀ 0.35
ꢀ 0.25
ꢀ 0.25
ꢀ 0.27
ꢀ 0.24
ꢀ 0.10
ꢀ 0.22
ꢀ 0.11
ꢀ 0.12
ꢀ 0.15
ꢀ 0.17
ꢀ 0.15
ꢀ 0.15
ꢀ 0.25
ꢀ 0.16
ꢀ 0.16
ꢀ 0.19
ꢀ 0.21
0.08
0.00
0.02
0.01
8k
8l
0.06
0.29
8m
8n
8o
8p
8q
8r
0.07
0.30
0.02
0.00
0.03
0.47
0.04
0.08
0.03
ꢀ 0.04
ꢀ 0.23
0.04
ꢀ 0.04
0.02
8 s
8 t
8u
8v
0.03
0.03
ꢀ 0.02
ꢀ 0.01
ꢀ 0.29
0.29
GPCR-G-Protein-Coupled Receptors.
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Carboxylic Acid Esters. J Med Chem. 2009;52:6966–6978.(c) Jayaprakash S, Iso Y,
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Acknowledgments
The authors are obliged to DST-PURSE Phase-II, SAIF, University
Scientific Instrumentation Center (USIC), Karnatak University, Dharwad
and Institution of Excellence, University of Mysore, Mysuru, India for
providing the UPLC-mass spectral data and facilities to conduct the ex-
periments. The authors acknowledge the NGH College of Dental Sci-
ences and Research Centre Belgaum, Karnataka, India for anti-
tubercular activity. One of the authors (ARN) is grateful to DST-
KSTePS, Govt. of Karnataka for providing the Fellowship.
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