Arylquinolinecarboxamides: Synthesis, in vitro and in silico studies against Mycobacterium tuberculosis

Article abstract of DOI:10.1002/jhet.4340

A series of fourteen 6-substituted-2-(methoxyquinolin-3-yl) methyl)-N-(pyridin-3-ylmethyl) benzamides was prepared from commercially available anilines in five simple and convenient synthetic steps. The structures of all new products were confirmed by routine spectroscopic methods: IR, ¹H and ¹³C NMR, and HRMS (electrospray ionization). The resulting arylquinolinecarboxamides were subjected to biological screening assay for in vitro inhibitory activity against Mycobacterium tuberculosis (Mtb) H37Rv strain. Several compounds exhibited modest antitubercular activity with compounds 8–11, 15 and 19 exhibiting MIC₉₀ values in the range of 32–85 μM. The antitubercular data suggested that inhibition of Mtb can be imparted by the introduction of a non-polar substituent on C-6 of the quinoline scaffold. Further, to understand the possible mode of action of the series, the reported compounds and bedaquiline were subjected to in silico docking studies against MtbATPase to determine their potential to interfere with the mycobacterial adenosine triphosphate (ATP) synthase. The results showed that these compounds have the potential to serve as antimycobacterial agents. In silico ADME pharmacokinetic prediction results showed the ability of these arylquinolinecarcboxamides to be absorbed, distributed, metabolized and excreted efficiently.

Full text of DOI:10.1002/jhet.4340

Received: 5 May 2021
DOI: 10.1002/jhet.4340
Revised: 25 June 2021
Accepted: 2 July 2021
A R T I C L E
Arylquinolinecarboxamides: Synthesis, in vitro and in silico
studies against Mycobacterium tuberculosis
Fostino R. B. Bokosi1
Ronnet Seldon4 | Digby F. Warner3,5
Kevin Lobb1 | Setshaba D. Khanye1,6,7
| Richard M. Beteck1,2
| Audrey Jordaan3
|
| Tendamudzimu Tshiwawa1
|
1Department of Chemistry, Faculty of Science, Rhodes University, Makhanda, South Africa
2Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa
3SAMRC/NHLS/UCT Molecular Mycobacteriology Research Unit, Department of Pathology, Faculty of Health Sciences, Institute of Infectious
Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
4SAMRC Drug Discovery and Development Unit, University of Cape Town, Cape Town, South Africa
5Wellcome Centre for Infectious Diseases Research in Africa, University of Cape Town, Cape Town, South Africa
6Centre for Chemico- and Biomedicinal Research, Rhodes University, Makhanda, South Africa
7Division of Pharmaceutical Chemistry, Faculty of Pharmacy, Rhodes University, Makhanda, South Africa
Correspondence
Setshaba D. Khanye, Division of
Abstract
Pharmaceutical Chemistry, Faculty of
Pharmacy, Rhodes University, Makhanda
6140, South Africa.
A series of fourteen 6-substituted-2-(methoxyquinolin-3-yl) methyl)-N-(pyridin-
3-ylmethyl) benzamides was prepared from commercially available anilines in
five simple and convenient synthetic steps. The structures of all new products
Email: s.khanye@ru.ac.za
were confirmed by routine spectroscopic methods: IR, H and 13C NMR, and
1
Fostino R. B. Bokosi, Department of
Chemistry, Faculty of Science, Rhodes
University, Makhanda 6140, South Africa.
Email: bokosifostino@gmail.com
HRMS (electrospray ionization). The resulting arylquinolinecarboxamides were
subjected to biological screening assay for in vitro inhibitory activity against Myco-
bacterium tuberculosis (Mtb) H37Rv strain. Several compounds exhibited modest
antitubercular activity with compounds 8–11, 15 and 19 exhibiting MIC90 values
in the range of 32–85 μM. The antitubercular data suggested that inhibition of
Mtb can be imparted by the introduction of a non-polar substituent on C-6 of the
quinoline scaffold. Further, to understand the possible mode of action of the
series, the reported compounds and bedaquiline were subjected to in silico dock-
ing studies against MtbATPase to determine their potential to interfere with the
mycobacterial adenosine triphosphate (ATP) synthase. The results showed that
these compounds have the potential to serve as antimycobacterial agents. In silico
ADME pharmacokinetic prediction results showed the ability of these
arylquinolinecarcboxamides to be absorbed, distributed, metabolized and
excreted efficiently.
Funding information
Malawi Goverment Scholarship Fund;
South African Medical Research Council;
Rhodes University; National Research
Foundation, Grant/Award Number: SDK,
Grant No. 107270
K E Y W O R D S
antitubercular, arylquinolinecarboxamides, MtbATPase, Mycobacterium tuberculosis
J Heterocyclic Chem. 2021;1–12.
wileyonlinelibrary.com/journal/jhet
© 2021 Wiley Periodicals LLC.
1

2
BOKOSI ET AL.
1 | INTRODUCTION
bacterium [6,9–15]. The identification of bedaquiline as a
new class of antimycobacterial drug with a novel mode of
action has renewed interests to explore compounds con-
taining the quinoline nucleus in a campaign to develop
bioactive compounds capable of targeting different bio-
chemical pathways within the microorganisms.
Tuberculosis (TB) is one of the oldest infectious diseases,
which has claimed scores of human lives worldwide. TB
is caused by Mycobacterium tuberculosis (Mtb). Despite a
global reduction in TB mortality, 1.4 million people died
from TB in 2019 [1]. The disease is currently treated
using the first line regiment of four drugs, rifampicin
(RIF), isoniazid (INH), pyrazinamide (PZA), ethambutol
(EMT), which must be taken daily for a duration of at
least six months [2]. The current clinical management of
TB is complex, and the situation has been worsened by
the emergence of multi-drug resistant TB (MDR-TB), a
form of Mtb strains resistant to at least RIF and INH, and
extensively drug resistance TB (XDR-TB), another form
of MDR Mtb strains with additional resistance to at least
one fluoroquinolone and one second-line injectable drug
[3,4]. Both these TB resistant forms compromise the
effectiveness of the existing therapy as well as control
and clinical management of TB infections.
Quinoline nucleus represents an essential scaffold in
many biologically active natural products and a variety of
synthetic compounds with attractive pharmacological
profiles [5]. A typical example is bedaquiline ((TMC207,
Sirturo, Janssen Pharmaceuticals; Figure 1), a dia-
rylquinoline (DARQ) which was recently approved under
an accelerated programme for orphan drugs as an effec-
tive clinically approved drug reserved for MDR-TB along-
side with other TB armaments [6–8]. It potently inhibits
both drug-sensitive and drug-resistant Mtb by interfering
with the mycobacterial adenosine triphosphate (ATP)
synthase, an enzyme involved in ATP production in the
In an attempt to identify new chemical entities, ratio-
nally designed novel arylquinolines as potential
antitubercular agents by retaining the core unit of
bedaquiline, 2-methoxyquinoline (drawn in blue), and its
required 3D geometry were reported [16]. The
synthesised compounds showed encouraging growth
inhibition against Mtb H37Rv with MIC values in the
range of 5–140 μM. Compound I (Figure 1) emerged as
the most active member of the arylquinoline series with
MIC value of 5.18 μM using a resazurin microtitre assay
(REMA) plate method. In a separate study, a library of
compounds containing a 2-chloroquinoline framework
were synthesized and found to display superior growth
inhibition against Mtb H37Rv [17]. Amongst the hits
identified was compound II, which showed appreciable
percentage viability inhibition of 96% against Mtb.
Considering the above accounts, we undertook an
assemblage of a focused series of compounds containing
the bedaquiline core; 2-methoxyquinoline as a main
nucleus, while strategically varying substituents at posi-
tion 6 of the quinoline scaffold as potential starting com-
pounds for treatment of Mtb. The substituents R1 and R2
on the quinoline and benzoyl ring respectively were cho-
sen in order to assess the influence that the electronic
effects may have on the antimycobacterial activity. In this
work, we report synthesis, spectroscopic characterization,
and preliminary in vitro biological evaluation alongside
in silico studies of
a
representative series of
2-(methoxyquinolin-3-yl) methyl)-N-(pyridin-3-ylmethyl)
benzamides against Mtb H37Rv strain.
N
N
S
HO
N
OH
Br
R
2 | RESULTS AND DISCUSSION
2.1 | Chemistry
N
O
N
O
I
Bedaquiline
R2
Despite some limitations such as toxicity, bedaquline
exhibits significant activity against Mtb by targeting the
mycobacterial adenosine triphosphate (ATP) synthase,
which is an essential enzyme in ATP production. Over the
years, strategic modification of the bedaquiline structure to
address some of observed limitations has led to several ana-
logues showing significant antimycobacterial activity
against Mtb [18]. In this study, we embarked on a rational
design approach by retaining the 2-methoxyquinoline core
structure of bedaquiline while modifying substituents at
position 6 of the quinolone scaffold [19,20]. The targeted
Ar
N
N
N
O
N
N
O
N
O
R1
N
N
Cl
Target compounds
II
FIGURE 1 Chemical structures of bedaquiline and related
quinoline derivatives showing activity against Mtb

BOKOSI ET AL.
3
compounds (Figure 1) were achieved following the syn-
thetic route presented in Scheme 1. N-acylation of starting
para-substituted anilines (1a ꢀ d) using the acetic
anhydrideꢀglacial acetic acid (1:1) at room temperature
for 30 minutes yielded amides 2a–d, which were obtained
in 96–98% yields. Subsequent Vilsmeier-Haack cyclization
of amides 2aꢀd afforded key starting intermediates
6-substituted 2-chloroquinoline-3-carbaldehydes 3aꢀd,
which were sequentially treated with methanol/KOH to
afford 2-methoxyquinoline derivatives 4aꢀd in 60–70%
yields [21,22]. The Schiff-base condensation reaction of
aldehydes 4aꢀd with 3-aminomethylpyridine in ethanol
and catalytic amount of glacial acetic acid under refluxing
conditions generated imine intermediates, which were
reduced in situ using sodium borohydride at room temper-
ature to give rise to amines 5aꢀd in 62–70% yields. The
final N-amidation step of 5aꢀd was achieved by treatment
with cold TEA and 4-DMAP at 0ꢁC in the presence of
selected benzoyl chlorides to afford carboxamides 6–19
with yields in the range of 41–72%. Structures of critical
intermediate compounds (2aꢀd, 3aꢀd, 4aꢀd and 5aꢀd)
and corresponding target arylquinolinecarboxamide deriva-
tives (6–19) were confirmed using various spectroscopic
conversion from secondary amine to the amide func-
tional group. Various aromatic/hetero-aromatic H sig-
1
nals were observed between δ 8.60 and 6.90 ppm. The
most deshielded protons, found in the range 8.57–
8.43 ppm, were assignable to the protons adjacent to
nitrogen in the 3-(aminomethyl) pyridine scaffold. Th
intense singlet signal observed between 7.94 and
8.04 ppm in all the compounds was due to the proton on
1
C4 of the quinoline ring. The H-NMR spectra of com-
pounds reveal expected methylene protons integrating
1
for four. More importantly, H and 13C NMR spectra of
target arylquinolinecarboxamides displayed duplicate
and/or broad proton signals at 298 K (see electronic sup-
plementary information Figure S39) attributed to possi-
ble existence of the rotational isomers caused by the
restricted rotation around the C–N amide bond known as
rotamers [23–27]. The assignment of signals was facili-
tated by conducting NMR experiments of each compound
in DMSO-d6 at variable temperatures ranging from 298 to
353 K [26,28–30]. A characteristic 13C NMR signal appe-
aring around δ 171.9–171.0 ppm indicated the presence
of carbonyl carbon (C=O) of the amide unit in the target
compounds. The 13C NMR spectra of most prepared com-
pounds showed the apparent absence of expected N-
methylene signals and this phenomenon is attributed to
site-exchange line-broadening effects [31]. Additionally,
high-resolution mass spectroscopy (HRMS) analysis for
all the compounds unequivocally confirmed the existence
of molecular ions consistent with molecular weights of
prepared compounds, thereby confirming the respective
chemical structures.
1
techniques (IR, H-NMR, 13C-NMR and HRMS). A com-
prehensive spectral data is presented as an Electronic Sup-
plementary Information (ESI) file.
The FT-IR of all target compounds showed consistent
broad intense stretch bands in the range ꢂ 1617–
1628 cmꢀ1, which are assignable to ꢀC=O of amide unit.
The disappearance of the characteristic strong band ca
3320–3050 cmꢀ1 of the NꢀH group confirmed successful
R1
R1
R1
R1
i
O
O
ii
iii
O
NH2
N
4a-d
O
N
H
N
3a-d
Cl
1a-d
2a-d
R2
iv,
v
R1
a
b
c
d
H
Me
MeO
F
HN
O
N
O
N
O
N
R1
vi
R1
SCHEME 1 Synthetic route for the
synthesis of arylquinolinecarboxamide
derivatives 6–19. Reagents and
conditions: (i) Ac2O, AcOH, r.t, 30 min;
(ii) DMF–POCl3, 80ꢁC, 5–18 h;
(iii) MeOH, KOH, reflux, 3–4 h;
(iv) 3-Picolylamine, EtOH, AcOH (cat),
reflux, 12 h; (v) EtOH, sodium
N
N
5a-d
6-19
6
7
8
9
: R1 = H,
: R1 = H,
: R1 = H,
R2 = H
R2 = MeO
R2 = F
13
14
15
16
17
18
19
: R1 = OMe, R2 = OMe
: R1 = OMe, R2 = F
: R1 = OMe, R2 = Br
: R1 = Me, R2 = H
: R1 = F,
: R1 = F,
: R1 = F,
: R1 = F,
R2 = H
10
11
12
: R1 = Me, R2 = F
: R1 = Me, R2 = Br
: R1 = OMe, R2 = H
R2 = MeO
R2 = F
borohydride, rt, 6 h; (vi) substituted
benzoyl chlorides, DCM, TEA, 4-DMAP
(cat), 0ꢁC, 12 h
R2 = Br

4
BOKOSI ET AL.
2.2 | Antimycobacterial activity
the docking score that is within the same range as that of
the known inhibitor bedaquiline (Table 1). All docking
scores less than ꢀ5 kcal/mol indicate good affinity
between the ligands and the target receptor. As shown in
Figure 2, there are several intramolecular interactions
observed between ligands and receptor residues. These
interactions include conventional intramolecular hydro-
gen bonds, pi-pi stacking and pi-cation. All these interac-
tions are a good indicator of binding affinity between the
ligands and the receptor [33].
In drug discovery, several potential therapeutic agents
fail to enter the clinical trials due to their unfavorable
drug-likeliness and poor ADME properties [34]. Thus, for
an efficient drug molecule, a compound should possess
desirable high biological activity, low toxicity and appro-
priate ADME property profile. In an attempt to assess
drug-likeliness and ADME properties, a computational
study of synthesized compounds (6–19) was performed
and values obtained are tabulated in Table 2. The
observed drug-like properties and analysis of in silico
ADME prediction suggest that these compounds are
exhibiting acceptable ADME profile despite some of the
compounds within the series showing predicted octanol/
water partition coefficient QPlogPo/w > 5.0 (Table 2).
Compounds 6–19 were evaluated for potential in vitro
antitubercular activity using a broth microdilution assay
against H37Rv, the drug susceptible strain of Mtb with
rifampicin included as a standard drug. The antitubercular
activities are reported as the minimum inhibitory concen-
tration (MIC90), which is a required concentration to
inhibit 90% of mycobacterial growth. Antitubercular activ-
ity data of target compounds is presented in Table 1. The
data revealed that the structural variation at position
6 (R1) of the quinoline ring and the functionalization of
the benzoyl scaffold (R2) to some extent influenced the
antitubercular activity. Analysis of the substituents at posi-
tion 6 of the quinoline nucleus suggested that a methyl
substituent promoted antitubercular activity better than
methoxy, fluoro and non-substituted derivatives. For
example, modest activity was observed for compounds
9 (MIC90; 84.2 μM), 10 (MIC90; 32.5 μM) and 11 (MIC90;
40.3 μM) – all bearing a methyl substituent at position 6 of
the quinoline ring. Similarly, compounds 11 (MIC90;
40.3 μM), 15 (MIC90; 55.1 μM) and 19 (MIC90; 50.1 μM)
which contain a combination of methyl, methoxy and
fluoro substituents at position 6 coupled with the carbox-
amide aromatic ring bearing bromine at the para position
were at most moderately active. It is important to note that
compound 11 (MIC90; 40.3 μM), which bears both the
favored 6-methyl group on position 6 of the quinoline ring
and a bromine group on para position of the benzoyl moi-
ety, proved to be one of the most active compounds of the
series as anticipated from the preliminary structure activ-
ity relationships (SAR).
3 | EXPERIMENTAL
All chemicals and reagents used were purchased from
Merck® and where necessary, they were purified
according to the methods reported in literature [36]. The
reaction progress was monitored by thin layer chroma-
tography (TLC) using Merck 60-F254 silica gel plates
supported on aluminum and viewed under UV light. The
purification of synthesised compounds was carried out
using a silica gel column chromatography using Merck
Kieselgel 60 Å: 70–230 (0.068–0.2 mm) silica gel mesh.
NMR spectra were recorded on Bruker Fourier 300 MHz,
AMX 400 MHz or Biospin 600 MHz spectrometers in
CDCl3 or DMSO-d6 and calibrated using solvents signals
[δH: 7.26 ppm for CDCl3 and 2.50 ppm for DMSO-d6; δC:
77.0 ppm for CDCl3 and 39.4 ppm for DMSO-d6]. The
spectra were processed using processed using
MestReNova Software version 5.3.2–4936 or Bruker Top-
spin 3.5 software®. High-resolution electrospray ioniza-
tion mass spectrometry data (HRMS) were recorded on a
Waters Synapt G2 quadrupole time-of-flight (QTQF)
mass spectrometer (Stellenbosch University, Stellen-
bosch, South Africa). The IR spectra were recorded on
PerkinElmer 100 FT-IR Spectrometer in the mid-IR range
(640–4000 cmꢀ1). Melting points were measured using
Stuart melting point apparatus SMP30 and were reported
uncorrected.
2.3 | In silico studies
An in silico binding interaction study of bedaquiline
using the homology model of MtbATPase was conducted
to gain better insight into the key residues involved in
the binding of bedaquiline and functioning of
MtbATPase. The homology model of MtbATPase DARQ
binding site scored very well in ERRAT (see electronic
supplementary information Figures 40S and 41S) with
all the residues below the error region and only a few res-
idues appeared above the warning site. The molecular
docking values measure the fitness of ligand into the
binding site of a protein or an enzyme, and more negative
docking value is an indication of the better fitness of the
molecule at the binding site of the protein [32]. The result
of the docking analysis from this study showed the stan-
dard drug (Bedaquiline) exhibited the best binding fitness
at the binding site of the MtbATPase with a docking score
of ꢀ7.934 kcal/mol. The majority of docked ligands had

BOKOSI ET AL.
5

6
BOKOSI ET AL.

BOKOSI ET AL.
7
FIGURE 2 Bedaquiline and the best docked ligand 7 receptor ligand interactions
TABLE 2 The drug likeliness and in silico ADME properties of all the synthesized compounds
cQPlogPo/
w
g%Human
dQPlogS eQPlogBB fQPPMDCK OralAbsorption
hRule
of 5
Compound aQPlogHERG bMw
6
4.0
3.8
4.0
4.3
4.5
5.2
4.0
4.3
4.3
5.0
4.2
4.2
3.9
4.5
413.475 4.59
383.449 4.77
401.439 5.01
397.476 5.23
415.466 5.09
476.372 5.69
413.475 4.85
443.501 4.67
431.465 5.09
492.371 5.24
431.465 4.83
ꢀ4.53
ꢀ5.19
ꢀ5.50
ꢀ5.73
ꢀ5.49
ꢀ6.51
ꢀ5.19
ꢀ4.67
ꢀ5.56
ꢀ5.34
ꢀ4.88
ꢀ5.88
ꢀ5.79
ꢀ6.328
ꢀ0.449
ꢀ0.406
ꢀ0.306
ꢀ0.364
ꢀ0.236
ꢀ0.186
ꢀ0.429
ꢀ0.525
ꢀ0.318
ꢀ0.167
ꢀ0.338
ꢀ0.197
ꢀ0.29
1326.645
1389.388
2406.163
1554.356
2779.078
4119.007
1533.986
1331.025
2780.182
4478.546
2403.837
4354.318
2619.793
6263.976
100
100
100
100
100
100
100
100
100
100
100
100
100
100
0
0
1
1
1
1
0
0
1
1
0
1
1
1
7
8
9
10
11
12
13
14
15
16
17
18
19
419.43
5.25
401.439 5.15
480.335 5.561
ꢀ0.135
aQPlogHERG: Predicted IC50 value for blockage of HERG K+ channels.
bMw: Molecular weight of the molecule.
cQPlogPo/w: Predicted octanol/water partition coefficient.
dQPlogS: Predicted aqueous solubility.
eQPlogBB: Predicted brain/blood partition coefficient.
fQPPMDCK: Predicted apparent MDCK cell permeability in nm/sec.
g%HumanOralAbsorption: Predicted human oral absorption on 0–100% scale.
hRule of 5: Denotes the number of violations of Lipinski's rule of five. Compounds that satisfy these rules are considered drug like [35].
3.1 | General procedure for the synthesis
of target compounds (6–19)
dissolved in 10 mL of CH2Cl2. The flask was cooled down
to 0ꢁC and appropriate benzoyl chloride (2.0 equiv) was
added dropwise. The resulting mixture was stirred over-
night at room temperature. The reaction was quenched
with water (5 mL) extracted with CH2Cl2 (3 ꢃ 15 mL).
The combined organic layers washed with brine (20 mL),
dried (Na2SO4) and concentrated under reduced pressure.
Target compounds were synthesized by employing an
efficient amide coupling protocol [37]. To a suitable sec-
ondary amines 5aꢀd (1.0 equiv), triethylamine (2.0
equiv) and few granules of catalytic 4-DMAP were

8
BOKOSI ET AL.
The crude product was purified by silica gel column chro-
matography (EtOAc:Hexane 2:8) to yield desired
benzamides 6–19. Characterization of synthesized com-
pounds is given below.
(3H, s, OCH3); 13C NMR (150 MHz, DMSO-d6 at 328 K):
δC = 171.1, 163.1 (d, J = 246.9 Hz), 160.2, 149.3, 148.9,
145.7, 137.1, 135.6, 133.4, 133.0 (d, J = 3.3 Hz), 129.9,
129.7 (d, J = 8.6 Hz), 128.2, 126.8, 125.3, 124.7, 123.9,
121.1, 115.9 (d, J = 21.5 Hz), 53.7; m/z (ESI) calcd for
C24H21N3O2F [M + H]+: 402.1618, found 402.1623.
3.1.1 | N-([2-Methoxyquinolin-3-yl] methyl)-
N-(pyridin-3-ylmethyl) benzamide (6)
3.1.4 | N-([2-Methoxy-6-methylquinolin-3-yl]
methyl)-N-(pyridin-3-ylmethyl) benzamide (9)
White crystalline solid. Yield = 71%; M.p: 147–149 ꢁC;
ν
max/cmꢀ1 1626 (C=O); 1H NMR (400 MHz, CDCl3):
δH = 8.51–8.33 (2H, m, overlapping H-80 and H-90), 8.25–
7.93 (1H, m, H-4), 7.79–7.77 (1H, m, H-8), 7.75–7.63 (2H,
m, H-5, H-60), 7.57–7.56 (1H, m, H-500), 7.42–7.38 (2H, m,
H-300), 7.33–7.30 (4H, m, H-6, H-7, H-400), 7.23–7.22 (1H,
m, H-70), 4.72 (2H, s, CH2, H-30), 4.59–4.53(2H, m, CH2,
H-40), 4.07–3.98 (3H, m, OCH3); 13C NMR (100 MHz,
CDCl3) δC = 172.9, 159.9, 149.6, 149.1, 146.0, 138.1,
136.1, 135.7, 132.8, 130.1, 129.7, 128.6, 127.3, 127.0, 126.7,
124.9, 124.6, 123.7, 120.5, 53.6, 48.1, 45.7; m/z (ESI) calcd
for C24H22N3O2 [M + H]+: 384.1712, found 384.1714.
White crystalline solid. Yield = 72%; M.p: 136–138 ꢁC;
ν
max/cmꢀ1 1621 (C=O); 1H NMR (300 MHz, CDCl3):
δH = 8.56–8.51 (2H, m, overlapping H-80 and H-90), 7.76–
7.72 (3H, m, H-4, H-8, H-60), 7.51 (1H, s, H-5), 7.49–7.44
(3H, m, H-300, H-500), 7.42–7.37 (3H, m, H-7, H-400), 7.31–
7.26 (1H, m, H-70), 4.78 (2H, bs, CH2, H-30), 4.52 (2H, bs,
CH2, H-40), 3.97 (3H, bs, OCH3), 2.51 (3H, s, CH3); 13C
NMR (75 MHz, CDCl3): δC = 172.8, 159.6, 149.5, 149.1,
144.3, 136.1, 135.7, 135.3, 134.6, 134.1, 132.8, 131.7, 130.0,
128.6, 126.7, 126.5, 124.9, 123.7, 120.3, 53.4, 48.1, 45.7,
21.3; m/z (ESI) calcd for C25H24N3O2 [M + H]+:
398.1869, found 398.1878.
3.1.2 | 4-Methoxy-N-([2-methoxyquinolin-
3-yl]methyl)-N-(pyridin-3-ylmethyl)
benzamide (7)
3.1.5 | 4-Fluoro-N-([2-methoxy-
6-methylquinolin-3-yl]methyl)-N-(pyridin-
3-ylmethyl) benzamide (10)
White crystalline solid. Yield = 65%; M.p: 142–144 ꢁC;
1
ν
max/cmꢀ1: 1625 (C=O); H NMR (600 MHz, DMSO-d6 at
328 K): δH = 8.46–8.42 (2H, m, overlapping H-80 and H-
90), 8.10 (1H, s, H-4), 7.93 (1H, d, J = 7.8 Hz, H-8), 7.77–
7.76 (1H, m, H-5), 7.68 (1H, bs, H-60), 7.66–7.64 (1H, m, H-
7), 7.50 (2H, d, J = 8.1 Hz, H-300), 7.46–7.43 (1H, m, H-6),
7.33 (1H, dd, J = 7.5, 4.9 Hz, H-70), 6.97 (2H, d, J = 8.1 Hz,
H-400), 4.71 (2H, s, CH2, H-30), 4.61 (2H, s, CH2, H-40), 3.93
(3H, s, OCH3), 3.77 (3H, s, OCH3); 13C NMR (150 MHz,
DMSO-d6 at 328 K): δC = 171.9, 160.8, 160.2, 149.3, 148.8,
145.6, 136.7, 135.5, 133.5, 130.0, 129.0, 128.5, 128.2, 126.8,
125.3, 124.7, 124.0, 121.3, 114.2, 55.7, 53.8; m/z (ESI) calcd
for C25H24N3O3 [M + H]+: 414.1818, found 414.1813.
White crystalline solid. Yield = 49%; M.p: 139–141 ꢁC;
1
ν
max/cmꢀ1 1632 (C=O); H NMR (600 MHz, DMSO-d6 at
308 K): δH = 8.47–8.44 (2H, m, overlapping H-80 and H-
90), 7.99 (1H, s, H-4), 7.71–7.63 (3H, m, H-60, H-5, H-8),
7.63–7.58 (2H, m, H-300), 7.48 (1H, dd, J = 8.5, 1.7 Hz, H-
7), 7.32 (1H, dd, J = 7.6, 4.9 Hz, H-70), 7.26 (2H, t,
J = 8.6 Hz, H-400), 4.68 (2H, s, CH2, H-30), 4.59 (2H, s,
CH2, H-40), 3.91 (3H, s, OCH3), 2.46 (3H, s, CH3); 13C
NMR (150 MHz, DMSO-d6 at 308 K): δC = 171.1, 163.1
(d, J = 246.9 Hz), 159.7, 149.3, 148.8, 144.0, 136.5, 135.6,
133.9, 133.4, 133.0 (d, J = 3.2 Hz), 131.8, 129.6 (d,
J = 8.6 Hz), 127.2, 126.6, 125.2, 123.9, 120.9, 115.9 (d,
J = 21.7 Hz), 53.6, 49.0, 46.6, 21.3; m/z (ESI) calcd for
C25H23N3O2F [M + H]+: 416.1774, found 416.1779.
3.1.3 | 4-Fluoro-N-([2-methoxyquinolin-3-yl]
methyl)-N-(pyridin-3-ylmethyl) benzamide (8)
White crystalline solid. Yield = 55%; M.p: 122–124 ꢁC;
3.1.6 | 4-Bromo-N-([2-methoxy-
6-methylquinolin-3-yl]methyl)-N-(pyridin-
3-ylmethyl) benzamide (11)
1
ν
max/cmꢀ1: 1632 (C=O); H NMR (600 MHz, DMSO-d6 at
328 K): δH = 8.46–8.42 (2H, m, overlapping H-80 and H-
90), 8.10 (1H, s, H-4), 7.93 (1H, d, J = 7.9 Hz, H-8), 7.77–
7.76 (1H, m, H-5), 7.68–7.67 (1H, m, H-60), 7.66–7.64 (1H,
m, H-7), 7.62–7.59 (2H, m, H-300), 7.46–7.43 (1H, m, H-6),
7.32 (1H, dd, J = 7.6, 4.9 Hz, H-70), 7.26 (2H, t, J = 8.7 Hz,
H-400), 4.70 (2H, s, CH2, H-30), 4.60 (2H, s, CH2, H-40), 3.93
White crystalline solid. Yield = 42%; M.p: 114–116 ꢁC;
1
ν
max/cmꢀ1 1621 (C=O); H NMR (600 MHz, DMSO-d6 at
308 K): δH = 8.46–8.44 (2H, m, overlapping H-80 and H-90),
7.98 (1H, s, H-4), 7.70–7.62 (5H, m, H-60, H-5, H-8, H-

BOKOSI ET AL.
9
300), 7.50–7.47 (3H, m, H-7, H-400), 7.34–7.30 (1H, m, H-70),
4.68 (2H, s, CH2, H-30), 4.56 (2H, s, CH2, H-40), 3.90 (3H, s,
OCH3), 2.46 (3H, s, CH3); 13C NMR (150 MHz, DMSO-d6 at
308 K): δC = 171.0, 159.6, 149.3, 148.9, 144.0, 135.7, 135.2,
133.9, 131.9, 129.3, 129.2, 127.2, 127.1, 126.6, 125.2, 123.9,
123.5, 121.0, 120.7, 53.6, 46.6, 44.0, 21.3; m/z (ESI) calcd for
C25H23N3O2Br [M + H]+: 476.0974, found 476.0972.
H-70), 7.30 (1H, d, J = 9.0 Hz, H-7), 7.26 (2H, t,
J = 8.3 Hz, H-400), 4.70 (2H, s, CH2, H-30), 4.59 (2H, s,
CH2, H-40), 3.91–3.89 (6H, m, 2 ꢃ OCH3); 13C NMR
(150 MHz, DMSO-d6 at 328 K): δC = 171.1, 163.1 (d,
J = 246.6 Hz), 158.8, 156.4, 149.3, 148.9, 141.0, 136.1,
135.6, 133.3, 133.0 (d, J = 3.4 Hz), 129.6 (d, J = 8.1 Hz),
128.1, 126.1, 123.9, 121.3, 121.1, 115.9 (d, J = 21.9 Hz),
107.5, 56.0, 53.5; m/z (ESI) calcd for C25H23N3O3F [M
+ H]+: 432.1723, found 432.1719.
3.1.7 | N-([2,6-Dimethoxyquinolin-3-yl]
methyl)-N-(pyridin-3-ylmethyl) benzamide (12)
3.1.10 | 4-Bromo-N-([2,6-dimethoxyquinolin-
3-yl]methyl)-N-(pyridin-3-ylmethyl)
benzamide (15)
White crystalline solid. Yield = 70%; M.p: 148–150 ꢁC;
1
ν
max/cmꢀ1 1628 (C=O); H NMR (600 MHz, DMSO-d6 at
328 K): δH = 8.47–8.44 (2H, m, overlapping H-80 and H-
90), 8.04 (1H, s, H-4), 7.67–6.66 (2H, m, H-60, H-8), 7.52
(2H, bs, H-300), 7.47–7.41 (4H, m, H-5, H-400 H-500), 7.34
(1H, dd, J = 7.8, 4.8 Hz, H-70), 7.29 (1H, dd, J = 9.0,
2.9 Hz, H-7), 4.70 (2H, s, CH2, H-30), 4.56 (2H, s, CH2, H-
40), 3.91–3.87 (6H, m, 2 ꢃ OCH3); 13C NMR (150 MHz,
DMSO-d6 at 328 K): δC = 172.0, 158.7, 156.3, 149.3, 148.9,
140.9, 136.6, 136.0, 135.5, 133.3, 130.1, 128.9, 128.1, 127.0,
126.1, 124.0, 121.3, 121.2, 107.4, 55.9, 53.6; m/z (ESI) calcd
for C25H24N3O3 [M + H]+: 414.1818, found 414.1816.
White crystalline solid. Yield = 47%; M.p: 107–109 ꢁC;
1
ν
max/cmꢀ1 1621 (C=O); H NMR (600 MHz, DMSO-d6 at
328 K): δH = 8.46–8.44 (2H, m, overlapping H-80 and H-
90), 8.00 (1H, s, H-4), 7.68–7.66 (2H, m, H-8, H-60), 7.63
(2H, d, J = 7.9 Hz, H-300), 7.48 (2H, d, J = 7.9 Hz, H-400),
7.38 (1H, d, J = 2.6 Hz, H-5), 7.31 (1H, dd, J = 7.5,
4.9 Hz, H-70), 7.28 (1H, dd, J = 9.0, 2.7 Hz, H-7), 4.68
(2H, s, CH2, H-30), 4.56 (2H, s, CH2, H-40), 3.93–3.86 (6H,
m, 2 ꢃ OCH3); 13C NMR (150 MHz, DMSO-d6 at 328 K)
δC = 171.0, 158.8, 156.4, 149.3, 148.9, 141.0, 136.3, 135.8,
131.9, 129.2, 128.1, 126.1 (2C), 123.9, 123.5, 121.3, 121.0
(2C), 107.5, 56.0, 53.5; m/z (ESI) calcd for C25H23N3O3Br
[M + H]+: 492.0931, found 492.0927.
3.1.8 | N-([2,6-Dimethoxyquinolin-3-yl]
methyl)-4-methoxy-N-(pyridin-3-ylmethyl)
benzamide (13)
White crystalline solid. Yield = 64%; M.p: 99–101 ꢁC;
3.1.11 | N-([6-Fluoro-2-methoxyquinolin-3-yl]
methyl)-N-(pyridin-3-ylmethyl) benzamide (16)
1
ν
max/cmꢀ1 1613 (C=O); H NMR (600 MHz, DMSO-d6 at
328 K): δH = 8.46–8.43 (2H, m, overlapping H-80 and H-90),
8.04 (1H, s, H-4), 7.69–7.66 (2H, m, H-60, H-8), 7.49 (2H, d,
J = 7.7 Hz, H-300), 7.42 (1H, d, J = 2.6 Hz, H-5), 7.34 (1H,
dd, J = 7.4, 4.9 Hz, H-70), 7.28 (1H, dd, J = 9.0, 2.6 Hz, H-
7), 6.97 (2H, d, J = 7.7 Hz, H-400), 4.69 (2H, s, CH2, H-30),
4.57 (2H, s, CH2, H-40), 3.89–3.85 (6H, s, 2 ꢃ OCH3), 3.76
(3H, s, OCH3); 13C NMR (150 MHz, DMSO-d6 at 328 K):
δC = 171.9, 160.8, 158.7, 156.3, 154.8, 149.4, 148.9, 140.9,
135.7, 133.5, 129.0, 128.5, 128.1, 126.1, 124.0, 121.4, 121.3,
114.2, 107.3, 55.9, 55.7, 53.6; m/z (ESI) calcd for
C26H26N3O4 [M + H]+: 444.1923, found 444.1920.
White crystalline solid. Yield = 69%; M.p: 127–129 ꢁC;
ν
max/cmꢀ1 1636 (C=O); 1H NMR (300 MHz, CDCl3):
:
δH = 8.55–8.33 (2H, m, overlapping H-80 and H-90), 7.89–
7.87 (1H, m, H-4), 7.75–7.65 (1H, m, H-8), 7.59–7.53 (1H,
m, H-60), 7.46–7.25 (7H, m, H-5, H-7, H-300, H-400, H-500),
7.25–7.19 (1H, m, H-70), 4.74–4.60 (2H, m, CH2, H-30),
4.55–4.46 (2H, m, CH2, H-40), 3.92–3.89 (3H, m, OCH3);
13C NMR (75 MHz, CDCl3): δC = 172.2, 159.5, 159.2 (d,
J = 242.9 Hz), 149.5, 149.2, 142.8, 136.1, 135.5, 134.9,
132.5, 130.1, 129.0 (d, J = 7.6 Hz), 128.6, 126.7, 125.3 (d,
J = 5.2 Hz), 123.7, 121.6, 119.1 (d, J = 23.4 Hz), 110.8 (d,
J = 22.4 Hz), 53.6, 48.1, 45.8; m/z (ESI) calcd for
C24H21N3O2F [M + H]+: 402.1618, found 402.1619.
3.1.9 | N-([2,6-Dimethoxyquinolin-3-yl]
methyl)-4-fluoro-N-(pyridin-3-ylmethyl)
benzamide (14)
3.1.12 | N-([6-Fluoro-2-methoxyquinolin-3-yl]
methyl)-4-methoxy-N-(pyridin-3-ylmethyl)
benzamide (17)
White crystalline solid. Yield = 51%; M.p: 106–108 ꢁC;
ν
max/cmꢀ1 1632 (C=O); 1H NMR (600 MHz, DMSO-d6 at
328 K): δH = 8.47–8.44 (2H, m, overlapping H-80 and H-
90), 8.03 (1H, s, H-4), 7.68–7.67 (2H, m, H-60, H-8), 7.63–
7.58 (2H, m, H-300), 7.40 (1H, s, H-5), 7.35–7.32 (1H, m,
White crystalline solid. Yield = 41%; M.p: 129–131 ꢁC;
1
ν
max/cmꢀ1 1617 (C=O); H NMR (600 MHz, DMSO-d6 at

10
BOKOSI ET AL.
328 K): δH = 8.46–8.42 (2H, m, overlapping H-80 and H-
90), 8.09 (1H, s, H-4), 7.79 (1H, dd, J = 9.1, 5.3 Hz, H-8),
7.74 (1H, dd, J = 9.4, 3.0 Hz, H-5), 7.66 (1H, d,
J = 7.7 Hz, H-60), 7.52 (1H, td, J = 9.1, 3.0 Hz, H-7), 7.48
(2H, d, J = 8.5 Hz, H-300), 7.31 (1H, dd, J = 7.7, 4.8 Hz,
H-70), 6.97 (2H, d, J = 8.5 Hz, H-400), 4.69 (2H, s, CH2, H-
30), 4.60 (2H, s, CH2, H-40), 3.93 (3H, s, OCH3), 3.77 (3H,
s, OCH3); 13C NMR (150 MHz, DMSO-d6 at 328 K):
δC = 171.9, 160.8, 159.9, 159.0 (d, J = 241.6 Hz), 149.3,
148.9, 142.6, 136.2, 135.6, 133.5, 129.1 (d, J = 8.9 Hz),
129.0, 128.5, 125.9 (d, J = 10.3 Hz), 123.9, 122.5, 119.1 (d,
J = 25.1 Hz), 114.3, 111.7 (d, J = 22.2 Hz), 55.7, 53.8; m/z
(ESI) calcd for C25H23N3O3F [M + H]+: 432.1723, found
432.1721.
(ESI) calcd for C24H20N3O2FBr [M + H]+: 480.0723,
found 480.0733.
3.2 | In vitro antimycobacterial
screening assay
The minimum inhibitory concentration (MIC) was deter-
mined using the standard broth microdilution method.
Briefly, a 10 mL culture of Mycobacterium tuberculosis
pMSp12: GFP [38–40] was grown to an optical density
(OD600) of 0.6–0.7 in Middlebrook 7H9 supplemented
with 0.03% casitone, 0.4% glucose, and 0.05% tyloxapol
[41]. Cultures were diluted 1:500 prior to inoculation into
the MIC assay. The compounds to be tested were rec-
onstituted to a concentration of 10 mM in DMSO. Two-
fold serial dilutions of the test compound were prepared
across a 96-well microtitre plate, after which 50 μL of the
diluted M. tuberculosis cultures were added to each well
in the serial dilution. The plate layout was a modification
of the method previously described [41]. Assay controls
used were a minimum growth control (Rifampicin at
2 ꢃ MIC), and a maximum growth control (5% DMSO).
The microtitre plates were sealed in a secondary con-
tainer and incubated at 37ꢁC with 5% CO2 and humidifi-
cation. Relative fluorescence (excitation 485 nM;
emission 520 nM) was measured using a plate reader
(FLUOstar OPTIMA, BMG LABTECH, Ortenberg, Ger-
many) at day 14. The raw fluorescence data were
archived and analyzed using the CDD Vault from Collab-
orative Drug Discovery, in which data were normalized
to the minimum and maximum inhibition controls to
generate a dose response curve (% inhibition) using the
Levenberg–Marquardt damped least squares method,
from which the MIC90 was calculated (Burlingame, CA,
USA, www.collaborativedrug.com). The lowest concen-
tration of drug that inhibited growth of more than 90% of
the bacterial population was considered the MIC90.
3.1.13 | 4-Fluoro-N-([6-fluoro-
2-methoxyquinolin-3-yl]methyl)-N-(pyridin-
3-ylmethyl) benzamide (18)
White crystalline solid. Yield = 43%; M.p: 109–111 ꢁC;
ν
max/cmꢀ1 1625 (C=O); 1H NMR (600 MHz, DMSO-d6 at
328 K): δH = 8.46–8.42 (2H, m, overlapping H-80 and H-
90), 8.11 (1H, s, H-4), 7.79 (1H, dd, J = 8.8, 5.3 Hz, H-8),
7.74 (1H, dd, J = 7.6, 2.0 Hz, H-5), 7.67 (1H, bs, H-60),
7.63–7.58 (2H, m, H-300), 7.52 (1H, td, J = 8.8, 2.9 Hz, H-
7), 7.31 (1H, dd, J = 7.6, 4.8 Hz, H-70), 7.26 (2H, t,
J = 8.7 Hz, H-400), 4.70 (2H, s, CH2, H-30), 4.61 (2H, s,
CH2, H-40), 3.93 (3H, s, OCH3); 13C NMR (150 MHz,
DMSO-d6 at 328 K): δC = 171.2, 163.1 (d, J = 247.1 Hz),
159.9, 159.0 (d, J = 241.6 Hz), 149.3, 148.9, 142.6, 136.4,
135.6, 133.3, 132.9 (d, J = 3.2 Hz), 129.6 (d, J = 8.5 Hz),
129.1 (d, J = 9.0 Hz), 125.8 (d, J = 9.8 Hz), 123.9, 122.3,
119.2 (d, J = 24.8 Hz), 115.9 (d, J = 21.8 Hz), 111.7 (d,
J
=
22.2 Hz), 54.8, 53.8; m/z (ESI) calcd for
C24H20N3O2F2 [M + H]+: 420.1524, found 420.1525.
3.1.14 | 4-Bromo-N-([6-fluoro-
2-methoxyquinolin-3-yl]methyl)-N-(pyridin-
3-ylmethyl) benzamide (19)
3.3 | In silico Molecular docking studies
White crystalline solid. Yield = 46%; M.p: 143–145 ꢁC;
The X-ray crystal structure (PDB code: 1C17) [42] was
obtained from the Research Collaboratory for Structural
Bioinformatics (RCSB) protein data bank (PDB). The
ligands were prepared for docking with Ligprep form
Schrödinger [43] suite with OPLS3e force field and Epik
by adding appropriate hydrogens, and generating possi-
ble ionization states and tautomers. Receptor-ligand
docking was also carried out in Maestro with glide [44]
using SP (Standard precision) with flexible ligands.
ADME calculations were carried out with QikProp form
Schrödinger suite [43].
ν
max/cmꢀ1: 1636 (C=O); 1H NMR (600 MHz, DMSO-d6 at
328 K): δH = 8.45–8.43 (2H, m, overlapping H-80 and H-
90), 8.11 (1H, s, H-4), 7.81–7.48 (8H, m, H-60, H-8, H-300,
H-5, H-7, H-400), 7.35–7.28 (1H, m, H-70), 4.69 (2H, s,
CH2, H-30), 4.57 (2H, s, CH2, H-40), 3.91 (3H, s, OCH3);
13C NMR (150 MHz, DMSO-d6 at 328 K): δC = 171.1,
159.8, 158.9 (d, J = 241.6 Hz), 149.5, 148.9, 142.6, 136.6,
135.7, 133.4, 131.9, 129.2, 129.1 (d, J = 9.0 Hz), 125.8 (d,
J = 8.7 Hz), 125.1, 123.9, 123.5, 122.1, 119.2 (d,
J = 21.8 Hz), 111.7 (d, J = 22.1 Hz), 53.8, 48.8, 46.4; m/z

BOKOSI ET AL.
11
4 | CONCLUSIONS
compounds can be obtained from corresponding authors
on request.
In summary, this paper is reporting a focused library of
easily accessible arylquinolinecarboxamides bearing
2-methoxyquinoline core specifically intended for growth
inhibition of Mtb. All the synthesized derivatives were
fully characterized by routine spectroscopic methods
such as FT-IR, mass and NMR (1H, 13C). However, albeit
not impressive, modest anti-Mtb activity against drug sus-
ceptible Mtb H37Rv was observed. Compounds 10 and 11
with methyl substitution at position 6 of the quinoline
ring showed promising inhibition with MIC90 = 32.5 and
40.3 μM, respectively. The preliminary structure–activity
relationship data revealed that a methyl moiety at posi-
tion 6 of the quinoline ring favors anti-Mtb activity over
methoxy and fluoro substituents. Introducing para
bromo benzamides at the side chain attached to position
3 of the quinoline ring influence positively the biological
activity of the series against Mtb H37Rv. Furthermore,
we conducted in silico docking studies of the synthesized
compounds and bedaquiline against MtbATPase to deter-
mine their potential to interfere with the mycobacterial
adenosine triphosphate (ATP) synthase. Despite weak
antimycobacterial activity, in silico ADME prediction and
drug-likeliness of the series suggested that these com-
pounds are exhibiting acceptable ADME and physico-
chemical properties. Further optimization and strategic
modification of the score scaffold with respect to intro-
duction of alternative functionalities such as electron
withdrawing and lipophilic alkyl groups of varying sizes
in the molecular structure could lead to new potent
antimycobacterial derivatives. Thus, these research find-
ings emanating from this study are likely to make desir-
able contribution for future development of
diarylquinoline-based antitubercular lead molecules.
ORCID
Fostino R. B. Bokosi https://orcid.org/0000-0002-7923-
3709
Richard M. Beteck https://orcid.org/0000-0002-6282-
043X
Digby F. Warner https://orcid.org/0000-0002-4146-0930
Tendamudzimu Tshiwawa https://orcid.org/0000-0002-
2747-1406
Setshaba D. Khanye https://orcid.org/0000-0003-0725-
5738
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ACKNOWLEDGMENTS
The authors acknowledge the financial support for the
research by the Thuthuka National Research Foundation
(SDK, Grant No. 107270), Rhodes University Sandisa
Imbewu Fund (SDK). The Mtb screening work was con-
ducted with the financial support of South African Medi-
cal Research Council (SAMRC) with funds from National
Treasury under its Economic Competitiveness and Sup-
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Health Innovation Partnerships (SHIP) initiative. FRBB
was supported by the Malawi Government Scholarship
Fund through the University of Malawi.
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DATA AVAILABILITY STATEMENT
The data that supports the findings of this study are avail-
able in the supplementary material of this article. Target

12
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How to cite this article: F. R. B. Bokosi, R.
M. Beteck, A. Jordaan, R. Seldon, D. F. Warner,
T. Tshiwawa, K. Lobb, S. D. Khanye, J. Heterocycl.
Chem. 2021, 1. https://doi.org/10.1002/jhet.4340