Synthesis of 2-(N-cyclicamino)quinoline combined with methyl (E)-3-(2/3/4-aminophenyl)acrylates as potential antiparasitic agents

Article abstract of DOI:10.1002/ardp.202000331

A rationally designed series of 2-(N-cyclicamino)quinolines coupled with methyl (E)-3-(2/3/4-aminophenyl)acrylates was synthesized and subjected to in vitro screening bioassays for potential antiplasmodial and antitrypanosomal activities against a chloroquine-sensitive (3D7) strain of Plasmodium falciparum and nagana Trypanosoma brucei brucei 427, respectively. Substituent effects on activity were evaluated; meta-acrylate 24 and the ortho-acrylate 29 exhibited the highest antiplasmodial (IC₅₀ = 1.4 μM) and antitrypanosomal (IC₅₀ = 10.4 μM) activities, respectively. The activity against HeLa cells showed that the synthesized analogs are not cytotoxic at the maximum tested concentration. The ADME (absorption, distribution, metabolism, and excretion) drug-like properties of the synthesized compounds were predicted through the SwissADME software.

Full text of DOI:10.1002/ardp.202000331

Received: 1 September 2020
DOI: 10.1002/ardp.202000331
Revised: 12 February 2021
Accepted: 16 February 2021
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F U L L P A P E R
Synthesis of 2‐(N‐cyclicamino)quinoline combined with
methyl (E)‐3‐(2/3/4‐aminophenyl)acrylates as potential
antiparasitic agents
Fostino R. B. Bokosi1
Heinrich C. Hoppe3,4
| Richard M. Beteck1,2
| Tendamudzimu Tshiwawa1
| Dustin Laming3
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| Setshaba D. Khanye1,3,5
1Department of Chemistry, Faculty of Science,
Rhodes University, Makhanda, South Africa
Abstract
2Centre of Excellence for Pharmaceutical
Sciences, North‐West University,
Potchefstroom, South Africa
A rationally designed series of 2‐(N‐cyclicamino)quinolines coupled with methyl (E)‐
3‐(2/3/4‐aminophenyl)acrylates was synthesized and subjected to in vitro screening
bioassays for potential antiplasmodial and antitrypanosomal activities against a
chloroquine‐sensitive (3D7) strain of Plasmodium falciparum and nagana Trypanoso-
ma brucei brucei 427, respectively. Substituent effects on activity were evaluated;
meta‐acrylate 24 and the ortho‐acrylate 29 exhibited the highest antiplasmodial
(IC50 = 1.4 µM) and antitrypanosomal (IC50 = 10.4 µM) activities, respectively. The
activity against HeLa cells showed that the synthesized analogs are not cytotoxic at
the maximum tested concentration. The ADME (absorption, distribution, metabo-
lism, and excretion) drug‐like properties of the synthesized compounds were pre-
dicted through the SwissADME software.
3Centre for Chemico‐ and Biomedicinal
Research, Rhodes University, Makhanda,
South Africa
4Department of Biochemistry and
Microbiology, Faculty of Science, Rhodes
University, Makhanda, South Africa
5Division of Pharmaceutical Chemistry,
Faculty of Pharmacy, Rhodes University,
Makhanda, South Africa
Correspondence
Fostino R. B. Bokosi, Faculty of Science,
Department of Chemistry, Rhodes University,
Makhanda 6140, South Africa.
Email: bokosifostino@gmail.com
K E Y W O R D S
2‐(N‐cyclicamino)quinolines, ADME, aminophenylacrylates, antiplasmodial, antitrypanosomal
Setshaba D. Khanye, Faculty of Pharmacy,
Division of Pharmaceutical Chemistry, Rhodes
University, Makhanda 6140, South Africa.
Email: s.khanye@ru.ac.za
Funding information
National Research Foundation,
Grant/Award Number: 107270
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1
INTRODUCTION
there is a pressing need to develop new and safe therapeutics
with desirable therapeutic window and low propensity for drug
Malaria and human African trypanosomiasis (HAT) remain serious
health risks and are caused by infection with Plasmodium spp. and
Trypanosoma brucei spp., respectively. These protozoan parasitic
diseases are responsible for significant morbidity and mortality
and are predominantly rife in low‐income countries.[1–4] Despite
progress regarding the development of vaccines and new com-
pounds with sought‐after activity, the rising incidence of drug
resistance and excessive peril of systemic toxicity have limited
the efficacy of the frontline therapeutic agents.[5–9] Therefore,
resistance.
Quinoline‐containing compounds display
a
broad range of
biological activities including antimalarial,[10] antitrypanosomal,[11]
antitubercular,[12] antifungal,[13] antibacterial,[14] anticancer,[15] and
anti‐human immunodeficiency virus (HIV)[16] activities. Quinoline
derivatives diversely functionalized with 2‐N‐cyclicamino moieties
have been demonstrated to exhibit a variety of pharmacological
activities. For example, the research group of Raval prepared
quinoline‐containing morpholine derivative 1 (Figure 1) that showed
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Arch Pharm. 2021;e2000331.
wileyonlinelibrary.com/journal/ardp
© 2021 Deutsche Pharmazeutische Gesellschaft
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https://doi.org/10.1002/ardp.202000331

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FIGURE 1 Representative biologically active 2‐(N‐cyclicamino)quinolines (1, 2), cinnamic compounds (3−5), and the target hybrid
compounds 23−35
effects as an antimalarial agent.[17] In a separate study, Dias and
coworkers reported compound 2 containing the pyrrolidine ring that
displayed a superior (IC50 = 22 nM) antimalarial potency.[18] How-
ever, cinnamic acid 3 and its derivatives are widely distributed in
nature and have attracted the attention of many medicinal chemists
due to the common occurrence in plants and the low toxicity for
humans, animals, and environment.[19,20] The potential of cinnamic
acid derivatives as therapeutics for the treatment of malaria,[21]
HAT,[22] tuberculosis,[23] fungal infections,[24] HIV,[25] and cancer[26]
is well documented in the literature. For instance, cinnamic acid ester
derivative 4 isolated from the bark of Erythrina caffra exhibited
moderate antiplasmodial activity against a chloroquine‐sensitive
(NF54) strain of the Plasmodium falciparum parasite. More recently,
the groups of Alson[27] and Schmidt[28] reported readily accessible
cinnamic acid derivatives 5a−c that displayed good antiplasmodial
and antitrypanosomal activities against P. falciparum and Trypanoso-
ma brucei rhodesiense, respectively.
quinoline derivatives, alongside their in vitro antiplasmodial and
antitrypanosomal activities.
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2
RESULTS AND DISCUSSION
Chemistry
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2.1
Synthesis of our target compounds 23–35 followed the general
pathway illustrated in Scheme 1. Treatment of aniline 6 with acetic
anhydride in glacial acetic acid afforded the corresponding N‐
phenylacetamide 7 in an excellent yield (98%). Cyclization of com-
pound 7 through the Vilsmeier−Haack reaction conditions afforded
quinoline scaffold 8, which contains –Cl and –CHO moieties on C‐2
and C‐3, respectively. Both moieties serve as handles to expand the
series by exploring the chemical space around the quinoline ring.
Thus, treatment of quinoline 8 with various cyclic amines under re-
fluxing conditions led to the nucleophilic substitution of the –Cl atom
on C‐2 to obtain critical precursors 9−13 in yields ranging from 61%
to 80%. Esterification of the trans‐nitro cinnamic acids 14–16 was
carried out using acidified methanol solution to afford methyl trans‐
nitro cinnamate esters 17–19 in 88−98% yields. Selective reduction
of the NO2 moiety in the obtained esters using activated Zn powder
and NH4Cl as a hydrogen source furnished methyl trans amino cin-
namate esters 20–22 in good yields. Finally, Schiff base condensation
reaction between precursors 9−13 and trans amino cinnamate esters
20−22, followed by in situ reduction of the imine intermediates with
sodium cyanoborohydride, afforded target compounds 23–35 in
31–75% yields.
The hybridization of two or more bioactive structural units into
a single molecule is an appealing approach that has been ex-
tensively utilized to design bioactive compounds in the field of
medicinal chemistry.[29] This recent rational approach of drug
design characterized as covalent biotherapy involves linking two
known biologically active molecules by virtue of the presence of
critical structural features essential for desired pharmacologic
effect into a single agent, thus imprinting dual activities into a single
hybrid molecule.[30] In this study, we employed
a molecular
hybridization approach to design a target series of functiona-
lized quinoline 2‐(N‐cyclicamino) scaffold and cinnamic acid esters.
From the above observations, we hoped that the synthesis of novel
quinolines incorporating the cinnamic acid ester structural motif
could lead to potent anti‐infective compounds against protozoan
infectious parasitic diseases caused by P. falciparum and T. b. brucei.
Consequently, we wish to report the synthesis and characterization
of a representative series of novel and nontoxic cinnamate‐based
All the target compounds were fully characterized by routine
spectroscopic techniques. Infrared (IR) spectra of 23−35 showed a
single spike weak band at ca. 3450−3300 cm−1, which is indicative of
the secondary amino (N−H) group. The 1H NMR spectra confirmed
all the aromatic and aliphatic protons, thus supporting key structural

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SCHEME 1 Synthesis of the target compounds 23–35. Reagents and conditions: (i) Ac2O, AcOH, reflux, 30 min; (ii) DMF‐POCl3, 80°C,
5‐18 h; (iii) DMF, K2CO3, cyclic amines, reflux, 2.5−10 h; (iv) MeOH, H2SO4 (cat), reflux, 3 h; (v) Zn, NH4Cl, MeOH, r.t, 3 h; (vi) (a) MeOH, AcOH
(cat), reflux, 12 h, (b) NaCNBH3, 0°C to r.t, 12 h
features of each compound. More importantly, the disappearance of
aldehydic signal at ca. 10.5 ppm observed in intermediates 9−13 and
the appearance of a singlet methylene group at chemical shift ca.
4.48 ppm in the target compounds served as an indication of suc-
cessful reductive amination between compounds 9−13 and 20−22 to
form the desired compounds. The 1H NMR of the target compounds
showed a broad singlet at ca. 5.05–4.40 ppm on their respective
spectrum, suggesting the successful formation of −HN–CH2− moiety.
Furthermore, the two doublets (J = 15.7−16.0 Hz) at δ ca. 6.13−6.39
and 7.62−7.86 ppm are attributed to the two −CH groups of methyl
acrylate. These coupling constants are consistent with a trans geo-
metry (Jtrans) at the double bond found in our cinnamate ester bond.
13C NMR spectra of precursors 9−13 showed a peak at ca. 190 ppm
that was assigned to the –CHO unit of the aldehyde, and the ap-
pearance of a new peak at ca. 51.5 ppm in compounds 23–35 further
corroborates the coupling of an aldehyde unit and the primary amine
to yield the secondary −HN–CH2− amine functionality.
initially tested at a single concentration (20 µM) to determine cell viabi-
lity, and the results are summarized in Figure 2. Cytotoxicity against
HeLa cells, antiplasmodial activity against the chloroquine‐sensitive strain
(3D7) of P. falciparum, and antitrypanosomal activity against T. b. brucei
427 were evaluated using solutions of the synthesized compounds.
Emetine, chloroquine, and pentamidine were used as positive controls for
cytotoxicity, antiplasmodial, and antitrypanosomal activity, respectively.
From Figure 2, none of the compounds reported herein reduced
HeLa cell viability to below 50% during a 24 h incubation, suggesting
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2.2
Pharmacology
FIGURE 2 Percentage viability assessments of the 3D7
chloroquine‐sensitive strain of Plasmodium falciparum, Trypanosoma
brucei brucei 427 strain, and HeLa cells at 20 μM concentration of
test compounds 23−35
The synthesized compounds were subjected to in vitro screening bioas-
says, as described in the experimental section. Compounds 23−25 were

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TABLE 1 IC50 values for inhibition of
3D7, T. b. brucei, and ADME values of
compounds 23–35
IC50 (µM)
Compound
23
P. falciparum 3D7a
T. b. bruceia
>50
XlogP3
4.9
5.3
4.0
4.8
4.8
5.3
4.0
4.8
6.0
4.8
5.3
4.0
6.0
–
Mw
ROF
None
None
None
None
None
None
None
None
None
None
None
None
None
–
PA
9.1 0.25
1.4 0.05
3.1 0.13
3.1 0.17
26.3 2.43
7.0 1.23
16.6 1.78
16.7 2.55
1.8 0.08
>50
397.47
401.50
403.47
419.54
387.47
401.50
403.47
419.54
478.58
387.47
401.50
403.47
478.58
–
None
None
None
None
None
None
None
None
None
None
None
None
None
–
24
21.1 2.35
41.8 2.67
27.3 1.79
33.7 3.23
>50
25
26
27
28
29
10.4 0.58
13.3 1.82
>50
30
31
32
>50
33
>50
>50
34
7.5 0.98
8.3 1.24
0.023
10.7 1.61
>50
35
CQ
PMD
–
–
0.017
–
–
–
–
Note: All the parameters were calculated or predicted using the free online SwissADME tool.
Abbreviations: ADME, absorption, distribution, metabolism, and excretion; CQ, chloroquine; Mw,
molecular weight; PA, pain alert; PMD, pentamidine; ROF, Lipinski's rule of five; XlogP3, calculated
lipophilicity.
aThe values are the mean SD of experiments performed in triplicate.
that they possess little overt cytotoxicity risk at the concentrations
used for antiplasmodial and antitrypanosomal evaluation. With regard
to antiplasmodial activity, eleven quinoline−cinnamate derivatives (ex-
cluding 32 and 33) exhibited required activities with a P. falciparum cell
viability of less than 50%, whereas six analogs from the series (25, 26,
27, 29, 30, and 34) showed an antitrypanosomal activity with a T. b.
brucei cell viability as low as less than 3% at 20 µM.
position 27 (26.3 µM), 28 (7.0 µM), 29 (16.6 µM), 30 (16.7 µM), 31
(1.8 µM) > ortho position 32 (>50 µM), 33 (>50 µM), 34 (7.5 µM), 35
(8.3 µM). The ADME (absorption, distribution, metabolism, and excre-
tion) drug‐like properties of the synthesized compounds were predicted
through the SwissADME software.[31] The calculated lipophilicity
(XlogP3) value for these compounds was four or above, but not more
than six, and their water solubility profiles were predicted to be mod-
erately or poorly soluble. These compounds were also predicted to have
a low risk of acting as pan‐assay interference (PAIN) compounds and
they all satisfied Lipinski's rule of five.
Subsequently, dose–response analyses were conducted for com-
pounds exhibiting a reduced parasite viability of less than 50% to
generate the corresponding IC50 values (Table 1). It is observed that
structural variation around the quinoline ring (R) and/or position of
acrylate scaffold influenced the antiparasitic activity. Compound in-
hibition levels, as evidenced by the IC50 data, vary significantly from
ligand to ligand, and observed structure–activity trends suggested that
the target compounds were more selective toward P. falciparum as
compared with the T. b. brucei. Majority of compounds showed a
moderate antiplasmodial activity with IC50 values in the low micromolar
range, and compound 24 emerged as the most active compound with an
IC50 value of 1.4 µM. Compounds 23, 27, and 32 exhibiting the pyrro-
lidine moiety at position 2 of the quinoline scaffold showed poor ac-
tivity in the respective meta, para, and ortho acrylates, and this suggests
that the size of the cycloamine influences biological activity. Regarding
the trans‐cinnamic acid ester, the inhibitory activities of the ligands
against P. falciparum appear in the following order: meta position as
shown by 23 (9.11 µM), 24 (1.4 µM), 25 (3.10 µM), 26 (3.09 µM) > para
In silico docking studies were undertaken to assess the binding af-
finity of compounds 23–35 on an X‐ray structure of falcipain‐2 (a well‐
studied P. falciparum drug target) co‐crystallized with E‐64 (PDB ID
3BPF). Studied using Glide Ligand Docking as implemented in Maestro in
the Schrödinger package, the detailed results are summarized (Table 1S)
in the Supporting Information file. The crystal structure ligand has a
binding affinity of −5.985 kcal/mol, whereas the structures presented in
this study have a binding affinity between −4.711 and −5.775 kcal/mol.
These values indicate that the compounds presented in this study have a
relatively good binding affinity, comparable to the crystal ligand. The
crystal ligand has an intramolecular interaction with CYS42 residue of
3BPF; the same interaction is observed for compound 30 that has the
best binding affinity of −5.775 kcal/mol, as shown in Figures 3a and 3b,
respectively. Compound 26 that has the least binding affinity of
−4.711 kcal/mol has no similar interactions with 3BPF, as shown in

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FIGURE 3 (a) Protein–ligand interaction of 3BPF and its crystal ligand reference E‐64. (b) Docking pose of crystal ligand and compound 30
and protein–ligand interaction of compound 30. (c) Docking pose of crystal ligand and compound 26 and protein–ligand interaction of
compound 26. (d) Docking pose of crystal ligand and compound 24 and protein–ligand interaction of compound 24
Figure 3c. Compound 24 that showed the best antiplasmodial activity
experimentally has the binding affinity of −5.405 kcal/mol. The
protein–ligand interactions of compound 24 in Figure 3d show the pre-
sence of two intramolecular hydrogen bonds, one with TRP206 residue
where oxygen of compound 24 acts as an acceptor in the hydrogen
bonding and the other with ASN173 residue where hydrogen of the
amine of compound 24 serves as a donor.
displayed high inhibition potency against 3D7 of the P. falciparum
parasite. Molecular docking insights of these derivatives have shown
comparable binding affinities as falcipain‐2 inhibitors. Even in the event
that additional assays related to toxicity on other human cells, geno-
toxicity, in vivo experiments, and mechanism of action will be required
to estimate their real potential, more important, biological data gen-
erated in this report revealed that this structurally new class of
bioactive compounds has potential medicinal applications in the search
for improved therapy, warranting further investigations.
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3
CONCLUSION
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Herein, we presented a focused series of 2‐(N‐cyclicamino)quinolines
incorporating a cinnamic acid ester unit. Target compounds were rea-
lized through a simple hybridization strategy and tested against HeLa
cells, 3D7 strain of P. falciparum, and T. b. brucei to evaluate the cyto-
toxicity, antiplasmodial, and antitrypanosomal potentials, respectively.
Although none of the compounds showed a potential cytotoxic risk, 11
exhibited antiplasmodial and seven exhibited antitrypanosomal activ-
ities. The preliminary structure–activity relationship suggested that the
presence of the meta acrylate in the quinoline–cinnamate derivatives
4
EXPERIMENTAL
Chemistry
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4.1
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4.1.1
General
All chemicals and solvents used were purchased from Merck®. Where
necessary, solvents were purified according to procedures described by
Vogel et al.[32] Thin‐layer chromatography was performed using Merck

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silica gel 60 PF254 plates and viewed under the UV light, and the silica gel
column chromatography was carried out using Merck Kieselgel 60 Å:
70–230 (0.068–0.2 mm). Melting points were determined using a Stuart
melting point apparatus SMP30 and were uncorrected. 1H and 13C NMR
spectra were recorded on Bruker Biospin 300, 400, or 600 MHz spec-
trometers, and the chemical shifts were reported in parts per million
(ppm). The high‐resolution mass spectra (HRMS) were recorded on a
Waters API Q‐TOF Ultima spectrometer (Stellenbosch University) and
the IR spectra were recorded on a PerkinElmer 100 FT‐IR spectrometer
in the mid‐IR range (640–4000 cm−1). Compounds 7−13 and 17−22 were
synthesized as per reported procedures; physical and spectral properties
were in accordance with literature values.[33–36] The original spectra of
the investigated compounds are provided as electronic supporting in-
formation (electrospray ionization [ESI]).
(1H, d, J = 8.4 Hz, H‐8), 7.64–7.55 (3H, m, H‐5, H‐6, H‐1⁗), 7.35–7.31
(1H, m, H‐7), 7.17 (1H, t, J = 7.8 Hz, H‐5‴), 6.89 (1H, d, J = 7.6 Hz, H‐
6‴), 6.76 (1H, s, H‐2‴), 6.65 (1H, dd, J = 8.0, 1.9 Hz, H‐4‴), 6.37 (1H, d,
J = 16.0 Hz, H‐2⁗), 4.73 (1H, s, NH), 4.44 (2H, s, H‐3′), 3.79 (3H, s,
OCH3), 3.30–3.25 (4H, m, H‐2″), 1.81–1.76 (4H, m, H‐3″), and
1.70–1.65 (2H, m, H‐4″); 13C NMR (100 MHz, CDCl3): δC 167.6,
161.2, 148.4, 146.5, 145.5, 136.6, 135.4, 129.8, 129.0, 127.5, 127.1,
126.7, 125.5, 124.4, 117.8, 117.5, 115.1, 112.0, 51.7 (2C), 44.7, 26.4,
and 24.6; HRMS (ESI): m/z calcd for C25H28N3O2 [M+H]+: 402.2182,
found 402.2180.
Methyl‐(E)‐3‐(3‐{[(2‐morpholinoquinolin‐3‐yl)methyl]amino}phenyl)‐
acrylate (25)
Brown solid; yield: 70%; m.p.: 131–133°C; νmax/cm 3395 (N–H) and
1696 (CO); 1H NMR (400 MHz, CDCl3): δH 8.09 (1H, s, H‐4), 7.90
(1H, d, J = 8.4 Hz, H‐8), 7.66 (1H, d, J = 8.0 Hz, H‐5), 7.63–7.58 (2H, m,
H‐6, H‐1⁗), 7.39–7.35 (1H, m, H‐7), 7.18 (1H, t, J = 7.9 Hz, H‐5‴), 6.91
(1H, d, J = 7.5 Hz, H‐6‴), 6.76 (1H, s, H‐2‴), 6.65 (1H, dd, J = 8.0,
1.9 Hz, H‐4‴), 6.36 (1H, d, J = 16.0 Hz, H‐2⁗), 4.58 (1H, s, NH), 4.45
(2H, s, H‐3′), 3.93–3.90 (4H, m, H‐3″), 3.79 (3H, s, OCH3), and
3.38–3.34 (4H, m, H‐2″); 13C NMR (100 MHz, CDCl3): δC 167.5,
159.9, 148.1, 146.5, 145.3, 137.2, 135.4, 129.9, 129.3, 127.7, 127.2,
126.0, 125.7, 124.8, 118.0, 117.6, 115.1, 111.9, 67.2, 51.7, 50.9, and
44.7; HRMS (ESI): m/z calcd for C24H26N3O3 [M+H]+: 404.1974,
found 404.1974.
The InChI codes of the investigated compounds, together with
some biological activity data, are also provided as ESI.
|
4.1.2
General procedure for the synthesis of
compounds 23–35
To a solution of 2‐(N‐cyclicaminoquinoline‐3‐carbaldehydes 9−13
(0.50 mmol) in methanol (10 ml) and methyl amino cinnamate esters
20−22 (0.50 mmol), a few drops of glacial acetic acid were added, and
the resultant reaction mixture was heated under reflux for 12 h.
Thereafter, the reaction mixture was cooled to 0°C in an ice bath and
sodium cyanoborohydride (1.0 mmol) was added portion‐wise over a
period of 10 min. The reaction mixture was allowed to stir at room
temperature overnight. The solvent was evaporated in vacuo and the
residue was dissolved in water (10 ml) and extracted with EtOAc
(2 × 20 ml). The organic layers were combined and washed with brine
(25 ml) and dried (MgSO4). The solvent was removed in vacuo and
the crude product was purified by silica gel column chromatography
(EtOAc−hexane 1:1) to give the desired products.
Methyl‐(E)‐3‐(3‐{[(2‐thiomorpholinoquinolin‐3‐yl)methyl]amino}‐
phenyl) acrylate (26)
Brown solid; yield: 45%; m.p.: 73–75°C; νmax/cm 3418 (N–H) and
1704 (C═O); 1H NMR (400 MHz, CDCl3): δH 8.08 (1H, s, H‐4), 7.90
(1H, d, J = 8.4 Hz, H‐8), 7.65 (1H, d, J = 8.3 Hz, H‐5), 7.63–7.56 (2H, m,
H‐6, H‐1⁗), 7.37 (1H, t, J = 7.5 Hz, H‐7), 7.18 (1H, t, J = 7.8 Hz, H‐5‴),
6.90 (1H, d, J = 7.4 Hz, H‐6‴), 6.74 (1H, s, H‐2‴), 6.64 (1H, dd, J = 8.1,
2.0 Hz, H‐4‴), 6.35 (1H, d, J = 16.0 Hz, H‐2⁗), 4.52 (1H, s, NH), 4.42
(2H, s, H‐3′), 3.78 (3H, s, OCH3), 3.63−3.60 (4H, m, H‐2″), and
2.88–2.85 (4H, m, H‐3″); 13C NMR (100 MHz, CDCl3): δC 167.5,
160.7, 148.1, 146.4, 145.3, 137.0, 135.4, 129.9, 129.3, 127.7, 127.2,
126.3, 125.7, 124.8, 118.0, 117.6, 115.1, 111.9, 52.9, 51.7, 44.5, and
28.0; HRMS (ESI): m/z calcd for C24H26N3O2S [M+H]+: 420.1746,
found 420.1745.
Methyl‐(E)‐3‐[3‐({[2‐(pyrrolidin‐1‐yl)quinolin‐3‐yl]methyl}amino)‐
phenyl] acrylate (23)
Yellow solid; yield: 35%; m.p.: 99–101°C; νmax/cm 3337 (N–H) and
1712 (CO); 1H NMR (400 MHz, CDCl3): δH 7.85 (1H, s, H‐4), 7.75
(1H, d, J = 8.3 Hz, H‐8), 7.62 (1H, d, J = 16.0 Hz, H‐1⁗), 7.54–7.52 (2H,
m, H‐6, H‐5), 7.22–7.17 (2H, m, H‐5‴, H‐7), 6.92 (1H, d, J = 7.5 Hz, H‐
6‴), 6.77 (1H, s, H‐2‴), 6.65 (1H, dd, J = 8.0, 1.9 Hz, H‐4‴), 6.39 (1H, d,
J = 16.0 Hz, H‐2⁗), 4.42 (2H, s, H‐3′), 3.79 (3H, s, OCH3), 3.73–3.70
(4H, m, H‐2″), and 1.99–1.93 (4H, m, H‐3″); 13C NMR (100 MHz,
CDCl3): δC 166.5, 155.9, 147.0, 144.3, 136.7, 134.4, 128.8, 128.3,
126.0, 125.2, 122.6, 121.5, 121.1, 116.7, 116.5, 113.9, 112.8, 110.9,
50.6, 48.7, 45.7, and 24.6; HRMS (ESI): m/z calcd for C24H26N3O2 [M
+H]+: 388.2025, found 388.2023.
Methyl‐(E)‐3‐[4‐({[2‐(pyrrolidin‐1‐yl)quinolin‐3‐yl]methyl}amino)‐
phenyl] acrylate (27)
Yellow solid; yield: 31%; m.p.: 96–98°C; νmax/cm 3423 (N–H) and
1707 (C═O); 1H NMR (600 MHz, CDCl3): δH 7.88 (1H, s, H‐4), 7.61
(1H, d, J = 15.9 Hz, H‐1⁗), 7.57–7.51 (3H, m, H‐8, H‐5, H‐7), 7.38 (2H,
d, J = 8.5 Hz, H‐2‴), 7.22 (1H, t, J = 7.4 Hz, H‐6), 6.60 (2H, d,
J = 8.6 Hz, H‐3‴), 6.22 (1H, d, J = 15.9 Hz, H‐2⁗), 4.48 (2H, s, H‐3′),
3.78 (3H, s, OCH3), 3.73–3.71 (4H, m, H‐2″), and 1.98–196 (4H, m, H‐
3″); 13C NMR (150 MHz, CDCl3): δC 168.2, 161.2, 149.4, 145.1,
144.4, 134.0, 132.8, 130.0, 129.6, 127.0, 124.1, 122.7, 121.8, 112.9,
112.7, 111.9, 51.5, 49.8, 46.4, and 25.7; HRMS (ESI): m/z calcd for
C24H26N3O2 [M+H]+: 388.2025; found 388.2031.
Methyl‐(E)‐3‐[3‐({[2‐(piperidin‐1‐yl)quinolin‐3‐yl]methyl}amino)‐
phenyl] acrylate (24)
Yellow solid; yield: 57%; m.p.: 104–106°C; νmax/cm 3426 (N–H) and
1724 (CO); 1H NMR (400 MHz, CDCl3): δH 8.03 (1H, s, H‐4), 7.90

BOKOSI ET AL.
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Methyl‐(E)‐3‐[4‐({[2‐(piperidin‐1‐yl)quinolin‐3‐yl]methyl}amino)‐
phenyl] acrylate (28)
Methyl‐(E)‐3‐[2‐({[2‐(pyrrolidin‐1‐yl)quinolin‐3‐yl]methyl}amino)‐
phenyl] acrylate (32)
Yellow solid; yield: 35%; m.p.: 146–148°C; νmax/cm 3422 (N–H) and
1704 (C═O); 1H NMR (600 MHz, CDCl3): δH 8.00 (1H, s, H‐4), 7.89 (1H,
d, J = 8.2 Hz, H‐8), 7.63 (1H, d, J = 8.0 Hz, H‐5), 7.61–7.56 (2H, m, H‐7,
H‐1⁗), 7.37–7.32 (3H, m, H‐6, H‐2‴), 6.60 (2H, d, J = 8.6 Hz, H‐3‴), 6.21
(1H, d, J = 15.9 Hz, H‐2⁗), 4.96 (1H, s, NH), 4.48 (2H, s, H‐3′), 3.77 (3H,
s, OCH3), 3.29–3.23 (4H, m, H‐2″), 1.78–1.76 (4H, m, H‐3″), and
1.69–1.63 (2H, m, H‐4″); 13C NMR (150 MHz, CDCl3): δC 168.2, 161.1,
149.8, 146.5, 145.2, 136.6, 132.9, 130.0, 129.2, 127.5, 127.1, 126.2,
125.4, 124.5, 123.9, 112.8, 51.6, 51.4, 44.6, 26.4, and 24.5; HRMS (ESI):
m/z calcd for C25H28N3O2 [M+H]+: 402.2182; found 402.2181.
Yellow solid; yield: 52%; m.p.: 98–100°C; νmax/cm 3341 (N–H) and
1704 (C═O); 1H NMR (400 MHz, CDCl3): δH 7.89 (1H, s, H‐4), 7.86
(1H, d, J = 15.9 Hz, H‐1⁗), 7.77 (1H, d, J = 8.4 Hz, H‐8), 7.57 (1H, d,
J = 8.1 Hz, H‐5), 7.56–7.51 (1H, m, H‐6), 7.40 (1H, dd, J = 8.0, 0.96 Hz,
H‐6‴), 7.25–7.20 (2H, m, H‐7, H‐4‴), 6.76 (1H, t, J = 7.5 Hz, H‐5‴),
6.60 (1H, d, J = 8.2 Hz, H‐3‴), 6.38 (1H, d, J = 15.7 Hz, H‐2⁗), 4.66
(1H, s, NH), 4.48 (2H, d, J = 4.5 Hz, H‐3′), 3.79 (3H, s, OCH3),
3.71–3.68 (4H, m, H‐2″), and 1.99–1.95 (4H, m, H‐3″); 13C NMR
(100 MHz, CDCl3): δC 167.6, 157.2, 147.0, 146.1, 140.2, 137.5, 131.7,
129.4, 128.4, 127.1, 126.5, 123.8, 122.7, 122.1, 120.2, 118.3, 117.9,
111.7, 51.7, 49.7, 46.8, and 25.7; HRMS (ESI): m/z calcd for
C24H26N3O2 [M+H]+: 388.2025, found 388.2025.
Methyl‐(E)‐3‐(4‐{[(2‐morpholinoquinolin‐3‐yl)methyl]amino}phenyl)‐
acrylate (29)
Yellow solid; yield: 40%; m.p.: 147–149°C; νmax/cm 3422 (N–H) and
1708 (C═O); 1H NMR (600 MHz, CDCl3): δH 8.05 (1H, s, H‐4), 7.91
(1H, d, J = 8.0 Hz, H‐8), 7.66 (1H, d, J = 8.0 Hz, H‐5), 7.63–7.57 (2H, m,
H‐7, H‐1⁗), 7.39−7.35 (3H, m, H‐6, H‐2‴), 6.59 (2H, d, J = 8.5 Hz, H‐
3‴), 6.22 (1H, d, J = 15.9 Hz, H‐2⁗), 4.83 (1H, s, NH), 4.48 (2H, s, H‐
3′), 3.92–3.89 (4H, m, H‐3″), 3.77 (3H, s, OCH3), and 3.36–3.33 (4H,
m, H‐2″); 13C NMR (150 MHz, CDCl3): δC 168.1, 159.7, 149.5, 146.1,
145.0, 137.2, 132.9, 130.0, 129.5, 127.6, 127.2, 125.6, 124.9, 124.2,
113.0, 112.8, 67.1, 51.5, 50.8, and 44.5; HRMS (ESI): m/z calcd for
Methyl‐(E)‐3‐[2‐({[2‐(piperidin‐1‐yl)quinolin‐3‐yl]methyl}amino)‐
phenyl] acrylate (33)
Yellow solid; yield: 65%; m.p.: 111–113°C; νmax/cm 3368 (N–H) and
1708 (C═O); 1H NMR (400 MHz, CDCl3): δH 7.93 (1H, s, H‐4), 7.84
(1H, d, J = 15.8 Hz, H‐1⁗), 7.80 (1H, d, J = 8.5 Hz, H‐8), 7.56 (1H, d,
J = 7.9 Hz, H‐5), 7.51–7.47 (1H, m, H‐6), 7.31 (1H, dd, J = 7.7, 1.1 Hz,
H‐6‴), 7.28–7.23 (1H, m, H‐7), 7.14–7.09 (1H, m, H‐4‴), 6.64 (1H, t,
J = 7.5 Hz, H‐5‴), 6.51 (1H, d, J = 8.2 Hz, H‐3‴), 6.31 (1H, d,
J = 15.7 Hz, H‐2⁗), 5.08 (1H, s, NH), 4.42 (2H, s, H‐3′), 3.71 (3H, s,
OCH3), 3.20–3.16 (4H, m, H‐2″), 1.70–1.66 (4H, m, H‐3″), and
1.59–1.54 (2H, m, H‐4″); 13C NMR (100 MHz, CDCl3): δC 167.7,
161.1, 146.6, 146.4, 140.3, 136.6, 131.7, 129.1, 128.3, 127.5, 127.2,
126.3, 125.5, 124.5, 120.2, 118.1, 117.8, 111.8, 51.7, 51.6, 45.2, 26.3,
and 24.6; HRMS (ESI): m/z calcd for C25H28N3O2 [M+H]+: 402.2182,
found 402.2178.
C
24H26N3O3 [M+H]+: 404.1974; found 404.1975.
Methyl‐(E)‐3‐(4‐{[(2‐thiomorpholinoquinolin‐3‐yl)methyl]amino}‐
phenyl) acrylate (30)
Yellow solid; yield: 32%; m.p.: 94–98°C; νmax/cm 3379 (N–H) and
1685 (C═O); 1H NMR (600 MHz, CDCl3): δH 7.96 (1H, s, H‐4), 7.83
(1H, d, J = 8.3 Hz, H‐8), 7.57 (1H, d, J = 8.2 Hz, H‐5), 7.54–7.49 (2H, m,
H‐7, H‐1⁗), 7.29–7.27 (3H, m, H‐6, H‐2‴), 6.50 (2H, d, J = 8.5 Hz, H‐
3‴), 6.13 (1H, d, J = 15.9 Hz, H‐2⁗), 4.70 (1H, s, NH), 4.37 (2H, s, H‐
3′), 3.68 (3H, s, OCH3), 3.54–3.50 (4H, m, H‐2″), and 2.79–2.77 (4H,
m, H‐3″); 13C NMR (150 MHz, CDCl3): δC 168.1, 160.4, 149.6, 145.0,
144.4, 136.1, 132.6, 130.0, 129.9, 127.6, 127.2, 126.0, 125.6, 125.0,
124.2, 112.8, 52.9, 51.5, 44.3, and 28.0; HRMS (ESI): m/z calcd for
Methyl‐(E)‐3‐(2‐{[(2‐thiomorpholinoquinolin‐3‐yl)methyl]amino}‐
phenyl) acrylate (34)
Yellow solid; yield: 38%; m.p.: 117–119°C; νmax/cm 3399 (N–H) and
1696 (C═O); 1H NMR (400 MHz, CDCl3): δH 7.96 (1H, s, H‐4),
7.85–7.80 (2H, m, H‐8, H‐1⁗), 7.57 (1H, d, J = 7.7 Hz, H‐5), 7.52 (1H,
t, J = 7.7 Hz, H‐6), 7.32 (1H, d, J = 7.7 Hz, H‐6‴), 7.29 (1H, t, J = 7.5 Hz,
H‐7), 7.12 (1H, t, J = 7.7 Hz, H‐4‴), 6.66 (1H, t, J = 7.5 Hz, H‐5‴), 6.47
(1H, d, J = 8.3 Hz, H‐3‴), 6.32 (1H, d, J = 15.7 Hz, H‐2⁗), 4.88 (1H, s,
NH), 4.39 (2H, s, H‐3′), 3.71 (3H, s, OCH3), 3.54–3.50 (4H, m, H‐2″),
and 2.78–2.75 (4H, m, H‐3″); 13C NMR (100 MHz, CDCl3): δC 167.7,
160.6, 146.4, 146.2, 140.1, 137.0, 131.7, 129.3, 128.3, 127.7, 127.2,
126.0, 125.7, 124.9, 120.2, 118.3, 118.0, 111.7, 52.8, 51.7, 44.9, and
27.9; HRMS (ESI): m/z calcd for C24H26N3O2S [M+H]+: 420.1746,
found 420.1745.
C
24H26N3O2S [M+H]+: 420.1746; found 420.1742.
Methyl‐(E)‐3‐[4‐({[2‐(4‐phenylpiperazin‐1‐yl)quinolin‐3‐yl]methyl}‐
amino)phenyl] acrylate (31)
Yellow solid; yield: 35%; m.p.: 160–162°C; νmax/cm 3426 (N–H) and
1704 (C═O); 1H NMR (400 MHz, CDCl3): δH 8.06 (1H, s, H‐4), 7.93
(1H, d, J = 8.0 Hz, H‐8), 7.67 (1H, d, J = 8.0 Hz, H‐5), 7.64–7.59 (2H, m,
H‐1⁗, H‐7), 7.40–7.36 (3H, m, H‐5, H‐2‴), 7.31 (2H, t, J = 7.9 Hz, H‐
6″), 7.01 (2H, d, J = 8.2 Hz, H‐5″), 6.90 (1H, t, J = 7.3 Hz, H‐7″), 6.61
(2H, d, J = 8.5 Hz, H‐3‴), 6.23 (1H, d, J = 15.9 Hz, H‐2⁗), 4.87–4.84
(1H, m, NH), 4.52 (2H, d, J = 3.9 Hz, H‐3′), 3.78 (3H, s, OCH3),
3.55–3.51 (4H, m, H‐3″), and 3.42–3.39 (4H, m, H‐2″); 13C NMR
(100 MHz, CDCl3): δC 168.2, 159.8, 151.2, 149.6, 146.5, 145.1, 137.0,
130.0, 129.4, 129.2, 127.7, 127.2, 125.7, 125.6, 124.9, 124.1, 120.0,
116.2, 112.9, 112.8, 51.5, 50.3, 49.4, and 44.5; HRMS (ESI): m/z calcd
for C30H31N4O2 [M+H]+: 479.2447, found 479.2439.
Methyl‐(E)‐3‐[2‐({[2‐(4‐phenylpiperazin‐1‐yl)quinolin‐3‐yl]methyl}‐
amino)phenyl] acrylate (35)
Pale yellow solid; yield: 75%; m.p.:122–124°C; νmax/cm 3445 (N–H)
and 1904 (C═O); 1H NMR (400 MHz, CDCl3): δH 8.09 (1H, s, H‐4),
7.97–7.90 (2H, m, H‐8, H‐1⁗), 7.69 (1H, d, J = 7.9 Hz, H‐5), 7.63 (1H,
t, J = 7.6 Hz, H‐6), 7.42–7.38 (2H, m, H‐7, H‐6‴), 7.30 (2H, t,
J = 7.8 Hz, H‐6″), 7.23 (1H, t, J = 7.7 Hz, H‐4‴), 7.00 (2H, d, J = 8.1 Hz,

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BOKOSI ET AL.
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H‐5″), 6.90 (1H, t, J = 7.2 Hz, H‐7″), 6.76 (1H, t, J = 7.4 Hz, H‐5‴), 6.61
(1H, d, J = 8.2 Hz, H‐3‴), 6.39 (1H, d, J = 15.7 Hz, H‐2⁗), 5.07 (1H, s,
NH), 4.55 (2H, s, H‐3′), 3.77 (3H, s, OCH3), 3.56–3.53 (4H, m, H‐3″),
and 3.43–3.38 (4H, m, H‐2″); 13C NMR (100 MHz, CDCl3): δC 167.6,
159.7, 151.3, 146.3, 146.2, 140.2, 137.4, 131.7, 129.5, 129.2, 128.3,
127.5, 127.3, 125.7, 125.6, 124.9, 120.3, 120.0, 118.4, 118.1, 116.2,
111.7, 51.7, 50.3, 49.4, and 45.2; HRMS (ESI): m/z calcd for
emission 590 nm) in a Spectramax M3 plate reader (Molecular
Device). Fluorescence readings were converted to % parasite viabi-
lity, relative to the average readings obtained from untreated control
wells. IC50 values were determined by plotting % viability versus log
[compound] and performing nonlinear regression using GraphPad
Prism (v. 5.02) software.
C
30H31N4O2 [M+H]+: 479.2447, found 479.2449.
ACKNOWLEDGMENTS
The authors would like to acknowledge the National Research
Foundation (Grant No.: 107270) and Rhodes University Sandisa
Imbewu for financial support. The Centre for Chemico‐ and Biome-
dicinal Research at Rhodes University, which is supported by the
South African Medical Research Council with funds from National
Treasury under its Economic Competitiveness and Support Package,
is acknowledged for running pharmaceutical bioassays. Fostino R.B.
Bokosi was under Malawi Government Scholarship and on study
|
4.2
Biological assays
|
4.2.1
In vitro cytotoxicity assay
Cultures of HeLa cells (Cellonex) seeded in 96‐well plates were in-
cubated with test compounds, and cell viability was assessed by
adding 20 μl of resazurin as described previously.[37] Fluorescence
readings (excitation 560 nm, emission 590 nm) obtained for the in-
dividual wells were converted to % cell viability, relative to the
average readings obtained from untreated control wells.
leave from Chancellor College,
University of Malawi.
a constituent college of the
CONFLICTS OF INTERESTS
The authors declare that there are no conflicts of interest.
|
4.2.2
In vitro antiplasmodial assay
ORCID
Fostino R. B. Bokosi
Richard M. Beteck
https://orcid.org/0000-0002-7923-3709
http://orcid.org/0000-0002-6282-043X
The 3D7 strain of P. falciparum was routinely cultured in a medium
consisting of RPMI1640 containing 25 mM Hepes (Lonza), sup-
plemented with 0.5% (w/v) Albumax II (Thermo Fisher Scientific),
22 mM glucose, 0.65 mM hypoxanthine, 0.05 mg/ml gentamicin,
and 2–4% (v/v) human erythrocytes. Cultures were maintained at
37°C under an atmosphere of 5% CO2, 5% O2, and 90% N2. To
assess antiplasmodial activity, threefold serial dilutions of test
compounds in culture medium were added to parasite cultures
(adjusted to 2% parasitaemia, 1% hematocrit) in 96‐well plates and
incubated for 48 h. Three wells per compound concentration were
used. Parasite lactate dehydrogenase (pLDH) enzyme activity in
the individual wells was determined as previously described.[37]
Absorbance values were converted to % parasite viability, relative
to untreated control cultures, and plotted against log[compound]
to derive IC50 values by nonlinear regression using GraphPad
Prism (v. 5.02) software.
Dustin Laming
http://orcid.org/0000-0003-2734-0999
http://orcid.org/0000-0003-4409-1955
Heinrich C. Hoppe
Tendamudzimu Tshiwawa
http://orcid.org/0000-0002-2747-1406
Setshaba D. Khanye
http://orcid.org/0000-0003-0725-5738
REFERENCES
[1] P. N. Kalaria, S. C. Karad, D. K. Raval, Eur. J. Med. Chem. 2018,
158, 917.
[2] World Health Organisation, World malaria report, 2019, Geneva,
Switzerland.
[3] J. R. Franco, P. P. Simarro, A. Diarra, J. G. Jannin, Clin. Epidemiol.
2014, 6, 257.
[4] P. P. Simarro, A. Diarra, J. A. R. Postigo, J. R. Franco, J. G. Jannin,
PLOS. Negl. Trop. Dis. 2011, 5, e1007.
[5] P. Babokhov, A. O. Sanyaolu, W. A. Oyibo, A. F. Fagbenro‐Beyioku,
N. C. Iriemenam, Pathog. Global Health 2013, 107, 242.
[6] M. C. Field, D. Horn, A. H. Fairlamb, M. A. J. Ferguson, D. W. Gray,
K. D. Read, M. deRycker, L. S. Torrie, P. G. Wyatt, S. Wyllie,
I. H. Gilbert, Nat. Rev. Microbiol. 2017, 15, 217.
[7] D. Zofou, R. B. Nyasa, D. S. Nsagha, F. Ntie‐Kang, H. D. Meriki,
J. C. N. Assob, V. Kuete, Infect. Dis. Poverty 2014, 3, 1.
[8] C. Wongsrichanalai, C. Sibley, Clin. Microbiol. Infect. 2013, 19, 908.
[9] B. M. Greenwood, D. A. Fidock, D. E. Kyle, S. H. I. Kappe,
P. L. Alonso, F. H. Collins, P. E. Duffy, J. Clin. Invest. 2008, 118, 1266.
[10] P. Nasveld, S. Kitchener, Trans. R. Soc. Trop. Med. Hyg. 2005, 99, 2.
[11] M. A. Fakhfakh, A. Fournet, E. Prina, J.‐F. Mouscadet, X. Franck,
R. Hocquemiller, B. Figadère, Bioorg. Med. Chem. 2003, 11, 5013.
[12] A. Lilienkampf, J. Mao, B. Wan, Y. Wang, S. G. Franzblau,
A. P. Kozikowski, J. Med. Chem. 2009, 52, 2109.
|
4.2.3
In vitro antitrypanosomal assay
T. b. brucei 427 trypomastigotes were cultured in Iscove's modified
Dulbecco's medium (Lonza) and supplemented with 10% fetal calf
serum, HMI‐9 supplement,[38] hypoxanthine, and penicillin/strepto-
mycin at 37°C in a 5% CO2 incubator. Serial dilutions of test com-
pounds were incubated with the parasites in 96‐well plates for 24 h.
Residual parasite viability in the wells was determined by adding
20 μl resazurin toxicology reagent (Sigma‐Aldrich) and incubating for
an additional 24 h. Reduction of resazurin to resorufin by viable
parasites was assessed by fluorescence readings (excitation 560 nm,
[13] S. Kumar, S. Bawa, S. Drabu, H. Gupta, L. Machwal, R. Kumar, Eur.
J. Med. Chem. 2011, 46, 670.
[14] A. Mahamoud, J. Chevalier, A. Davin‐Regli, J. Barbe, J. M. Pagès,
Curr. Drug Targets 2006, 7, 843.

BOKOSI ET AL.
9 of 9
|
[15] K. Gopaul, S. A. Shintre, N. A. Koorbanally, Anticancer Agents. Med.
Chem. 2015, 15, 631.
[31] A. Daina, O. Michielin, V. Zoete, Sci. Rep. 2017, 7, 42717.
[32] T. A. Vogel AI, B. S. Furnis, A. J. Hannaford, S.mith PWG, Vogel's
Textbook of Practical Organic Chemistry, John Wiley and Sons, New
York, NY 1989.
[16] N. Ahmed, K. G. Brahmbhatt, S. Sabde, D. Mitra, I. P. Singh,
K. K. Bhutani, Bioorg. Med. Chem. 2010, 18, 2872.
[17] S. C. Karad, V. B. Purohit, P. Thakor, V. R. Thakkar, D. K. Raval, Eur.
J. Med. Chem. 2016, 112, 270.
[33] B. Wang, C. Jiang, J. Qian, S. Zhang, X. Jia, Y. Yuan, Org. Biomol.
Chem. 2018, 16, 101.
[18] P. D. Martinez, S. H. Krake, M. L. Poggi, S. F. Campbell, P. A. Willis,
L. C. Dias, An. Acad. Bras. Ciênc. 2018, 90, 1215.
[19] P. Sharma, J. Chem. Pharm. Res. 2011, 3, 403.
[20] S. Lafay, A. Gil‐Izquierdo, Phytochem. Rev. 2007, 7, 301.
[21] J. Wiesner, A. Mitsch, P. Wissner, H. Jomaa, M. Schlitzer, Bioorg.
Med. Chem. Lett. 2001, 11, 423.
[34] O. Meth‐Cohn, B. Narine, B. Tarnowski, J. Chem. Soc., Perkin Trans. 1
1981, 1520.
[35] O. Pinto, J. Sardinha, P. D. Vaz, F. Piedade, M. J. Calhorda,
R. Abramovitch, N. Nazareth, M. Pinto, M. S. J. Nascimento,
A. P. Rauter, J. Med. Chem. 2011, 54, 3175.
[36] J. H. Kim, H. R. Jeong, D. W. Jung, H. B. Yoon, S. Y. Kim, H. J. Kim,
K.‐T. Lee, V. M. Gadotti, J. Huang, F.‐X. Zhang, G. W. Zamponi,
J. Y. Lee, Bioorg. Med. Chem. 2017, 25, 4656.
[22] F. A. Bernal, M. Kaiser, B. Wünsch, T. J. Schmidt, ChemMedChem
2020, 15, 68.
[23] J. D. Guzman, P. N. Mortazavi, T. Munshi, D. Evangelopoulos,
T. D. McHugh, S. Gibbons, J. Malkinson, S. Bhakta, MedChemComm
2014, 5, 47.
[37] M. Mbaba, A. N. Mabhula, N. Boel, A. L. Edkins, M. Isaacs,
H. C. Hoppe, S. D. Khanye, J. Inorg. Biochem. 2017, 172, 88.
[38] H. Hirumi, K. Hirumi, J. Parasitol. 1989, 75, 985.
[24] K. Zhou, D. Chen, B. Li, B. Zhang, F. Miao, L. Zhou, PLOS One 2017,
12, e0176189.
SUPPORTING INFORMATION
[25] S. U. Lee, C.‐G. Shin, C.‐K. Lee, Y. S. Lee, Eur. J. Med. Chem. 2007, 42,
1309.
Additional Supporting Information may be found online in the
supporting information tab for this article.
[26] P. De, M. Baltas, F. Bedos‐Belval, Curr. Med. Chem. 2011, 18, 1672.
[27] S. G. Alson, O. Jansen, E. Cieckiewicz, H. Rakotoarimanana,
H. Rafatro, G. Degotte, P. Francotte, M. Frederich, J. Pharm.
Pharmacol. 2018, 70, 1349.
[28] F. A. Bernal, M. Kaiser, B. Wünsch, T. J. Schmidt, ChemMedChem
2020, 15, 68.
How to cite this article: F. R. B. Bokosi, R. M. Beteck, D.
Laming, H. C. Hoppe, T. Tshiwawa, S. D. Khanye, Arch. Pharm.
2021, e2000331.
[29] C. Viegas‐Junior, A. Danuello, V. daSilva Bolzani, E. J. Barreiro,
C. A. M. Fraga, Curr. Med. Chem. 2007, 14, 1829.
[30] F. W. Muregi, A. Ishih, Drug Dev. Res. 2010, 71, 20.