Design, synthesis and biological evaluation of mono- and bisquinoline methanamine derivatives as potential antiplasmodial agents

Article abstract of DOI:10.1016/j.bmcl.2021.127855

Several classes of antimalarial drugs are currently available, although issues of toxicity and the emergence of drug resistant malaria parasites have reduced their overall therapeutic efficiency. Quinoline based antiplasmodial drugs have unequivocally been long-established and continue to inspire the design of new antimalarial agents. Herein, a series of mono- and bisquinoline methanamine derivatives were synthesised through sequential steps; Vilsmeier-Haack, reductive amination, and nucleophilic substitution, and obtained in low to excellent yields. The resulting compounds were investigated for in vitro antiplasmodial activity against the 3D7 chloroquine-sensitive strain of Plasmodium falciparum, and compounds 40 and 59 emerged as the most promising with IC₅₀ values of 0.23 and 0.93 μM, respectively. The most promising compounds were also evaluated in silico by molecular docking protocols for binding affinity to the {0 0 1} fast-growing face of a hemozoin crystal model.

Full text of DOI:10.1016/j.bmcl.2021.127855

Bioorg. Med. Chem. Lett. 38 (2021) 127855
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis and biological evaluation of mono- and bisquinoline
methanamine derivatives as potential antiplasmodial agents
,
,
,
Fostino R.B. Bokosia *, Richard M. Betecka b, Mziyanda Mbabaa c, Thanduxolo E. Mtshared,
Dustin Laminge, Heinrich C. Hoppee,f, Setshaba D. Khanyea
,d,e,*
a Department of Chemistry, Faculty of Science, Rhodes University, Makhanda 6140, South Africa
b Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom 2520, South Africa
c Department of Chemistry, Faculty of Science, University of Cape Town, Rondebosch 7701, South Africa
d Division of Pharmaceutical Chemistry, Faculty of Pharmacy, Rhodes University, Makhanda 6140, South Africa
e Centre for Chemico- and Biomedicinal Research, Rhodes University, Makhanda 6140, South Africa
f Department of Biochemistry and Microbiology, Faculty of Science, Rhodes University, Makhanda 6140, South Africa
A R T I C L E I N F O
A B S T R A C T
Keywords:
Several classes of antimalarial drugs are currently available, although issues of toxicity and the emergence of
drug resistant malaria parasites have reduced their overall therapeutic efficiency. Quinoline based anti-
plasmodial drugs have unequivocally been long-established and continue to inspire the design of new antima-
larial agents. Herein, a series of mono- and bisquinoline methanamine derivatives were synthesised through
sequential steps; Vilsmeier-Haack, reductive amination, and nucleophilic substitution, and obtained in low to
excellent yields. The resulting compounds were investigated for in vitro antiplasmodial activity against the 3D7
chloroquine-sensitive strain of Plasmodium falciparum, and compounds 40 and 59 emerged as the most promising
with IC50 values of 0.23 and 0.93 µM, respectively. The most promising compounds were also evaluated in silico
by molecular docking protocols for binding affinity to the {001} fast-growing face of a hemozoin crystal model.
Antiplasmodial
Quinoline
Chloroquine-sensitive
Plasmodium falciparum
Introduction
(dihydroartemisinin, artemether or artesunate) is administered in
combination with a longer-lasting partner drug such as amodiaquine,
Malaria is one of the deadliest protozoan diseases transmitted by the
female Anopheles mosquito. Five species of the genus Plasmodium are
known to cause malaria infections in humans.1 These include:
P. falciparum, P. vivax, P. malariae, P. ovale and P. knowlesi. P. falciparum
is responsible for majority of malaria deaths and is the most prevalent
species in sub-Saharan Africa.2 Despite numerous endeavours to reduce
malaria incidence over the last decades, this tropical disease still re-
mains far from being vanquished. According to the 2020 report by
World Health Organization (WHO), an estimated 229 million malaria
cases and 409 000 malaria deaths were reported worldwide in 2019.
Predominantly, the disease has a high toll on pregnant women and
children aged under 5 years in sub-Saharan Africa.1,3–6 Chemothera-
peutics have proven to be an effective means of reducing the burden of
malaria. Currently, the best available treatments, particularly for un-
complicated and severe malaria infections caused by P. falciparum are
artemisinin combination therapies (ACTs). In ACTs, a fast-acting, albeit
mefloquine,
piperaquine,
lumefantrine,
sulfadoxine
and
pyrimethamine.7–9 Although ACTs are highly efficacious with a high
pharmacological tolerance profile, several cases of ACTs treatment
failure are being reported in parts of South-East Asia.10 With increasing
cases of resistance to available antimalarial agents, intensive drug dis-
covery efforts aimed at developing new antimalarial drugs or modifying
existing agents are ongoing. Ideally, highly efficacious, novel antima-
larial compounds need to be developed to supplement or replace clini-
cally available drugs.11–13
The quinoline scaffold is prominent in most drugs and continues to
receive substantial attention in medicinal chemistry due to its broad
spectrum of biological activities. Specifically, quinolines have been
known to display antimalarial,14–17 antitubercular,18 antibacterial,19
antitrypanosomal,20 anticancer,21,22 antifungal23 and anti-HIV24 prop-
erties. Within the quinoline class, 2,3-disubstituted quinolines have
recently gained significant attention as bioactive drug template in ma-
laria drug discovery. Vandekerckhove and colleagues synthesised a
short-lived
artemisinin
or
its
semi-synthetic
derivatives
* Corresponding authors at: Department of Chemistry, Faculty of Science, Rhodes University, Makhanda 6140, South Africa (S.D. Khanye).
E-mail addresses: bokosifostino@gmail.com (F.R.B. Bokosi), s.khanye@ru.ac.za (S.D. Khanye).
https://doi.org/10.1016/j.bmcl.2021.127855
Received 14 December 2020; Received in revised form 1 February 2021; Accepted 5 February 2021
Available online 18 February 2021
0960-894X/© 2021 Elsevier Ltd. All rights reserved.

F.R.B. Bokosi et al.
Bioorganic & Medicinal Chemistry Letters 38 (2021) 127855
novel class of (hydroxyalkylamino)quinoline derivatives via cyclisation
of diallylaminoquinolines and 4-chloro-N-quinolinylbutanamides and
investigated their in vitro antiplasmodial potential against NF54
chloroquine-sensitive (CQS) strain and Dd2 chloroquine-resistant strain
(CQR) of P. falciparum.25 Among the investigated derivatives, 2-methyl-
3-(2-methylpyrrolidin-1-yl) quinoline (1) was found to be the most
potent agent, having IC50 values of 13.3 and 38 µM against chemo-
sensitive (NF54) and multidrug-resistant (Dd2) P. falciparum strains,
respectively. The research team of Patel and Ladani synthesised a library
of compounds containing the 2-chloroquinoline nucleus and identified
hit compound 2 (0.089 µM) with excellent inhibitory activity against
P. falciparum comparable to quinine (0.826 µM).26 Subsequently, Akhter
et al (2015) investigated 3-[(2-chloroquinolin-3-yl)methylene]-5-phe-
nylfuran-2(3H)-one derivatives (3) as antiplasmodial agent targeting
P. falciparum falcipain-2 (PfFP-2).27 By conjugating quinoline to a
chalcone moiety, Rosenthal and co-workers developed novel class of
substituted quinolinyl-chalcone hybrids (4) with in vitro antimalarial
activities.28 Similarly, Karad et al (2016) prepared 2,3-disubstituted
quinoline conjugates under microwave, with derivative 5 possessing
impressive antiplasmodial activity against 3D7 P. falciparum strain.29
Arylaminobiquinoline derivatives were synthesised and evaluated for
their antimalarial activity against 3D7 strain of P. falciparum by Patel
and colleagues.30 Some of them showed antimalarial activity with IC50
quinoline scaffold (bearing a varied substitution pattern) with a syn-
thetically and biologically suited heterocyclic moiety might reveal new
perspectives in development of bioactive compounds. In order to
examine the effect of key structural features critical for inhibitory
antiplasmodial effects of the compounds and as part of examining
structure–activity relationship (SAR), the proposed compounds were
designed as highlighted in Fig. 2.
In light of the impressive pharmacological profile of the quinoline
scaffold from previous studies, especially for targeting the heme
detoxification pathway38,39 and inhibiting P. falciparum falcipain-2
(PfFP2),40 the quinoline moiety (A) served as the core backbone onto
which heteroaryl units (B) could be appended. Since protonation of
quinolinyl antimalarial drugs inside the acidic target site of the parasite
digestive vacuole (DV) is important for activity,15 we incorporated a
basic, trimethylamine linker to promote protonation and consequently
enhance the antiplasmodial activity of the conceptualised compounds.
Positions 2, 5, 6 and 7 of the quinoline scaffold were substituted with
various moieties (F, Cl, H, Me, OH and OMe) to probe substitution
patterns and electronic effects on the overall activity of the compounds.
Lastly, a second quinoline nucleus (C) was appended via the linker to
attain bisquinoline analogues.41–45 In summary, the design of the target
compounds entails: (i) substitution of C-2 of the quinoline scaffold with
chloro or methoxy moieties as the core pharmacophoric backbone, (ii)
variation of bioisosteric heterocycles appended to C-3 of the quinoline
nucleus, (iii) interrogation of electronic and substituents effects on the
core quinoline skeleton (mainly at positions ꢀ 5, ꢀ 6 and ꢀ 7) and (iv)
generation of bisquinolines. Hence, the objective of this study consists of
the design, synthesis and antiplasmodial evaluation of a range of novel
substituted mono and bisquinolines. An attempt to explore possible
mode of action of this chemical series is also undertaken by assessing the
most promising compounds.
values as low as 0.005–0.009 μg/mL. The most active compound 6 of the
N-arylaminobiquinoline derivatives had superior antimalarial activity
compared to chloroquine, highlighting the appeal of conjugating two
pharmacophoric quinoline units to produce potent plasmocidal com-
pounds (See Fig. 1).
In continuation of our search for new molecules with anti-infective
properties,31–34 we decided to investigate the antiplasmodial proper-
ties of novel substituted quinoline derivatives. The quinoline scaffold
was derivatized using various simple bioactive, bioisosteric heterocy-
cles, namely: 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiophenyl and 2-furfuryl
units. Some of these heterocycles have been reported to exhibit excellent
antiplasmodial activity.35–37 The combination of the privileged
Acetanilides 7–12 were subjected to Vilsmeier-Haack reaction to
afford intermediates 13–18 in 36–84% yields.46 Compounds 13–18
were refluxed in a methanolic KOH solution, inducing nucleophilic
substitution at the C-2 position to obtain 2-methoxyquinoline-3-carbal-
dehydes 19–24, which were subsequently subjected to reductive ami-
nation with a selection of primary heteroaryl methylamines to form the
secondary amines 33–51.47,48 Treatment of 33–51 with corresponding
2-chloromethylquinolines 29–32 afforded the desired bisquinolinyl
amines 52–64 (Scheme 1) in yields ranging 17–82%. Intermediates
29–32 were prepared in two consecutive steps: reduction of in-
termediates 13–16 to 25–28, followed by alcohol chlorination. Bisqui-
nolinyl amines 65–68 with identical quinoline units were readily
obtained via double nucleophilic substitution of 2-(aminomethyl)pyri-
dine with 2-chloro-3-(chloromethyl)-6-substituted quinolines 29–32 in
absolute ethanol in the presence of Et3N49 in moderate to excellent
yields (Scheme 2). However, substitution of the 2-chloro-3-(chloro-
methyl)-6-substituted quinolines with the other aminomethyl hetero-
cycles (containing B – E units shown in Table 1) under similar conditions
was unsuccessful. Thus, the 2-methoxy congeners 70–72 of these de-
rivatives were achieved by nucleophilic substitution employing the re-
action conditions described for synthesis of compounds 19–24. Lastly,
demethylation of 67 with BBr3 under an inert atmosphere yielded the
corresponding phenolic analogue 69 in 69% yield.50
The structures of all newly synthesised compounds were unambig-
uously characterised by common spectroscopic techniques: FTIR, 1H and
13C NMR, 2D NMR and HRMS. The full spectral data of prepared com-
pounds are provided in the Electronic Supporting Information (ESI). The
IR spectra of 33–51 contain bands ca 3370–3240 cmꢀ 1, which indicate
secondary amine absorption. The broad absorption band around 3206
cmꢀ 1 in compound 69 is due to the aromatic O H stretching. The 1H
–
NMR spectra of N-(quinolin-3-ylmethyl)methanamines (33–51) show a
broad singlet ca δ 2.86–1.99 ppm, which is diagnostic of the aliphatic N
1
–
H group. Disappearance of the aldehydic signals ca δ 10.5 ppm ( H
NMR) and δ 189 ppm (13C NMR) observed from the starting materials
Fig. 1. Representative chemical structures of 2,3-disubstituted quinoline de-
19–24 and the appearance of two singlet methylene groups ca δ
rivatives exhibiting antimalarial activity.
2

F.R.B. Bokosi et al.
Bioorganic & Medicinal Chemistry Letters 38 (2021) 127855
(iii)
(iv)
Interrogation of substitution and
electronic effects at positions 5, 6 and 7
Addition of a second
quinoline nucleus for
improved activity
(ii)
C
Heteroaryl rings as bioisosteric
units: 2-, 3- or 4-pyridyl, 2-
thiophenyl and furyl rings
N
B
N
(v)
A
Quinoline core serves as
the pharmacophoric
backbone
Incorporation of a basic N atom
to facilitate protonation in the DV
and enhance biological activity
N
(i)
Substitution
with Cl or OMe
Fig. 2. Design of proposed compounds.
4.09–3.81 ppm, confirmed the transformation of a carbonyl unit into
desired amines 33–51. Lastly, a prominent proton signal integrating for
two protons for 69 was observed at δ 10.12 ppm assignable to the aro-
matic OH groups. The molecular ion peaks of all the compounds were
observed as protonated molecular ions [M + H]+ corresponding to their
respective molecular weights.
0.93 µM) in the entire series despite its mono-quinoline congener (37)
not showing any discernible activity at the highest tested concentration
(IC50 > 20 µM). Furthermore, we noted that the activity of the previ-
ously less active 3-pyridyl variants (42, 44, 45, 47 and 48) showed
improvement in activity by approximately 2-fold upon coupling of a
second quinoline unit (53–56). Therefore, it is clear from these obser-
vations that the second quinoline unit and a tertiary amine are indeed
beneficial for antiplasmodial activity. On the other hand, grafting a
second quinoline unit to the 2-pyridyl monoquinolines 39 and 40 did
not exert marked effects on the antiplasmodial activity of the resulting
compounds (64 and 70) albeit displaying somewhat reduced activities.
Consequently, these findings further suggest that a trimethylamine
linker in lieu of a secondary dimethylamine might be essential for ac-
tivity. Regarding effects of substituents on the quinoline ring; replace-
ment of 2-Cl with 2-OMe led to increased antiplasmodial activity. For
All compounds were evaluated for in vitro antiplasmodial activity
against the CQS (3D7) of P. falciparum while cytotoxicity against healthy
cells was determined using mammalian HeLa cells. The activities indi-
cated by their corresponding IC50 values of the synthesised mono-
quinoline 33–51 and bisquinoline derivatives 52–72 along with the
activities of the antimalarial drug chloroquine and cytotoxic agent
emetine as controls are summarised in Tables 1 and 2, respectively. HeLa
cell activity was presented as percentage viability of cells remaining
after incubation with 20 µM of the test compounds. In the N-(quinolin-3-
ylmethyl)methanamine subseries (33–51), compounds 33–38 featuring
2-furfuryl or 2-thiophenyl bioisosteric heterocyclic systems shed
important antiplasmodial insight as were inactive at the maximum
example, replacing the 2-Cl moiety in 65 (IC50 > 20
20 M) with 2-OMe afforded compounds 70, (IC50: 3.5 µМ) and 72 (IC50
3.4 M), respectively, with low micromolar antiplasmodial activity.
μ
M) and 67 (IC50
>
μ
:
μ
tested concentration (IC50 > 20
μ
M). With the exception of compounds
Moreover, substituents at positions C-5, C-6 and C-8 (F, Me, OMe, H, OH
and 5,7-diMe) seemed to be tolerated for activity across all compounds,
especially the derivatives containing the 2-OMe substituent on the
quinoline scaffold, with F and OH being the most favourable sub-
stituents (Table 2). Superior antiplasmodial activity of compounds 40
and 59 concurred with several antiprotozoal 2- or 6-methoxy quinolines
that have been reported by others in literature.26,51–58
41 and 47–48, all the pyridyl-substituted quinoline derivatives from this
subseries exhibited antiplasmodial activity with IC50 values in the range
of 0.23 – 17.9 µМ; with compound 40 exhibiting superior potency with
IC50 = 0.23 μM. Analysis of the data revealed that the 6-membered
pyridyl groups promote antiplasmodial activity better than 5-membered
counterparts (2-furfuryl and 2-thiophenyl). Antiplasmodial activity
seems to increase in the order: 2-pyridyl > 4-pyridyl > 3-pyridy within
the pyridyl containing compounds. The influence of substituents at C2,
C5, C6 and C7 of the quinoline ring on the antiplasmodial activity was
not clear-cut. Most importantly, majority of compounds in the N-(qui-
nolin-3-ylmethyl)methanamine subseries (33–51) showed little or no
cytotoxic effects on the HeLa cell line, exhibiting > 50% cell viability at
20 µM. Although 39 had promising antiplasmodial activity with an IC50
value of 1.4 µM against the 3D7 strain, it moderately reduced HeLa cell
viability to 44.3% at 20 µM (Table 1).
To rationalise the possible mechanism of action of the investigated
compounds, the most promising compounds 40 and 59 were evaluated
in silico by molecular docking protocols for binding affinity to the {001}
fast-growing face of a hemozoin crystal model (a validated antimalarial
target of quinoline-based drugs) according to previously published
methods.31,59,60 Models of the binding ligands were protonated at pH
4.0 ± 1.0 to mimic the acidic environment inside the DV of the malaria
parasite prior to docking. In all cases the nitrogenous linker of the pre-
dicted compounds was protonated under the used conditions, which
suggests that this moiety may indeed be beneficial for accumulation of
the compounds into the parasitic DV and potentially improve their
antimalarial activity by pH trapping.15 Examples of generated diproto-
nated states of the compounds at both the quinoline and linker N atoms
are shown in Fig. 3A, B. Both compounds exhibited high affinity for the
Next, we generated bisquinoline subseries (52–63) to investigate the
concurrent effect of two quinoline units and a tertiary amine on anti-
plasmodial activity. As shown in Table 2, the addition of a second
quinoline moiety general promotes antiplasmodial activity. This is
evident when comparing 33–38 (which are all not active, IC50 > 20 µM)
against compounds 58–63, which generally exhibited antiplasmodial
activity in the sub-micromolar to low micromolar concentration (with
the exception of 61 and 62, which are inactive; IC50 > 20 µM). The
{001} hemozoin side face, forming multiple π-assisted contacts (π-π,
π
-anion/cation, π-alkyl) with the heme moieties inside the crevices of
this corrugated face (Fig. 3C, D). This is further substantiated by the
negative docking scores of –9.23 and –8.41 kcal/mol for 40 and 59,
thiophenyl bisquinoline 59 demonstrated the highest activity (IC50
=
3

F.R.B. Bokosi et al.
Bioorganic & Medicinal Chemistry Letters 38 (2021) 127855
Scheme 1. Reagents and conditions: (i) Ac2O, AcOH, reflux, 30 min; (ii) DMF/POCl3, 80 ◦C, 5–18 h; (iii) MeOH/KOH, 60 ◦C, 2.5–6 h; (iv) MeOH, NaBH4, r.t., 30
min; (v) SOCl2, DCM, 50 ◦C, 6 h; (vi) heteroaryl methylamine, EtOH, AcOH (cat), 78 ◦C, 12–48 h followed by EtOH, NaBH4, r.t. 6 h; (vii) EtOH, TEA, 78 ◦C, 12–18 h.
4

F.R.B. Bokosi et al.
Bioorganic & Medicinal Chemistry Letters 38 (2021) 127855
Scheme 2. Synthesis of bisquinolines with identical quinoline nuclei. Reagents and conditions: (i) 2-(Aminomethyl)pyridine, EtOH, Et3N, 78 ◦C, 36–48 h; (ii) MeOH/
NaH, 70 ◦C, 36 h; (iii) BBr3 in DCM (1.0 M), ꢀ 78 ◦C, N2, 30 min → r.t., 3 h.
Table 1
Structures of compounds 33–51, IC50 values against 3D7 strain of P. falciparum and % viability of HeLa cells at 20 μM.
Compd
Structure
3D7 IC50 (µM)a
% HeLa Viabilitya
Compd
Structure
3D7 IC50 (µM)a
13.4 ± 1.47
% HeLa Viabilitya
33
>20
88.9 ± 3.33
43
99.5 ± 5.98
34
35
36
>20
>20
>20
89.9 ± 5.15
99.7 ± 2.19
87.5 ± 5.93
44
45
46
12.8 ± 1.28
17.9 ± 1.98
16.8 ± 1.61
100.4 ± 7.18
97.2 ± 5.59
100.5 ± 4.89
37
38
39
40
>20
93.2 ± 12.79
93.5 ± 2.60
44.3 1.31
56.7 3.25
47
48
49
50
>20
76.7 ± 7.64
77.23 ± 3.62
69.9 5.93
60.7 ± 2.31
>20
>20
1.40 0.07
0.23 0.02
2.10 0.56
12.0 ± 1.16
41
42
>20
65.6 ± 1.65
89.9 ± 1.22
51
2.30 0.61
73.7 6.25
13.4 ± 0.31
Chloroquine
–
–
0.023
–
Emetine
–
0.013
respectively, which illustrates a trend correlating with the observed
quinoline derivatives and evaluated them for their in vitro anti-
plasmodial activity against the 3D7 strain of P. falciparum. Bioassay
screening culminated in the identification of hit compounds 40 and 59,
which displayed IC50 values in the sub-micromolar range. The SAR
antiplasmodial activity evaluated on the 3D7 P. falciparum strain, i.e., 40
(0.23 μM) > 59 (0.93 μM).
Herein, we reported the synthesis of thirty nine structurally simple
5

F.R.B. Bokosi et al.
Bioorganic & Medicinal Chemistry Letters 38 (2021) 127855
Table 2
Structures of compounds 52–72, IC50 values against 3D7 strain of P. falciparum and % viability of HeLa cells at 20 μM.
Compd.
Structure
3D7 IC50 (µM)a
% HeLa Viabilitya
Compd
Structure
3D7 IC50 (µM)a
2.80 ± 0.18
% HeLa Viabilitya
52
>20
89.9 ± 11.98
64
90.1 ± 4.71
53
54
55
9.80 ± 1.24
9.60 ± 1.12
12.3 ± 1.32
98.3 ± 8.65
92.6 ± 10.76
77.6 ± 11.9
65
66
67
>20
>20
>20
90.6 ± 12.56
93.0 ± 2.02
83.8 ± 9.01
56
57
7.60 ± 0.73
12.6 ± 1.51
80.3 ± 4.66
87.9 ± 3.35
68
69
9.80 ± 1.23
98.7 ± 9.56
88.8 ± 9.74
2.50 0.41
58
59
60
13.4 ± 1.74
0.93 0.04
11.3 ± 1.18
103.2 ± 3.95
99.2 ± 4.74
95.2 ± 1.08
70
71
72
3.50 ± 0.12
89.0 ± 8.79
93.3 ± 11.5
79.5 ± 0.93
>20
3.40 0.71
(continued on next page)
6

F.R.B. Bokosi et al.
Bioorganic & Medicinal Chemistry Letters 38 (2021) 127855
Table 2 (continued)
Compd.
Structure
3D7 IC50 (µM)a
>20
% HeLa Viabilitya
Compd
Structure
3D7 IC50 (µM)a
% HeLa Viabilitya
61
86.0 ± 7.17
Chloroquine
–
0.023
–
62
>20
85.4 ± 2.97
84.4 ± 3.37
Emetine
–
–
0.013
63
12.8 1.11
a
The values are the mean ± SD of experiments performed in triplicate.
Fig. 3. Results of the computational simulation study. (A-B) Examples of predicted forms of the compounds diprotonated at N atoms of the quinoline and linker
motifs. (C-D) Low-energy binding conformations of protonated structures (at pH 4.0 ± 1.0) of compounds 40 and 59 bound to the {001} fast-growing face of the
hemozoin crystal interacting with the heme moieties.
analysis suggest that the introduction of a second quinoline moiety
significantly promoted both antiplasmodial activity and low cytotoxicity
towards the HeLa cell line at 20 µM. Computational molecular docking
simulation of tool compounds 40 and 59 suggests hemozoin binding as a
plausible mechanism of action of the investigated compounds. The
enriched SAR profile obtained from this study, as well as the convenient
preparation of these compounds, make the reported organic frameworks
attractive in antimalarial drug discovery and warrant further explora-
tion and mechanistic evaluation to fully comprehend their plasmocidal
effects.
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.
Acknowledgements
Financial support for the chemistry component of this project was
provided by the Rhodes University Sandisa Imbewu fund (SDK, HCH),
7

F.R.B. Bokosi et al.
Bioorganic & Medicinal Chemistry Letters 38 (2021) 127855
25 Vandekerckhove S, Van Herreweghe S, Willems J, et al. Eur J Med Chem. 2015;92:
91–102.
the National Research Foundation of South Africa and Thuthuka Na-
tional Research Foundation (Grant No. 107270, SDK). The South African
Medical Research Council (SAMRC) funded the antiplasmodial and HeLa
cytotoxicity bioassay component of the project. FRBB gratefully ac-
knowledges financial support from the Malawi Government Scholarship
Fund and Chancellor College, one of the constituent colleges of the
University of Malawi. Authors thank Dr. Tendamudzimu Tshiwawa
(Postdoc, Rhodes University) for assistance with computational molec-
ular docking.
26 Ladani GG, Patel MP. New J Chem. 2015;39:9848–9857.
27 Akhter M, Saha R, Tanwar O, Mumtaz Alam M, Zaman MS. Med Chem Res. 2015;24:
879–890.
28 Dominguez JN, Charris JE, Lobo G, et al. Eur J Med Chem. 2001;36:555–560.
29 Karad SC, Purohit VB, Thakor P, Thakkar VR, Raval DK. Eur J Med Chem. 2016;112:
270–279.
30 Shah NM, Patel MP, Patel RG. Eur J Med Chem. 2012;54:239–247.
31 Mbaba M, Dingle LMK, Swart T, et al. ChemBioChem. 2020;21:2643–2658. https://
doi.org/10.1002/cbic.202000132.
32 Mbaba M, Dingle LMK, Cash D, et al. Eur J Med Chem. 2020;187:111924.
33 Darrell OT, Hulushe ST, Mtshare TE, et al. S Afr J Chem. 2018;71:174–181.
34 Zulu AI, Oderinlo OO, Kruger C, et al. Molecules. 2020;25:1668.
35 Rice DR, Mendiola MDLB, Murillo-Solano C, Checkley LA, Ferdig MT, Pizarro JC,
Smith BD. Bioorg Med Chem. 2017;25:2754–2760.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bmcl.2021.127855.
36 Glans L, Ehnbom A, De Kock C, et al. Dalton Trans. 2012;41:2764–2773.
37 Gilson PR, Tan C, Jarman KE, et al. J Med Chem. 2017;60:1171–1188.
38 Sullivan DJ. PNAS. 2017;114:7483–7485.
´
´
˜
´
39 Herraiz T, Guillen H, Gonzalez-Pena D, Aran VJ. Sci Rep. 2019;9:1–16.
40 Singh A, Kalamuddin M, Mohmmed A, Malhotra P, Hoda N. RSC Adv. 2019;9:
39410–39421.
References
41 Liebman KM, Burgess SJ, Gunsaru B, et al. Molecules. 2020;25:2251.
42 Kondaparla S, Agarwal P, Srivastava K, Puri SK, Katti SB. Chem Bio Drug Des. 2017;
89:901–906.
1
2
3
4
Singh B, Daneshvar C. Clin Microbiol Rev. 2013;26:165–184.
White NJ. Clin Infect Dis. 2008;46:172–173.
World Health Organization, World malaria report, Geneva, 2019.
Qin H-L, Zhang Z-W, Lekkala R, Alsulami H, Rakesh KP. Eur J Med Chem. 2020;193,
112215.
43 Fielding AJ, Evans P, Alizadeh S, et al. Chem Eur J. 2017;23:6811–6828.
44 Van Heerden L, Cloete TT, Breytenbach JW, et al. Eur J Med Chem. 2012;55:335–345.
45 Kaur K, Jain M, Khan SI, et al. Bioorg Med Chem. 2011;19:197–210.
46 Meth-Cohn O, Narine B, Tarnowski B. J Chem Soc. Perkin Trans. 1981;1:1520–1530.
47 Kuethe JT, Wong A, Qu C, Smitrovich J, Davies IW, Hughes DL. J Org Chem. 2005;70:
2555–2567.
5
6
7
8
9
Cox FEG. Parasites Vectors. 2010;3:5.
Visser BJ, van Vugt M, Grobusch MP. Expert Opin Pharmacother. 2014;15:2219–2254.
Eastman RT, Fidock DA. Nat Rev Microbiol. 2009;7:864–874.
Nosten F, White NJ. Am J Trop Med Hyg. 2007;77:181–192.
World Health Organization, Guidelines for the treatment of malaria, Geneva, 2015.
48 Jain PP, Degani MS, Raju A, Ray M, Rajan M. Bioorg Med Chem Lett. 2013;23:
6097–6105.
10 World Health Organization, Artemisinin resistance and artemisinin-based
combination therapy efficacy: status report, 2018.
49 Kumar S, Bawa S, Drabu S, Gupta H, Machwal L, Kumar R. Eur J Med Chem. 2011;46:
670–675.
11 Menard D, Dondorp A. Cold Spring Harb Perspect Med. 2017;7, a025619.
12 Ross LS, Fidock DA. Cell Host Microbe. 2019;26:35–47.
50 Choi W-K, El-Gamal MI, Choi HS, Baek D, Oh C-H. Eur J Med Chem. 2011;46:
5754–5762.
13 Phillips MA, Rathod PK. Infect Disord Drug Targets. 2010;10:226–239.
14 Foley M, Tilley L. Pharmacol Ther. 1998;79:55–87.
51 Upadhayaya RS, Vandavasi JK, Vasireddy NR, Sharma V, Dixit SS, Chattopadhyaya J.
Bioorg Med Chem. 2009;17:2830–2841.
15 Egan TJ. Expert Opin Ther Pat. 2001;11:185–209.
52 Mitton-Fry MJ, Brickner SJ, Hamel JC, et al. Bioorg Med Chem Lett. 2017;27:
3353–3358.
16 Kaur K, Jain M, Reddy RP, Jain R. Eur J Med Chem. 2010;45:3245–3264.
˜
17 Baragana B, Hallyburton I, Lee MCS, et al. Nature. 2015;522:315–320.
53 Carroll FI, Berrang B, Linn CP, Twine Jr CE. J Med Chem. 1979;22:694–699.
54 Carroll FI, Berrang BD, Linn CP. J Med Chem. 1980;23:581–584.
55 Drake NL, Van Hook J. J Am Chem Soc. 1946;68:1529–1531.
56 Bawa S, Kumar S, Drabu S, Kumar R. J Pharm Bioallied Sci. 2010;2:64–71.
57 Panda SS, Bajaj K, Meyers MJ, Sverdrup FM, Katritzky AR. Org Biomol Chem. 2012;
10:8985–8993.
18 Keri RS, Patil SA. Biomed Pharmacother. 2014;68:1161–1175.
19 Marella A, Tanwar OP, Saha R, et al. Saudi Pharm J. 2013;21:1–12.
˜
20 Chanquia SN, Larregui F, Puente V, Labriola C, Lombardo E, García Linares G. Bioorg
Chem. 2019;83:526–534.
21 Afzal O, Kumar S, Haider MR, et al. Eur J Med Chem. 2015;97:871–910.
22 Kaalin G, Suhas AS, Neil AK. Anti-Cancer Agents Med Chem. 2015;15:631–646.
23 Musiol R, Serda M, Hensel-Bielowka S, Polanski J. Curr Med Chem. 2010;17:
1960–1973.
¨
58 Upadhayaya RS, Dixit SS, Foldesi A, Chattopadhyaya J. Bioorg Med Chem Lett. 2013;
23:2750–2758.
59 Veale CG, Jayram J, Naidoo S, et al. RSC Med Chem. 2020;11:85–91.
60 L’abbate FP, Müller R, Openshaw R, et al. Eur J Med Chem. 2018;159:243–254.
24 Nisha C, Sourav K, Monika C, Raj K. Mini-Rev Med Chem. 2019;19:510–526.
8