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