Synthesis and evaluation of chalcone-quinoline based molecular hybrids as potential anti-malarial agents

Article abstract of DOI:10.3390/molecules26134093

Molecular hybridization is a drug discovery strategy that involves the rational design of new chemical entities by the fusion (usually via a covalent linker) of two or more drugs, both active compounds and/or pharmacophoric units recognized and derived from known bioactive molecules. The expected outcome of this chemical modification is to produce a new hybrid compound with improved affinity and efficacy compared to the parent drugs. Additionally, this strategy can result in compounds presenting modified selectivity profiles, different and/or dual modes of action, reduced undesired side effects and ultimately lead to new therapies. In this study, molecular hybridization was used to generate new molecular hybrids which were tested against the chloroquine sensitive (NF54) strain of P. falciparum. To prepare the new molecular hybrids, the quinoline nucleus, one of the privileged scaffolds, was coupled with various chalcone derivatives via an appropriate linker to produce a total of twenty-two molecular hybrids in 11%–96% yield. The synthesized compounds displayed good antiplasmodial activity with IC₅₀ values ranging at 0.10–4.45 μM.

Full text of DOI:10.3390/molecules26134093

molecules
Article
Synthesis and Evaluation of Chalcone-Quinoline Based
Molecular Hybrids as Potential Anti-Malarial Agents
Bonani Vinindwa 1, Godwin Akpeko Dziwornu 2 and Wayiza Masamba 1,
*
1
Department of Chemical and Physical Sciences, Faculty of Natural Sciences, Walter Sisulu University,
Nelson Mandela Drive, Mthatha 5117, South Africa; athulevinindwa@gmail.com
Department of Chemistry, University of Cape Town, Rondebosch 7700, South Africa;
godwin.dziwornu@uct.ac.za
2
*
Correspondence: wmasamba@wsu.ac.za
Abstract: Molecular hybridization is a drug discovery strategy that involves the rational design of
new chemical entities by the fusion (usually via a covalent linker) of two or more drugs, both active
compounds and/or pharmacophoric units recognized and derived from known bioactive molecules.
The expected outcome of this chemical modification is to produce a new hybrid compound with
improved affinity and efficacy compared to the parent drugs. Additionally, this strategy can result in
compounds presenting modified selectivity profiles, different and/or dual modes of action, reduced
undesired side effects and ultimately lead to new therapies. In this study, molecular hybridization
was used to generate new molecular hybrids which were tested against the chloroquine sensitive
(NF54) strain of P. falciparum. To prepare the new molecular hybrids, the quinoline nucleus, one of
the privileged scaffolds, was coupled with various chalcone derivatives via an appropriate linker to
produce a total of twenty-two molecular hybrids in 11%–96% yield. The synthesized compounds
displayed good antiplasmodial activity with IC50 values ranging at 0.10–4.45 µM.
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Citation: Vinindwa, B.; Dziwornu,
G.A.; Masamba, W. Synthesis and
Evaluation of Chalcone-Quinoline
Based Molecular Hybrids as Potential
Anti-Malarial Agents. Molecules 2021,
26, 4093. https://doi.org/10.3390/
molecules26134093
Keywords: chalcones; malaria; molecular hybrids; quinoline-sulfonamide; P. falciparum
1. Introduction
Academic Editors:
Malaria is a life-threatening disease caused by the Plasmodium parasites that are trans-
Giuseppe Manfroni,
mitted to people through the bites of infected female Anopheles mosquitoes [
women, children under the age of 5 years, and people with weakened immune system are
most likely to succumb to the morbidity and transience of the disease [ ]. In 2019 the
estimated malaria cases were 229 million with an approximated death toll of 409,000 [ ].
1]. Pregnant
Tommaso Felicetti and Robert Musioł
2,3
Received: 30 May 2021
Accepted: 1 July 2021
Published: 5 July 2021
4
Worldwide, children aged under 5 years, the most vulnerable group, accounted for 67%
of the total malaria deaths in 2019. The World Health Organization (WHO) Africa region
accounted for 82% of all cases and about 10% in the WHO South-East Asia region. P. falci-
parum is the most prevalent malaria parasite in the WHO regions of Africa, South-East Asia,
the Eastern Mediterranean and the Western Pacific, accounting for 99.7% of all malaria
cases in Africa, 50% in South-East Asia, 69% in Eastern Mediterranean, and 65% in Western
Pacific. On the other hand, P. vivax is predominant in the WHO region of the Americas,
representing 75% of malaria cases [5].
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
For a long time, chloroquine (CQ) remained the antimalarial drug of choice due to its
high efficacy, low cost, and tolerable adverse effects. However, large scale use of CQ soon
led to the emergence of CQ-resistant parasite strains [2]. Many other alternative drugs
followed, including artemisinin combined therapies (ACTs), which for some time became
one of the most effective, especially against P. falciparum, allowing millions of patients to be
Copyright:
© 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
cured [
1–
3,
6–8]. However, recent evidence of resistance to artemisinin reported in South
Asia and along the Cambodia–Thailand border threatens this strategy [
9
]. Indeed, as soon
as a new drug is introduced, it is just a matter of time before resistance appears. Under
these circumstances, there is need to be one step ahead of the malaria parasite by designing
Molecules 2021, 26, 4093. https://doi.org/10.3390/molecules26134093
https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 4093
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new strategies in the fight against this pathology. Hence, multi-target hybrid drugs are
needed as an alternative or compliment to existing therapies.
Molecular hybridization (MH) is a strategy of rational design of new ligands or pro-
totypes based on the recognition of pharmacophoric subunits in the molecular structure
of two or more known bioactive derivatives which through the adequate fusion of these
subunits, leads to the formation of new hybrid architectures that maintain pre-selected
characteristics of the original templates [8,10,11]. Hybrid drugs are designed to counterbal-
ance the known side effects associated with the other hybrid part or to augment its effect
through action on another biological target or to interact with multiple targets as one single
molecule, lowering the risk of drug-drug interactions and surmount drug resistance [11].
Over the last few years, molecular hybridization has emerged as a novel approach that
involves a combination of pharmacophoric elements which are so far known for different
enzyme inhibition, leading to active compounds which show a balanced inhibition of en-
zyme and offers the opportunity to treat different diseases with better tolerated drugs, thus
enhancing patient compliance [11]. We therefore sought to apply this concept of molecular
hybridization in the design and synthesis of new hybrid compounds based on new hybrid
compounds based on the quinoline and chalcone privileged scaffolds connected by an
aminoalkylsulphonamide linker.
Privileged structures are core structural units known for binding to proteins, and
which can be coupled to other active molecules to generate potential new drugs. 1,3-
Diarylprop-2-en-1-ones or benzalacetophenones commonly known as chalcones belong
to an important class of natural products widely distributed in the plant kingdom. They
display an array of biological activities [12] such as antifungal [13], antiparasitic [14], anti-
tumor and antioxidant [15], immunomodulatory [16] antileishmania [17], antimitotic [18],
anti-invasive [19
,20], anti-inflammatory [21,22] and antimalarial [23,24]. Licochalcone
(Figure 1 ), for example, is a natural compound isolated from Chinese liquorice roots,
I
which has shown potent antiplasmodial activity [25]. Due to this broad range of biological
activities, the chalcone molecule is one of the templates extensively used in molecular
hybridization. When combined with quinolines, chalcones may be expected to exhibit high
antiplasmodial activity.
Of the several antimalarial compounds described in literature, quinoline derivatives
are still the dominant class [7]. Furthermore, the diverse pharmacological properties
of the quinoline scaffold and derivatives attracted worldwide attention in the last few
decades because of their wide occurrence in natural products, and drugs [26]. Synthetic
hybrid compounds have been designed to increase the efficacy of quinoline derivatives
because the antimalarial hybrid drugs have a lower risk of drug–drug adverse interac-
tions and greater treatment adherence than the combined drugs. Some of the quinoline
derivatives shown in Figure 1 have reached the stage of clinical trials. They include
chalcone–chloroquinoline (II) [8], AZT–CQ (III) [27], quinine–dihydroartemisinin (IV) [28]
and artesunate–mefloquine MEFAS (V) [7].
Quinoline–sulfonamide hybrid compounds such as those in Figure 2, which contain
various linker groups connecting arylsulfonamide moieties to the aminoquinoline molecule,
have been reported as potential antimalarial drugs [7,29–33]. Though most of them were
less active when compared to chloroquine, they showed good antimalarial activity, acting
by inhibiting parasite growth without interfering with the integrity of the red blood cell
membrane [29].

Molecules 2021, 26, 4093
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Figure 1. Structures of licochalcone (I) and molecular hybrids II–V.
O
S
O
O
S
O
RHN
O
NHR
HN
N
HN
n
S
O
R
HN
Cl
Cl
N
(VI)
(VII)
Cl
N
O
S
O
(VIII)
NH2
O
R
S
HN
R
HN
O
Cl
N
Cl
N
(IX)
(X)
Figure 2. Representative quinoline–sulfonamide molecular hybrids VI–X.

Molecules 2021, 26, 4093
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Based on the above properties and literature precedents, we sought in this study to
synthesize molecular hybrids comprising of a quinoline–sulfonamide and the relevant
chalcones as potential antiplasmodial agents.
2. Results
2.1. Chemistry
The synthesis of molecular hybrids was carried out in three consecutive steps as
outlined in Scheme 1. In a first step, the nucleophilic aromatic substitution reaction (SNAr)
between 4,7-dichloroquinoline and the relevant diamines (n = 2 and 3) afforded the corre-
sponding N-(7-chloroquinol-4-yl) alkyldiamines
respectively) [ 34], which were condensed with 4-acetylbenzenesulfonyl chloride in the
presence of NaOH to afford 4-acetyl-N-(2-[(7-chloroquinolin-4-yl)amino]alkyl)benzenesulfo-
namides and in moderate yields (29 and 41%, respectively). Finally, a base-catalyzed
2 and 3 in excellent yields (89% and 95%,
7,
4
5
Claisen-Schmidt coupling of these intermediates with various aryl aldehydes led to the
expected molecular hybrids in 11%–96% yield. Table 1 summarizes the overall results
in these reactions. Except for compounds 11, 12, 14, 18, 23, and 25, good to excellent
yields were obtained in the condensation step. Only trans isomers of the chalcone moiety
were obtained as confirmed by the coupling constant between the two olefinin protons
(~15.65 Hz in all cases).
Table 1. Hybrid compounds with isolated yields.
Compound
n
Ar
Yield (%)
4
5
6
7
8
9
2
3
3
3
3
3
3
3
3
3
3
3
3
2
3
2
3
3
2
3
2
2
3
3
-
-
Ph
29
41
72
59
78
61
70
35
20
65
11
66
76
89
38
45
66
50
56
31
71
39
66
96
4-Me-Ph
2-Br-Ph
4-F-Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
2,6-F2-Ph
4-Cl-Ph
4-OMe-Ph
3,4-F2-Ph
3,4-(OMe)2-Ph
2-F-Ph
3,4,5-(OMe)3-Ph
4-OMe-Ph
2,4-F2-Ph
3,4-(OMe)2-Ph
2,5-F2-Ph
2-furanyl
4-Me-Ph
ferrocenyl
4-F-Ph
2-Cl-Ph
3,4-OCH2O-Ph
4-OCF3-Ph

Molecules 2021, 26, 4093
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Scheme 1. Synthesis of molecular hybrids 1–2. Reagents and conditions: (i) appropriate diamine, reflux, 16 h; (ii) 4-
acetylbenzenesulfonyl chloride, dioxane, NaOH, rt, 24 h; (iii) benzaldehyde derivative, MeOH, NaOH, reflux overnight.
2.2. In-Vitro Antiplasmodial Activity Evaluation
All the synthesized molecular hybrids (6–27) were evaluated for in vitro antiplas-
modial activity against the drug-sensitive strain (NF54) of P. falciparum and for cytotoxicity
against the Chinese Hamster Ovary (CHO) mammalian cell line using emetine as a refer-
ence drug. Aqueous solubility was determined at pH 6.5 (Table 2).
Table 2. In vitro antiplasmodial activity, solubility, and cytotoxicity of the hybrid compounds.
Solubility b
PfNF54
CHO
SI d
Compound
n
Ar
(µM)
pH 6.5
IC50 (µM) a
IC50 (µM) c
Chloroquine
Emetine
-
-
0.011
-
-
0.0034
26.32
>50
4
5
6
7
8
9
10
2
3
3
3
3
3
3
-
-
Ph
0.45
0.48
1.67
0.37
0.10
0.28
0.54
200
<5
ND
130
ND
<5
58.4
>104
>29
67.8
435
52.5
51.1
>50
4-Me-Ph
2-Br-Ph
4-F-Ph
2,6-F2-Ph
25.08
43.25
14.65
27.62
<5

Molecules 2021, 26, 4093
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Table 2. Cont.
Solubility b
(µM)
PfNF54
CHO
SI d
Compound
n
Ar
IC50 (µM) a
IC50 (µM) c
pH 6.5
11
12
13
14
15
3
3
3
3
3
4-Cl-Ph
4-OMe-Ph
3,4-F2-Ph
3,4-(OMe)2-Ph
2-F-Ph
2,3,4-(OMe)3-
Ph
0.10
0.11
2.58
0.32
0.86
ND
ND
<5
ND
5
41.2
43.3
>300
43.4
416.2
393.6
>116
135.6
52.9
45.53
16
3
0.58
15
22.62
39.0
17
18
19
20
21
22
23
24
25
26
27
a
2
3
2
3
3
2
3
2
2
3
3
4-OMe-Ph
2,4-F2-Ph
3,4-(OMe)2-Ph
2,5-F2-Ph
2-furanyl
4-Me-Ph
ferrocenyl
4-F-Ph
2-Cl-Ph
0.49
0.50
0.33
0.79
4.45
0.39
1.53
0.57
0.37
0.69
0.51
185
130
ND
17.53
22.44
45.1
43.7
>50
35.7
45.2
136.7
55.3
>11
63.8
ND
25.5
95.7
49.5
86.3
200
190
ND
<5
19
200
ND
24.89
14.54
35.41
34.13
44.04
3,4-OCH2O-Ph
4-OCF3-Ph
b
Mean from n values of
≥
2 independent experiments with sensitive (NF54) strains of P. falciparum; Aqueous solubility using high-
performance liquid chromatography (HPLC)-diode array detector (DAD)-mass spectrometry (MS); c CHO = Chinese hamster ovarian cell
line; d selectivity index (SI) = (IC50 (CHO)/IC50 (PfNF54)). ND = not determined.
3. Discussion
All synthesized compounds presented good activity with IC50 values ranging from
0.10 to 4.45 µM against the NF54 sensitive strain of P. falciparum.
Compared to the unsubstituted molecular hybrid
derivatives 15, and 24 are all more active (with IC50 (NF54) values of 0.28, 0.86, and
0.57 M, respectively), suggesting the importance of electronic effects brought about by
the more electronegative fluorine atom. The same trend can be noted with other halogens,
such as bromine (compound ; IC50 = 0.10 M), chlorine (compound 11, IC50 = 0.10 M),
as well as a methoxy group (compound 12, IC50 = 0.11 M). Compounds 8, 11, and 12
were the most active, displaying IC50 values of 0.10, 0.10, and 0.11 M, respectively. These
6 (IC50 = 1.67µM), fluoro-substituted
9,
µ
8
µ
µ
µ
µ
compounds were further tested against the multi-drug resistant K1 strain of P. falciparum.
Compound 12 showed about two-fold improvement in resistivity index ((RI = 5.36), PfK1
IC50 = 0.59
µM) relative to CQ, making it the frontrunner compound in the present study.
Meanwhile, compounds
8
and 11 were less active against the K1 strain with IC50 values of
2.97 µM and 6 µM, respectively.
In accordance with literature precedents [7], compounds with three methylene groups
(n = 3) as linker showed greater activity against P. falciparum than those with two methylene
groups (n = 2). Indeed, the introduction of an additional CH2 group (n = 3) in compound
12 enhances its potency approximately five-fold as compared to compound 17 (n = 2),
while a two-fold increase is noticed going from compound
24 n = 3, 0.57 M). In addition, almost all molecular hybridscontaining three methylene
groups as linker (7–12 14–20) were amongst the most active of the series, with IC50 values
9 (n = 2, 0.28 µM) to compound
(
µ
,
ranging from 0.10–0.86 µM.
The less polar methyl group has very little effect on the activity as is observed in
compounds 7 and 22 which both have a methyl group in para position and exhibited the
same activity (IC50 = 0.37 µM and 0.39 µM, respectively).
Compounds 21 and 23, respectively, containing a 2-furanyl and ferrocenyl as the
aromatic rings are among the less active, suggesting the importance of the chalcone unit in
the overall activity of the molecule.

Molecules 2021, 26, 4093
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Except for compounds
7
,
17
,
18
,
22, and 26, most compounds were poorly soluble
(
<5 µM). As previously noted, a methyl group has no significant effect on the activity but
its presence in compounds and 22 significantly increases the solubility (130 and 190 M,
respectively) most likely by the disruption of the crystalline packing [35 36]. The high
solubility of compounds 17 and 26 (185 and 200 M) may be attributed to a combination of
7
µ
,
µ
steric and polar effect of the electronegative oxygen atoms.
4. Materials and Methods
4.1. General
All commercially available chemicals were purchased from local chemical suppliers.
Analytical thin-layer chromatography (TLC) was performed on aluminium-backed silica-
gel 60 F254 (70–230 mesh) plates. Flash column chromatography was performed with Merck
silica-gel 60 (70–230 mesh) on a Biotage Isolera
Products were characterized by 1H- and 13C-NMR spectra recorded on a 300 MHz, 400 MHz
or 600 MHz Varian or Bruker NMR spectrometers. Chemical shifts ( ) are given in ppm
™ system (Biotage AB, Uppsala, Sweden).
δ
downfield from trimethylsilane (TMS) as the internal standard. Coupling constants (J), are
recorded in hertz (Hz). Purity was determined by HPLC. The NMR spectra and HPLC-MS
spectra of compounds described in this study can be found in Supplementary Materials.
Aqueous solubility. Water solubility was analyzed using a miniaturized shake flask
method. Ten millimolar stock solutions of each of the compounds were used to prepare
calibration standards (10 220 µM) in DMSO. The same 10 mM stock solutions were
−
accurately dispensed in duplicate into 96-well plates, and the DMSO, dried down (MiVac
◦
GeneVac,90 min, 37 C). Thereafter, the samples were reconstituted (200
µM) in an aqueous
solution and shaken (20 h, 25 ◦C). The solutions were analyzed by means of HPLC-DAD
(Agilent1200 Rapid Resolution HPLC with a diode array detector). Best fit calibration
curves were constructed using the calibration standards, which were used to determine
the aqueous samples’ solubility [1,37].
In-vitro anti-plasmodium assay. Compounds were tested using parasite lactate de-
hydrogenase assay as a marker for parasite survival. The respective stock solutions of
CQ diphosphate and test compounds were prepared by dissolving 2 mg/mL in distilled
water (for CQ) and 100% DMSO for test compounds. The solutions were then stored
◦
at
−
20 C, with further dilutions prepared on the day of the experiment. The cultures
were synchronized in the ring stage as described previously using 15 mL of 5% (w/v)
d-sorbitol in water. Synchronous cultures of PfNF54 (CQS) in the late trophozoite stage
were prepared to 2% parasitemia and 2% hematocrit. Compounds were tested at starting
concentrations of 10 000 ng/mL (1000 ng/mL for CQ), which were then serially diluted
two-fold in complete medium to give 10 concentrations with a final volume of ◦200
µL
in each well. Parasites were incubated in the presence of the compounds at 37 C in a
specialized atmosphere of 4% CO2 and 3% O2 in nitrogen for 48 h. Following incubation,
100
µL of MalStat reagent and 15
µL of resuspended culture were combined, followed by
addition of 25
µL of nitro blue tetrazolium chloride (NBT). The plates were kept in the dark
for about 10 min to fully develop, and absorbance was measured at 620 nm on a microplate
reader. Raw data were exported to Microsoft Excel for dose-response analysis [1,37].
Cytotoxicity assay. Compounds were screened for in vitro cytotoxicity against Chi-
nese hamster ovarian (CHO) mammalian cell lines, using the 3-(4,5-dimethylthiazol-2-
yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The reference standard, emetine, was
prepared to 2 mg/mL in distilled water while stock solutions of test compounds were pre-
pared to 20 mg/mL in 100% DMSO with the highest concentration of solvent to which the
cells were exposed having no measurable effect on the cell viability. The initial concentra-
tion of the compounds and control was 100
medium with 10-fold dilutions to give six concentrations, the lowest being 0.001
Plates were incubated for 48 h with 100 L of drug and 100 L of cell suspension in each
well and developed afterward by adding 25 L of sterile MTT (Thermo Fisher Scientific) to
each well, followed by 4 h of incubation in the dark. The plates were then centrifuged; the
µg/mL, which was serially diluted in complete
µg/mL.
µ
µ
µ

Molecules 2021, 26, 4093
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medium was aspirated, and 100
µL of DMSO was added to dissolve crystals before reading
the absorbance at 540 nm. Data were analyzed, and the sigmoidal dose-response was
derived using GraphPad Prism v 4.0 software (La Jolla). All experiments were performed
for at least three independent biological repeats, each with technical triplicates [1].
4.2. Experimental Section
General procedure for preparing 4-acetyl-N-(((7-chloroquinolin-4-yl)amino)alkyl) ben-
zenesulfonamides
4
and
5: 4-acetylbenzenesulfonyl chloride was treated with the respective
N-(7-chloroquinolin-4-yl) alkyldiamine (
2
or ) in 7.5 mL dioxane as solvent and 2.5 mL
3
10 M NaOH. The reaction mixture was stirred at room temperature for 24 h and poured
into 50 mL of ice-cold water. The precipitate was filtered, dried and the crude product
purified using Biotage Isolera One® column chromatography in a gradient mixture of
CH2Cl2/MeOH. Fractions were monitored and collected at 254 and 280 nm. The solvent of
the combined fractions was removed under reduced pressure to afford compounds
as white solids in 27 and 41% yield, respectively.
4 and 5
4-acetyl-N-(2-((7-chloroquinolin-4-yl)amino)ethyl)benzenesulfonamide (
27%); m.p. 200–204 ◦C; Rf = 0.61 (MeOH-CH2Cl2 1:9); 1H NMR (600 MHz, DMSO-d6)
8.35 (d, J = 5.4 Hz, 1H), 8.09 (d, J = 9.1 Hz, 1H), 8.01 (t, J = 5.7 Hz, 1H), 7.99–7.94 (m, 2H),
7.90–7.84 (m, 2H), 7.75 (d, J = 2.2 Hz, 1H), 7.43 (dd, J = 9.0, 2.3 Hz, 1H), 7.23 (t, J = 5.8 Hz
1H), 6.40 (d, J = 5.5 Hz, 1H), 3.37 (q, J = 6.3 Hz, 2H), 3.10 (t, J = 6.1 Hz, 2H), 2.56 (s, 3H). 13
NMR (151 MHz, DMSO-d6) 197.48, 152.10, 150.20, 149.24, 144.55, 139.67, 133.99, 129.31,
4); white solid (0.97 g,
δ
,
C
δ
127.81, 127.15, 124.63, 124.38, 117.81, 99.02, 42.46, 41.26, 27.34; HPLC-MS (APCI/ESI):
Purity = 80%. tR = 0.898 min, calcd. m/z = 403.88, m/z [M]+ = 404.0.
4-acetyl-N-(3-((7-chloroquinolin-4-yl)amino)propyl)benzenesulfonamide (
5
); white solid
(0.144 g, 41%); m.p. 181–183 C; Rf = 0.46 (MeOH-CH2Cl2,1:9); 1H NMR (600 MHz, DMSO-
d6) 8.36 (d, J = 5.4 Hz, 1H), 8.19 (d, J = 9.0 Hz, 1H), 8.08–8.03 (m, 2H), 7.92–7.84 (m,
◦
δ
3H), 7.77 (d, J = 2.2 Hz, 1H), 7.43 (dd, J = 9.0, 2.3 Hz, 1H), 7.21 (t, J = 5.5 Hz, 1H), 6.38 (d,
J = 5.5 Hz, 1H), 3.24 (td, J = 6.9, 5.3 Hz, 2H), 2.97–2.90 (m, 2H), 2.59 (s, 3H), 1.77 (p, J = 7.0 Hz,
2H). 13C NMR (151 MHz, DMSO-d6)
δ 197.64, 152.17, 150.45, 149.33, 144.60, 139.79, 133.90,
129.41, 127.83, 127.24, 124.55, 124.49, 117.85, 99.14, 40.57, 40.31, 28.22, 27.41; HPLC-MS
(APCI/ESI): Purity = 100%. tR = 2.186 min, calcd. m/z = 417.91, m/z [M]+ = 418.0.
General procedure for the synthesis of molecular hybrids 6–27: To a solution of chloro-
quinolinesulfonamide (4 or 5) and aryl aldehyde derivatives in methanol (2 mL), NaOH
(24 mg, 6 mmoles, 2.5 equiv.) was added. The reaction mixture was stirred under reflux
overnight. The product was purified using Biotage Isolera One ® column chromatography
in a gradient mixture of CH2Cl2/MeOH. Fractions were monitored and collected at 254
and 280 nm. The solvent of the combined fractions was removed under reduced pressure.
In some cases, the products were further purified by recrystallization in CH2Cl2 and MeOH
to afford crystalline solids with 11–88% yield.
N-(3-((7-chloroquinolin-4-yl)amino)propyl)-4-cinnamoylbenzenesulfonamide (
6
); white solid
(0.087 g, 72%); m.p. 210–212 C; Rf = 0.39 (MeOH-CH2Cl2, 1:9); H NMR (600 MHz,
DMSO-d6) 8.37 (d, J = 5.4 Hz, 1H), 8.28–8.23 (m, 2H), 8.21 (d, J = 9.1 Hz, 1H), 7.97–7.92 (m,
2H), 7.92–7.88 (m, 3H), 7.88 (d, J = 13.5 Hz, 1H), 7.78 (d, J = 15.7 Hz, 1H), 7.76 (d, J = 2.2 Hz
◦
1
δ
,
1H), 7.64–7.58 (m, 1H), 7.53–7.46 (m, 2H), 7.46–7.36 (m, 1H), 7.30 (t, J = 5.4 Hz, 1H), 6.40
(d, J = 5.5 Hz, 1H), 3.25 (q, J = 6.6 Hz, 2H), 2.96 (q, J = 6.7 Hz, 2H), 1.79 (p, J = 7.0 Hz,
2H). 13C NMR (151 MHz, DMSO-d6)
δ 188.99, 167.83, 151.87, 150.65, 145.48, 144.52, 140.76,
134.96, 134.06, 133.24, 131.39, 129.77, 129.71, 127.55, 127.31, 124.64, 124.54, 122.35, 117.79,
99.14, 41.01, 40.56, 28.25; HPLC-MS (APCI/ESI): Purity = 100%. tR = 2.470 min, calcd.
m/z = 506.0, m/z [M]+ = 506.0.
(E)-N-(3-((7-chloroquinolin-4-yl)amino)propyl)-4-(3-(p-tolyl)acryloyl)benzenesulfonamide (
7
);
white solid (0.0738 g, 59%); m.p. 209–213 C; Rf = 0.48 (MeOH-CH2Cl2, 1:9); H NMR
(600 MHz, DMSO-d6) 8.36 (d, J = 5.4 Hz, 1H), 8.27–8.22 (m, 2H), 8.20 (d, J = 9.0 Hz, 1H),
◦
1
δ
7.96–7.91 (m, 2H), 7.89 (t, J = 5.8 Hz, 1H), 7.83 (d, J = 15.6 Hz, 1H), 7.81–7.78 (m, 2H),
7.78–7.73 (m, 2H), 7.42 (dd, J = 9.0, 2.2 Hz, 1H), 7.30 (d, J = 7.9 Hz, 2H), 7.23 (t, J = 5.4 Hz,

Molecules 2021, 26, 4093
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1H), 6.39 (d, J = 5.5 Hz, 1H), 3.24 (t, J = 6.5 Hz, 2H), 2.96 (q, J = 6.7 Hz, 2H), 2.37 (s, 3H),
1.79 (q, J = 7.0 Hz, 2H). 13C NMR (151 MHz, DMSO-d6)
δ 188.92, 152.13, 150.50, 149.28,
145.58, 144.43, 141.57, 140.90, 133.92, 132.26, 130.06, 129.71, 129.57, 127.79, 127.29, 124.56,
124.49, 121.28, 117.85, 99.15, 41.03, 40.17, 28.27, 21.60; HPLC-MS (APCI/ESI): Purity = 100%,
tR = 2.528 min, calcd. m/z = 520.0, m/z [M]+ = 520.1.
(E)-4-(3-(2-bromophenyl)acryloyl)-N-(3-((7-chloroquinolin-4-yl)amino)propyl)benzenesulfon-
amide (
NMR (600 MHz, DMSO-d6)
8
); white solid (0.1089 g, 78%); m.p. 211–213 ◦C; Rf = 0.48 (MeOH-CH2Cl2, 1:9); 1H
δ
8.36 (d, J = 5.4 Hz, 1H), 8.28–8.24 (m, 2H), 8.23–8.16 (m, 2H),
8.02 (d, J = 15.5 Hz, 1H), 7.95 (s, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.92–7.85 (m, 2H), 7.80–7.72
(m, 2H), 7.56–7.49 (m, 1H), 7.49–7.39 (m, 2H), 7.26–7.16 (m, 1H), 6.44–6.36 (m, 1H), 3.24 (q,
mboxemphJ = 6.5 Hz, 2H), 2.96 (q, J = 6.6 Hz, 2H), 1.77 (h, J = 7.1 Hz, 2H). 13C NMR
(151 MHz, DMSO-d6) δ 188.25, 151.78, 151.75, 149.91, 148.95, 144.22, 142.09, 139.90, 133.74,
133.33, 132.42, 129.39, 128.82, 128.24, 127.40, 126.82, 125.50, 124.62, 124.05, 123.95, 117.36,
98.64, 40.50, 40.46, 27.71; HPLC-MS (APCI/ESI): Purity = 100%. tR = 2.530 min, calcd. m/z
= 584.9, m/z [M + H]+ = 585.9.
(E)-N-(3-((7-chloroquinolin-4-yl)amino)propyl)-4-(3-(4-fluorophenyl)acryloyl)benzenesulfon-
amide (
NMR (600 MHz, DMSO-d6)
9
); white solid (0.0763 g, 61%); m.p. 216–218 ◦C; Rf = 0.46 (MeOH-CH2Cl2, 1:9); 1H
δ
8.37 (d, J = 5.5 Hz, 1H), 8.27–8.23 (m, 2H), 8.21 (d, J = 9.0 Hz,
1H), 8.02–7.73 (m, 8H), 7.44 (dd, J = 8.9, 2.2 Hz, 1H), 7.35–7.28 (m, 3H), 6.41 (d, J = 5.5 Hz,
1H), 3.26 (q, J = 6.5 Hz, 2H), 2.96 (q, J = 6.6 Hz, 2H), 1.78 (p, J = 7.0 Hz, 2H). 13C NMR
(151 MHz, DMSO-d6)
δ 188.86, 164.04 (d, JC-F = 249.6 Hz), 151.65, 150.78, 144.52, 144.23,
140.73, 134.17, 131.95, 131.93 (d, JC-F = 8.5 Hz), 131.68, 129.77, 127.34, 127.30, 124.71, 124.57,
122.23, 117.74, 116.47 (d, JC-F = 21.8 Hz), 99.14, 41.00, 40.23, 28.24. HPLC-MS (APCI/ESI);
Purity = 100%, tR = 2.476 min, calcd. m/z = 524.0, m/z [M]+ = 524.0.
(E)-N-(3-((7-chloroquinolin-4-yl)amino)propyl)-4-(3-(2,6-difluorophenyl)acryloyl)benzenesulf-
onamide (10); white solid (0.1216 g, 70%); m.p. 223–225 ◦C; Rf = 0.44 (MeOH-CH2Cl2, 1:9);
1H NMR (600 MHz, DMSO-d6)
δ
8.34 (d, J = 5.3 Hz, 1H), 8.17 (d, J = 9.0 Hz, 1H), 8.15–8.11
(m, 2H), 7.97–7.92 (m, 2H), 7.90 (q, J = 5.5 Hz, 1H), 7.77 (s, 1H), 7.75–7.68 (m, 2H), 7.59 (tt,
J = 8.2, 6.4 Hz, 1H), 7.40 (dd, J = 9.0, 2.3 Hz, 1H), 7.27 (t, J = 8.8 Hz, 2H), 7.16 (t, J = 5.5 Hz
1H), 6.37 (d, J = 5.4 Hz, 1H), 3.23 (q, J = 6.5 Hz, 2H), 2.96 (q, J = 6.5 Hz, 2H), 1.78 (p,
J = 6.9 Hz, 2H). 13C NMR (151 MHz, DMSO-d6)
188.48, 161.10 (d, JC-F = 253.9 Hz), 151.81,
,
δ
149.92, 148.98, 144.27, 139.69, 133.32, 132.89 (t, JC-F = 11.2 Hz), 130.08, 129.20, 127.42, 127.17,
126.99, 124.02, 123.98, 117.39, 112.49, 112.32 (d, JC-F = 21.7 Hz), 98.63, 40.49, 40.04, 27.78.
HPLC-MS (APCI/ESI); Purity = 100%, tR = 2.477 min, calcd. m/z = 542.0, m/z [M]+ = 542.0.
(E)-4-(3-(4-chlorophenyl)acryloyl)-N-(3-((7-chloroquinolin-4-yl)amino)propyl)benzenesulfon-
amide (11); white solid (0.045 g, 35%); m.p. 222–225 ◦C; Rf = 0.47 (MeOH-CH2Cl2, 1:9); 1H
NMR (600 MHz, DMSO-d6)
δ 8.35 (d, J = 5.3 Hz, 1H), 8.27–8.23 (m, 2H), 8.18 (d, J = 9.0 Hz,
1H), 7.95 (s, 1H), 7.96–7.88 (m, 5H), 7.77 (d, J = 15.7 Hz, 1H), 7.74 (d, J = 2.2 Hz, 1H),
7.57–7.52 (m, 2H), 7.41 (dd, J = 9.0, 2.3 Hz, 1H), 7.18 (t, J = 5.4 Hz, 1H), 6.37 (d, J = 5.4 Hz,
1H), 3.23 (q, J = 6.5 Hz, 2H), 2.96 (t, J = 6.9 Hz, 2H), 1.78 (p, J = 7.0 Hz, 2H). 13C NMR
(151 MHz, DMSO-d6) δ 188.36, 151.80, 149.87, 148.98, 144.08, 143.44, 140.11, 135.37, 133.44,
133.32, 130.69, 129.30, 128.96, 127.45, 126.79, 123.99, 123.93, 122.54, 117.37, 98.63, 48.55,
40.51, 27.73; HPLC-MS (APCI/ESI): Purity = 100%. tR = 2.527 min, calcd. m/z = 540.4,
m/z [M]+ = 540.0.
(E)-N-(3-((7-chloroquinolin-4-yl)amino)propyl)-4-(3-(4-methoxyphenyl)acryloyl)benzenesulf-
onamide (12); white solid (0.0261 g, 20%); m.p. 221–223 ◦C; Rf = 0.45 (MeOH-CH2Cl2, 1:9);
1H NMR (600 MHz, DMSO-d6)
δ 8.36 (d, J = 5.4 Hz, 1H), 8.25–8.21 (m, 2H), 8.19 (d,
J = 9.0 Hz, 1H), 7.98–7.91 (m, 2H), 7.91–7.84 (m, 3H), 7.75 (d, J = 3.0 Hz, 3H), 7.42 (dd,
J = 9.0, 2.3 Hz, 1H), 7.20 (t, J = 5.5 Hz, 1H), 7.06–7.01 (m, 2H), 6.38 (d, J = 5.4 Hz, 1H),
3.83 (s, 3H), 3.26–3.21 (m, 2H), 2.96 (q, J = 6.6 Hz, 2H), 1.78 (p, J = 7.0 Hz, 2H). 13C NMR
(151 MHz, DMSO-d6) δ 188.29, 161.63, 151.76, 149.93, 148.92, 145.05, 140.62, 133.38, 131.88,
131.00, 129.14, 127.40, 127.11, 126.77, 124.04, 123.96, 119.30, 117.37, 114.46, 98.65, 55.40, 54.85,
40.53, 27.76; HPLC-MS (APCI/ESI): Purity = 100%. tR = 2.471 min, calcd. m/z = 536.04,
m/z [M]+ = 536.1.

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(E)-N-(3-((7-chloroquinolin-4-yl)amino)propyl)-4-(3-(3,4-difluorophenyl)acryloyl)benzenesul-
◦
fonamide (13); light yellow solid (0.0651 g, 38%); m.p. 212–214 C; Rf = 0.43 (MeOH-CH2Cl2,
1:9); H NMR (600 MHz, DMSO-d6)
1
δ 8.35 (d, J = 5.4 Hz, 1H), 8.28–8.23 (m, 2H), 8.18
(d, J = 9.1 Hz, 1H), 8.13 (ddd, J = 12.1, 7.9, 2.1 Hz, 1H), 7.96–7.88 (m, 4H), 7.78–7.72 (m,
3H), 7.54 (dt, J = 10.6, 8.5 Hz, 1H), 7.41 (dd, J = 9.0, 2.3 Hz, 1H), 7.20 (t, J = 5.4 Hz,
1H), 6.37 (d, J = 5.4 Hz, 1H), 3.24 (q, J = 6.5 Hz, 2H), 2.97 (q, J = 6.5 Hz, 2H), 1.78 (p,
J = 7.0 Hz, 2H). 13C NMR (151 MHz, DMSO-d6)
δ 188.22, 151.71, 151.67, 149.9 (d, JC-F
=10.9 Hz), 148.92 (d, JC-F = 13.3 Hz), 142.59, 140.01, 132.44 (d, JC-F = 2.8 Hz), 129.51,
129.34, 127.36, 127.0 (d, JC-F = 3.4 Hz), 126.98 (d, JC-F =6.9 Hz), 123.95, 123.01, 118.06,118.0
(d, JC-F = 17.4 Hz), 117.98, 117.35, 117.26, 117.08, 98.63, 40.51, 40.04, 27.73; HPLC-MS
(APCI/ESI): Purity = 100%. tR = 2.475 min, calcd. m/z = 542.11, m/z [M]+ = 542.0.
(E)-N-(3-((7-chloroquinolin-4-yl)amino)propyl)-4-(3-(3,4-dimethoxyphenyl)acryloyl)benzene-
sulfonamide (14); white solid (0.0146 g, 11%); m.p. 222–224 ◦C; Rf = 0.37 (MeOH-CH2Cl2,
1
1:9); H NMR (600 MHz, DMSO-d6)
δ 8.36 (d, J = 5.4 Hz, 1H), 8.26–8.22 (m, 2H), 8.19
(d, J = 9.0 Hz, 1H), 7.96–7.91 (m, 2H), 7.89 (t, J = 5.7 Hz, 1H), 7.80–7.71 (m, 3H), 7.55 (d,
J = 2.0 Hz, 1H), 7.45–7.39 (m, 2H), 7.20 (t, J = 5.5 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.38 (d, J
= 5.5 Hz, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.24 (q, J = 6.5 Hz, 2H), 2.96 (q, J = 6.6 Hz, 2H), 1.78
(p, J = 7.0 Hz, 2H). 13C NMR (151 MHz, DMSO-d6)
δ 188.33, 151.76, 151.58, 149.92, 149.03,
148.92, 145.57, 143.79, 140.67, 133.36, 129.14, 127.39, 127.29, 126.74, 124.25, 124.03, 123.95,
119.38, 117.37, 111.59, 110.96, 98.65, 55.75, 55.62, 40.52, 40.04, 27.76; HPLC-MS (APCI/ESI):
Purity = 100%. tR = 2.417 min, calcd. m/z = 566.07, m/z [M]+ = 566.1.
(E)-N-(3-((7-chloroquinolin-4-yl)amino)propyl)-4-(3-(2-fluorophenyl)acryloyl)benzenesulfona-
◦
mide (15); white solid (0.1093 g, 65%); m.p. 223–225 C; Rf = 0.40 (MeOH-CH2Cl2, 1:9);
1H NMR (600 MHz, DMSO-d6)
δ 8.35 (d, J = 5.5 Hz, 1H), 8.25–8.22 (m, 2H), 8.22–8.16
(m, 1H), 8.14–8.06 (m, 1H), 7.94 (dd, J = 7.6, 5.9 Hz, 2H), 7.92–7.81 (m, 3H), 7.78–7.70
(m, 1H), 7.58–7.49 (m, 1H), 7.41 (dd, J = 9.0, 2.3 Hz, 1H), 7.37–7.31 (m, 2H), 7.24–7.16 (m,
1H), 6.37 (d, J = 5.4 Hz, 1H), 3.24 (p, J = 6.5, 6.1 Hz, 2H), 2.96 (q, J = 6.5 Hz, 2H), 1.78 (p,
J = 7.1 Hz, 2H). 13C NMR (151 MHz, DMSO-d6)
δ 188.31, 160.98 (d, JC-F = 252.0 Hz), 151.81,
149.93, 148.98, 144.20, 139.95, 136.08, 133.36, 132.99,132.96 (d, JC-F = 8.8 Hz), 129.29 (d,
JC-F = 3.0 Hz), 127.42, 127.38 (d, JC-F = 9.4 Hz), 127.01, 126.75, 124.98 (d, JC-F = 3.3 Hz),
124.03, 122.07, 117.40, 116.11 (d, JC-F = 21.5 Hz), 98.67, 40.51, 40.04, 27.72. HPLC-MS
(APCI/ESI); Purity = 100%, tR = 2.444 min, calcd. m/z = 524.0, m/z [M]+ = 524.1.
(E)-N-(3-((7-chloroquinolin-4-yl)amino)propyl)-4-(3-(3,4,5-t◦rimethoxyphenyl)acryloyl)benz-
enesulfonamide (16); white solid (0.1088 g, 76%); m.p. 197–200 C; Rf = 0.48 (MeOH-CH2Cl2,
1:9); 1H NMR (600 MHz, DMSO-d6)
δ 8.37 (d, J = 5.5 Hz, 1H), 8.24–8.18 (m, 3H), 7.96–7.91
(m, 3H), 7.89 (t, J = 5.8 Hz, 1H), 7.82–7.73 (m, 3H), 7.43 (dd, J = 9.0, 2.2 Hz, 1H), 7.30 (t,
J = 5.5 Hz, 1H), 6.95 (d, J = 8.9 Hz, 1H), 6.40 (d, J = 5.5 Hz, 1H), 3.89 (s, 3H), 3.88 (s, 3H),
3.78 (s, 3H), 3.25 (t, J = 6.5 Hz, 2H), 2.96 (q, J = 6.6 Hz, 2H), 1.78 (p, J = 7.0 Hz, 2H). 13
C
NMR (151 MHz, DMSO-d6) δ 188.88, 156.58, 153.74, 151.86, 150.66, 148.96, 144.32, 142.24,
141.13, 139.99, 134.06, 129.60, 127.54, 127.29, 124.65, 124.53, 124.19, 121.27, 120.66, 117.79,
109.00, 99.14, 62.03, 60.96, 56.62, 41.02, 40.57, 28.26; HPLC-MS (APCI/ESI): Purity = 100%,
tR = 2.459 min, calcd m/z = 596.1, m/z [M]+ = 596.0.
(E)-N-(2-((7-chloroquinolin-4-yl)amino)ethyl)-4-(3-(4-methoxyphenyl)acryloyl)benzenesulfo-
namide (17); yellow solid (0.1144 g, 89%); m.p. 222–225 ◦C; Rf = 0.38 (MeOH-CH2Cl2, 1:9);
1H NMR (600 MHz, DMSO-d6)
δ 8.36 (d, J = 5.3 Hz, 1H), 8.19–8.14 (m, 2H), 8.10 (d,
J = 9.0 Hz, 1H), 8.04 (t, J = 5.9 Hz, 1H), 7.94–7.89 (m, 2H), 7.89–7.83 (m, 2H), 7.78–7.72 (m,
2H), 7.70 (d, J = 15.6 Hz, 1H), 7.43 (dd, J = 9.0, 2.2 Hz, 1H), 7.23 (t, J = 5.7 Hz, 1H), 7.06–7.01
(m, 2H), 6.41 (d, J = 5.5 Hz, 1H), 3.83 (s, 3H), 3.38 (q, J = 6.3 Hz, 2H), 3.11 (q, J = 6.3 Hz,
2H). 13C NMR (151 MHz, DMSO-d6)
δ 188.64, 162.11, 152.19, 150.19, 149.36, 145.45, 144.25,
141.05, 133.96, 131.48, 129.56, 127.90, 127.63, 127.20, 124.62, 124.35, 119.78, 117.84, 114.95,
99.02, 55.91, 42.55, 41.29; HPLC-MS (APCI/ESI): Purity = 100%, tR = 2.440 min, calcd. m/z
= 522.12, m/z [M]+ = 522.0.
(E)-N-(3-((7-chloroquinolin-4-yl)amino)propyl)-4-(3-(2,4-difluorophenyl)acryloyl)benzenesu-
◦
lfonamide (18); light yellow solid (0.01118 g, 65%); m.p. 216–218 C; Rf = 0.39 MeOH-CH2Cl2,

Molecules 2021, 26, 4093
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1:9); 1H NMR (600 MHz, DMSO-d6)
δ
8.35 (dd, J = 5.4, 1.9 Hz, 1H), 8.25–8.16 (m, 3H), 8.07–
8.03 (m, 1H), 7.94 (d, J = 8.3 Hz, 1H), 7.94–7.86 (m, 2H), 7.82–7.72 (m, 2H), 7.46–7.37 (m,
2H), 7.29–7.19 (m, 2H), 6.38 (dd, J = 5.5, 2.2 Hz, 1H), 3.24 (t, J = 6.4 Hz, 2H), 2.98–2.90
(m, 2H), 1.77 (h, J = 6.8 Hz, 2H). 13C NMR (151 MHz, DMSO-d6)
δ 188.19, 162.54 (d,
JC-F = 100.6 Hz), 161.32 (d, JC-F = 242.3 Hz), 151.64, 151.62, 149.97, 148.80, 144.18, 143.95,
133.42, 130.31, 129.10 (d, JC-F = 58.9 Hz), 128.91, 126.73, 124.06, 123.98, 123.60, 118.97 (d,
JC-F = 3.7 Hz), 117.34, 112.65 (d, JC-F = 3.4 Hz), 112.50 (d, JC-F = 3.7 Hz), 98.64, 40.49,
39.90, 27.70; HPLC-MS (APCI/ESI): Purity = 96%, tR = 2.464 min, calcd. m/z = 541.99,
m/z [M]+ = 542.0.
(E)-N-(2-((7-chloroquinolin-4-yl)amino)ethyl)-4-(3-(3,4-dimethoxyphenyl)acryloyl)benzenes-
ulfonamide (19); yellow solid (0.0609 g, 45%); m.p. 223–225 ◦C; Rf = 0.44 (MeOH-CH2Cl2,
1
1:9); H NMR (600 MHz, DMSO-d6)
δ 8.36 (d, J = 5.4 Hz, 1H), 8.18 (d, J = 8.2 Hz, 2H),
8.09 (d, J = 9.0 Hz, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.77–7.71 (m, 3H), 7.54 (d, J = 2.0 Hz, 1H),
7.42 (ddd, J = 7.9, 5.9, 2.1 Hz, 2H), 7.22 (t, J = 5.8 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.41 (d,
J = 5.4 Hz, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 3.38 (q, J = 6.4 Hz, 2H), 3.17 (d, J = 4.7 Hz, 2H). 13
C
NMR (151 MHz, DMSO-d6) δ 188.24, 151.83, 151.79, 151.57, 149.65, 149.02, 145.49, 143.73,
140.64, 133.42, 129.08, 127.47, 127.31, 126.68, 124.33, 124.19, 123.83, 119.40, 117.35, 111.60,
110.98, 98.52, 55.75, 48.56, 42.04; HPLC-MS (APCI/ESI): Purity = 100%. tR = 2.387 min,
calcd. m/z = 552.04, m/z [M]+ = 552.1.
(E)-N-(3-((7-chloroquinolin-4-yl)amino)propyl)-4-(3-(2,5-difl◦uorophenyl)acryloyl)benzenesu-
lfonamide (20); light yellow solid (0.1134 g, 66%); m.p. 219–221 C; Rf = 0.39 (MeOH-CH2Cl2,
1:9); 1H NMR (600 MHz, DMSO-d6)
δ 8.35 (d, J = 5.5 Hz, 1H), 8.27–8.23 (m, 2H), 8.19 (d,
J = 9.0 Hz, 1H), 8.11–8.02 (m, 1H), 7.99 (d, J = 15.7 Hz, 1H), 7.95–7.87 (m, 2H), 7.79 (dd,
J = 15.8, 1.4 Hz, 1H), 7.77–7.71 (m, 1H), 7.46–7.37 (m, 3H), 7.24 (t, J = 5.5 Hz, 1H), 6.38 (d,
J = 5.5 Hz, 1H), 3.24 (q, J = 6.6 Hz, 2H), 2.97 (q, J = 6.6 Hz, 2H), 1.78 (p, J = 7.0 Hz, 2H). 13
C
NMR (151 MHz, DMSO-d6) δ 188.07, 158.59 (d, JC-F = 180.3 Hz), 156.97 (d, JC-F = 188.9 Hz),
155.42, 151.50, 150.04, 148.63, 144.30, 139.72, 134.64, 133.47, 129.39, 127.22, 126.84, 125.00,
124.99 (d, JC-F = 3.5 Hz), 123.99, 119.44 (d, JC-F = 9.0 Hz), 117.30, 117.07 (d, JC-F = 8.9 Hz),
114.87 (d, JC-F = 2.6 Hz), 98.63, 40.46, 40.04, 27.73; HPLC-MS (APCI/ESI): Purity = 100%.
tR = 2.490 min, calcd. m/z = 542.11, m/z [M]+ = 542.0.
(E)-N-(3-((7-chloroquinolin-4-yl)amino)propyl)-4-(3-(furan-2-yl)acryloyl)benzenesulfonamide
◦
21); light yellow solid (0.0798 g, 50%); m.p. 222–224 C; Rf = 0.41 (MeOH-CH2Cl2, 1:9); 1H
(
NMR (600 MHz, DMSO-d6)
δ 8.36 (d, J = 5.5 Hz, 1H), 8.21 (d, J = 9.0 Hz, 1H), 8.18–8.14 (m,
2H), 7.97–7.91 (m, 2H), 7.93–7.85 (m, 2H), 7.76 (d, J = 2.2 Hz, 1H), 7.60 (d, J = 15.4 Hz, 1H),
7.44 (dd, J = 9.4, 7.1 Hz, 1H), 7.15 (d, J = 3.4 Hz, 1H), 6.72 (dd, J = 3.5, 1.8 Hz, 1H), 6.40 (d, J
= 5.6 Hz, 1H), 3.27–3.21 (m, 2H), 2.95 (q, J = 6.6 Hz, 2H), 1.78 (p, J = 6.9 Hz, 2H). 13C NMR
(151 MHz, DMSO-d6) δ 187.89, 151.21, 150.98, 150.24, 148.29, 146.57, 143.89, 140.21, 133.63,
131.27, 129.05, 126.91, 126.88, 124.19, 124.05, 118.39, 117.83, 117.25, 113.27, 98.63, 48.56,
40.48, 27.72. HPLC-MS (APCI/ESI); Purity = 100%, tR = 2.368 min, calcd. m/z = 495.97,
m/z [M]+ = 496.0.
(E)-N-(2-((7-chloroquinolin-4-yl)amino)ethyl)-4-(3-(p-tolyl)acryloyl)benzenesulfonamide (22);
yellow solid (0.0704 g, 56%); m.p. 184–187 ◦C; Rf = 0.39 (MeOH-CH2Cl2, 1:9); 1H NMR
(600 MHz, DMSO-d6) δ 8.36 (d, J = 5.4 Hz, 1H), 8.20–8.14 (m, 2H), 8.10 (d, J = 9.1 Hz, 1H),
8.05 (t, J = 5.9 Hz, 1H), 7.94–7.89 (m, 2H), 7.82–7.71 (m, 5H), 7.43 (dd, J = 9.0, 2.2 Hz, 1H),
7.33–7.23 (m, 3H), 6.41 (d, J = 5.5 Hz, 1H), 3.38 (q, J = 6.3 Hz, 2H), 3.11 (q, J = 6.3 Hz, 2H),
2.36 (s, 3H). 13C NMR (151 MHz, DMSO-d6)
δ 188.77, 152.10, 150.25, 149.25, 145.49, 144.38,
141.55, 140.81, 134.01, 132.27, 130.06, 129.63, 129.55, 127.81, 127.21, 124.64, 124.37, 121.24,
117.82, 99.02, 42.54, 41.29, 21.60; HPLC-MS (APCI/ESI): Purity = 100%, tR = 2.481 min,
calcd. m/z = 506.02, m/z [M]+ = 506.0.
(E)-N-(2-((7-chloroquinolin-4-yl)amino)ethyl)-4-(3-ferrocenyl)acryloyl)benzenesulfonamide 23
purple solid (0.0601 g, 41%); m.p. 222–224 ◦C; Rf = 0.39 (MeOH-CH2Cl2, 1:9); 1H NMR
(600 MHz, DMSO-d6) 8.41 (d, J = 7.5 Hz, 1H), 8.17–7.19 (m, 14H), 6.56–6.47 (m, 6H), 3.15
(q, J = 6.6 Hz, 2H), 2.95 (q, J = 6.6 Hz, 2H), 1.76 (p, J = 7.1 Hz, 2H). 13C NMR (151 MHz,
DMSO-d6) 187.29, 151.60, 149.75, 147.70, 143.47, 140.72, 133.16, 132.01, 128.84, 127.47,
;
δ
δ

Molecules 2021, 26, 4093
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126.63, 123.90, 118.48, 78.66, 71.51, 69.54, 69.35, 54.73, 48.44, 27.65; HPLC-MS (APCI/ESI):
Purity = 100%, tR = 2.498 min, calcd. m/z = 613.9, m/z [M]+ = 614.0.
(E)-N-(2-((7-chloroquinolin-4-yl)amino)ethyl)-4-(3-(4-fluorophenyl)acryloyl)benzenesulfonam-
ide (24); light yellow solid (0.0893 g, 71%); m.p. 222–224 ◦C Rf = 0.45 (MeOH-CH2Cl2, 1:9);
1H NMR (600 MHz, DMSO-d6)
δ 8.37 (d, J = 5.5 Hz, 1H), 8.20–8.14 (m, 2H), 8.10 (d,
J = 9.1 Hz, 1H), 8.05 (t, J = 5.9 Hz, 1H), 8.03–7.95 (m, 2H), 7.94–7.89 (m, 2H), 7.84–7.71
(m, 3H), 7.43 (dd, J = 9.0, 2.3 Hz, 1H), 7.36–7.28 (m, 3H), 6.42 (d, J = 5.5 Hz, 1H), 3.39 (q,
J = 6.3 Hz, 2H), 3.12 (q, J = 6.3 Hz, 2H). 13C NMR (151 MHz, DMSO-d6)
δ 188.71, 163.22
(d, JC-F = 249.6 Hz), 151.83, 150.41, 148.92, 144.48, 144.14, 134.14, 131.93 (d, JC-F = 8.5 Hz),
131.88, 131.68, 129.68, 127.21, 124.72, 124.42, 122.17, 117.75, 116.54 (d, JC-F = 21.8 Hz),
116.40, 99.02, 42.55, 41.30; HPLC-MS (APCI/ESI): Purity = 100%, tR = 2.427 min, calcd.
m/z = 509.98, m/z [M]+ = 510.0.
(E)-4-(3-(2-chlorophenyl)acryloyl)-N-(2-((7-chloroquinolin-4-yl)amino)ethyl)benzenesulfonam-
ide (25); light yellow solid (0.0508 g, 39%); m.p. 209–211 ◦C Rf = 0.42 (MeOH-CH2Cl2, 1:9);
1H NMR (600 MHz, DMSO-d6)
δ
8.43 (td, J = 8.7, 5.9 Hz, 1H), 8.30–8.25 (m, 2H), 8.25–6.90
(m, 12H), 6.75 (d, J = 9.7 Hz, 1H), 6.55 (d, J = 9.1 Hz, 1H), 3.45 (dd, J = 12.1, 5.8 Hz, 2H), 3.07
(q, J = 6.3 Hz, 2H). 13C NMR (151 MHz, DMSO-d6)
192.18, 144.60, 139.91, 138.38, 134.46,
132.86, 132.51, 131.08, 130.64, 130.00, 129.74, 129.60, 128.22, 127.39, 127.19, 126.90, 125.90,
δ
125.55, 124.93, 124.13, 121.62, 99.04, 42.75, 41.23; HPLC-MS (APCI/ESI): Purity = 82%
,
tR = 2.451 min, calcd. m/z = 526.4, m/z [M]+ = 526.0.
(E)-4-(3-(benzo[d][1,3]dioxol-5-yl)acryloyl)-N-(3-((7-chloroquinolin-4-yl)amino)propyl)benz-
◦
enesulfonamide (26); yellow solid (0.058 g, 66%); m.p. 222–224 C; Rf = 0.46 (MeOH-CH2Cl2,
1:9); 1H NMR (600 MHz, DMSO-d6)
δ
8.35 (d, J = 5.4 Hz, 1H), 8.25 (d, J = 8.2 Hz, 2H), 8.19
(d, J = 9.0 Hz, 1H), 7.94–7.64 (m, 7H), 7.42 (dd, J = 9.0, 2.3 Hz, 1H), 7.36 (dd, J = 8.1, 1.7 Hz,
1H), 7.19 (t, J = 5.6 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.38 (d, J = 5.5 Hz, 1H), 6.12 (s, 2H),
3.24 (q, J = 6.5 Hz, 2H), 2.96 (q, J = 6.6 Hz, 2H), 1.78 (p, J = 7.1 Hz, 2H). 13C NMR (151 MHz,
DMSO-d6)
δ 188.16, 151.79, 149.89, 149.85, 148.97, 148.12, 145.05, 143.86, 140.50, 133.34,
129.17, 129.00, 127.43, 126.75, 126.30, 124.01, 123.94, 119.71, 117.38, 108.55, 107.02, 101.72,
98.64, 40.53, 40.48, 27.76. HPLC-MS (APCI/ESI); Purity = 100%, tR = 2.423 min, calcd. m/z
= 550.0, m/z [M]+ = 550.0.
(E)-N-(3-((7-chloroquinolin-4-yl)amino)propyl)-4-(3-(4-(trifluoromethoxy)phenyl)acryloyl)be-
nzenesulfonamide (27); light yellow solid (0.0901 g, 96% yield); m.p. 223–225 ◦C; Rf = 0.43
(10% MeOH-CH2Cl2); 1H NMR (600 MHz, DMSO-d6)
δ 8.36 (d, J = 5.5 Hz, 1H), 8.27–8.23
(m, 2H), 8.20 (d, J = 8.9 Hz, 1H), 8.10–8.02 (m, 2H), 7.96–7.86 (m, 4H), 7.79 (d, J = 15.7 Hz,
1H), 7.74 (d, J = 2.3 Hz, 1H), 7.49–7.41 (m, 2H), 7.30 (t, J = 5.3 Hz, 1H), 6.40 (d, J = 5.5 Hz, 1H),
3.25 (q, J = 6.6 Hz, 2H), 2.96 (q, J = 6.5 Hz, 2H), 1.78 (p, J = 7.1 Hz, 2H). 13C NMR (151 MHz,
DMSO-d6)
δ 188.41, 151.30, 150.20, 149.74, 148.38, 144.12, 143.13, 140.08, 134.20, 133.61,
130.99, 129.33(d, JC-F = 25.3 Hz), 126.97, 126.74, 124.17, 124.04, 123.00, 121.26, 117.42, 117.27,
98.64, 40.49, 40.04, 27.72; HPLC-MS (APCI/ESI): Purity = 100%. tR = 2.559 min, MW = 590.1
,
m/z [M]+ = 590.0.
5. Conclusions
In conclusion, 22 molecular hybrids were successfully synthesized in good to excellent
yields. They were all fully characterized using spectroscopic techniques such as 1H- and
13C-NMR spectroscopy and HPLC-MS. These compounds were evaluated for in vitro
antiplasmodial activity against the chloroquine sensitive (NF54) strain of P. falciparum and
displayed promising activity with IC50 values ranging at 0.10–4.45 µM. The frontrunner
compound 12 showed improved resistivity index compared to CQ, as well as good safety
profile (SI = 393.6).
Supplementary Materials: The following are available online. The NMR spectra and HPLC-MS
spectra of compounds described in this study are available online.
Author Contributions: Conceptualization, W.M.; methodology, W.M.; validation, G.A.D., W.M.;
formal analysis, B.V., G.A.D. and W.M.; investigation, B.V., G.A.D. and W.M.; resources, W.M.; data

Molecules 2021, 26, 4093
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curation, B.V., G.A.D. and W.M.; writing—original draft preparation, W.M.; writing—review and
editing, G.A.D., W.M.; supervision, G.A.D., W.M.; project administration, W.M.; funding acquisition,
W.M. All authors have read and agreed to the published version of the manuscript.
Funding: This research was funded by the South African Medical Research Council and The Direc-
torate of Research and Innovation of Walter Sisulu University.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments: The logistical support received from the Drug Discovery and Development
Centre (H3D) at the University of Cape Town is gratefully acknowledged.
Conflicts of Interest: The authors declare no conflict of interest.
Sample Availability: Samples of the compounds are available from the authors.
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