Synthesis of functionalized 3-, 5-, 6- and 8-aminoquinolines via intermediate (3-pyrrolin-1-yl)- and (2-oxopyrrolidin-1-yl)quinolines and evaluation of their antiplasmodial and antifungal activity

Article abstract of DOI:10.1016/j.ejmech.2014.12.020

(3-Pyrrolin-1-yl)- and (2-oxopyrrolidin-1-yl)quinolines were prepared via cyclization of diallylaminoquinolines and 4-chloro-N-quinolinylbutanamides, respectively, as novel synthetic intermediates en route to N-functionalized 3-, 5-, 6- and 8-aminoquinolines with potential biological activity. (3-Pyrrolin-1-yl)quinolines were subjected to bromination reactions, and the reactivity of (2-oxopyrrolidin-1-yl)quinolines toward lithium aluminum hydride and methyllithium was assessed, providing an entry into a broad range of novel functionalized (pyrrolidin-1-yl)- and (hydroxyalkylamino)quinolines. Antiplasmodial evaluation of these novel quinolines and their functionalized derivatives revealed moderate micromolar potency against a chloroquine-sensitive strain of the malaria parasite Plasmodium falciparum, and the two most potent compounds also showed micromolar activity against a chloroquine-resistant strain of P. falciparum. Antifungal assessment of (hydroxyalkylamino)quinolines revealed three compounds with promising MIC values against Rhodotorula bogoriensis and one compound with potent activity against Aspergillus flavus.

Full text of DOI:10.1016/j.ejmech.2014.12.020

Accepted Manuscript
Synthesis of functionalized 3-, 5-, 6- and 8-aminoquinolines via intermediate
(3-pyrrolin-1-yl)- and (2-oxopyrrolidin-1-yl)quinolines and evaluation of their
antiplasmodial and antifungal activity
Stéphanie Vandekerckhove , Sofie Van Herreweghe , Jasmine Willems , Barbara
Danneels , Tom Desmet , Carmen de Kock , Peter J. Smith , Kelly Chibale , Matthias
D’hooghe
PII:
S0223-5234(14)01129-5
10.1016/j.ejmech.2014.12.020
EJMECH 7580
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 16 September 2014
Revised Date: 28 November 2014
Accepted Date: 11 December 2014
Please cite this article as: S. Vandekerckhove, S. Van Herreweghe, J. Willems, B. Danneels, T.
Desmet, C. de Kock, P.J. Smith, K. Chibale, M. D’hooghe, Synthesis of functionalized 3-, 5-, 6- and 8-
aminoquinolines via intermediate (3-pyrrolin-1-yl)- and (2-oxopyrrolidin-1-yl)quinolines and evaluation
of their antiplasmodial and antifungal activity, European Journal of Medicinal Chemistry (2015), doi:
10.1016/j.ejmech.2014.12.020.
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Graphical Abstract
Synthesis of functionalized 3-, 5-, 6- and 8-aminoquinolines via
intermediate (3-pyrrolin-1-yl)- and (2-oxopyrrolidin-1-yl)quinolines
and evaluation of their antiplasmodial and antifungal activity
Stéphanie Vandekerckhovea, Sofie Van Herreweghea, Jasmine Willemsa, Barbara Danneelsb,
Tom Desmetb, Carmen de Kockc, Peter J. Smithc, Kelly Chibaled and Matthias D’hooghea,
Corresponding author. Tel. +32 9 264 93 94; fax: +32 9 364 62 21
E-mail address: Matthias.Dhooghe@UGent.be (M. D’hooghe)

ACCEPTED MANUSCRIPT
Synthesis of functionalized 3-, 5-, 6- and 8-aminoquinolines via
intermediate (3-pyrrolin-1-yl)- and (2-oxopyrrolidin-1-yl)quinolines
and evaluation of their antiplasmodial and antifungal activity
Stéphanie Vandekerckhovea, Sofie Van Herreweghea, Jasmine Willemsa, Barbara Danneelsb,
Tom Desmetb, Carmen de Kockc, Peter J. Smithc, Kelly Chibaled and Matthias D’hooghea,
a SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering,
Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
bCentre for Industrial Biotechnology and Biocatalysis, Faculty of Bioscience Engineering, Ghent University, Coupure Links
653, B-9000 Ghent, Belgium
cDivision of Pharmacology, University of Cape Town, K45, OMB, Groote Schuur Hospital, Observatory, 7925, South Africa
dSouth African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry and
Institute of Infectious Disease & Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa
ABSTRACT
(3-Pyrrolin-1-yl)- and (2-oxopyrrolidin-1-yl)quinolines were prepared via cyclization of diallylaminoquinolines
and 4-chloro-N-quinolinylbutanamides, respectively, as novel synthetic intermediates en route to N-
functionalized 3-, 5-, 6- and 8-aminoquinolines with potential biological activity. (3-Pyrrolin-1-yl)quinolines
were subjected to bromination reactions, and the reactivity of (2-oxopyrrolidin-1-yl)quinolines toward lithium
aluminium hydride and methyllithium was assessed, providing an entry into a broad range of novel
functionalized (pyrrolidin-1-yl)- and (hydroxyalkylamino)quinolines. Antiplasmodial evaluation of these novel
quinolines and their functionalized derivatives revealed moderate micromolar potency against a chloroquine-
sensitive strain of the malaria parasite Plasmodium falciparum, and the two most potent compounds also
showed micromolar activity against a chloroquine-resistant strain of P. falciparum. Antifungal assessment of
(hydroxyalkylamino)quinolines revealed three compounds with promising MIC values against Rhodotorula
bogoriensis and one compound with potent activity against Aspergillus flavus.
Keywords: quinolines, pyrrolidine derivatives, antimalarial agents, antimicrobial agents
1. Introduction
Quinoline or benzo[b]pyridine is an azaheterocyclic aromatic compound and a weak tertiary base
that can undergo both nucleophilic and electrophilic substitution reactions. The quinoline moiety is
nontoxic to humans on oral absorption and inhalation and therefore occurs in several
Corresponding author. Tel. +32 9 264 93 94; fax: +32 9 364 62 21
E-mail address: Matthias.Dhooghe@UGent.be (M. D’hooghe)
1

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pharmacologically active compounds, displaying a wide range of biological activities. In particular,
quinoline derivatives have been found to exhibit antimalarial [1-4], antibacterial [5-7], antiprotozoal
[8-11], anti-HIV [12-14], anticancer [15-17] and antifungal activity [18-20], pointing to their versatility
as templates in drug discovery.
The majority of known quinoline drugs have a side chain on the 4- or 8-position of the quinoline
building block. However, recently, it has been reported that moving a functionalized side chain
around the quinoline core to the 3-, 5- or 6-position can result in retention of biological (in casu
antiplasmodial) activity [21-22], providing new opportunities for the design of bioactive compounds.
Therefore, the combination of the privileged quinoline scaffold (bearing a varied substitution
pattern) with a synthetically and biologically interesting heterocyclic moiety (like pyrrolidine
derivatives) in a conjugate system might reveal new perspectives in bioactive compound
development. Thus, antiplasmodial and antimicrobial evaluation of novel pyrrolidinyl-quinoline
chimeras and their functionalized derivatives could potentially provide new hit compounds in this
field of research. Hence, the objective of this study consists of the design, synthesis and biological
evaluation of a range of novel (3-pyrrolin-1-yl)quinoline and (2-oxopyrrolidin-1-yl)quinoline
intermediates and their derivatives.
2. Results and discussion
2.1. Chemistry
A first synthetic approach envisioned the initial synthesis of (3-pyrrolin-1-yl)quinolines starting from
aminoquinolines. Diallylaminoquinolines had to be prepared as intermediates, but since they have
only been reported as (minor) side products of the monoallylation of aminoquinolines [23-26],
optimization of the reaction conditions was required to realize selective diallylation. Complete
diallylation of aminoquinolines could be accomplished by sequentially adding lithium
bis(trimethylsilyl)amide to a mixture of aminoquinoline 1 and allyl bromide in tetrahydrofuran,
affording the desired diallylaminoquinolines 2a-d in good to excellent yields (50-99%) and purities
(Scheme 1 and Table 1). Diallylamines 2a-d were subsequently treated with 1st or 2nd generation
Grubbs catalyst in tetrahydrofuran or dichloromethane yielding the desired new (3-pyrrolin-1-
yl)quinolines 3a-d. 1st Generation Grubbs catalyst was preferred over 2nd generation since it was
shown to be more active toward 3-diallylaminoquinoline derivatives. However, 1st generation Grubbs
catalyst was unable to effect ring closure of 8-diallylaminoquinolines, and it appeared that 2nd
generation Grubbs catalyst was required in that case. Conversion rates of diallylaminoquinolines 2a-d
to (3-pyrrolin-1-yl)quinolines 3a-d varied between 50 and 100%, but 3-pyrrolines 3a-d could be
isolated in pure form in yields of 16-82% by preparative thin layer chromatography (Scheme 1 and
Table 1). The reactivity of (3-pyrrolin-1-yl)quinoline intermediates 3a-c was then evaluated by adding
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bromine to a solution of quinolines 3a-c in tetrahydrofuran or dichloromethane. Surprisingly, next to
the anticipated anti-addition of bromine across the pyrroline double bond, bromination of the
quinoline core occurred as well. The position of quinoline bromination was dependent on the
substitution pattern; seemingly bromination of the quinoline core took place in the α-position with
respect to the pyrrolidinyl side chain. Electron donation by the nitrogen atom into the aromatic
quinoline ring enhanced electrophilic aromatic substitution at the neighboring positions. For the 3-
and 5-substituted quinolines 3a-b, this resulted in additional bromination at the 4-and 6-position of
the quinoline core, respectively. 6-Substituted quinolines 3c, however, yielded two products in a 3/1
ratio, with the major product brominated at the 5-position and the minor product brominated at the
7-position of the quinoline core. Only the major product 4c could be isolated. The small scale
synthesis and troublesome purification step(s) affected the overall yields (14-34%) of the final
obtained products (Scheme 1 and Table 1).
Scheme 1: Synthesis and bromination of (3-pyrrolin-1-yl)quinolines 3
In order to increase the yield of the reaction, 6-(3-pyrrolin-1-yl)quinoline 3c was treated with
bromine in dichloromethane and stirred at room temperature. However, in that case a complex
reaction mixture was obtained, but after two purification steps over silica gel (column
chromatography followed by preparative TLC), a pure fraction could be isolated. Further analysis
proved that 1-(5-bromoquinolin-6-yl)-2,3,4,5-tetrabromopyrrole 5 was obtained in 9% yield (Scheme
1 and Table 1). The very low yield of the reaction can be attributed to the small scale of the reaction
(0.5 mmol), the cumbersome purification steps and the fact that insufficient bromine was added to
the reaction to achieve full conversion to compound 5.
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Table 1: Substitution pattern and isolated yields of quinolines 2, 3, 4 and 5
Compound
Quinolin-
3-yl
Position Br Yield (%)
2a
2b
2c
2d
3a
3b
3c
3d
4a
4b
4c
5
-
90-99a
79-95
50-70a
71
5-yl
-
6-yl
-
8-yl
-
3-yl
-
-
20-53
48-82
50-80
16-53
28
5-yl
6-yl
-
8-yl
-
3-yl
4-Br
6-Br
5-Br
5-Br
5-yl
28-34
14
6-yl
6-yl
9
a Crude yields, purity >90% (NMR)
A second approach commenced with the synthesis of 1-quinolinylpyrrolidin-2-ones from the
aminoquinoline building blocks 1. The first step in the synthesis of these intermediates comprised the
N-acylation of aminoquinolines 1 with 4-chlorobutyryl chloride in the presence of potassium
carbonate in dichloromethane. This approach afforded the required N-(quinolinyl)butanamides 6a-d
in excellent yields (71-99%) and high purities (Scheme 2 and Table 2). The crude products 6a-d were
subjected to an intramolecular ring closure by adding potassium tert-butoxide to an acetonitrile
solution of butanamides 6a-d, this yielded the desired novel (2-oxopyrrolidin-1-yl)quinolines 7a-d in
good yields (60-62%) (Scheme 2 and Table 2).
Subsequently, various strategies for further derivatization of the pyrrolidin-2-one moiety were
evaluated. Firstly, lithium aluminium hydride was added to lactams 7b-c and reaction at refluxing
temperature mediated the reductive removal of the carbonyl group, furnishing (pyrrolidin-1-
yl)quinolines 8b-c in moderate to good yields (37-68%) (Scheme 2 and Table 2). However, when
lactams 7a-d were treated with lithium aluminium hydride at room temperature, the corresponding
intermediate aldehydes were formed and addition of methanol and sodium borohydride to this
reaction mixture afforded further reduction towards primary alcohols 9a-d. Analytically pure samples
of these 4-(quinolinylamino)butanols 9a-d were obtained in low yields (12-40%) due to difficult
purification steps (Scheme 2 and Table 2). Thirdly, lactams 7a-d were sequentially treated with 4
equiv of a methyllithium solution, providing full conversion to 5-quinolinylamino-2-methylpentan-2-
ols 10a-d, but again the polar nature of these compounds accounted for a cumbersome purification,
resulting in reduced yields (23-43%). It should be noted, however, that when this method was
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applied to 3-(2-oxopyrrolidin-1-yl)quinoline 7a, an additional methylation occurred at the 2-position
of the quinoline scaffold affording methylketone 10a’ (R = Me) (Scheme 2 and Table 2). This reaction
is expected to proceed via the 2-methyl-1,2-dihydroquinoline intermediate, followed by
rearomatization mediated by light-induced oxidation. This type of nucleophilic alkyllithium addition
onto a quinoline ring has been described in the literature [27]. Lastly, when lactams 7a-c were
sequentially treated with only 2 equiv of a methyllithium solution, 5-(quinolinylamino)pentan-2-ones
11a-c were obtained in good to excellent yields (70-99%) and high purities (Scheme 2 and Table 2).
Again methylation of the 2-position of the quinoline core took place when applying this method to 3-
(2-oxopyrrolidin-1-yl)quinoline 7a, yielding 5-(2-methylquinolin-3-ylamino)pentan-2-one 11a’ (R =
Me). Temperature control appeared to be crucial in this reaction step, since the intermediate lithiate
is only stable at temperatures below 0 °C. When the reaction was performed at higher temperatures,
mixtures of methylketones 11a-c and tertiary alcohols 10a-c were obtained. However, this was not
the case when 8-(2-oxopyrrolidin-1-yl)quinoline 7d was used as substrate, as this reaction always
resulted in the synthesis of 5-(quinolin-8-ylamino)-2-methylpentan-2-ol 10d, even at reaction
temperatures as low as -78 °C. This difference in reactivity has been explained by considering the
formation of a coordination complex between the metal (lithium) and 8-aminoquinolines [28-29].
Furthermore, the newly synthesized methylketones 11a-c were rather unstable and could not be
purified over silica gel. Fortunately, these ketones were obtained in sufficiently high purities (>90%,
NMR), allowing for direct further synthetic modification. The first modification strategy consisted of
intramolecular ring closure by adding acetic acid and sodium cyanoborohydride to methylketones
11a-c, affording full conversion to novel (2-methylpyrrolidin-1-yl)quinolines 12a-c and analytically
pure samples were obtained in low to good yields (27-61%) (Scheme 2 and Table 2). In order to get
the full range of 4-aminobutanol side chains, 5-(quinolinylamino)pentan-2-ones 11a-c were treated
with sodium borohydride, affording 5-(quinolinylamino)pentan-2-ols 13a-c in low to moderate yields
(15-50%) (Scheme 2 and Table 2).
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Scheme 2: Synthesis and functionalization of 1-(quinolinyl)pyrrolidin-2-ones 6
It should be noted that 5-(quinolinylamino)pentan-2-ols 13a-c could also be synthesized in a one-pot
process by treating lactams 7a-c with 2 equiv of a methyllithium solution for 2h, whereafter sodium
borohydride and methanol were added to the mixture. 5-Quinolinylamino-2-methylpentan-2-ols 10a-
b could also be obtained through an alternative route where methylketones 11a-b were treated with
methylmagnesium iodide.
Table 2: Substitution pattern and isolated yields of quinolines 6, 7, 8, 9, 10, 11, 12 and 13
Compound
Quinolin-
3-yl
R
-
-
-
-
-
-
-
-
-
-
-
-
Yield (%)
84a
95a
93a
97a
75
Compound
10b
Quinolin-
5-yl
R
H
Yield (%)
23
6a
6b
6c
6d
7a
7b
7c
7d
8b
8c
9a
9b
5-yl
10c
6-yl
H
43
6-yl
10d
8-yl
H
40
8-yl
11a
3-yl
H
83a
85a
88a
94a
61
3-yl
11a’
11b
3-yl
CH3
H
5-yl
62
5-yl
6-yl
80
11c
6-yl
H
8-yl
72
12a
3-yl
H
5-yl
37
12a’
12b
3-yl
CH3
H
33
6-yl
68
5-yl
31
3-yl
40
12c
6-yl
H
27
5-yl
15
13a
3-yl
H
20
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9c
9d
6-yl
8-yl
3-yl
-
-
40
25
15
13a’
13b
13c
3-yl
5-yl
6-yl
CH3
H
20
17
50
10a’
CH3
H
a Crude yields, purity >90% (NMR)
2.2. Biological assay
With this small library of (pyrrolidin-1-yl)quinolines 3a-d, 4a-c, 5, 7a-d, 8c, 12a-c and their ring-
opened derivatives 9a-d, 10a-d, 13a-c in hand, biological screening was performed. All 30 quinoline
derivatives were subjected to antiplasmodial testing. (Hydroxyalkylamino)quinoline derivatives 9a-d,
10a-d and 13a-c were also selected for an antimicrobial assay since they are closely related to 4-
(aminobutyloxy)quinolines which are known to display antimicrobial activity [19].
2.2.1. In vitro antiplasmodial activity
For the antiplasmodial assay, all samples were tested in triplicate against a chloroquine-sensitive
(CQS) strain of Plasmodium falciparum (NF54). Subsequently, those samples showing promising
antiplasmodial activity (i.e. compounds 9b and 12a’) were tested against a chloroquine-resistant
(CQR) strain of P. falciparum (Dd2) and screened for in vitro cytotoxicity against a mammalian cell-
line, Chinese Hamster Ovarian (CHO), using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide (MTT)-assay. Continuous in vitro cultures of asexual erythrocyte stages of P. falciparum
were maintained using a modified method of Trager and Jensen [30]. Quantitative assessment of
antiplasmodial activity in vitro was determined via the parasite lactate dehydrogenase assay using a
modified method described by Makler [31]. The test samples were tested in triplicate on one
occasion. The MTT-assay was used to measure all growth and survival, and compares well with other
available assays [32-33]. The tetrazolium salt MTT was used to measure growth and
chemosensitivity. The test samples were tested in triplicate on one occasion. The results of the
biological evaluation are summarized in Table 3 and 4.
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Table 3: IC50 values of (pyrrolidin-1-yl)quinolines 3a-d, 4a-c, 5, 7a-d, 8c, 12a-c and their ring-opened derivatives 9a-d, 10a-d,
13a-c tested for in vitro antimalarial activity against a CQS P. falciparum strain.
Compound
NF54: IC50 (µM)
Compound
8a
NF54: IC50 (µM)
>50
Compound
NF54: IC50 (µM)
31.1 ± 8.5
13.3 ± 3.5
>45
3a
3b
3c
3d
4a
4b
5
>50
>50
>50
>50
>20
>20
>15
>45
>45
>45
>45
12a
8b
>50
12a’
8c
>50
12b
9a
>45
12c
13a
41.9 ± 5.7
>40
9b
19.9 ± 5.6
>45
9c
13a’
>40
9d
>45
13b
32.6 ± 6.5
>40
7a
7b
7c
7d
10a’
10b
10c
10d
>35
13c
28.2 ± 4.5
>40
CQ (n=14)
Artesunate (n=8)
0.021 ± 0.005
0.005
>40
CQ = chloroquine.
Table 4: IC50 values of quinolines 9b and 12a’ tested for in vitro antimalarial activity (against a CQR P. falciparum strain) and
cytotoxicity.
Compound
9b
NF54: IC50 (µM)
19.9 ± 5.6
13.3 ± 3.5
0.021
Dd2: IC50 (µM)
49.0 ± 10.2
38.0 ± 4.4
0.274
CHO: IC50 (µM)
SIa
23
22
-
RIb
2.5
2.9
13.0
2.2
-
>100
12a’
293.5 ± 50.4
CQ (n=14)
Artunesate (n=8)
Emetine
-
-
0.005
0.011
-
-
-
0.125
-
CQ = chloroquine; a SI (Selectivity Index) = IC50 CHO/IC50 NF54; b RI (Resistance Index) = IC50 Dd2/IC50 NF54.
It can be seen that some of the tested compounds exhibited micromolar potencies against a
chloroquine-sensitive NF54 strain of P. falciparum, with six samples displaying IC50 values between 13
and 42 µM. Subsequently, the activity of the two most potent compounds 9b and 12a’ (IC50 < 20 µM)
was determined against a chloroquine-resistant strain of P. falciparum (Dd2), which resulted in
micromolar activities with IC50 values ranging between 38 and 49 µM (Table 4). With regard to
structure-activity relationships, this assay shows that (hydroxyalkylamino)quinolines 9, 10 and 13
display the best activities when they are linked to the quinoline ring at position 5. Quinolines 12 on
the other hand give better results when the 2-methylpyrrolidinyl side chain is present at the 3- or 6-
position of the quinoline ring. Due to the diversity of this library (focusing on various substitution
patterns across the quinoline core), these results cannot be generalized, but they can be seen as a
valuable starting point for further research on 3-, 5-, 6- or 8-functionalized quinolines.
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2.2.2. Antimicrobial activity
Finally, the antimicrobial activity of (hydroxyalkylamino)quinoline derivatives 9, 10 and 13 was tested
against two yeast strains (Candida albicans (IHEM 374) and Rhodotorula bogoriensis (MUCL11796))
and one mold strain (Aspergillus flavus (IHEM5785)) by the Disk Diffusion method to carry out a
preliminary assessment of their antimicrobial potency [34]. This test revealed an interesting profile
for six compounds (9c, 9d, 10b, 10d, 13a and 13c), displaying antimicrobial activity against all 3
microorganisms. These compounds were subsequently subjected to a Minimum Inhibitory
Concentration (MIC) determination test via microdilution [35]. The MIC values are reported in Table
5.
Table 5: MIC values
Compound
Candida albicans
Rhodotorula bogoriensis
Aspergillus flavus
(mg/L)
250.0
250.0
500.0
250.0
250.0
250.0
<0.2
(mM)
(mg/L)
250.0
7.8
(mM)
1.2
(mg/L)
2.0
(mM)
0.01
0.1
9c
1.2
1.2
9d
0.04
0.02
0.03
0.3
31.6
62.5
15.6
31.3
62.5
3.1
10b
2.0
3.9
0.3
10d
13a
1.0
7.8
0.06
0.1
1.1
62.5
250.0
<0.2
13c
1.1
1.1
0.3
Amphotericin B
<0.0002
<0.0002
0.03
The obtained MIC values confirm compounds 9d, 10b and 10d to display promising activity against
the Rhodotorula bogoriensis yeast strain (MIC values between 0.016 and 0.036 mM) and can be
considered as promising hit compounds. Furthermore, all (hydroxyalkylamino)quinoline derivatives
exhibit activity toward the Aspergillus flavus strain, but particularly interesting is the fact that
compound 9c displays antifungal activity toward A. flavus comparable to Amphotericin B, the best-
known commercially available antifungal agent. Therefore, compound 9c can be considered as a
promising novel antifungal (anti-Aspergillus flavus) lead structure. When comparing these results to
the antimicrobial activities of similar molecules such as 3-, 5-, 6- and 8-(4-aminobutyloxy)quinolines,
previously described in the literature, it appears that (hydroxyalkylamino)quinolines 9, 10 and 13
retain potency when the side chain is moved around the quinoline core, while only 8-substituted (4-
aminobutyloxy)quinolines displayed antifungal activity [21]. Future research should verify whether
changing the substitution pattern of other amino side chains also provides retention of antifungal
activity. The presence of one or two methyl groups on the hydroxyalkylamino side chain however,
does not seem to have a significant influence on the compounds’ antifungal potency.
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3. Conclusion
In summary, preparation of (3-pyrrolin-1-yl)- and (2-oxopyrrolidin-1-yl)quinoline intermediates was
established by cyclization of diallylaminoquinolines and 4-chloro-N-quinolinylbutanamides,
respectively. The reactivity of (3-pyrrolin-1-yl)quinolines was subsequently evaluated by bromination
reactions and the susceptibility of (2-oxopyrrolidin-1-yl)quinolines toward lithium aluminium hydride
and methyllithium was assessed. Furthermore, the antiplasmodial activity of the novel functionalized
(pyrrolidin-1-yl)- and (hydroxyalkylamino)quinolines was evaluated. Some of the tested compounds
displayed micromolar activity against a chloroquine-sensitive strain of P. falciparum, and two
compounds exhibited micromolar activity against a chloroquine-resistant strain of P. falciparum.
Finally, antifungal assessment of (hydroxyalkylamino)quinolines resulted in the identification of three
compounds displaying considerable activity against R. bogoriensis and one compound showing
significant potency against A. flavus.
4. Experimental methods
4.1. General information
All reagents were purchased from commercial suppliers (Sigma–Aldrich, Acros, TCI), and were used
as received without any purification unless otherwise noted. Solvents were dried with sodium (THF)
or calcium hydride (dichloromethane), and distilled before use. Other solvents were purchased from
commercial suppliers and used as supplied. The petroleum ether used during product purification
steps had a boiling range of 40–60 °C. Crude reaction mixtures were analyzed by LC/MS/UV. Thin-
layer chromatography was carried out on silica gel 60F254 plates (Merck). Column chromatography
was performed in a glass column with silica gel (particle size 70−200 μm, pore diameter 60 Å).
1
Preparative TLC was executed with 2000 μm 20 × 20 cm TLC plates. High-resolution H and 13C
magnetic resonance (NMR) spectra were recorded with Jeol Eclipse+ 300 or Bruker AVANCE III 400 FT
NMR spectrometers in CDCl3, unless otherwise noted. Chemical shifts were calibrated using
tetramethylsilane, which was used as an internal reference, unless otherwise indicated. Peak
assignments were obtained with the aid of APT and HSQC spectra. Attenuated total reflection (ATR)
IR spectra were recorded with a Perkin–Elmer Spectrum BX spectrometer, equipped with a ZnSe
crystal, at room temperature (neat). Low-resolution mass spectra were recorded with an Agilent
Technologies 1100 series VL mass spectrometer (ESI, 70 eV). High-resolution mass were obtained
with an HPLC coupled to an Agilent Technologies 6210 series time-of-flight mass spectrometer
equipped with an ESI/APCI-multimode source. Melting points were measured with a Büchi B-540
apparatus.
4.2. General procedure for the synthesis of diallylaminoquinolines 2a-d
10

ACCEPTED MANUSCRIPT
To a solution of aminoquinoline 1 (3.5 mmol) in dry tetrahydrofuran (50 mL), 5.3 mL lithium
bis(trimethylsilyl)amide (1M in THF) (5.3 mmol; 1.5 equiv) and 1.2 mL allyl bromide (14.0 mmol, 4
equiv) were added at 0 °C. After stirring for 1 h at reflux conditions under inert atmosphere (N2), the
flask was cooled to 0 °C and again lithium bis(trimethylsilyl)amide (1M in THF) (5.3 mmol; 1.5 equiv)
was slowly added to the solution. The mixture was again stirred for 1 h at reflux conditions. The
reaction mixture was quenched with 10 mL of a saturated ammonium chloride solution, poured into
water (30 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried
over anhydrous magnesium sulfate and filtration of the drying agent and removal of the solvent in
vacuo afforded diallylaminoquinolines 2a-d in high purities (>90%, 1H NMR).
4.2.1. 3-Diallylaminoquinoline 2a (90-99%)
Spectral data of 3-diallylaminoquinoline 2a corresponded with data described in the literature [23].
4.2.2. 5-Diallylaminoquinoline 2b (79-95%)
1
Orange-brown oil. Rf (SiO2) = 0.27 (Petroleumether/EtOAc 4/1). H NMR (300 MHz, CDCl3): 3.78 (4H,
d, J = 6.1 Hz); 5.16 (2H, d, J = 10.5 Hz); 5.24 (2H, d, J = 17.1 Hz); 5.78-5.91 (2H, m); 7.13 (1H, d, J = 8.3
Hz); 7.38 (1H, dd, J = 8.3, 4.4 Hz); 7.60 (1H, t, J = 8.3 Hz); 7.80 (1H, d, J = 8.3 Hz); 8.60 (1H, d, J = 8.3
Hz); 8.89 (1H, d, J = 4.4 Hz). 13C NMR (75.6 MHz, ref = CDCl3): δ 56.4, 117.6, 118.0, 120.3, 124.4,
125.2, 129.0, 132.6, 134.5, 147.9, 149.5, 150.0. IR (cm-1): νmax = 3074, 2818, 1588, 1572, 1397, 986,
918, 799. MS (70 eV): m/z (%): 225 (M++1,100). HRMS (ESI) calcd for C15H17N2 225.1386 [M+H]+,
found 225.1392.
4.2.3. 6-Diallylaminoquinoline 2c (50-70%)
Brown-yellow oil. Rf (SiO2) = 0.3 (Petroleumeter/EtOAc 9/1). 1H NMR (400 MHz, CDCl3): δ 3.89 (4H, d,
J = 4.7 Hz); 5.03-5.09 (4H, m); 5.71-5.80 (2H, m); 6.65 (1H, d, J = 2.9 Hz); 7.08 (1H, dd, J = 8.2, 4.2 Hz);
7.13 (1H, dd, J = 9.3, 2.9 Hz); 7.75 (1H, dd, J = 8.2, 1.6 Hz); 7.76 (1H, d, J = 9.3); 8.44 (1H, dd, J = 4.2,
1.6 Hz). 13C NMR (100.6 MHz, ref = CDCl3): δ 52.9, 104.8, 116.4, 119.2, 121.3, 129.8, 130.0, 133.4,
134.0, 142.3, 146.2, 146.8. IR (cm-1): νmax = 3078, 1618, 1589, 1507, 1388, 1356, 1227, 920, 822. MS
(70 eV): m/z (%): 225 (M++1, 100) HRMS (ESI) calcd for C15H17N2 225.1386 [M+H]+, found 225.1396.
4.2.4. 8-Diallylaminoquinoline 2d (71%)
1
Orange-brown oil. Rf (SiO2) = 0.28 (Petroleumether/EtOAc 9/1). H NMR (300 MHz, CDCl3): 4.07 (4H,
d, J = 6.1 Hz); 5.04 (2H, d, J = 10.5 Hz); 5.09 (2H, d, J = 17.6 Hz); 5.78-5.92 (2H, m); 7.00 (1H, dd, J =
7.2, 1.7 Hz); 7.21 (1H, dd, J = 8.3, 3.9 Hz); 7.25 (1H, dd, J = 7.2, 1.7 Hz); 7.29 (1H, t, J = 7.2 Hz); 7.94
(1H, dd, J = 8.3, 1.7 Hz); 8.80 (1H, dd, J = 3.9, 1.7 Hz). 13C NMR (75.6 MHz, ref = CDCl3): δ 55.6, 117.5,
118.5, 120.8, 120.9, 126.4, 129.8, 135.2, 136.5, 143.1, 147.4, 147.9. IR (cm-1): νmax = 2976, 1565, 1498,
1469, 1389, 1241, 1098, 915, 822, 805, 788, 749. MS (70 eV): m/z (%): 225 (M++1,100). HRMS (ESI)
calcd for C15H17N2 225.1386 [M+H]+, found 225.1386.
4.3. General procedure for the synthesis of (3-pyrrolin-1-yl)quinolines 3a-d
To a solution of diallylaminoquinoline 2 (1.6 mmol) in dry dichloromethane or tetrahydrofuran (25
mL), 1st generation Grubbs catalyst (0.2 mmol, 10 mol%) was added (for 8-diallylaminoquinoline 2d
11

ACCEPTED MANUSCRIPT
2nd generation Grubbs catalyst was necessary). After stirring for 24 h at room temperature under
nitrogen atmosphere, the solvent was removed in vacuo and the crude reaction mixture was purified
by means of preparative thin layer chromatoghraphy (pTLC) or column chromatography on silica gel,
affording (3-pyrrolin-1-yl)quinolines 3a-d.
4.3.1. 3-(3-pyrrolin-1-yl)quinoline 3a (20-53%)
1
Brown crystals. Rf (SiO2) = 0.39 (Petroleumether/EtOAc 1/1). H NMR (300 MHz, CDCl3): δ 4.29 (4H,
s); 6.03 (2H, s); 6.96 (1H, d, J = 2.8 Hz); 7.36-7.45 (2H, m); 7.64 (1H, dd, J = 7.2, 2.8 Hz); 7.96 (1H, dd);
13
8.54 (1H, d, J = 2.8 Hz). C NMR (75.6 MHz, ref = CDCl3): δ 54.5, 110.6, 124.5, 125.9, 126.2, 126.9,
129.1, 129.7, 140.1, 140.5, 141.3. IR (cm-1): νmax = 3028, 2922, 2834, 1597, 1437, 1402, 834, 740, 674,
673. MS (70 eV): m/z (%): 197 (M++1, 100). HRMS (ESI) calcd for C13H13N2 197.1073 [M+H]+, found
197.1073. Tm = 134 °C.
4.3.2. 5-(3-pyrrolin-1-yl)quinoline 3b (48-82%)
1
Orange-brown oil. Rf (SiO2) = 0.13-0.31 (Petroleumether/EtOAc 4/1). H NMR (400 MHz, CDCl3): δ
4.37 (4H, s); 5.98 (2H, s); 6.98 (1H, dd, J = 7.6, 0.9 Hz); 7.31 (1H, dd, J = 8.7, 4.1 Hz); 7.59 (1H, dd, J =
8.3, 7.6 Hz); 7.65 (1H, dd, J = 8.3, 0.9 Hz); 8.64 (1H, dd, J = 8.7, 1.7 Hz); 8.85 (1H, dd, J = 4.1, 1.7 Hz).
13C NMR (100.6 MHz, ref = CDCl3) δ 59.0, 111.5, 118.8, 121.4, 122.4, 126.5, 129.6, 133.4, 147.0,
149.7, 149.9. IR (cm-1): νmax = 2848, 1570, 1461, 1410, 1307, 907, 784, 727, 674. MS (70 eV): m/z (%):
197 (M++1,100). HRMS (ESI) calcd for C13H13N2 197.10732 [M+H]+, found 197.1076.
4.3.3. 6-(3-pyrrolin-1-yl)quinoline 3c (50-80%)
Brown-yellow oil. Rf (SiO2) = 0.15 (Petroleumether/EtOAc 2/1). 1H NMR (400 MHz, CDCl3): δ 4.22 (4H,
s); 5.99 (2H, s); 6.59 (1H, d, J = 2,7 Hz); 7.15 (1H, dd, J = 9.2, 2.7 Hz); 7.25 (1H, dd, J = 8.4, 4.1 Hz); 7.93
(1H, dd, J = 8.4, 1.5 Hz); 7.97 (1H, d, J = 9.2 Hz); 8.59 (1H, dd, J = 4.1, 1.5 Hz). 13C NMR (100.6 MHz, ref
= CDCl3): δ 54.6, 103.1, 118.5, 121.4, 126.3, 130.1, 130.2, 133.9, 141.8, 145.1, 145.5. IR (cm-1): νmax
=
3030, 1629, 1615, 1588, 1508, 1467, 1438, 1375, 1346, 1173, 1124, 672. MS (70 eV): m/z (%): 197
(M++1, 100). HRMS (ESI) calcd for C13H13N2 197.1073 [M+H]+, found 197.1077.
4.3.4. 8-(3-pyrrolin-1-yl)quinoline 3d (16-53%)
1
Orange viscous oil. Rf (SiO2) = 0.59-0.67 (Petroleumether/EtOAc 4/1). H NMR (400 MHz, CDCl3): δ
4.72 (4H, s); 5.99 (2H, s); 6.68 (1H, dd, J = 7.9, 0.9 Hz); 7.09 (1H, dd, J = 7.9, 0.9 Hz); 7.29 (1H, dd, J =
13
8.3, 4.1 Hz); 7.38 (1H, t, J = 7.9 Hz); 8.02 (1H, dd, J = 8.3, 1.9 Hz); 8.72 (1H, dd, J = 4.1, 1.9 Hz). C
NMR (100.6 MHz, ref = CDCl3) δ 58.3, 109.4, 115.2, 120.6, 126.2, 127.3, 130.1, 135.6, 140.6, 145.4,
145.5. IR (cm-1): νmax = 2853, 1561, 1503, 1476, 1461, 1426, 1398, 1363, 1336, 1166, 1121, 810, 784,
747, 733, 674. MS (70 eV): m/z (%): 197 (M++1,100). HRMS (ESI) calcd for C13H13N2 197.1073 [M+H]+,
found 197.1075.
4.4. General procedure for the synthesis of 1-bromoquinolinyl-3,4-dibromopyrrolidines 4a-c
To a solution of (3-pyrrolin-1-yl)quinolines 3 (0.5 mmol) in dry dichloromethane or tetrahydrofuran
(25 mL) at 0 °C, bromine (1.0 mmol, 2 equiv) was slowly added. After stirring for 1 h at 0 °C under
inert atmosphere (N2), the reaction mixture was poured into water (20 mL) and extracted with ethyl
acetate (3 × 15 mL). The combined organic layers were washed with a saturated sodium bicarbonate
12

ACCEPTED MANUSCRIPT
solution (20 mL) and subsequently dried over anhydrous magnesium sulfate. Filtration of the drying
agent and removal of the solvent in vacuo afforded the crude products 4a-c, which were purified by
means of column chromatography on silica gel followed by purification by means of pTLC.
4.4.1. 1-(4-Bromoquinolin-3-yl)-trans-3,4-dibromopyrrolidine 4a (28%)
1
Light-yellow powder. Rf (SiO2) = 0.51 (Petroleumether/EtOAc 3/1). H NMR (300 MHz, CDCl3): δ 3.91
(2H, d, J = 11.6 Hz); 4.73 (2H, d, J = 3.9 Hz); 4.93 (2H, dd, J = 11.6, 3.9 Hz); 7.59-7.61 (2H, m); 8.02 (1H,
dd, J = 6.1, 3.3 Hz); 8.19 (1H, dd, J = 6.1, 3.3 Hz); 8.70 (1H, s). 13C NMR (75.6 MHz, ref = CDCl3): δ 51.2,
58.0, 120.3, 126.0, 127.6, 128.4, 129.0, 129.5, 140.6, 143.1, 144.4. IR (cm-1): νNH = 3330, νmax = 2924,
1552, 1368, 1343, 1316, 759, 732. MS (70 eV): m/z (%): 433/435/437/439 (M++1, 100). HRMS (ESI)
calcd for C13H12Br3N2 432.8545 [M+H]+, found 432.8543. Tm = 118.5 °C.
4.4.2. 1-(6-Bromoquinolin-5-yl)-trans-3,4-dibromopyrrolidine 4b (28-34%)
1
Orange-red powder. Rf (SiO2) = 0.24-0.38 (Petroleumether/EtOAc 4/1). H NMR (400 MHz, CDCl3): δ
3.75 (2H, dt, J = 11.7, 1.1 Hz); 4.58 (2H, dd, J = 11.7, 4.1 Hz); 4.71 (2H, dt, J = 4.1, 1.1 Hz); 6.95 (1H, d, J
= 8.3 Hz); 7.44 (1H, dd, J = 8.6, 4.2 Hz); 7.92 (1H, d, J = 8.3 Hz); 8.48 (1H, dd, J = 8.6, 1.6 Hz); 9.03 (1H,
13
dd, J = 4.2, 1.6 Hz). C NMR (100.6 MHz, ref = CDCl3) δ 50.8, 59.5, 113.3, 120.0, 124.2, 128.2, 134.8,
136.7, 143.1, 146.3, 149.6. IR (cm-1): νmax = 2922, 1577, 1558, 1453, 1407, 1389, 1361, 1312, 1269,
1219, 1212, 1148, 786, 764. MS (70 eV): m/z (%): 433/435/437/439 (M++1,100). HRMS (ESI) calcd for
C13H12Br3N2 432.8545 [M+H]+, found 432.8530. Tm = 145.5 °C
4.4.3. 1-(5-Bromoquinolin-6-yl)-trans-3,4-dibromopyrrolidine 4c (14%)
Brown-yellow oil. Rf (SiO2) = 0.32 (Petroleumether/EtOAc 3/1). 1H NMR (400 MHz, CDCl3): δ 3.83 (2H,
d, J = 12.0 Hz); 4.69 (2H, dt, J = 3.9, 1.0 Hz); 4.84 (2H, dd, J = 12.0, 3.9 Hz); 7.43 (1H, dd, J = 8.6, 4.2
Hz); 7.52 (1H, d, J = 9.2 Hz); 8.01 (1H, d, J = 9.2 Hz); 8.55 (1H, dd, J = 8.6, 1.5 Hz); 8.76 (1H, dd, J = 4.2,
1.5 Hz). 13C NMR (100.6 MHz, ref = CDCl3): δ 51.3, 58.2, 109.7, 122.0, 122.4, 129.5, 129.6, 134.7,
144.8, 145.4, 148.4. IR (cm-1): νmax = 2850, 1610, 1498, 1356, 800. MS (70 eV): m/z (%):
433/435/437/439 (M++1, 100). HRMS (ESI) calcd for C13H12Br3N2 432.8545 [M+H]+, found 432.8545.
4.5. Procedure for the synthesis of 1-(5-bromoquinolin-6-yl)-2,3,4,5-tetrabromopyrrole 5
To an ice-cooled solution of 6-(3-pyrrolin-1-yl)quinoline 3c (0.5 mmol) in dry dichloromethane (25
mL), bromine (2.0 mmol, 2 equiv) was slowly added. After stirring for 2 h at room temperature, the
reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (3 × 15 mL). The
combined organic layers were washed with a saturated sodium bicarbonate solution (20 mL) and
subsequently dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of
the solvent in vacuo afforded the crude mixture, and 1-(5-bromoquinolin-6-yl)-2,3,4,5-
tetrabromopyrrole 5 was isolated after column chromatography on silica gel followed by purification
by means of pTLC.
4.5.1. 1-(5-Bromoquinolin-6-yl)-2,3,4,5-tetrabromopyrrolidine 5 (9%)
Yellow oil. Rf (SiO2) = 0.4 (Petroleumether/EtOAc 4/1). 1H NMR (400 MHz, CDCl3): δ 7.56 (1H, d, J = 8.9
Hz); 7.64 (1H, dd, J = 8.6, 4.2 Hz); 8.24 (1H, dd, J = 8.9, 0.7 Hz); 8.68 (1H, ddd, J = 8.6, 1.6, 0.7 Hz); 9.07
(1H, dd, J = 4.2, 1.6 Hz). 13C NMR (100.6 MHz, ref = CDCl3): δ 103.1, 104.2, 123.2, 124.8, 128.2, 130.0,
13

ACCEPTED MANUSCRIPT
130.6, 135.8, 136.5, 148.7, 152.6. IR (cm-1): νmax = 2922, 1490, 1458, 1367, 1318, 1297, 1284, 955,
833, 808, 770. MS (70 eV): m/z (%): 585/587/589/591/593/595 (M++1, 100). HRMS (ESI) calcd for
C13H6Br5N2 584.6442 [M+H]+, found 584.6452.
4.6. General procedure for the synthesis of 4-chloro-N-(quinolinyl)butanamides 6a-d
To a solution of aminoquinoline 1 (3.5 mmol) in dry dichloromethane (40 mL) under nitrogen
atmosphere were added potassium carbonate (10.5 mmol, 3 equiv) and butyryl chloride (3.5 mmol, 1
equiv). After stirring for 2 h at room temperature, the reaction mixture was poured into water (30
mL) and extracted with dichloromethane (3 × 15 mL). The combined organic layers were
subsequently dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of
the solvent in vacuo afforded the crude 4-chloro-N-(quinolinyl)butanamides 6a-d (purity > 90%,
NMR), which were used as such for the next reaction.
4.6.1. 4-Chloro-N-(quinolin-3-yl)butanamide 6a (71-97%)
Light-yellow crystals. Rf (SiO2) = 0.27 (Petroleumether/EtOAc 1/2). 1H NMR (300 MHz, CDCl3): δ 2.27
(2H, p, J = 6.6 Hz); 2.69 (2H, t, J = 6.6 Hz); 3.71 (2H, t, J = 6.6 Hz); 7.55 (1H, t, J = 7.2 Hz); 7.55 (1H, s
(broad); 7.65 (1H, t, J = 7.2 Hz); 7.81 (1H, d, J = 7.2 Hz); 8.05 (1H, d, J = 7.2 Hz); 8.75 (1H, d, J = 2.2 Hz);
8.78 (1H, d, J = 2.2 Hz). 13C NMR (75.6 MHz, ref = CDCl3): δ 27.9, 34.0, 44.5, 124.8, 127.6, 127.9, 128.2,
128.4, 128.8, 131.9, 143.6, 144.4, 171.3. IR (cm-1): νNH = 3324, νC=O = 1549, νmax = 2964, 1695, 1676,
1581, 1532, 1384, 746. MS (70 eV): m/z (%): 249/251 (M++1, 100). HRMS (ESI) calcd for C13H14ClN2O
249.0789 [M+H]+, found 249.0792. Tm = 138 °C.
4.6.2. 4-Chloro-N-(quinolin-5-yl)butanamide 6b (44-98%)
1
Light yellow powder. Rf (SiO2) = 0.25 (100% EtOAc). H NMR (300 MHz, CDCl3): δ 2.26 (2H, p, J = 6.6
Hz); 2.71 (2H, t, J = 6.6 Hz); 3.71 (2H, t, J = 6.6 Hz); 7.40 (1H, dd, J = 8.3, 4.4 Hz); 7.67 (1H, t, J = 8.3 Hz);
7.78 (1H, d, J = 8.3 Hz); 7.80 (1H, d, J = 4.4 Hz); 7.97 (1H, d, J = 8.3 Hz); 8.18 (1H, d, J = 8.2 Hz); 8.91
(1H, s (broad)). 13C NMR (75.6 MHz, ref = CDCl3) δ 28.0, 33.8, 44.6, 121.2, 122.4, 123.2, 127.8, 129.3,
130.2, 132.2, 148.5, 150.5, 171.1. IR (cm-1): νNH = 3283, νC=O = 1660, νmax = 1524, 1492, 796, 698, 644.
MS (70 eV): m/z (%): 249/251 (M++1,100). HRMS (ESI) calcd for C13H14ClN2O 249.0789 [M+H]+, found
249.0797. Tm = 115 °C.
4.6.3. 4-Chloro-N-(quinolin-6-yl)butanamide 6c (65-99%)
Light-yellow crystals. Rf (SiO2) = 0.19 (Petroleumether/EtOAc 1/2). 1H NMR (300 MHz, CDCl3): δ 2.25
(2H, p, J = 6.6 Hz); 2.65 (2H, t, J = 6.6 Hz); 3.69 (2H, t, J = 6.6 Hz); 7.40 (1H, dd, J = 8.8, 4.4 Hz); 7.57
(1H, dd, J = 8.8, 2.8 Hz); 7.98 (1H, s (broad)); 8.04 (1H, d, J = 8.8 Hz); 8.12 (1H, d, J = 8.8 Hz); 8.41 (1H,
13
s); 8.84 (1H, d, J = 4.4 Hz). C NMR (75.6 MHz, ref = CDCl3): δ 27.9, 34.2, 44.5, 116.3, 121.8, 123.3,
128.9, 130.1, 135.9, 136.2, 145.4, 149.4, 170.6. IR (cm-1): νNH = 3259, νC=O = 1684, νmax = 2922, 1581,
1561, 1382, 1239, 1233, 828, 802. MS (70 eV): m/z (%): 249/251 (M++1, 100). HRMS (ESI) calcd for
C13H14ClN2O 249.0789 [M+H]+, found 249.0794. Tm = 144 °C.
4.6.4. 4-Chloro-N-(quinolin-8-yl)butanamide 6d (37-99%)
Beige powder. Rf (SiO2) = 0.25 (Petroleumether/EtOAc 9/1). 1HNMR (300 MHz, CDCl3): δ 2.29 (2H, p, J
= 6.6 Hz); 2.78 (2H, t, J = 6.6 Hz); 3.72 (2H, t, J = 6.6 Hz); 7.47 (1H, dd, J = 8.3, 4.4 Hz); 7.52 (1H, t, J =
6.6 Hz); 7.53 (1H, d, J = 6.6 Hz); 8.18 (1H, d, J = 8.3 Hz); 8.76 (1H, d, J = 6.6 Hz); 8.82 (1H, d, J = 4.4 Hz);
9.87 (1H, s (broad)). 13C NMR (75.6 MHz, ref = CDCl3) δ 28.1, 34.7, 44.6, 116.7, 121.70, 121.74, 127.5,
14

ACCEPTED MANUSCRIPT
128.1, 134.4, 136.6, 138.2, 148.2, 170.5. IR (cm-1): νC=O = 1695, νNH = 3355, νmax = 1519, 1483, 1322,
1144, 826, 790, 661. MS (70 eV): m/z (%): 249 /251 (M++1,100). HRMS (ESI) calcd for C13H14ClN2O
249.0789 [M+H]+, found 249.0790. Tm = 64 °C.
4.7. General procedure for the synthesis of (2-oxopyrrolidin-1-yl)quinolines 7a-d
To a solution of 1-quinolinyl-4-chlorobutyramides 6 (2.7 mmol) in acetonitrile (40 mL) was added
potassium tert-butoxide (4.1 mmol, 1.5 equiv). After stirring for 2 h at reflux conditions the reaction
mixture was poured into brine (30 mL) and extracted with ethyl acetate (3 × 15 mL). The combined
organic layers were subsequently dried over anhydrous magnesium sulfate. Filtration of the drying
agent and removal of the solvent in vacuo afforded (2-oxopyrrolidin-1-yl)quinolines 7a-d, which were
purified by means of column chromatography on silica gel.
4.7.1. 3-(2-oxopyrrolidin-1-yl)quinoline 7a (60-90%)
Spectral data of 3-(2-oxopyrrolidin-1-yl)quinoline 7a corresponded with data described in the
literature [36].
4.7.2. 5-(2-oxopyrrolidin-1-yl)quinoline 7b (62%)
1
Yellow oil. Rf (SiO2) = 0.03 (100% EtOAc). H NMR (300 MHz, CDCl3): δ 2.35 (2H, p, J = 7.7 Hz); 2.72
(2H, t, J = 7.7 Hz); 3.89 (2H, t, J = 7.7 Hz); 7.44 (1H, dd, J = 8.3, 2.9 Hz); 7.45 (1H, d, J = 8.3 Hz); 7.73
13
(1H, t, J = 8.3 Hz); 8.10 (2H, d, J = 8.3 Hz); 8.94 (1H, d, J = 2.8 Hz). C NMR (75.6 MHz, ref = CDCl3) δ
19.4, 31.6, 52.0, 121.6, 124.4, 125.0, 129.1, 129.7, 131.8, 135.7, 149.0, 150.9, 175.5. IR (cm-1): νC=O
=
1678, νmax = 1595, 1416, 1402, 1297, 1246, 802, 726, 668. MS (70 eV): m/z (%): 213 (M++1,100).
HRMS (ESI) calcd for C13H13N2O 213.1022 [M+H]+, found 213.1032.
4.7.3. 6-(2-oxopyrrolidin-1-yl)quinoline 7c (70-90%)
Brown-red crystals. Rf (SiO2) = 0.10 (100% EtOAc). 1H NMR (300 MHz, CDCl3): δ 2.20 (2H, p, J = 7.7 Hz);
2.66 (2H, t, J = 7.7 Hz); 3.96 (2H, t, J = 7.7 Hz); 7.73 (1H, dd, J = 7.7, 3.9 Hz); 7.96 (1H, s); 8.07-8.15 (3H,
m); 8.84 (1H, d, J = 3.9 Hz). 13C NMR (75.6 MHz, ref = CDCl3): δ 17.9, 32.8, 48.8, 116.2, 121.6, 122.9,
128.4, 129.9, 135.8, 137.6, 145.4, 149.7, 174.6. IR (cm-1): νC=O = 1689, νmax = 2924, 1505, 1402, 1370,
1332, 1295, 1242, 1219, 879, 838. MS (70 eV): m/z (%): 213 (M++1, 100). HRMS (ESI) calcd for
C13H13N2O 213.1022 [M+H]+, found 213.1029. Tm = 125 °C.
4.7.4. 8-(2-oxopyrrolidin-1-yl)quinoline 7d (72%)
Spectral data of 8-(2-oxopyrrolidin-1-yl)quinoline 7d corresponded with data described in the
literature.[37]
4.8. General procedure for the synthesis of 6-(pyrrolidin-1-yl)quinolines 8a-c
To a solution of (2-oxopyrrolidin-1-yl)quinolines 7 (0.5 mmol) in dry tetrahydrofuran (25 mL), a
lithium aluminium hydride solution (1M in THF) (0.8 mmol, 1.5 equiv) was added slowly under inert
atmosphere (N2) at 0 °C. After stirring for 3 h at reflux conditions, the reaction mixture was quenched
with 10 mL of saturated ammonium chloride solution, poured into water (20 mL) and extracted with
15

ACCEPTED MANUSCRIPT
ethyl acetate (3 × 15 mL). The combined organic layers were dried over anhydrous magnesium
sulfate. Filtration of the drying agent and removal of the solvent in vacuo afforded (pyrrolidin-1-
yl)quinoline 8a-c, which was purified by means of column chromatography on silica gel.
4.8.1. 3-(Pyrrolidin-1-yl)quinoline 8a (40%)
Spectral data of 3-(pyrrolidin-1-yl)quinoline 8a corresponded with data described in the literature
[38].
4.8.2. 5-(Pyrrolidin-1-yl)quinoline 8b (37%)
Spectral data of 5-(pyrrolidin-1-yl)quinoline 8b corresponded with data described in the literature
[39].
4.8.3. 6-(Pyrrolidin-1-yl)quinoline 8c (68%)
Spectral data of 6-(pyrrolidin-1-yl)quinoline 8c corresponded with data described in the literature
[40].
4.9. General procedure for the synthesis of 4-(quinolinylamino)butanols 9a-d
To a solution of (2-oxopyrrolidin-1-yl)quinolines 7 (0.5 mmol) in dry tetrahydrofuran (25 mL) lithium
aluminium hydride solution (1M in THF) (0.8 mmol, 1.5 equiv) was added slowly under inert
atmosphere at 0 °C. After stirring for 2.5 h at room temperature, methanol (25 mL) and sodium
borohydride (0.8 mmol, 1.5 equiv) were added to the mixture. The solution was stirred for three
additional hours at room temperature. Finally the reaction mixture was poured into water (20 mL)
and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over
anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent in vacuo
afforded 4-(quinolinylamino)butanols 9a-d, which were purified by means of pTLC.
4.9.1. 4-(Quinolin-3-ylamino)butanol 9a (40%)
Yellow oil. Rf (SiO2) = 0.11 (100% EtOAc). 1H NMR (300 MHz, CDCl3): δ 1.70-1.87 (4H, m); 3.27 (2H, t, J
= 6.6 Hz); 3.75 (2H, t, J = 6.6 Hz); 7.03 (1H, d, J = 2.2 Hz); 7.38-7.45 (2H, m); 7.62 (1H, d, J = 7.7 Hz);
13
7.94 (1H, d, J = 7.7 Hz); 8.84 (1H, d, J = 2.2 Hz). C NMR (75.6 MHz, ref = CDCl3): δ 25.7, 30.3, 43.6,
62.5, 110.1, 125.0, 126.0, 127.1, 128.9, 129.7, 141.8, 141.9, 143.4. IR (cm-1): νOH,NH = 3328, 3162, νmax
=
2941, 2859, 1612, 1537, 1060, 1017, 778, 753. MS (70 eV): m/z (%): 217 (M++1, 100). HRMS (ESI)
calcd for C13H17N2O 217.1335 [M+H]+, found 217.1343. Tm = 122 °C.
4.9.2. 4-(Quinolin-5-ylamino)butanol 9b (12-17%)
Yellow crystals. Rf (SiO2) = 0.11-0.30 (100% EtOAc). 1H NMR (400 MHz, (CD3)2CO): δ 1.58 (2H, p, J = 6.7
Hz); 1.74 (2H, p, J = 6.7 Hz); 2.78 (2H, s (broad)); 3.20 (2H, t, J = 6.7 Hz); 3.51 (2H, t, J = 6.7 Hz); 6.50
(1H, d, J = 8.1 Hz); 7.18 (1H, d, J = 8.1 Hz); 7.21 (1H, dd, J = 8.6, 4.2 Hz); 7.39 (1H, t, J = 8.1 Hz); 8.56
(1H, dd, J = 8.6, 1.7 Hz); 8.66 (1H, dd, J = 4.2, 1.7 Hz). 13C NMR (100.6 MHz, ref = CDCl3) δ 23.9, 28.5,
42.2, 60.6, 102.6, 116.2, 116.6, 117.3, 127.0, 128.6, 141.9, 147.2, 147.9. IR (cm-1): νNH, OH = 3353, νmax
=
2925, 15.86, 1418, 1351, 1329, 1050, 1025, 793. MS (70 eV): m/z (%): 217 (M++1,100). HRMS (ESI)
calcd for C13H17N2O 217.1335 [M+H]+, found 217.1338. Tm = 124 °C.
16

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4.9.3. 4-(Quinolin-6-ylamino)butanol 9c (40%)
1
Yellow oil. Rf (SiO2) = 0.17 (CH3CN/CH2Cl2 1/3). H NMR (400 MHz, CDCl3): δ 1.69-1.83 (4H, m); 3.23
(2H, t, J = 6.7 Hz); 3.73 (2H, t, J = 6.1 Hz); 6.66 (1H, d, J = 2.6 Hz); 7.05 (1H, dd, J = 9.1, 2.6 Hz); 7.25
(1H, dd, J = 8.2, 4.3 Hz); 7.85 (1H, d, J = 9.1 Hz); 7.91 (1H, dd, J = 8.2, 1.6 Hz); 8.57 (1H, dd, J = 4.3, 1.6
Hz). 13C NMR (100.6 MHz, Ref = CDCl3): δ 25.8, 30.3, 43.7, 62.4, 102.7, 121.3, 121.7, 129.8, 130.3,
134.1, 142.7, 145.6, 146.4. IR (cm-1): νOH, NH = 3313, νmax = 2935, 2864, 1624, 1523, 1383, 1247, 828.
MS (70 eV) m/z (%): 217 (M++1, 100). HRMS (ESI) calcd for C13H17N2O: 217.1335 [M+H]+, found:
217.1337.
4.9.4. 4-(Quinolin-8-ylamino)butanol 9d (25%)
Light yellow-green oil. Rf (SiO2) = 0.23-0.32 (Petroleumether/EtOAc 1/1). 1H NMR (400 MHz, CDCl3): δ
1.71-1.78 (2H, m); 1.81-1.88 (2H, m); 1.96 (1H, s (broad)); 3.32 (2H, t, J = 6.2 Hz); 3.70 (2H, t, J = 6.2
Hz); 6.13 (1H, s (broad)); 6.66 (1H, dd, J = 7.9, 0.9 Hz); 7.03 (1H, dd, J = 7.9, 0.9 Hz); 7.34 (1H, dd, J =
13
8.3, 4.2 Hz); 7.37 (1H, t, J = 7.9 Hz); 8.03 (1H, dd, J = 8.3, 1.7 Hz); 8.69 (1H, dd, J = 4.4, 1.7 Hz). C
NMR (100.6 MHz, ref = CDCl3) δ 25.7, 30.5, 43.2, 62.6, 104.7, 113.7, 121.4, 127.8, 128.7, 136.1, 138.2,
144.8, 146.8. IR (cm-1): νNH, OH = 3400, νmax = 2936, 1575, 1519, 1476, 1379, 1337, 907, 817, 789, 728.
MS (70 eV): m/z (%): 217 (M++1,100). HRMS (ESI) calcd for C13H17N2O 217.1335 [M+H]+, found
217.1333.
4.10. Procedures for the synthesis of 5-quinolinylamino-2-methylpentan-2-ols 10a’-d
1st method: To a solution of 6-(2-oxopyrrolidin-1-yl)quinoline 7c (0.5 mmol) in dry tetrahydrofuran
(25 mL), a methyllithium solution (1.6M in Et2O) (0.5 mmol, 1 equiv) was added slowly under inert
atmosphere (N2) at 0 °C. After stirring for 1 h at 0 °C, again methyllithium solution (1.6M in Et2O) (0.5
mmol, 1 equiv) was added slowly to the mixture, which was stirred for one additional hour at 0 °C.
This step was repeated two more times until a total of 4 equiv of methyllithium was added. Finally
the reaction mixture was quenched with 20 mL of saturated ammonium chloride solution, poured
into water (30 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were
washed with a saturated sodium bicarbonate solution (20 mL) and subsequently dried over
anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent in vacuo
afforded 5-quinolin-6-ylamino-2-methylpentan-2-ol 10c, which was purified by means of pTLC.
2nd method: To a solution of 5-(quinolinylamino)pentan-2-ones 11a-b (0.5 mmol) in dry
tetrahydrofuran (25 mL), methylmagnesium iodide (3M in THF) (1.0 mmol, 2 equiv) was added under
inert atmosphere (N2) at 0 °C. After stirring for 2 h at 0 °C the reaction mixture was quenched with a
solution of saturated ammonium chloride (10 mL) and extracted with ethyl acetate (3 × 15 mL). The
combined organic layers were dried over anhydrous magnesium sulfate. Filtration of the drying agent
and removal of the solvent in vacuo afforded 5-quinolinylamino-2-methylpentan-2-ols 10a-b, which
were purified by means of pTLC.
3rd method: To a solution of 8-(2-oxopyrrolidin-1-yl)quinoline 7d (0.5 mmol) in dry tetrahydrofuran
(25 mL), a methyllithium solution (1.6M in Et2O) (0.5 mmol, 1 equiv) was added slowly under inert
17

ACCEPTED MANUSCRIPT
atmosphere (N2) at 0 °C. After stirring for 1 h at 0 °C, again a methyllithium solution (1.6M in Et2O)
(0.5 mmol, 1 equiv) was added slowly to the mixture. Afterward, the solution was stirred for one
additional hour at 0 °C. Finally the reaction mixture was quenched with 10 mL of saturated
ammonium chloride solution, poured into water (30 mL) and extracted with ethyl acetate (3 × 15
mL). The combined organic layers were washed with a saturated sodium bicarbonate solution (15
mL) and subsequently dried over anhydrous magnesium sulfate. Filtration of the drying agent and
removal of the solvent in vacuo afforded 5-(quinolin-8-ylamino)-2-methylpentan-2-ol 10d, which was
purified by means of pTLC.
4.10.1. 5-(2-Methylquinolin-3-ylamino)-2-methylpentan-2-ol 10a’ (15%)
Yellow oil. Rf (SiO2)= 0.21; (100% EtOAc). 1H NMR (400 MHz, CDCl3): δ 1.28 (6H, s); 1.63-1.68 (2H, m);
1.82-1.92 (2H, m); 2.59 (3H, s); 3.25 (2H, t, J = 7.0 Hz); 7.00 (1H, s); 7.35-7.41 (2H, m); 7.59-7.63 (1H,
13
m); 7.87-7.90 (1H, m). C NMR (100.6 MHz, Ref = CDCl3): δ 19.5, 22.1, 27.6, 39.2, 42.3, 58.5, 107.3,
122.8, 123.7, 124.1, 126.2, 127.2, 138.6, 139.1, 147.4. IR (cm-1): νOH, NH = 3346, νmax = 2965, 2929,
1608, 1515, 1487, 1467, 1486, 1438, 1386, 1360, 1331, 1243, 1183, 749. MS (70 eV) m/z (%): 259
(M++1, 100). HRMS (ESI) calcd for C16H23N2O 259.1805 [M+H]+, found 259.1810.
4.10.2. 5-(Quinolin-5-ylamino)-2-methylpentan-2-ol 10b (23%)
Green oil. Rf (SiO2) = 0.09-0.15 (Petroleumether/EtOAc 4/1). 1H NMR (400 MHz, CDCl3): δ 1.25 (6H, s);
1.63-1.68 (2H, m); 1.83-1.90 (2H, m); 3.33 (2H, t, J = 6.9 Hz); 6.15 (1H, s (broad)); 6.67 (1H, dd, J = 7.9,
0.9 Hz); 7.03 (1H, dd, J = 7.9, 0.9 Hz); 7.35 (1H, dd, J = 8.2, 4.3 Hz); 7.37 (1H, t, J = 7.9 Hz); 8.04 (1H,
dd, J = 8.2, 1.7 Hz); 8.70 (1H, dd, J = 4.3, 1.7 Hz). 13C NMR (100.6 MHz, ref = CDCl3) δ 24.3, 29.3, 41.4,
43.9, 70.8, 104.6, 113.7, 121.4, 127.8, 128.7, 136.0, 138.2, 144.9, 146.8. IR (cm-1): νNH, OH = 3401, νmax
=
2967, 1575, 1520, 1378, 13.36, 817, 789, 731. MS (70 eV): m/z (%): 245 (M++1,100). HRMS (ESI) calcd
for C15H21N2O 245.1648 [M+H]+, found 245.1650.
4.10.3. 5-(Quinolin-6-ylamino)-2-methylpentan-2-ol 10c (43%)
Yellow oil. Rf (SiO2) = 0.21 (100% EtOAc). 1H NMR (400 MHz, CDCl3): δ 1.26 (6H, s); 1.59-1.65 (2H, m);
1.76-1.83 (2H, m); 3.23 (2H, t, J = 7.0 Hz); 6.68 (1H, d, J = 2.6 Hz); 7.07 (1H, dd, J = 9.1, 2.6 Hz); 7.25
(1H, dd, J = 8.4, 4.2 Hz); 7.86 (1H, d, J = 9.1 Hz); 7.91 (1H, dd, J = 8.4, 1.6 Hz); 8.59 (1H, dd, J = 4.2, 1.6
Hz). 13C NMR (100.6 MHz, Ref = CDCl3): δ 24.1, 29.5, 41.1, 44.4, 70.7, 102.7, 121.4, 121.5, 130.0,
130.2, 133.9, 143.0, 145.9, 146.3. IR (cm-1): νOH, NH = 3314, νmax = 2966, 1624, 1523, 1469, 1381, 1243,
828. MS (70 eV) m/z (%): 245 (M++1, 100). HRMS (ESI) calcd for C15H21N2O 245.1648 [M+H]+, found
245.1657.
4.10.4. 5-(Quinolin-8-ylamino)-2-methylpentan-2-ol 10d (26-43%)
Yellow oil. Rf (SiO2) = 0.29 (Petroleumether/EtOAc 1/1). 1H NMR (300 MHz, CDCl3): δ 1.24 (6H, s); 1.64
(2H, t, J = 7.7 Hz); 1.86 (2H, p, J = 7.7 Hz); 3.32 (2H, t, J = 7.7 Hz); 6.15 (1H, s (broad)); 6.66 (1H, d, J =
7.7 Hz); 7.03 (1H, d, J = 7.7 Hz); 7.34 (1H, dd, J = 8.3, 4.4 Hz); 7.38 (1H, t, J = 7.7 Hz); 8.04 (1H, d, J =
13
8.3 Hz); 8.70 (1H, d, J = 4.4 Hz). C NMR (75.6 MHz, ref = CDCl3) δ 24.4, 29.4, 41.5, 44.0, 70.9, 104.7,
113.7, 121.5, 127.9, 128.8, 136.1, 138.2, 144.9, 146.9. IR (cm-1): νNH/OH = 3400, νmax = 2965, 1574,
1519, 1378, 1336, 817, 789, 739. MS (70 eV): m/z (%): 245 (M++1,100). HRMS (ESI) calcd for
C15H21N2O 245.1648 [M+H]+, found 245.1654.
18

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4.11. General procedure for the synthesis of 5-(quinolinylamino)pentan-2-ones 11a-c
To a solution of 1-quinolinylpyrrolidin-2-one 7 (0.5 mmol) in dry tetrahydrofuran (25 mL), a
methyllithium solution (1.6M in Et2O) (0.5 mmol, 1 equiv) was added slowly under inert atmosphere
(N2) at 0 °C. After stirring for 1 h at 0 °C, again a methyllithium solution (1.6M in Et2O) (0.5 mmol, 1
equiv) was added slowly to the mixture. Afterward, the solution was stirred for one additional hour
at 0 °C. Finally the reaction mixture was quenched with 10 mL of saturated ammonium chloride
solution and poured into water (30 mL) and extracted with ethyl acetate (3 × 15 mL). The combined
organic layers were washed with a saturated sodium bicarbonate solution (15 mL) and subsequently
dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent in
vacuo afforded 5-(quinolinylamino)pentan-2-ones 11a-c. These methylketones were not stable
enough to purify over silica gel and were thus used as such for further reactions (purity > 90%, NMR).
For the synthesis of 5-(2-methylquinolin-3-yl)pentan-2-one 11a’, the reaction was performed at room
temperature instead of at 0 °C.
4.11.1. 5-(Quinolin-3-ylamino)pentan-2-one 11a (70-97%)
Yellow-orange oil. Rf (SiO2) = 0.51 (CH3CN/CH2Cl2 3/1). 1H NMR (300 MHz, CDCl3): δ 1.97 (2H, p, J = 6.6
Hz); 2.18 (3H, s); 2.62 (2H, t, J = 6.6 Hz); 3.21 (2H, t, J = 6.6 Hz); 4.19 (1H, s (broad)); 7.01 (1H, d, J =
2.2 Hz); 7.37-7.44 (2H, m); 7.61 (1H, d, J = 7.7 Hz); 7.93 (1H, d, J = 7.7 Hz); 8.41 (1H, d, J = 2.2 Hz). 13C
NMR (75.6 MHz, ref = CDCl3): δ 22.8, 30.1, 41.1, 43.0, 109.7, 124.8, 126.0, 127.0, 127.7, 128.6, 128.8,
129.7, 143.5, 208.7. IR (cm-1): νNH = 3362, νC=O = 1709, νmax = 2949, 1608, 1389, 1368, 1350, 780, 748.
MS (70 eV): m/z (%): 229 (M++1, 100). HRMS (ESI) calcd for C14H17N2O 229.1335 [M+H]+, found
229.1340.
4.11.2. 5-(Quinolin-3-ylamino)pentan-2-one 11a’ (75-95%)
1
Due to the instability of this compound complete characterization was not possible, and only the H
NMR data are depicted below.
1H NMR (400 MHz, CDCl3): δ 2.05 (2H, t, J = 6.6 Hz, CH2CH2CO); 2.05 (1H, s (broad), NH); 2.21 (3H, s);
2.63-2.70 (5H, m); 3.25 (2H, t, J = 6.6 Hz); 7.04 (1H, s); 7.39-7.42(2H, m); 7.61-7.64 (1H, m); 7.94-7.99
(1H, m).
4.11.3. 5-(Quinolin-5-ylamino)pentan-2-one 11b (84-92%)
1
Yellow oil. Rf (SiO2) = 0.30 (100% EtOAc). H NMR (300 MHz, CDCl3): δ 2.03 (2H, p, J = 6.6 Hz); 2.16
(3H, s); 2.65 (2H, t, J = 6.6 Hz); 3.23 (2H, t, J = 6.6 Hz); 4.85 (1H, s (broad)); 6.55 (1H, d, J = 8.3 Hz);
7.30 (1H, dd, J = 8.3, 4.4 Hz); 7.45 (1H, d, J = 8.3 Hz); 7.54 (1H, t, J = 8.3 Hz); 8.18 (1H, d, J = 8.3 Hz);
8.84 (1H, d, J = 4.4 Hz). 13C NMR (75.6 MHz, ref = CDCl3) δ 22.5, 30.2, 41.9, 44.1, 104.0, 117.9, 118.5,
119.4, 129.2, 130.6, 144.0, 149.2, 149.9, 209.7. IR (cm-1): νC=O = 1707, νNH = 3368, νmax = 2360, 1586,
1576, 1415, 1327, 788, 731. MS (70 eV): m/z (%): 229 (M++1,100). HRMS (ESI) calcd for C14H17N2O
229.1335 [M+H]+, found 229.1340.
4.11.4. 5-(Quinolin-6-ylamino)pentan-2-one 11c (90-99%)
Brown-yellow oil. Rf (SiO2) = 0.15 (Petroleumether/EtOAc 1/2).1H NMR (400 MHz, CDCl3): δ 1.99 (2H,
p, J = 6.8 Hz); 2.18 (3H, s); 2.63 (2H, t, J = 6.8 Hz); 3.24 (2H, t, J = 6.8 Hz); 6.69 (1H, d, J = 2.6 Hz); 7.07
19

ACCEPTED MANUSCRIPT
(1H, dd, J = 9.1, 2.6 Hz); 7.26 (1H, dd, J = 8.0, 4.2 Hz); 7.86 (1H, d, J = 9.1 Hz); 7.91 (1H, dd, J = 8,0, 1.6
13
Hz); 8.61 (1H, dd, J = 4.2, 1.6 Hz). C NMR (100.6 MHz, ref = CDCl3): δ 22.9, 30.0, 41.1, 43.3, 102.6,
121.3, 121.5, 130.0, 130.2, 133.8, 143.0, 145.9, 146.2, 208.5. IR (cm-1): νNH = 3342, νC=O = 1708, νmax
=
2928, 1608, 1504, 1378, 1292, 1244, 828, 208,5. MS (70 eV): m/z (%): 229 (M++1, 100). HRMS (ESI)
calcd for C14H17N2O 229.1335 [M+H]+, found 229.1343.
4.12. General procedure for the synthesis of (2-methylpyrrolidin-1-yl)quinolines 12a-c
To a solution of 5-(quinolinylamino)pentan-2-ones 11 (0.5 mmol) in methanol (25 mL), acetic acid
(2.5 mmol, 5 equiv) and sodium cyanoborohydride (1.0 mmol, 2 equiv) were added. After stirring for
3 h at room temperature, the reaction mixture was poured into water (20 mL) and extracted with
dichloromethane (3 × 15 mL). The combined organic layers were dried over anhydrous magnesium
sulfate and filtration of the drying agent and removal of the solvent in vacuo afforded the crude
products 12a-c, which were purified by means of column chromatography on silica gel or pTLC.
4.12.1. 3-(2-Methylpyrrolidin-1-yl)quinoline 12a (61%)
1
Yellow oil. Rf (SiO2) = 0.55 (Petroleumether/EtOAc 1/2). H NMR (300 MHz, CDCl3): δ 1.25 (3H, d, J =
6.6 Hz); 1.75-1.85 (1H, m); 2.05-2.21 (3H, m); 3.27-3.35 (1H, m); 3.56-3.61 (1H, m); 4.08 (1H, p, J = 6.6
Hz); 6.98 (1H, d, J = 2.2 Hz); 7.34-7.42 (2H, m); 7.61 (1H, d, J = 7.7 Hz); 7.94 (1H, d, J = 7.7 Hz); 8.57
(1H, d, J = 2.2 Hz). 13C NMR (75.6 MHz, ref = C6D6): δ 18.8, 22.8, 32.7, 47.5, 53.2, 110.6, 124.2, 125.8,
126.7, 129.8, 130.1, 140.6, 141.1, 141.9. IR (cm-1): νmax = 2963, 1594, 1432, 1393, 1379, 1370, 745. MS
(70 eV): m/z (%): 213 (M++1, 100). HRMS (ESI) calcd for C14H17N2 213.1386 [M+H]+, found 213.1393.
4.12.2. 2-Methyl-3-(2-methylpyrrolidin-1-yl)quinoline 12a’ (33%)
1
Brown-yellow oil. Rf (SiO2) = 0.5 (100% EtOAc). H NMR (400 MHz, CDCl3): δ 1.05 (3H, d, J = 6.0 Hz);
1.61-1.71 (1H, m); 1.80-1.91 (1H, m); 1.95-2.04 (1H, m); 2.19-2.29 (1H, m); 2.71 (3H, s); 2.89 (1H, td, J
= 8.7, 3.8 Hz); 3.66-3.73 (1H, m); 3.79-3.87 (1H, m); 7.39-7.43 (1H, m); 7.43 (1H, s); 7.47-7.51 (1H, m);
13
7.66 (1H, dd, J = 8.0, 1.2 Hz); 7.95 (1H, d, J = 8.3 Hz). C NMR (100.6 MHz, ref=CDCl3): δ 18.7, 23.7,
23.8, 33.9, 53.1, 55.0, 120.6, 125.8, 126.2, 126.6, 127.9, 142.71, 142.72, 143.0, 156.5. IR (cm-1): νmax
=
2964, 1594, 1424, 1375, 1362, 1347, 1325, 749. MS (70 eV): m/z (%): 227 (M++1, 100). HRMS (ESI)
calcd for C15H19N2 227.1543 [M+H]+, found 227.1541.
4.12.3. 5-(2-methylpyrrolidin-1-yl)quinoline 12b (31%)
Yellow oil. Rf (SiO2) = 0.13 (Petroleumether/EtOAc 4/1). 1H NMR (400 MHz, CDCl3): 1.08 (3H, d, J = 6.0
Hz); 1.65-1.74 (1H, m); 1.79-1.90 (1H, m); 1.96-2.04 (1H, m); 2.20-2.27 (1H, m); 2.99 (2H, td, J = 8.8,
4.7 Hz); 3.74 (1H, m); 7.03 (1H, d, J = 7.5 Hz); 7.32 (1H, dd, J = 8.6, 4.2 Hz); 7.59 (1H, dd, J = 8.4, 7.6
Hz); 7.72 (1H, d, J = 8.4 Hz); 8.54 (1H, dd, J = 8.5, 1.6 Hz); 8.85 (1H, dd, J = 4.2, 1.6 Hz). 13C NMR (100.6
MHz, ref = 100.6 MHz): δ 18.7, 23.8, 33.8, 55.7, 56.0, 114.0, 119.3, 122.8, 124.9, 129.4, 133.4, 147.2,
149.6, 149.9. IR (cm-1): νmax = 2963, 1587, 1570, 1464, 1398, 1315, 1286, 1089, 794. MS (70 eV): m/z
(%): 213 (M++1,100). HRMS (ESI) calcd for C14H17N2 213.1386 [M+H]+, found 213.1389.
4.12.4. 6-(2-methylpyrrolidin-1-yl)quinoline 12c (27%)
1
Brown-yellow oil. Rf (SiO2) = 0.3 (Petroleumether/EtOAc 1/2). H NMR (400 MHz, CDCl3): δ 1.24 (3H,
d, J = 6.2 Hz); 1.76-1.79 (1H, m); 2.03-2.18 (3H, m); 3.26-3.33 (1H, m); 3.51-3.56 (1H, m); 4.01-4.07
(1H, m); 6.63 (1H, d, J = 2.7 Hz); 7.21-7.25 (2H, m); 7.91 (1H, dd, J = 8.1, 1.4 Hz); 7.93 (1H, d, J = 9.4
Hz); 8.57 (1H, dd, J = 4.2, 1.4 Hz). 13C NMR (100.6 MHz, ref=CDCl3): δ 19.3, 23.3, 33.1, 48.3, 53.8,
20

ACCEPTED MANUSCRIPT
103.6, 119.4, 121.2, 129.7, 130.3, 133.9, 141.5, 145.1, 145.3. IR (cm-1): νmax = 2962, 1618, 1589, 1380,
1364, 1124, 1076, 823. MS (70 eV): m/z (%): 213 (M++1, 100). HRMS (ESI) calcd for C14H17N2 213.1386
[M+H]+, found 213.1394.
4.13. General procedure for the synthesis of 5-(quinolinylamino)pentan-2-ols 13a-c
To a solution of 5-(quinolinylamino)pentan-2-ones 11 (0.5 mmol) in methanol (25 mL), sodium
borohydride (0.8 mmol, 1.5 equiv) was added. After stirring for 2 h at room temperature, the
reaction mixture was poured into water (20 mL) and extracted with dichloromethane (3 × 15 mL).
The combined organic layers were dried over anhydrous magnesium sulfate, and filtration of the
drying agent and removal of the solvent in vacuo afforded the crude 5-(quinolinylamino)pentan-2-ols
13a-c, which were purified by means of pTLC.
4.13.1. 5-(Quinolin-3-ylamino)pentan-2-ol 13a (32%)
Yellow oil. Rf (SiO2) = 0.13 (100% EtOAc).1H NMR (400 MHz, CDCl3): δ 1.23 (3H, d, J = 6.2 Hz); 1.57-
1.62 (2H, m); 1.70-1.88 (2H, m); 3.20 (2H, t, J = 7.1 Hz); 3.88 (1H, sext, J = 6.2 Hz); 6.98 (1H, d, J = 2.8
Hz); 7.36-7.43 (2H, m); 7.59 (1H, dd, J = 7.3, 2.3 Hz); 7.93 (1H, dd, J = 7.3, 2.3 Hz); 8.40 (1H, d, J = 2.8
Hz). 13C NMR (100.6 MHz, ref = CDCl3): δ 23.8, 25.4, 36.6, 43.6, 67.6, 109.9, 124.8, 125.9, 126.9,
128.8, 129.6, 141.77, 141.81, 143.3. IR (cm-1): νOH, NH = 3306, νmax = 2962, 2930, 1611, 1535, 1488,
1473, 1392, 1372, 1350, 1223, 779, 748. MS (70 eV): m/z (%): 231 (M++1, 100). HRMS (ESI): calcd for
C14H19N2O 231.1492 [M+H]+, found 231.1491.
4.13.2. 5-(2-Methylquinolin-3-ylamino)pentan-2-ol 13a’ (20%)
Yellow oil. Rf (SiO2) = 0.18 (100% EtOAc).1H NMR (400 MHz, CDCl3): δ 1.25 (3H, d, J = 6.2 Hz); 1.59-
1.66 (2H, m); 1.77-1.91 (2H, m); 2.57 (3H, s); 3.24 (2H, t, J = 7.0 Hz); 3.91 (1H, sext, J = 6.2 Hz); 6.99
(1H, s); 7.35-7.40 (2H, m); 7.58-7.62 (1H, m); 7.87-7.91 (1H, m). 13C NMR (100.6 MHz, ref=CDCl3): δ
21.3, 23.9, 25.3, 36.7, 43.8, 67.7, 109.3, 124.7, 125.5, 126.0, 128.0, 129.1, 140.5, 140.9, 149.3. IR (cm-
1): νOH, NH = 3337, νmax = 2962, 2929, 1608, 1517, 1488, 1436, 1418, 1387, 1372, 1359, 1245, 749. MS
(70 eV): m/z (%): 245 (M++1, 100). HRMS (ESI): calcd for C15H21N2O 245.1648 [M+H]+, found 245.1655.
4.13.3. 5-(Quinolin-5-ylamino)pentan-2-ol 13b (15-18%)
Yellow oil. Rf (SiO2) = 0.19-0.36 (100% EtOAc).1H NMR (400 MHz, CDCl3): 1.26 (3H, d, J = 6.2 Hz); 1.63-
1.68 (2H, m); 1.83-1.95 (2H, m); 3.30 (2H, t, J = 6.8 Hz); 3.92 (1H, sext, J = 6.2 Hz); 6.62 (1H, dd, J = 7.8,
0.7 Hz); 7.30 (1H, dd, J = 8.5, 4.2 Hz); 7.47 (1H, dd, J = 8.4, 0.7 Hz); 7.56 (1H, dd, J = 8.4, 7.8 Hz); 8.17
(1H, dd, J = 8.5, 1.6 Hz); 8.85 (1H, dd, J = 4.2, 1.6 Hz). 13C NMR (100.6 MHz, ref = CDCl3): δ 23.9, 25.5,
36.8, 44.3, 67.9, 104.5, 118.1, 118.4, 119.2, 128.8, 130.5, 143.8, 149.1, 149.9. IR (cm-1): νNH, OH = 3344,
νmax = 2925, 1610, 1585, 1579, 1535, 1484, 1463, 1417, 1371, 1350, 1328, 1284, 1118, 789. MS (70
eV): m/z (%): 231 (M++1,100). HRMS (ESI) calcd for C14H19N2O 231.1492 [M+H]+, found 231.1499.
4.13.4. 5-(Quinolin-6-ylamino)pentan-2-ol 13c (50%)
Yellow oil. Rf (SiO2) = 0.13 (100% EtOAc).1H NMR (400 MHz, CDCl3): δ 1.22 (3H, d, J = 6.2 Hz); 1.55-
1.62 (2H, m); 1.67-1.85 (2H, m); 3.17 (2H, t, J = 6.9 Hz); 3.87 (1H, sext, J = 6.2 Hz); 6.62 (1H, d, J = 2.6
Hz); 7.01 (1H, dd, J = 9.1, 2.6 Hz); 7.21 (1H, dd, J = 8.3, 4.2 Hz); 7.83 (1H, d, J = 9.1 Hz); 7.87 (1H, dd, J
= 8.3, 1.4 Hz); 8.55 (1H, dd, J = 4.2, 1.4 Hz). 13C NMR (100.6 MHz, ref = CDCl3): δ 23.8, 25.5, 36.7, 43.9,
67.4, 102.6, 121.3, 121.6, 129.8, 130.3, 133.9, 142.8, 145.6, 146.4. IR (cm-1): νOH, NH = 3318, νmax
=
21

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2926, 1623, 1521, 1468, 1381, 1247, 1124, 826. MS (70 eV): m/z (%): 231 (M++1, 100). HRMS (ESI):
calcd for C14H19N2O 231.1492 [M+H]+, found 231.1503.
4.14. Bioactivity evaluation methods
4.14.1. In vitro antimalarial assay
The test samples were prepared to a 20 mg/mL stock solution in 100% DMSO. Stock solutions were
stored at -20 °C. Further dilutions were prepared on the day of the experiment. Chloroquine
andartenusate were used as the reference drugs in all experiments. A full dose-response was
performed for all compounds with a starting concentration of 10 µg/mL, which was then serially
diluted twofold in complete medium to give 10 concentrations; with the lowest concentration being
0.02 µg/mL. The same dilution technique was used for all samples. Reference drugs were tested at a
starting concentration of 1000 ng/mL against a CQS strain. The highest concentration of solvent to
which the parasites were exposed to had no measurable effect on the parasite viability (data not
shown).
4.14.2. In vitro assay for the evaluation of cytotoxic activity
The same stock solution which was prepared for antiplasmodial assays were used for this assay.
Dilutions were prepared on the day of the experiment. Emetine was used as the reference drug in all
experiments. The initial concentration of emetine was 100 µg/mL, which was serially diluted in
complete medium with 10-fold dilutions to give 6 concentrations, the lowest being 0.001 µg/mL. The
same dilution technique was applied to all test samples. The highest concentration of solvent to
which the cells were exposed to had no measurable effect on the cell viability. The 50% inhibitory
concentration (IC50) were obtained using a non-linear dose-response curve fitting analysis via Graph
Pad Prism v.4.0 software.
4.14.3. Antimicrobial evaluation - Disk diffusion method
The fungal strains were subcultured onto Sabouraud dextrose agar at 37 °C (C. albicans and A. flavus)
or 20 °C (R. bogoriensis). Inoculum was prepared by suspending distinct colonies (yeasts) or
mycelium and spores (A. flavus) into sterile saline, until a transmittance equivalent to a 0.5
McFarland standard was obtained. The fungal inocula were streaked evenly over the dried surface of
Mueller-Hinton + GMB plates (20% glucose, 0.5 µg/mL Methylene Blue dye) by using a sterile cotton
swab. The disks were then dispensed over the surface of the inoculated agar, nystatin and DMSO
disks were used as positive and negative control respectively. The compounds (dissolved in DMSO)
were applied to sterile antibiotic assay paper (Whattman, 6mm) and the disks were freeze-dried
22

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before being dispensed over the surface of the inoculated agar surface. The plates were incubated at
37 °C for 1 day (C. albicans and A. flavus) or 20 °C for 4 days (R. bogoriensis). In the experimental
setup, a compound dose of 600 µg/dish was tested in triplicate.
4.14.4. Antimicrobial evaluation – MIC determination test via microdilution
For each compound, a log2 dilution series was prepared in a 96-well microtiter plate starting from
stock solutions of the 6 compounds in 10% DMSO, which were then 1:5 diluted with RPMI 1640
medium, supplemented with glutamine and without bicarbonate (Sigma). A 1:1000 dilution with
RPMI 1640 medium was used as working suspension (1 × 103 CFU/mL) for C. albicans and A. flavus
and a 1:10 dilution with RPMI 1640 medium was used as working suspension (1 × 105 CFU/mL) for R.
bogoriensis; 100 µL of the working suspension was added to 100 µL of the log2 dilution series. The
plates were incubated at 37 °C (C. albicans and A. flavus) or 20 °C (R. bogoriensis), and the results
were read with a microtiter plate spectrophotometer (Bio-rad) at 530 nm. The MIC was decided to
be the concentration giving rise to an inhibition of growth of 50% of that of the negative control (1%
DMSO in medium), Amphotericin B was used as positive control.
Acknowledgements
The authors are indebted to Ghent University (BOF) for financial support. The University of Cape
Town, South African Medical Research Council, and South African Research Chairs Initiative of the
Department of Science and Technology, administered through the South African National Research
Foundation are gratefully acknowledged for support (K.C).
23

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Compound
Quinolin-
3-yl
Position Br Yield (%)
2a
2b
2c
2d
3a
3b
3c
3d
4a
4b
4c
5
-
90-99a
79-95
50-70a
71
5-yl
-
6-yl
-
8-yl
-
3-yl
-
-
20-53
48-82
50-80
16-53
28
5-yl
6-yl
-
8-yl
-
3-yl
4-Br
6-Br
5-Br
5-Br
5-yl
28-34
14
6-yl
6-yl
9
a Crude yields, purity >90% (NMR)

ACCEPTED MANUSCRIPT
Compound
Quinolin-
3-yl
5-yl
6-yl
8-yl
3-yl
5-yl
6-yl
8-yl
5-yl
6-yl
3-yl
5-yl
6-yl
8-yl
3-yl
R
Yield (%)
Compound
10b
Quinolin-
5-yl
6-yl
8-yl
3-yl
3-yl
5-yl
6-yl
3-yl
3-yl
5-yl
6-yl
3-yl
3-yl
5-yl
6-yl
R
H
Yield (%)
23
84a
95a
93a
97a
75
62
80
72
37
68
40
15
40
25
15
6a
6b
6c
-
-
10c
H
43
-
10d
H
40
6d
7a
7b
7c
-
11a
H
83a
85a
88a
94a
61
-
11a’
11b
CH3
H
-
-
11c
H
7d
8b
8c
-
12a
H
-
12a’
12b
CH3
H
33
-
31
9a
9b
9c
-
12c
H
27
-
13a
H
20
-
-
13a’
13b
CH3
H
20
9d
10a’
17
CH3
13c
H
50
a Crude yields, purity >90% (NMR)