The synthesis and evaluation of quinolinequinones as anti-mycobacterial agents

Article abstract of DOI:10.1016/j.bmc.2019.06.002

A library of thirty-two quinolinequinones (QQs) with various amine substituents at the 6- and 7-positions were synthesised efficiently and in good yields for evaluation as potential anti-tuberculosis agents. Mycobacterium tuberculosis growth inhibition as

Full text of DOI:10.1016/j.bmc.2019.06.002

Accepted Manuscript
The synthesis and evaluation of quinolinequinones as anti-mycobacterial agents
Kristiana T. Santoso, Ayana Menorca, Chen-Yi Cheung, Gregory M. Cook,
Bridget L. Stocker, Mattie S.M. Timmer
PII:
S0968-0896(19)30689-3
https://doi.org/10.1016/j.bmc.2019.06.002
BMC 14939
DOI:
Reference:
Bioorganic & Medicinal Chemistry
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Revised Date:
Accepted Date:
27 April 2019
30 May 2019
1 June 2019
Please cite this article as: Santoso, K.T., Menorca, A., Cheung, C-Y., Cook, G.M., Stocker, B.L., Timmer, M.S.M.,
The synthesis and evaluation of quinolinequinones as anti-mycobacterial agents, Bioorganic & Medicinal
Chemistry (2019), doi: https://doi.org/10.1016/j.bmc.2019.06.002
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The synthesis and evaluation of
quinolinequinones as anti-mycobacterial
agents
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Kristiana T. Santoso,a,b,c Ayana Menorca,d Chen-Yi Cheung,d Gregory M. Cook,c,d Bridget L. Stocker,a,b,c,*
Mattie S. M. Timmer a,b,c,*
a School of Chemical and Physical Sciences, Victoria University of Wellington, PO Box 600, Wellington, New
Zealand
b Centre for Biodiscovery, Victoria University of Wellington, PO Box 600, Wellington, New Zealand
c Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
d Department of Microbiology and Immunology, School of Biomedical Science, University of Otago, Dunedin,
New Zealand

Bioorganic & Medicinal Chemistry
The synthesis and evaluation of quinolinequinones as anti-mycobacterial agents
Kristiana T. Santosoa,b,c, Ayana Menorcad, Chen-Yi Cheungd, Gregory M. Cookc,d, Bridget L. Stockera,b,c,*
Mattie S. M. Timmera,b,c,*
,
a School of Chemical and Physical Sciences, Victoria University of Wellington, PO Box 600, Wellington, New Zealand
b Centre for Biodiscovery, Victoria University of Wellington, PO Box 600, Wellington, New Zealand
c Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
d Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A library of thirty-two quinolinequinones (QQs) with various amine substituents at the 6- and 7-
positions were synthesised efficiently and in good yields for evaluation as potential anti-
tuberculosis agents. Mycobacterium tuberculosis growth inhibition assays demonstrated that
QQs bearing moderate length alkyl chains (i.e. heptylphenylamino- and octylamino-QQs), and
aryl groups (i.e. phenylethylamino- and benzylamino-QQs) exhibited encouraging inhibitory
activity, while QQ analogue 7-chloro-6-propargylamino-quinoline-5,8-dione (16b) had excellent
inhibitory activity (MIC = 8 μM). The cLogP values and redox activities of the QQs were
determined, and neither readout correlated with the anti-mycobacterial activities of the
compounds. Notwithstanding, mode of action studies of 16b revealed that treatment of M.
tuberculosis with this compound led to activation of NADH-dependent oxygen consumption
suggesting a redox cycling mechanism. To this end, the promising anti-mycobacterial activity of
several QQs and their ability to perturb oxygen management leading to an uncontrolled
respiratory burst, as identified in this work and by others, demonstrates the merit of further
optimising the anti-mycobacterial activity of this readily synthesised class of compound.
Available online
Keywords:
Quinolinequinones
Tuberculosis
Organic Synthesis
©2019 Elsevier Ltd. All rights reserved.
1. Introduction
which the redox potentials of biologically active quinones
correlated with good therapeutic activity.15-18
The quinolinequinone (QQ) scaffold is an important structural
motif in many biologically active molecules, including a number
of anti-cancer,1-4 anti-malarial,5 anti-viral,6 and anti-bacterial7,8
agents. For example, structure-activity relationship studies of the
anti-cancer metabolite streptonigrin (1, Figure 1) revealed the QQ
scaffold to be essential for the natural product’s anti-proliferative
activity.9,10 Similarly, commercially available anti-cancer drug
LY83583 (2)11 was found to exhibit its anti-cancer activity
through the redox cycling of the QQ motif and the concomitant
overproduction of reactive oxygen species (ROS).11,12 In addition
to their anti-cancer properties, several anti-mycobacterial QQs
have been reported, including 6-cyclo-octyl-QQ (3), which
inhibits Mycobacterium tuberculosis growth at low
concentrations (MIC = 3.5 μM),8,13 and enamine-benzoquinone 4,
which exhibits inhibitory activity against drug-resistant strains of
M. tuberculosis (MIC = 1.2 μM),14 with SAR analysis of the
latter showing the quinone ring to be essential for anti-tubercular
activity.14 Indeed, the pharmaceutical properties of quinones is
often attributed to their propensity to undergo redox reactions,
with several studies demonstrating an optimal voltage window in
Figure 1. Examples of biologically active quinolinequinones
———
* Corresponding authors. Tel.: +64 4 463 6481 (B.L.S.); tel.: +64 4 463 6529 (M.S.M.T.). E-mail addresses: bridget.stocker@vuw.ac.nz (B.L.
Stocker), mattie.timmer@vuw.ac.nz (M.S.M.Timmer)

Previously, we synthesised a library of QQs that exhibited
bacteriostatic activity against M. bovis19 and M. tuberculosis.20
Further mechanistic studies revealed that amine-functionalised
QQ8c (5) can specifically activate the mycobacterial type II
NADH dehydrogenase (NDH-II), an essential enzyme for the
growth and viability of M. tuberculosis, and by doing so,
ultimately leads to oxygen mis-management and the production
of lethal levels of ROS.20 NDH-II is a small monotopic
membrane protein that catalyses the redox reactions between
bound substrates NADH, flavin adenine dinucleotide (FAD), and
menaquinone.21-24 As NDH-II is absent in mammalian cells, it is
an attractive target in the ongoing search for new anti-
tuberculosis agents.21 Accordingly, we set out to synthesise a
library of 6- and 7-arylamine- and alkylamine-substituted QQs
(I-IV, Figure 2) so as to better explore the anti-mycobacterial
SAR around this class of compounds. Here, the incorporation of
tertiary amines would provide insight into potential hydrogen
bonding interactions involving the amine proton, while aliphatic
amines will increase the lipophilicity of the QQs, which could
enhance the ability of the compounds to penetrate the bacterial
cell wall, and moreover, facilitate interactions with the
hydrophobic grooves surrounding the NDH-II quinone binding
site.22-25 Similarly, aryl-substituted QQs might better interact with
NDH-II due to potential π-stacking interactions with the FAD
isoalloxazine ring or other aromatic side chains in the NDH-II Q-
site (i.e. Y13 and Y383).22
With QQs 10-27 in hand, the compounds were then screened
for their ability to inhibit the growth of M. tuberculosis (Table 1).
The cLogP, the calculated partition coefficient between n-octanol
and water, which provides an indication of the hydrophilicity and
the capacity of compounds to penetrate the cell wall, was
calculated,30 and the redox potentials of the QQs were also
determined via cyclic voltammetry (CV) in acetonitrile against an
Ag/Ag+ electrode.
Figure 2. Target structures
2. Results and Discussion
The synthesis of 6- and 7-substituted QQs was achieved in
two steps from commercially available 8-hydroxy-quinolines.19
First, sodium chlorate oxidation of 8-hydroxyquinoline (6) and
8-hydroxyquinaldine (7) afforded dichloroquinones 8 and 9,
respectively, which were then treated with a variety of amines to
give the 6- and 7-substituted QQs 10-27 in good to excellent
combined yields (59-99%) and in an approximate 1:1 ratio
(Scheme 1).19,26 It should be noted that while the amine
substitution conditions were chosen to provide both the 6- and
7-isomers, the 6-isomer can be preferentially formed by using a
metal catalyst during the substitution reactions.19,27 In our
instance, however, both regioisomers were required, and these
were separable via silica gel flash column chromatography, with
the 7-isomer eluting first.19,28,29 Derivatives prepared included
those with bulky amines (i.e. QQs 10-13), aliphatic chains (i.e.
QQs 14-19) and aromatic groups (i.e. QQs 20-27), with the
structure of each isomer being corroborated using NMR
spectroscopy. Here, the carbon atoms involved in tautomerisation
were observed as broad resonances that were less visible than
typical quaternary carbon resonances in the 13C NMR spectra.19
The tautomeric carbonyl carbons were then assigned via an
HMBC between H-4 and C-5. 1H NMR spectroscopy also
revealed a smaller ΔH2-H4 value for the 7-isomer compared to
the 6-isomer in the QQs that were unfunctionalised at the 2-
position.19 In addition, the structural assignments of several
analogues were confirmed by XRD (see Figures S1-S3,
Supporting Information).
Scheme 1. Synthesis of QQs 10-27
When considering how the structure of the QQs influences
their anti-mycobacterial activity, several important trends were
observed. First, QQs bearing tertiary amines, such as
dimethylamino-QQs 10a and 10b (entries 1 and 2) and
piperidine-substituted QQs 11a and 12b (entries 3 and 4),
exhibited only low levels of M. tuberculosis growth inhibition.
Here, the replacement of a cyclo-octylamine, as in QQ 3, with a
piperidine appeared to have an adverse effect on the inhibitory
activity of the QQ, indicating that the presence of a secondary
amine may be important for activity.8,13 Similarly, phenylamine-
substituted QQs 20a, 21a, 21b were moderate to poor
mycobacterial growth inhibitors, with MIC values between 256
and 512 µM (entries 5, 7, and 8), while QQ 20b exerted no
inhibitory activity at the maximum concentration tested (entry 6).
When p-alkyl-phenylamine groups were installed on the QQ
scaffold, as in heptylphenylamino-QQs 24a and 24b (entries 9
and 10), an increase in anti-mycobacterial activity was observed,
however the addition of a much longer lipid chain, as in
tetradecylphenylamino QQs 25a and 25b (entries 11 and 12), led
to a complete loss of anti-mycobacterial activity. These findings
suggest that there may be an optimal carbon chain length on the
QQ scaffold that confers higher inhibitory activity. Indeed, 6-
cyclooctyl-QQ 3 exhibits excellent anti-mycobacterial activity,8,13

Table 1. MIC values (µM) and redox values (V, in acetonitrile) of synthesised QQ analogues 10-27 and menadione (28) in
acetonitrile.
Entry
Compound
MIC (µM)
>512
cLogPb
2.25
E1 (V)
-0.60
E2 (V)
-1.13
1
2
3
4
512
256
128
2.25
2.68
3.18
-0.62
-0.61
-0.57
-1.11
-1.17
-1.13
5
6
7
8
9
512
>512
256
512
32
3.70
3.70
4.20
4.20
7.37
-0.42
-0.46
-0.44
-0.47
-0.57
-1.00
-1.06
-0.90
-1.05
-1.08

Table 1. (continued)
Entry
Compound
MIC (µM)
cLogPb
7.37
E1 (V)
-0.58
E2 (V)
-1.15
10
11
12
13
64
>512
>512
16
11.07
11.07
3.45
-0.44a
-0.78a
-0.63
-1.00a
-1.10a
-1.24
14
32
3.45
-0.61
-1.18
15
16
3.94
-0.52
-1.10
16
16
3.84
-0.64
-1.21
17
128
3.84
-0.60
-1.15

Table 1. (continued)
Entry
Compound
MIC (µM)
cLogPb
4.33
E1 (V)
-0.70
E2 (V)
-1.30
18
16
19
128
4.33
-0.73
-1.30
20
21
22
23
24
25
128
128
128
512
64
3.33
3.33
3.30
3.30
5.44
5.44
-0.59
-0.60
-0.56
-0.60
-0.68
-0.67
-1.16
-1.16
-0.97
-1.17
-1.27
-1.26
16

Table 1. (continued)
Entry
Compound
MIC (µM)
128
cLogPb
5.94
E1 (V)
-0.72
E2 (V)
-1.27
26
27
28
29
30
31
32
33
>512
256
128
8
3.47
3.47
2.16
2.16
2.66
2.66
2.45
-0.59
-0.69
-0.49
-0.50
-0.51
-0.55
-0.70
-1.10
-1.25
-1.07
-1.10
-1.10
-1.05
-1.27
256
64
n.d.
a in ACN/toluene (2/1, v/v); b calculated using ChemDraw ®; n.d. not determined; MICs were determined using a microtitre plate assay.
M. tuberculosis mc26230 cultures were incubated with the compounds for 5 days before resazurin was added and MICs obtained;
Isoniazid (INH) was used as a positive control (MIC = 0.2 µM)
while Bohne and co-workers31 reported that quinolones with a
Next, the effect of the position of a phenyl group on the QQ
12-carbon alkyl chain exerted higher inhibitory activity against
Toxoplasma gandii NDH-II than a shorter 7-carbon chain.
Moreover, when HQNO, a heptyl-substituted quinolone was co-
crystallised with C. thermarum NDH-II, the authors proposed
that a hydrophobic groove adjacent to the quinone-binding site
could accommodate a longer alkyl chain.24
scaffold was investigated by screening M. tuberculosis growth
inhibition of methoxybenzylamino-QQ (26-27, entries 13-15)
and phenylethylamino-QQs 22-23 (entries 16-19). These QQs,
and in particular the 7-isomers 26a, 27a, 22a, 23a, all with an
MIC = 16 µM (entries 13, 15, 16, and 18), exhibited improved
anti-mycobacterial activity compared to phenylamine-substituted

QQs. On the whole, the incorporation of one or two methylene
groups between the amine nitrogen and the phenyl substituent did
not greatly affect the anti-mycobacterial activity of the
compounds.
there was any correlation between redox activity and anti-
mycobacterial activity. To serve as a reference, the redox
potentials of menadione (28), a methyl analogue of the NDH-II
substrate menaquinone, was measured. Due to the aprotic nature
of acetonitrile, two consecutive one-electron redox events
occurred for each QQ, giving two redox potentials for each
compound.33,34 The redox potentials of QQs 10-27 were
comparable to those of menadione (28, entry 33), whereby E1
ranged from -0.42 V to -0.78 V and E2 occurred between -0.90 V
and -1.30 V (entries 1-32). In addition, the difference in potential
between the two redox events (ΔE1-E2) was consistent among the
QQs, at approximately 0.55 V, indicating that the QQ
semiquinone radicals had a comparable stability to menadione
(28, ΔE1-E2 = 0.58 V). When considering the effects of
functional groups on redox potential, the trends observed within
our series agreed with the general observations in literature. For
example QQs bearing unsaturated functional groups
(propargylamines 16-17, entries 29-32, phenylamines 20-21,
entries 5-8, and benzylamines 25, entries 11 and 12), had the
highest redox potentials, while QQs bearing hydrocarbons, i.e.
octylamino-QQs 18-19 (entries 24-26) and tert-butylamino-QQ
13 (entry 28), had relatively low reduction potentials.35,36,37,38 In
many cases, there was negligible difference in redox potential
between regioisomers, however, when the regioisomers
possessed different reduction potentials, the 7-isomer tended to
accept electrons more readily than the corresponding 6-isomer,
particularly for the first electron transfer (i.e. QQ 13a/13b,
entries 27 and 28; and QQ 15a/15b, entries 22 and 23). The
discrepancy in redox potentials between regioisomers could be
the result of intramolecular hydrogen bonds within the QQ,
whereby the C-8 carbonyl oxygen in the 7-isomers can form
hydrogen bonds with the C7-amine proton and with the
protonated quinoline nitrogen, thereby enhancing the
electrophilicity of the 7-isomer and increasing its propensity to
undergo reduction.39 Despite these physical chemical
relationships, no correlation between redox potential and the
tuberculostatic activity of the QQs was observed (see Figure S4,
Supporting Information).
When the biological activity of QQs bearing aliphatic chains
was investigated, propylamine-substituted QQs 14-15 displayed a
modest growth inhibition of M. tuberculosis, with MIC values
between 128 µM and 512 µM (entries 20-23). Of note is the
difference in anti-mycobacterial activity between 6-propylamino-
QQ 14b (MIC = 128 µM, entry 21) and the previously
determined MIC value of QQ8c (5, MIC = 8 µM).20 Here, the
presence of the chloride group on QQ8c (5) led to a four-fold
increase in growth inhibition compared to propylamine 14b,
suggesting that the presence of a leaving group at this position
could be important for activity. Longer alkyl chains, as in
octylamino-QQs 18a and 18b (entries 24 and 25), led to
increased anti-mycobacterial activity, although this increase was
not observed in methyl-quinone 19b (entry 26). QQs bearing
bulky alkyl substituents, as in tert-butylamino-QQs 13a and 13b,
showed poor anti-mycobacterial activity (entries 27 and 28). In
contrast, similarly bulky cyclo-octylamine-QQ (3) was reported
to exhibit high anti- mycobacterial activity, which is perhaps due
to the flexibility of the cyclo-octyl group within the target
enzyme.
Finally, propargylamino-QQs 16-17 (entries 29-32) exhibited
a range of inhibitory activities (MIC = 8-256 µM), with 7-chloro-
6-propargylamino QQ 16b having the lowest MIC value of the
library (MIC = 8 µM, entry 30). As with QQ8c (5), QQ 16b
bears an electrophilic centre at the 6-position of the QQ scaffold.
Accordingly, it is postulated that the acetylene group in QQ 16b
could isomerise to form an electrophilic allene that could
covalently bind nucleophilic amino acid residues, such as Q317
and Q321, in the NDH-II quinone binding site,22 resulting in
irreversible inhibition.32 Similarly, QQ8c (5) may act as an
electrophilic trap, whereby the intramolecular displacement of
the chloride leaving group could form an aziridine group, making
it susceptible to nucleophilic attack. That said, the anti-
mycobacterial activity of QQ 16b does not appear to be due to
the potential reactivity of the alkyne moiety alone, but also the
position of this group, as observed by the higher mycobacterial
growth inhibition elicited by 6-propargylamino-QQs 16b and
17b compared to their respective 7-isomers 16a and 17a (8 µM
and 64 µM vs. 128 µM and 256 µM, respectively).
When considered as a whole, the position of the amine
functionality did not consistently correlate to better anti-
mycobacterial activity for one QQ regioisomer, however, some
trends were observed within the separate QQ sub-classes. For
QQs bearing aryl groups, the 7-isomers exhibited better anti-
mycobacterial activity compared to the 6-isomer in all cases aside
from tetradecylphenylamino-QQs 25a and 25b, which were both
inactive against M. tuberculosis (entries 11 and 12). Conversely,
for QQs bearing aliphatic chains, the 6-isomers tended to exhibit
higher inhibitory activity than the corresponding 7-isomers, with
the exceptions of propylamino-QQs 14a/14b (entries 20 and 21),
and 15a/15b (entries 22 and 23). The difference in anti-
mycobacterial activity between the same regioisomers in one
sub-series also points to a lack of correlation between the
lipophilicity of the compounds and their ability to inhibit M.
tuberculosis growth. Indeed, QQs that failed to exhibit anti-
mycobacterial activity differed markedly in lipophilicity, as
evidenced by the wide range of cLogP values (2.25-11.07, entries
1, 6, 11, 12, 27). Similarly, QQs that exhibited good inhibitory
activity had cLogP values that, while more limited, ranged
between 2.16 and 5.44 (entries 13, 15, 16, 18, 25, 30).
Given the promising anti-mycobacterial activity of
propargylamino-QQ 16b, which may have a mode of action
similar to the previously identified NDH-II activator QQ8c (5),20
we then determined whether QQ 16b could affect NADH
oxidation. Here, the rate of NADH oxidation in the presence of
QQ 16b was measured using inverted membrane vesicles (IMVs)
from M. smegmatis (Figure 3).40 The addition of QQ 16b led to a
significant activation of the NADH-dependent oxygen
consumption rate (OCR) as compared to the basal OCR,
suggesting that QQ 16b may activate OCR via a redox-cycling
mechanism in a manner similar to QQ8c (5).20
2500
2000
1500
1000
500
***
0
b
O
6
S
1
M
D
Next, the redox potentials of QQs 10-27 were determined via
Figure 3: Mycobacterium smegmatis mc2155 IMVs were energized with
CV in acetonitrile against an Ag/Ag+ electrode to establish if
0.5 mM NADH (final concentration) and oxygen consumption rate (OCR)

was measured. After the OCR was stabilized, the IMVs were treated with
DMSO as an untreated control or QQ 16b. The addition of QQ 16b increased
the OCR to levels greater than the DMSO control (P < 0.0006), indicating an
activation of NADH-dependent oxygen consumption.
4.1.1. 6,7-Dichloro-quinoline-5,8-dione (8). In
a round-
bottomed flask fitted with a condenser, 8-hydroxyquinoline (14.5
g, 0.10 mol) was dissolved in conc. HCl (600 mL). The reaction
was then warmed to 40 °C before sodium chlorate (53 g, 0.5 mol,
5 equiv.) was added in batches over 1 h, where each batch was
added after the production of yellow gas had receded. The
reaction was then left to stir for 2 h before it was diluted with
H2O (1400 mL). The white precipitate was filtered off, and the
filtrate extracted with CH2Cl2 (6 x 250 mL) before the organic
layer was collected and concentrated in vacuo. The bright orange
solid was then recrystallised from ethanol to yield the
dichloroquinolinequinone 8 as bright yellow crystals (6.60 g,
29%). The data obtained for this compound matched those
reported in literature.19
3. Conclusions:
In these studies, thirty-two QQs were prepared in two-steps
and good yield and subsequently assessed for their ability to
inhibit the growth of M. tuberculosis. The QQs functionalised
with phenylethylamine and benzylamine groups exhibited high
anti-mycobacterial activity, while those with phenylamine
substituents were poor M. tuberculosis growth inhibitors. QQ
analogues with alkyl chains tended to have a mixed range of anti-
mycobacterial activities, while those with tertiary amines did not
lead to growth inhibition. Notably, the most biologically active
compound was propargylamino-substituted QQ 16b, with an
MIC = 8 µM. The cLogP values and redox potentials of the QQs
were also determined, however no correlation was observed
between the lipophilicity or redox potentials of the compounds
and their anti-mycobacterial activity. Preliminary mode of action
studies of the lead QQ analogue 16b showed this compound was
a potent activator of NADH-dependent oxygen consumption
suggesting redox cycling activity in a manner similar to QQ8c
(5). This warrants further investigation.
4.1.2. 6,7-Dichloro-2-methyl-quinoline-5,8-dione (9). In
a
round-bottomed flask, 8-hydroxy-2-methyl-quinoline (14.5 g,
0.090 mol) was dissolved in conc. HCl (600 mL) and the reaction
warmed to 40 °C. Sodium chlorate (48.5 g, 0.45 mol, 5 equiv.)
was then slowly added to the reaction mixture over 1 h, after
which time the reaction was stirred at room temperature for an
additional 2 h. The solution was then diluted to 1 L with H2O and
the white precipitate filtered, the filtrate extracted with
dichloromethane (6 x 250 mL) and the organic layers combined
and concentrated in vacuo. The resulting bright orange solid was
recrystallised in ethanol to provide the title compound as bright
yellow crystals (6.20 g, 29%). The data obtained for this
compound matched those reported in the literature.19
4. Experimental:
4.1. Synthesis
General methods. Unless otherwise stated, all reactions were
performed under atmospheric air. Prior to use, dioxane (Sigma
Aldrich) was distilled over CaCl2, toluene (drum), EtOAc (drum),
and petroleum ether (drum) were distilled. CH2Cl2 (LabServ),
sodium chlorate (BDH), 8-hydroxyquinoline (BDH), 37% HCl
(Merck), EtOH (absolute, Pure Science), 8-hydroxyquinaldine
(Aldrich), NaHCO3 (Pure Science), MgSO4 (Pure Science),
pyridine (Roth), dimethylamine (BDH), piperidine (BDH),
tertbutylamine (Aldrich), propylamine (Aldrich), propargylamine
(AKSci), octylamine (Aldrich), aniline (BDH), 4-heptylaniline
(Aldrich), 4-tetradecylaniline (Aldrich), methoxybenzylamine
(Aldrich), and phenylethylamine (HW) were used as received.
All solvents were removed by evaporation under reduced
pressure. Reactions were monitored by TLC-analysis on
Macherey-Nagel silica gel coated plastic sheets (0.20 mm) with
either visual detection, or detection by UV-absorption (254 nm)
and by dipping in KMnO4 in H2O. Column chromatography was
performed using Pure Science silica gel (40–63 micron) as the
stationary phase and the solvent systems indicated. High-
resolution (ESI) mass spectra were recorded on an Agilent 6530
Accurate-Mass Q-TOF LC-MS equipped with a 1260 Infinity
binary pump. Infrared spectra were recorded as thin films using a
Bruker Alpha II FTIR spectrometer equipped with an Attenuated
Total Reflectance (ATR) sampling accessory and are reported in
wavenumbers (cm-1). Melting points (m.p.) were obtained on a
DigiMelt MPA160 melting point apparatus and UV data obtained
on a Cary 150 spectrophotometer. Nuclear magnetic resonance
(NMR) spectra were acquired at 20 C in CDCl3, as indicated
General procedure for the synthesis of substituted QQs. To
a solution of dichloroquinolinequinones 8 or 9 (1 equiv.) in
dioxane (5 mL/mmol) was added the desired amine (1.2 equiv.).
The coloured solution was stirred at room temperature before
pyridine (2.1 equiv.) was added and the reaction stirred for 4 h,
after which TLC analysis showed the disappearance of starting
materials. The reaction was then concentrated in vacuo,
redissolved in EtOAc and washed with sat. aq. NaHCO3,
followed by brine. The organic layers were collected and dried
using anhydrous MgSO4, which was filtered and the filtrate
concentrated in vacuo. The resulting solid was then purified
using silica gel flash column chromatography (CH2Cl2/EtOAc or
toluene/EtOAc) to give each regioisomer.
4.1.3.
6-Chloro-7-dimethylamino-2-methyl-quinoline-5,8-
dione (10a). By subjecting dichloroQQ 9 (227 mg, 1.0 mmol)
and dimethylamine (33%, 0.33 mL, 1.5 mmol) to the general
procedure for the synthesis of substituted QQs, the title
compound was isolated as red crystals (125 mg, 50%); Rf = 0.53
(CH2Cl2/EtOAc, 4/1, v/v); m.p.: 233.5 °C; IR (υmax): 2961, 2922,
2852, 1690, 1570, 1508, 1449, 1412, 1309, 1259, 1090, 1067,
1015, 796, 775, 751, 706, 645, 567 cm-1; UV–vis (toluene) λmax
1
(log ε): 500 (3.32) nm; H NMR (500 MHz, CDCl3) δ ppm 8.18
(d, J3,4 = 7.9 Hz, 1H, H4), 7.42 (d, J3,4 = 7.9 Hz, 1H, H3), 3.25 (s,
6H, -N(CH3)2), 2.73 (s, 3H, CH3); 13C NMR (125 MHz, CDCl3) δ
ppm 181.6 (C5), 176.6 (C8), 165.2 (C2), 150.1 (C7), 147.0
(C8a), 135.0 (C4), 126.8 (C3), 125.8 (C4a), 120.8 (C6), 44.5 (-
N(CH3)2), 25.3 (CH3); HRMS(ESI) m/z calcd. for
[C12H11ClN2O2+H]+: 251.0582, obsd.: 251.0587.
1
using a Varian Unity-INOVA 500 MHz spectrometer, where H
1
and 13C were measured at 500 and 125 MHz, respectively. H
NMR spectral data are presented as illustrated: chemical shift (δ)
in ppm, multiplicity [s (singlet), d (doublet), t (triplet), m
(multiplet over the range specified)], number of protons, (nH),
4.1.4.
7-Chloro-6-dimethylamino-2-methyl-quinoline-5,8-
dione (10b). By subjecting dichloroQQ 9 (227 mg, 1.0 mmol)
and dimethylamine (33%, 0.33 mL, 1.5 mmol) to the general
procedure for the synthesis of substituted QQs, the title
compound was isolated as red crystals (100 mg, 41%); Rf = 0.46
(CH2Cl2/EtOAc, 4/1, v/v); m.p.: 152.9 °C; UV–vis (toluene) λmax
1
coupling constants (J) in Hertz, assignment of protons). H NMR
spectra are referenced to the CHCl3 (δ 7.26 ppm), residual
solvent peaks. 13C NMR spectra were proton decoupled and
referenced to TMS (δ 0 ppm). NMR peak assignments were
made using COSY, HSQC, and HMBC experiments.

(log ε): 485 (2.32) nm; IR (υmax): 2945, 1671, 1639, 1553, 1435,
MHz, CDCl3) δ ppm 8.22 (d, J3,4 = 8.0 Hz, 1H, H4), 7.42 (d, J3,4
1372, 1286, 1202, 1158, 1138, 1098, 1064, 1010, 933, 869, 859,
= 8.0 Hz, 1H, H3), 6.04 (br s., 1H, NH), 2.76 (s, 3H, CH3), 1.57
1
t
830, 809, 772, 746, 700, 650, 565 cm-1; H NMR (500 MHz,
(s, 9H, Bu-CH3); 13C NMR (125 MHz, CDCl3) δ ppm 180.3
CDCl3) δ ppm 8.20 (d, J3,4 = 8.0 Hz, 1H, H4), 7.43 (d, J3,4 = 8.0
Hz, 1H, H3), 3.26 (s, 6H, -N(CH3)2), 2.75 (s, 3H, CH3); 13C NMR
(125 MHz, CDCl3) δ ppm 181.8 (C5), 176.8 (C8), 165.3 (C2),
150.3 (C6), 147.2 (C8a), 135.1 (C4), 126.9 (C3), 126.0 (C4a),
120.9 (C7), 44.7 (N(CH3)2), 25.44 (CH3); HRMS(ESI) m/z calcd.
for [C12H11ClN2O2+H]+: 251.0582, obsd.: 251.0587.
(C5), 165.6 (C2), 147.6 (C8a), 135.0 (C4), 126.5 (C3), 125.1
(C4a), 55.4 (tBu-Cq), 31.57 (tBu-CH3), 25.4 (CH3); HRMS-ESI
(m/z) calcd. for [C14H15ClN2O2+H]+: 279.0895, obsd.: 279.0896.
4.1.9. 6-Chloro-7-propylamino-quinoline-5,8-dione (14a). By
subjecting dichloroQQ 8 (44.2 mg, 0.50 mmol) and propylamine
(0.05 mL, 0.60 mmol) to the general procedure for the synthesis
of substituted QQs, the title compound was isolated as red
crystals (75 mg, 60%); Rf = 0.43 (CH2Cl2/EtOAc, 4/1, v/v); m.p.:
145.7 °C (lit.41 135-136 °C); IR (υmax): 3284, 2929, 1693, 1576,
1553, 1506, 1464, 1431, 1375, 1284, 1259, 1236, 1195, 1165,
1151, 1137, 1093, 1036, 1026, 1006, 984, 871, 834, 818, 726,
611, 551, 493, 455, 439, 418 cm-1; UV–vis (toluene) λmax (log ε):
4.1.5. 6-Chloro-7-piperidinyl-quinoline-5,8-dione (11a). By
subjecting dichloroQQ 8 (139 mg, 0.61 mmol) and piperidine
(0.070 mL, 0.73 mmol) to the general procedure for the synthesis
of substituted QQs, the title compound was isolated as purple
crystals (68 mg, 40%); Rf = 0.59 (4/1, CH2Cl2/EtOAc, v/v); m.p.:
95.2 °C; IR (υmax): 2934, 2849, 1689, 1641, 1587, 1555, 1450,
1397, 1314, 1293, 1244, 1218, 1187, 1141, 1118, 1073, 1035,
987, 852, 834, 809, 784, 722, 644, 509, 562, 444, 420 cm-1; UV–
480 (2.64) nm; 1H NMR (500 MHz, CDCl3) δ ppm 8.92 (d, J2,3
4.7 Hz, 1H, H2), 8.47 (d, J3,4 = 7.9 Hz, 1H, H4), 7.65 (dd, J3,4
=
=
1
vis (toluene) λmax (log ε): 465 (2.32) nm; H NMR (500 MHz,
7.9 Hz, J2,3 = 4.7 Hz, 1H, H3), 6.28 (br. s, 1H, NH), 3.85 (q, J1',2'
= 6.9 Hz, 2H, H1'), 1.75 (sext., J1',2' = J2',3' = 7.2 Hz, 2H, H2'),
1.03 (t, J2',3' = 7.3 Hz, 2H, H3'); 13C NMR (125 MHz, CDCl3) δ
179.0 (C8), 175.7 (C5) 153.4 (C2), 146.0 (C8a), 134.8 (C4),
131.5 (C7), 130.1 (C4a), 128.5 (C3), 46.9 (C1'), 24.4 (C2'), 11.2
(C3'); HRMS-ESI (m/z) calcd. for [C12H11ClN2O2+H]+: 251.0582,
obsd.: 251.0588. The data obtained for this compound matched
those reported in literature.41
CDCl3) δ ppm 8.90 (dd, J2,3 = 4.6 Hz, J2,4 = 1.7 Hz, 1H, H2), 8.40
(dd, J3,4 = 7.9 Hz, J2,4 = 1.7 Hz, 1H, H4), 7.61 (dd, J3,4 = 7.9 Hz,
J2,3 = 4.7 Hz, 1H, H3), 3.58-3.56 (m, 4H, H1'), 3.45, 1.79-1.75
(m, 4H, H2'), 1.72--1.68 (m, 2H, H3'); 13C NMR (125 MHz,
CDCl3) δ ppm 180.3 (C8), 176.9 (C5), 153.8 (C2), 151.20 (C7),
147.2 (C8a), 134.5 (C4), 128.5 (C4a), 127.8 (C3), 120.8 (C6),
53.2 (C1'), 26.9 (C2'), 24.0 (C3'); HRMS(ESI) m/z calcd. for
[C14H13ClN2O2+H]+: 277.0738, obsd.: 277.0736.
4.1.10. 7-Chloro-6-propylamino-quinoline-5,8-dione (14b). By
subjecting dichloroQQ 8 (44.2 mg, 0.50 mmol) and propylamine
(0.050 mL, 0.60 mmol) to the general procedure for the synthesis
of substituted QQs, the title compound was isolated as red
crystals (48 mg, 39%); Rf = 0.26 (CH2Cl2/EtOAc, 4/1, v/v); m.p.:
154.4 °C (lit.41 134-135 °C); IR (υmax): 3227, 2956, 2919, 1676,
1560, 1551, 1458, 1330, 1304, 1266, 1207, 1134, 1110, 1071,
1040, 1023, 831, 821, 803, 746, 732, 710, 677, 656, 649, 563,
492 cm-1; UV–vis (toluene) λmax (log ε): 480 (3.48) nm; 1H NMR
(500 MHz, CDCl3) δ ppm 9.02 (dd, J2,3 = 4.7 Hz, J2,4 = 1.4 Hz,
1H, H2), 8.35 (dd, J3,4 = 8.1 Hz, J2,4 = 1.4 Hz, 1H, H4), 7.59 (dd,
J3,4 = 7.9 Hz, J2,3 = 4.7 Hz, 1H, H3), 6.06 (br. s, 1H, NH), 3.85 (q,
J1',2' = 7.0 Hz, 2H, H1'), 1.74 (sext., J1',2' = J2',3' = 7.0 Hz, 2H, H2'),
1.03 (t, J2',3' = 7.5 Hz, 2H, H3'); 13C NMR (125 MHz, CDCl3) δ
ppm 180.3 (C5), 155.4 (C2), 134.8 (C4), 126.6 (C3), 46.9 (C1'),
24.4 (C2'), 11.2 (C3'); HRMS-ESI (m/z) calcd. for
[C12H11ClN2O2+H]+: 251.0582, obsd.: 251.0588. The data
obtained for this compound matched those reported in
literature.41
4.1.6.
7-Chloro-2-methyl-6-piperidinyl-quinoline-5,8-dione
(12b). By subjecting dichloroQQ 9 (203 mg, 0.84 mmol) and
piperidine (0.10 mL, 1.0 mmol) to the general procedure for the
synthesis of substituted QQs, the title compound was isolated as
purple crystals (81 mg, 33%); Rf = 0.32 (CH2Cl2/EtOAc, 24/1,
v/v); m.p.: 153.2 °C; IR (υmax): 2922, 1672, 1648, 1548, 1443,
1293, 1242, 1206, 1101, 985, 859, 745, 702, 568, 448, 420 cm-1;
1
UV–vis (toluene) λmax (log ε): 515 (2.90) nm; H NMR (500
MHz, CDCl3) δ ppm 8.19 (d, J3,4 = 8.0 Hz, 1H, H4), 7.43 (d, J3,4
= 8.0 Hz, 1H, H3), 3.54 (m, 4H, H1ꞌ), 2.74 (s, 3H, CH3), 1.77 (m,
4H, H2ꞌ), 1.71 (m, 2H, H3ꞌ); 13C NMR (125 MHz, CDCl3) δ ppm
181.6 (C5), 176.8 (C8), 165.2 (C2), 150.1 (C6), 147.1 (C8a),
135.1 (C4), 127.0 (C3), 126.2 (C4a), 123.0 (C7), 53.2 (C1ꞌ), 27.0
(C2ꞌ), 25.3 (CH3), 24.2 (C3ꞌ); HRMS(ESI) m/z calcd. for
[C15H15ClN2O2+H]+: 291.0895, obsd.: 291.0899.
4.1.7.
6-Chloro-2-methyl-7-tert-butylamino-quinoline-5,8-
dione (13a). By subjecting dichloroQQ 9 (195 mg, 0.81 mmol)
and tert-butylamine (0.13 mL, 1.2 mmol) to the general
procedure for the synthesis of substituted QQs, the title
compound was isolated as red crystals (88 mg, 39%); Rf = 0.70
(CH2Cl2/EtOAc, 9/1, v/v); m.p.: 113.2 °C; IR (υmax): 3371, 1670,
1594, 1560, 1534, 1369, 1314, 1201, 1163, 1092, 848, 678, 422
cm-1; UV–vis (toluene) λmax (log ε): 485 (2.39) nm; 1H NMR (500
MHz, CDCl3) δ ppm 8.31 (d, J3,4 = 8.0 Hz, 1H, H4), 7.48 (d, J3,4
= 8.0 Hz, 1H, H3), 6.04 (br. s, 1H, NH), 2.73 (s, 3H, CH3), 1.57
4.1.11. 6-Chloro-2-methyl-7-propylamino-quinoline-5,8-dione
(15a). By subjecting dichloroQQ 9 (49.0 mg, 0.20 mmol) and
propylamine (0.020 mL, 0.24 mmol) to the general procedure for
the synthesis of substituted QQs, the title compound was isolated
as red crystals (27 mg, 51%); Rf = 0.40 (CH2Cl2/EtOAc, 9/1,
v/v); m.p.: 150.7 °C; IR (υmax): 3296, 1696, 1600, 1577, 1513,
1460, 1443, 1320, 1258, 1200, 1165, 1140, 1105, 1089, 851, 819,
738, 707, 595, 565, 525, 501, 474, 418 cm-1; UV-vis (CH2Cl2)
(s, 9H, Bu-CH3); 13C NMR (125 MHz, CDCl3) δ ppm 179.4
t
1
(C8), 175.8 (C5), 163.7 (C2), 146.1 (C8a), 134.8 (C4), 128.2
(C3), 127.2 (C4a), 55.8 (tBu-Cq), 31.6 (tBu-CH3), 25.2 (CH3);
HRMS-ESI (m/z) calcd. for [C14H15ClN2O2+H]+: 279.0895,
obsd.: 279.0896.
λmax (log ε): 480 (2.28), 310 (2.89) nm; H NMR (500 MHz,
CDCl3) δ ppm 8.35 (d, J3,4 = 7.9 Hz, 1H, H4), 7.49 (d, J3,4 = 8.0
Hz, 1H, H3), 6.18 (br. s, 1H, NH), 3.83 (q, J1',2' = J2',3' = 7.3 Hz,
2H, H1'), 2.73 (s, 3H, CH3), 1.73 (sext., J1',2' = J2',3' = 7.1 Hz, 2H,
H2'), 1.01 (t, J2',3' = 7.4 Hz, 2H, H3'); 13C NMR (125 MHz,
CDCl3) δ ppm 179.2 (C8), 176.0 (C5), 163.5 (C2), 145.5 (C8a),
144.4 (C7), 134.0 (C4), 128.4 (C3), 127.9 (C4a), 46.8 (C1'), 25.0
(CH3), 24.3 (C2'), 11.06 (C3'); HRMS-ESI (m/z) calcd. for
[C13H13ClN2O2+H]+: 265.0738, obsd.: 265.0740.
4.1.8.
7-Chloro-2-methyl-6-tert-butylamino-quinoline-5,8-
dione (13b). By subjecting dichloroQQ 9 (195 mg, 0.81 mmol)
and tert-butylamine (0.13 mL, 1.2 mmol) to the general
procedure for the synthesis of substituted QQs, the title
compound was isolated as red crystals (56 mg, 25%); Rf = 0.35
(CH2Cl2/EtOAc, 9/1, v/v); m.p.: 177.2 °C; IR (υmax): 3376, 1670,
1594, 1535, 1369, 1314, 1201, 1163, 1092, 849, 749, 678, 414
cm-1; UV–vis (toluene) λmax (log ε): 485 (1.48) nm; 1H NMR (500
4.1.12. 7-Chloro-2-methyl-6-propylamino-quinoline-5,8-dione
(15b). By subjecting dichloroQQ 9 (49.0 mg, 0.20 mmol) and
propylamine (0.020 mL, 0.24 mmol) to the general procedure for

the synthesis of substituted QQs, the title compound was isolated
as red crystals (25 mg, 47%); Rf = 0.3 (CH2Cl2/EtOAc, 9/1, v/v),
m.p.: 114.1 °C; IR (υmax): 2958, 1673, 1571, 1509, 1453, 1310,
1225, 1111, 1067, 839, 776, 748, 701, 649, 574, 419 cm-1; UV-
(C3), 79.1 (C2'), 73.8 (C3'), 35.2 (C1'), 25.2 (CH3); HRMS-ESI
(m/z) calcd. for [C13H9ClN2O2+H]+: 261.0425, obsd.: 261.0426.
4.1.16. 7-Chloro-2-methyl-6-propargylamino-quinoline-5,8-
dione (17b). By subjecting dichloroQQ 9 (77 mg, 0.32 mmol)
and propargylamine (0.030 mL, 0.48 mmol) to the general
procedure for the synthesis of substituted QQs, the title
compound was isolated as orange crystals (33 mg, 40%); Rf =
0.19 (CH2Cl2/EtOAc, 4/1, v/v); m.p.: 163.2 °C; IR (υmax): 3180,
2924, 1611, 1574, 1558, 1504, 1454, 1357, 1312, 1294, 1257,
1145, 1068, 1025, 930, 750, 734, 702, 612, 553, 509 cm-1; UV-
1
vis (CH2Cl2) λmax (log ε): 475 (2.30) nm; H NMR (500 MHz,
CDCl3) δ ppm 8.21 (d, J3,4 = 8.0 Hz, 1H, H4), 7.41 (d, J3,4 = 8.0
Hz, 1H, H3), 6.04 (br. s, 1H, NH), 3.82 (q, J1',2' = J2',3' = 6.9 Hz,
2H, H1'), 2.75 (s, 3H, CH3), 1.72 (sext., J1',2' = J2',3' = 7.2 Hz, 2H,
H2'), 1.01 (t, J2',3' = 7.4 Hz, 2H, H3'); 13C NMR (125 MHz,
CDCl3) δ ppm 180.2 (C5), 175.5 (C8), 166.0 (C2), 148.3 (C8a),
143.6 (C7), 134.9 (C4), 126.5 (C3), 124.6 (C4a), 46.8 (C1'), 25.6
(CH3), 24.4 (C2'), 11.2 (C3'); HRMS-ESI (m/z) calcd. for
[C13H13ClN2O2+H]+: 265.0738, obsd.: 265.0740.
1
vis (CH2Cl2) λmax (log ε): 455 (2.17) nm; H NMR (500 MHz,
CDCl3) δ ppm 8.25 (d, J3,4 = 8.0 Hz, 1H, H4), 7.45 (d, J3,4 = 8.0
Hz, 1H, H3), 6.00 (br. s, 1H, NH), 4.65 (dd, J1',NH = 4.7 Hz, J1',3'
=
4.1.13. 6-Chloro-7-propargylamino-quinoline-5,8-dione (16a).
By subjecting dichloroQQ 8 (189 mg, 0.83 mmol) and
propargylamine (0.060 mL, 1.0 mmol) to the general procedure
for the synthesis of substituted QQs, the title compound was
isolated as red crystals (64 mg, 31%); Rf = 0.27 (CH2Cl2/EtOAc,
4/1, v/v); m.p.: 199.8 °C (lit.42 140-142 °C); IR (υmax): 3189,
1697, 1599, 1565, 1507, 1422, 1348, 1322, 1196, 1152, 1093,
817, 724, 575 cm-1; UV-vis (CH2Cl2) λmax (log ε): 455 (1.71) nm;
2.5 Hz, 2H, H1'), 2.77 (s, 3H, CH3), 2.41 (t, J1',3' = 2.5 Hz, 1H,
H3'); 13C NMR (125 MHz, CDCl3) δ ppm 179.8 (C8), 175.9
(C5), 166.2 (C2), 147.8 (C8a), 143.1 (C6), 135.1 (C4), 126.8
(C3), 79.2 (C2'), 73.8 (C3'), 35.2 (C1'), 25.6 (CH3); HRMS-ESI
(m/z) calcd. for [C13H9ClN2O2+H]+: 261.0425, obsd.: 261.0426.
4.1.17. 6-Chloro-7-octylamino-quinoline-5,8-dione (18a). By
subjecting dichloroQQ 8 (176 mg, 0.77 mmol) and octylamine
(0.15 mL, 0.93 mmol) to the general procedure for the synthesis
of substituted QQs, the title compound was isolated as red
crystals (69 mg, 28%); Rf = 0.69 (EtOAc); m.p.: 148.9 °C; IR
(υmax): 2922, 2851, 1691, 1592, 1559, 1508, 1428, 1325, 1306,
1252, 1196, 1138, 1098, 820, 728 cm-1; UV–vis (toluene) λmax
(log ε): 485 (2.46) nm; 1H NMR (500 MHz, CDCl3) δ ppm 8.88
(d, J2,4 = 4.6 Hz, 1H, H2), 8.44 (d, J3,4 = 7.8 Hz, 1H, H4), 7.63
(dd, J3,4 = 7.8 Hz, J2,3 = 4.5 Hz, 1H, H3), 6.24 (br. s, 1H, NH),
1H NMR (500 MHz, CDCl3) δ ppm 8.96 (dd, J2,3 = 4.6 Hz, J2,4
=
1.5 Hz, 1H, H2), 8.49 (dd, J3,4 = 7.9 Hz, J2,4 = 1.5 Hz, 1H, H4),
7.69 (dd, J3,4 = 7.9 Hz, J2,3 = 4.6 Hz, 1H, H3), 6.21 (br. s, 1H,
NH), 4.69 (dd, J1',NH = 6.0 Hz, J1',3' = 2.5 Hz, 2H, H1'), 2.43 (t,
J1',3' = 2.5 Hz, 1H, H3'); 13C NMR (125 MHz, CDCl3) δ ppm
178.6 (C8), 176.0 (C5), 153.9 (C2), 146.1 (C8a), 144.1 (C7),
134.9 (C4), 129.7 (C4a), 128.6 (C3), 79.0 (C2'), 74.0 (C3'), 35.3
(C1'); HRMS-ESI (m/z) calcd. for [C12H7ClN2O2+H]+: 247.0269,
obsd.: 247.0260. The data obtained for this compound matched
those reported in literature.42
3.84 (q, J1',2' = J1',NH = 7.2 Hz, 2H, H1'), 1.68 (pent., J1',2' = J2',3'
=
7.6 Hz, 2H, H2'), 1.39- 1.25 (m, 8H, H3'- H7'), 0.85 (t, J7',8' = 7.0
Hz, 2H, H8'); 13C NMR (125 MHz, CDCl3) δ ppm 179.0 (C8),
175.7 (C5), 153.4 (C2), 144.6 (C7), 134.8 (C4), 130.1 (C4a),
128.5 (C3), 45.2 (C1'), 31.8 (C6'), 31.1 (C2'), 29.3 (C4'), 29.2
(C3'), 26.7 (C5'), 22.7 (C7'), 14.15 (C8'); HRMS-ESI (m/z) calcd.
for [C17H21ClN2O2+H]+: 321.1364, obsd.: 321.1364.
4.1.14. 7-Chloro-6-propargylamino-quinoline-5,8-dione (16b).
By subjecting dichloroQQ 8 (189 mg, 0.83 mmol) and
propargylamine (0.060 mL, 1.0 mmol) to the general procedure
for the synthesis of substituted QQs, the title compound was
isolated as orange crystals (57 mg, 28%); Rf
= 0.16
4.1.18. 7-Chloro-6-octylamino-quinoline-5,8-dione (18b). By
subjecting dichloroQQ 8 (176 mg, 0.77 mmol) and octylamine
(0.15 mL, 0.93 mmol) to the general procedure for the synthesis
of substituted QQs, the title compound was isolated as red
crystals (89 mg, 36%); Rf = 0.33 (EtOAc); m.p.: 116.2 °C; IR
(υmax): 3237, 2921, 1675, 1589, 1560, 1513, 1443, 1373, 1305,
1264, 1206, 1113, 1073, 827, 803, 748, 714, 654, 572, 411 cm-1;
(CH2Cl2/EtOAc, 4/1, v/v); m.p.: 137.1 °C (lit.42 140-142 °C); IR
(υmax): 3248, 1691, 1595, 1570, 1513, 1345, 1308, 1267, 1207,
1147, 1117, 1075, 832, 806, 759, 731, 680, 656, 595, 451, 411
cm-1; UV-vis (toluene) λmax (log ε): 460 (3.72), 300 (1.23) nm; 1H
NMR (500 MHz, CDCl3) δ ppm 9.04 (dd, J2,3 = 4.7 Hz, J2,4 = 1.7
Hz, 1H, H2), 8.40 (dd, J3,4 = 7.9 Hz, J2,4 = 1.8 Hz, 1H, H4), 7.63
(dd, J3,4 = 7.8 Hz, J2,3 = 4.7 Hz, 1H, H3), 6.04 (br. s, 1H, NH),
1
UV–vis (toluene) λmax (log ε): 485 (2.67) nm; H NMR (500
4.68 (dd, J1',NH = 6.0 Hz, J1',3' = 2.6 Hz, 2H, H1'), 2.44 (t, J1',3'
=
MHz, CDCl3) δ ppm 9.00 (d, J2,4 = 4.5 Hz, 1H, H2), 8.34 (d, J3,4
= 7.9 Hz, 1H, H4), 7.57 (dd, J3,4 = 7.8 Hz, J2,3 = 4.7 Hz, 1H, H3),
6.05 (br. s, 1H, NH), 3.85 (q, J1',2' = J1',NH = 7.2 Hz, 2H, H1'), 1.69
(pent., J1',2' = J2',3' = 7.2 Hz, 2H, H2'), 1.39-1.24 (m, 8H, H3'-
H7'), 0.87 (t, J7',8' = 7.0 Hz, 2H, H8'); 13C NMR (125 MHz,
CDCl3) δ ppm 180.1(C8), 175.2(C5), 155.4 (C2), 148.5 (C8a),
143.8 (C6), 134.8 (C4), 134.7 (C4a), 126.7 (C3), 45.2 (C1'), 31.8
(C6'), 31.0 (C2'), 29.20 (C4'), 29.16 (C3'), 26.6 (C5'), 22.6 (C7'),
14.05 (C8'); calcd. for [C17H21ClN2O2+H]+: 321.1364, obsd.:
321.1361.
2.5 Hz, 1H, H3'); 13C NMR (125 MHz, CDCl3) δ ppm 179.7
(C5), 155.3 (C2), 148.1 (C8a), 143.1 (C6), 134.8 (C4), 126.8
(C3), 78.9 (C2'), 73.7 (C3'), 35.2 (C1'); HRMS-ESI (m/z) calcd.
for [C12H7ClN2O2+H]+: 247.0269, obsd.: 247.0260. The data
obtained for this compound matched those reported in
literature.42
4.1.15. 6-Chloro-2-methyl-7-propargylamino-quinoline-5,8-
dione (17a). By subjecting dichloroQQ 9 (77 mg, 0.32 mmol)
and propargylamine (0.030 mL, 0.48 mmol) to the general
procedure for the synthesis of substituted QQs, the title
compound was isolated as red crystals (38 mg, 45%); Rf = 0.32
(CH2Cl2/EtOAc, 4/1, v/v); m.p.: 213.7 °C; IR (υmax): 3310, 3216,
1691, 1603, 1580, 1497, 1352, 1320, 1279, 1250, 1202, 1154,
1114, 830, 740, 706, 683, 600, 558, 473, 435, 421 cm-1; UV-vis
(CH2Cl2) λmax (log ε): 475 (2.22) nm; 1H NMR (500 MHz,
CDCl3) δ ppm 8.35 (d, J3,4 = 8.0 Hz, 1H, H4), 7.52 (d, J3,4 = 8.0
4.1.19. 6-Chloro-2-methyl-7-octylamino-quinoline-5,8-dione
(19a). By subjecting dichloroQQ 9 (114 mg, 0.47 mmol) and
octylamine (0.090 mL, 0.56 mmol) to the general procedure for
the synthesis of substituted QQs, the title compound was isolated
as red crystals (58 mg, 37%); Rf = 0.52 (CH2Cl2/EtOAc, 9/1,
v/v); m.p.: 118 °C; IR (υmax): 3304, 2923, 1694, 1598, 1574,
1553, 1509, 1443, 1318, 1258, 1202, 1162, 1143, 1109, 1090,
819, 739, 707, 587, 537, 479, 448, 417 cm-1; UV–vis (toluene)
Hz, 1H, H3), 6.12 (br. s, 1H, NH), 4.67 (dd, J1',NH = 4.7 Hz, J1',3'
=
2.5 Hz, 2H, H1'), 2.74 (s, 3H, CH3), 2.41 (t, J1',3' = 2.5 Hz, 1H,
H3'); 13C NMR (125 MHz, CDCl3) δ ppm 178.9 (C8), 176.1
(C5), 164.1 (C2), 145.6 (C8a), 143.9 (C7), 135.1 (C4), 128.6
1
λmax (log ε): 485 () nm; H NMR (500 MHz, CDCl3): δ ppm 8.32
(d, J3,4 = 7.9 Hz, 1H, H4), 7.48 (d, J3,4 = 8.0 Hz, 1H, H3), 6.19
(br. s, 1H, NH), 3.84 (q, J1',2' = 6.8 Hz, 2H, H1'), 2.71 (s, 3H,

CH3), 1.71-1.66 (m, 2H, H2'), 1.41-1.25 (m, 10H, H2'- H7'), 0.86
(t, J7',8' = 6.4 Hz, 2H, H8'); 13C NMR (125 MHz, CDCl3): δ ppm
179.2 (C8), 174.2 (C5), 163.5 (C2), 145.4 (C8a), 134.9 (C4),
128.4 (C3), 127.8 (C4a), 45.2 (C1'), 31.7 (C6'), 31.1 (C2'), 29.2
(C4'), 29.28 (C3'), 26.6 (C5'), 22.6 (C7'), 14.1 (C8'); HRMS-ESI
(m/z) calcd. for [C18H23ClN2O2+H]+: 335.1521, obsd.: 335.1525.
m.p.: 226.2 °C; IR (υmax): 3236, 1688, 1634, 1552, 1485, 1443,
1284, 1225, 1151, 1073, 986, 910, 872, 848, 815, 768, 736, 693,
574, 562, 501, 472, 448, 419 cm-1; UV-vis (CH2Cl2) λmax (log ε):
490 (2.68) nm; 1H NMR (500 MHz, CDCl3) δ ppm 8.38 (d, J3,4
=
8.0 Hz, 1H, H4), 7.81 (br. s, 1H, NH), 7.54 (d, J3,4 = 8.0 Hz, 1H,
H3), 7.36 (t, Jo-CH,m-CH, = Jm-CH p-CH3 = 7.9 Hz, 2H, m-PhCH), 7.24
(t, Jm-CH p-CH3 = 7.6 Hz, 1H, p-PhCH), 7.11 (d, Jo-CH,m-CH = 7.8 Hz,
,
,
4.1.20. 7-Chloro-2-methyl-6-octylamino-quinoline-5,8-dione
(19b). By subjecting dichloroQQ 9 (114 mg, 0.47 mmol) and
octylamine (0.090 mL, 0.56 mmol) to the general procedure for
the synthesis of substituted QQs, the title compound was isolated
as red crystals (54 mg, 34%); Rf = 0.49 (CH2Cl2/EtOAc, 9/1,
v/v); m.p.: 111.7 °C; IR (υmax): 2918, 2853, 1675, 1563, 1519,
1313, 1286, 1224, 1115, 839, 776, 750, 704, 645, 572 cm-1; UV–
2H, o-PhCH), 2.77 (s, 3H, CH3); 13C NMR (125 MHz, CDCl3) δ
ppm 179.4 (C8), 176.9 (C5), 164.3 (C2), 145.8 (C8a), 141.9 (C6
or C7), 137.2 (Ph-Cq), 135.3 (C4), 128.64 (C3), 128.62 (m-
PhCH), 128.0 (C4a), 126.1 (p-PhCH), 124.6 (o-PhCH), 25.2
(CH3); HRMS-ESI (m/z) calcd. for [C16H11ClN2O2+H]+:
299.0582, obsd.: 299.0586.
1
vis (toluene) λmax (log ε): 485 (2.19) nm; H NMR (500 MHz,
4.1.24. 7-Chloro-2-methyl-6-phenylamino-quinoline-5,8-dione
(21b). By subjecting dichloroQQ 9 (115 mg, 0.48 mmol) and
aniline (0.050 mL, 0.57 mmol) to the general procedure for the
synthesis of substituted QQs, the title compound was isolated as
red crystals (95 mg, 24%); Rf = 0.22 (CH2Cl2/EtOAc, 24/1, v/v) ;
m.p: 226.7 °C; IR (υmax): 2955, 2918, 1678, 1646, 1546, 1420,
1375, 1287, 1222, 1199, 1144, 1033, 905, 888, 849, 707, 707,
698, 586, 560, 509 cm-1; UV-vis (CH2Cl2) λmax (log ε): 485 (2.18)
CDCl3): δ ppm 8.21 (d, J3,4 = 8.0 Hz, 1H, H4), 7.41 (d, J3,4 = 8.0
Hz, 1H, H3), 6.03 (br. s, 1H, NH), 3.85 (q, J1',2' = 6.5 Hz, 2H,
H1'), 2.76 (s, 3H, CH3), 1.72-1.66 (m, 2H, H2'), 1.43-1.37 (m,
2H, H2'), 1.35-1.25 (m, 8H, H3'- H7'), 0.88 (t, J7',8' = 6.8 Hz, 2H,
H8'); 13C NMR (125 MHz, CDCl3): δ ppm 180.2 (C8), 166.1
(C2), 148.1 (C8a), 135.0 (C4), 126.5 (C3), 124.6 (C4a), 45.2
(C1'), 31.9 (C6'), 31.1 (C2'), 29.33 (C4'), 29.28 (C3'), 25.6 (C5'),
22.8 (C7'), 14.22 (C8'); HRMS-ESI (m/z) calcd. for
[C18H23ClN2O2+H]+: 335.1521, obsd.: 335.1525.
1
nm; H NMR (500 MHz, CDCl3) δ ppm 8.31 (d, J3,4 = 8.0 Hz,
1H, H4), 7.66 (br. s, 1H, NH), 7.48 (d, J3,4 = 8.0 Hz, 1H, H3),
7.37 (t, Jo-CH,m-CH, = Jm-CH p-CH3
,
= 7.8 Hz, 2H, m-PhCH), 7.24 (t,
4.1.21. 6-Chloro-7-phenylamino-quinoline-5,8-dione (20a). By
subjecting dichloroQQ 8 (121 mg, 0.53 mmol) and aniline (0.060
mL, 0.62 mmol) to the general procedure for the synthesis of
substituted QQs, the title compound was isolated as red crystals
(51 mg, 24%); Rf = 0.33 (CH2Cl2/EtOAc, 24/1, v/v); m.p.: 235.7
°C; IR (υmax): 2955, 2922, 2852, 1692, 1558, 1462, 1447, 1378,
1315, 1245, 1152, 1066, 852, 758, 723, 691, 629, 579, 550, 540,
Jm-CH p-CH3
,
= 7.8 Hz, 1H, p-PhCH), 7.09 (d, Jo-CH,m-CH = 7.8 Hz,
2H, o-PhCH), 2.79 (s, 3H, CH3); 13C NMR (125 MHz, CDCl3) δ
ppm 184.5 (C8), 180.1 (C5), 166.1 (C2), 148.1 (C8a), 140.8
(C7), 137.1 (Ph-Cq), 135.0 (C4), 128.5 (m-PhCH), 126.8 (C3),
125.9 (p-PhCH), 124.7 (C4a), 124.4 (o-PhCH), 25.5 (CH3);
HRMS-ESI (m/z) calcd. for [C16H11ClN2O2+H]+: 299.0582,
obsd.: 299.0586.
1
452, 418 cm-1; UV-vis (CH2Cl2) λmax (log ε): 490 (2.48) nm; H
NMR (500 MHz, CDCl3): δ ppm 9.00 (d, J2,4 = 4.5 Hz, 1H, H2),
8.52 (d, J3,4 = 7.2 Hz, 1H, H4), 7.86 (br. s, 1H, NH), 7.71 (dd, J3,4
= 7.8 Hz, J2,3 = 4.7 Hz, 1H, H3), 7.37 (t, Jo-CH2,m-CH2 = J m-CH2,p-CH2
4.1.25.
6-Chloro-7-phenylethylamino-quinoline-5,8-dione
(22a). By subjecting dichloroQQ 8 (169 mg, 0.74 mmol) and 2-
phenylethylamine (0.11 mL, 0.89 mmol) to the general procedure
for the synthesis of substituted QQs, the title compound was
= 7.6 Hz, 2H, m-PhCH), 7.25 (t, J
= 7.3 Hz, 2H, p-
m-CH2,p-CH2
PhCH), 7.12 (d, Jo-CH2,m-CH2 = 7.8 Hz, 2H, o-PhCH); 13C NMR
(125 MHz, CDCl3): δ ppm 179.0 (C8), 176.5 (C5), 153.9 (C2),
146.1 (C8a), 141.9 (C7), 136.9 (Ph-Cq), 135.0 (C4), 130.0 (C4a),
128.53 (C3), 128.5 (m-PhCH), 126.1 (p-PhCH), 124.6 (o-PhCH);
HRMS-ESI (m/z) calcd. for [C15H9ClN2O2+H]+: 285.0245, obsd.:
285.0426.
isolated as red crystals (39 mg, 17%); Rf
=
0.31
(EtOAc/petroleum ether, 2/1, v/v); m.p.: 170.7 °C; IR (υmax):
3286, 2164, 1638, 1639, 1591, 1583, 1520, 1356, 1307, 1253,
1189, 1142, 1096, 830, 817, 756, 732, 724, 699, 667, 647, 613,
530, 498, 482, 419 cm-1; UV–vis (toluene) λmax (log ε): 485
(3.69) nm; 1H NMR (500 MHz, CDCl3) δ ppm 8.92 (d, J2,3 = 4.5
Hz, 1H, H2), 8.47 (d, J3,4 = 7.8 Hz, 1H, H4), 7.65 (dd, J3,4 = 7.7
Hz, J2,3 = 4.7 Hz, 1H, H3), 7.34-7.31 (m, 2H, m-PhCH), 7.26-
7.24 (m, 3H, o-PhCH, p-PhCH), 6.25 (br. s, 1H, NH), 4.14 (q,
J1′,2′ = J1′,NH = 6.8 Hz, 2H, H1′), 3.01 (t, J1′,2′ = 6.9 Hz, 2H, H2′),
3.00; 13C NMR (125 MHz, CDCl3) δ ppm 178.8 (C8), 175.6
(C5), 153.4 (C2), 146.0 (C8a), 137.5 (Ph-Cq), 134.7 (C4), 128.9
(m-PhCH), 128.8 (o-PhCH), 128.4 (C3), 127.0 (p-PhCH), 46.2
4.1.22. 7-Chloro-6-phenylamino-quinoline-5,8-dione (20b). By
subjecting dichloroQQ 8 (121 mg, 0.53 mmol) and aniline (0.060
mL, 0.62 mmol) to the general procedure for the synthesis of
substituted QQs, the title compound was isolated as red crystals
(54 mg, 36%); Rf = 0.26 (CH2Cl2/EtOAc, 24/1, v/v); m.p. 205.8
°C; IR (υmax): 2923, 1674, 1646, 1588, 1559, 1484, 1444, 926,
858, 800, 757, 731, 685, 577, 549, 510, 449, 415 cm-1; UV-vis
(CH2Cl2) λmax (log ε): 485 (2.54) nm; 1H NMR (500 MHz,
CDCl3): δ ppm 9.06 (d, J2,4 = 4.8 Hz, 1H, H2), 8.44 (dd, J3,4 = 8.0
(C1'),
37.3
(C2');
HRMS-ESI
(m/z)
calcd.
for
[C17H13ClN2O2+H]+: 313.0738, obsd.: 313.0738.
Hz, J2,4 = 1.6 Hz, 1H, H4), 7.71 (br. s, 1H, NH), 7.68 (dd, J3,4
8.0 Hz, J2,3 = 4.7 Hz, 1H, H3), 7.37 (t, Jo-CH2,m-CH2 = J m-CH2,p-CH2
=
=
4.1.26. 7-Chloro-6-phenylethylamino-quinoline-5,8-dione
(22b). By subjecting dichloroQQ 8 (169 mg, 0.74 mmol) and 2-
phenylethylamine (0.11 mL, 0.89 mmol) to the general procedure
for the synthesis of substituted QQs, the title compound was
7.6 Hz, 2H, m-PhCH), 7.25 (t, J
= 7.3 Hz, 2H, p-
m-CH2,p-CH2
PhCH), 7.10 (d, Jo-CH2,m-CH2 = 7.8 Hz, 2H, o-PhCH); 13C NMR
(125 MHz, CDCl3) δ ppm 180.3 (C5), 176.0 (C8), 155.6 (C2),
148.5 (C8a), 141.2 (C6), 137.2 (Ph-Cq), 135.0 (C4), 128.69 (C3),
128.64 (m-PhCH), 127.1 (C4a), 126.2 (p-PhCH), 124.7 (o-
PhCH); HRMS-ESI (m/z) calcd. for [C15H9ClN2O2+H]+:
285.0245, obsd.: 285.0426.
isolated as red crystals (127 mg, 55%); Rf
=
0.18
(EtOAc/petroleum ether, 2/1, v/v); m.p.: 165.2 °C; IR (υmax):
3183, 2953, 2922, 2853, 1688, 1596, 1563, 1497, 1356, 1327,
1260, 1215, 1111, 1075, 744, 731, 680, 554, 498, 463, 410 cm-1;
1
UV–vis (toluene) λmax (log ε): 485 (2.72) nm; H NMR (500
MHz, CDCl3): δ ppm 9.01 (d, J2,3 = 5.1 Hz, 1H, H2), 8.32 (d, J3,4
= 7.8 Hz, 1H, H4), 7.57 (dd, J3,4 = 7.9 Hz, J2,3 = 4.6 Hz, 1H, H3),
7.35-7.32 (m, 2H, m-PhCH), 7.27-7.23 (m, 3H, o-PhCH, p-
PhCH), 6.07 (br. s, 1H, NH), 4.14 (q, J1′,2′ = J1′,NH = 6.8 Hz, 2H,
H1′), 3.00 (t, J1′,2′ = 7.1 Hz, 2H, H2′); 13C NMR (125 MHz,
4.1.23. 6-Chloro-2-methyl-7-phenylamino-quinoline-5,8-dione
(21a). By subjecting dichloroQQ 9 (115 mg, 0.48 mmol) and
aniline (0.050 mL, 0.57 mmol) to the general procedure for the
synthesis of substituted QQs, the title compound was isolated as
red crystals (34 mg, 24%); Rf = 0.32 (CH2Cl2/EtOAc, 24/1, v/v);

CDCl3): δ ppm 180.0 (C5), 155.2 (C2), 148.4 (C8), 143.6 (C6),
137.4 (Ph-Cq), 134.7 (C4), 128.9 (m-PhCH), 128.81 (o-PhCH),
127.7 (C4a), 127.0 (p-PhCH), 126.5 (C3), 46.1 (C1′), 37.2 (C2′);
HRMS-ESI (m/z) calcd. for [C17H13ClN2O2+H]+: 313.0738,
obsd.: 313.0738.
the synthesis of substituted QQs, the title compound was isolated
as red crystals (67 mg, 29%); Rf = 0.11 (petroleum ether/EtOAc,
1/1, v/v); m.p: 174.4 °C; IR (υmax): 3340, 2920, 1670, 1606, 1578,
1518, 1492, 1309, 1213, 1144, 863, 839, 813, 746, 687, 638. 525,
458 cm-1; UV–vis (toluene) λmax (log ε): 495 (2.72) nm; 1H NMR
(500 MHz, CDCl3) δ ppm 9.04 (dd, J3,4 = 4.7 Hz, J2,4 = 1.4 Hz,
1H, H4), 8.42 (dd, J2,3 = 7.8 Hz, J2,4 = 1.3 Hz, 1H, H2), 7.66
(NH), 7.63 (dd, J3,4 = 4.7 Hz, J2,3 = 7.8 Hz, 1H, H3), 7.16, (d, J2',3'
4.1.27. 6-Chloro-2-methyl-7-phenylethylamino-quinoline-5,8-
dione (23a). By subjecting dichloroQQ 9 (186 mg, 0.77 mmol)
and 2-phenylethylamine (0.12 mL, 0.92 mmol) to the general
procedure for the synthesis of substituted QQs, the title
compound was isolated as red crystals (71 mg, 28%); Rf = 0.42
(EtOAc/petroleum ether, 2/1, v/v); m.p.: 165.9 °C; IR (υmax):
3302, 1695, 1633, 1571, 1493, 1464, 1305, 1230, 1147, 1107,
851, 817, 735, 694, 665, 595, 579, 517, 492, 476, 449, 419, 404
cm-1; UV–vis (toluene) λmax (log ε): 490 (2.83) nm; 1H NMR (500
MHz, CDCl3) δ ppm 8.32 (d, J3,4 = 8.0 Hz, 1H, H4), 7.48 (d, J3,4
= 8.0 Hz, 1H, H3), 7.33-7.30 (m, 2H, m-PhCH), 7.25-7.22 (m,
= 8.3 Hz, 2H, H3'), 7.01 (d, J2',3' = 8.2 Hz, 2H, H2'), 2.61 (t, J5',6'
=
7.9 Hz, 2H, H5'), 1.61 (pent., J5',6',7' = 7.6 Hz, 2H, H6'), 1.32-1.27
(m, 8H, H7'- H10'), 0.87 (t, J10',11' = 6.9 Hz, 3H, H11'); 13C NMR
(125 MHz, CDCl3) δ ppm 180.2 (C5), 176.0 (C8), 155.5 (C2),
148.4 (C8a), 141.1 (C4'), 134.5 (C1'), 134.9 (C4), 128.6 (C3'),
127.0 (C3), 124.6 (C2'), 115.6 (C6), 35.6 (C5'), 31.9 (C9'), 31.5
(C6'), 29.3 (C7'), 29.3 (C8'), 22.8 (C10'), 14.2 (C11'); HRMS-ESI
(m/z) calcd. for [C22H23ClN2O2+H]+: 383.1521, obsd.: 358.1520.
3H, o-PhCH, p-PhCH), 6.21 (br. s, 1H, NH), 4.12 (q, JH1',H2'
=
4.1.31. 6-Chloro-7-(4-tetradecylphenyl)amino-quinoline-5,8-
dione (25a). By subjecting dichloroQQ 8 (130 mg, 0.57 mmol)
and 4-tetradecylaniline (196 mg, 0.68 mmol) to the general
procedure for the synthesis of substituted QQs, the title
compound was isolated as red crystals (91 mg, 33%); Rf = 0.67
(CH2Cl2/EtOAc, 5/1, v/v); m.p.: 152.3 °C; IR (υmax): 3236, 2913,
2848, 1691, 1637, 1588, 1556, 1513, 1467, 1322, 1303, 1217,
1151, 1067, 1018, 857, 834, 817, 725, 623, 571, 551, 825, 510,
469, 450, 417 cm-1; UV-vis (CH2Cl2) λmax (log ε): 495 (2.39) nm;
1H NMR (500 MHz, CDCl3) δ ppm 8.99 (d, J2,3 = 4.7 Hz, 1H,
H2), 8.52 (d, J3,4 = 7.9 Hz, 1H, H4), 7.83 (br. s, 1H, NH), 7.71
(dd, J3,4 = 7.8 Hz, J2,3 = 4.7 Hz, 1H, H3), 7.17 (d, J2',3' = 8.2 Hz,
2H, H3'), 7.02 (d, J2',3' = 8.2 Hz, 2H, H2'), 2.62 (t, J5',6' = 7.4 Hz,
2H, H5'), 1.62-1.55 (m, H6'), 1.31-1.26 (m, 22H, H7'-H17'), 0.88
(t, J17',18' = 7.0 Hz, 2H, H18'); 13C NMR (125 MHz, CDCl3) δ
ppm 179.1 (C8), 176.4 (C5), 153.8 (C2), 146.1 (C8a), 141.3
(C1'), 134.9 (C4), 134.5 (C4'), 130.0 (C4a), 128.5 (C3), 128.4
(C3'), 124.6 (C2'), 113.5 (C6), 35.5 (C5'), 31.9 (C6'), 31.4, 29.69,
29.68, 29.67, 29.65, 29.6, 29.5, 29.4, 29.3, 22.7 (C7'-C17'), 14.12
(C18'); HRMS-ESI (m/z) calcd. for [C29H37ClN2O2+H]+:
481.2616, obsd.: 481.2618.
JH1',NH = 6.9 Hz, 2H, H1'), 2.99 (t, J1',2' = 7.2 Hz, 2H, H2'), 2.72 (s,
3H, CH3); 13C NMR (125 MHz, CDCl3) δ ppm 179.1 (C8), 175.9
(C5), 163.6 (C2), 145.5 (C8a), 144.4 (C7). 137.7 (Ph-Cq), 134.9
(C4), 129.0 (m-PhCH), 128.9 (o-PhCH), 128.5 (C3), 128.3 (C4a),
127.0 (p-PhCH), 46.1 (C1'), 37.4 (C2'), 25.1 (CH3); HRMS-ESI
(m/z) calcd. for [C18H15ClN2O2+H]+: 327.0895, obsd.: 327.0895.
4.1.28. 7-Chloro-2-methyl-6-phenylethylamino-quinoline-5,8-
dione (23b). By subjecting dichloroQQ 9 (186 mg, 0.77 mmol)
and 2-phenylethylamine (0.12 mL, 0.92 mmol) to the general
procedure for the synthesis of substituted QQs, the title
compound was isolated as red crystals (93 mg, 37%); Rf = 0.27
(EtOAc/petroleum ether, 2/1, v/v); m.p.: 143.0 °C; IR (υmax):
3210, 1682, 1567, 1507, 1440, 1362, 1306, 1230, 1114, 1069,
844, 770, 749, 697, 645, 566, 506, 489, 460, 421 cm-1; UV–vis
(toluene) λmax (log ε): 475 (2.78) nm; 1H NMR (500 MHz,
CDCl3) δ ppm 8.20 (d, J3,4 = 8.0 Hz, 1H, H4), 7.41 (d, J3,4 = 8.0
Hz, 1H, H3), 7.33-7.32 (m, 2H, m-PhCH), 7.26-7.24 (m, 3H, o-
PhCH, p-PhCH), 6.06 (br. s, 1H, NH), 4.12 (q, JH1',H2' = JH1',NH
=
6.9 Hz, 2H, H1'), 2.99 (t, J1',2' = 7.2 Hz, 2H, H2'), 2.75 (s, 3H,
CH3); 13C NMR (125 MHz, CDCl3) δ ppm 179.9 (C5), 175.5
(C8), 165.9 (C2), 148.0 (C8a), 143.5 (C6), 137.5 (Ph-Cq), 134.8
(C4), 128.9 (o-PhCH), 128.8 (m-PhCH), 127.0 (p-PhCH), 126.4
(C3), 124.5 (C4a), 46.1 (C1'), 37.2 (C2'), 25.5 (CH3); HRMS-ESI
(m/z) calcd. for [C18H15ClN2O2+H]+: 327.0895, obsd.: 327.0895.
4.1.32. 7-Chloro-6-(4-tetradecylphenyl)amino-quinoline-5,8-
dione (25b). By subjecting dichloroQQ 8 (130 mg, 0.57 mmol)
and 4-tetradecylaniline (196 mg, 0.68 mmol) to the general
procedure for the synthesis of substituted QQs, the title
compound was isolated as red crystals (80 mg, 29%); Rf = 0.5
(CH2Cl2/EtOAc, 5/1, v/v); m.p.: 160.7 °C; IR (υmax): 3339, 2916,
2848, 1670, 1616, 1608, 1578, 1471, 1313, 1215, 1144, 863, 837,
818, 623, 453 cm-1; UV-vis (CH2Cl2) λmax (log ε): 495 (2.29) nm;
1H NMR (500 MHz, CDCl3) δ ppm 9.05 (d, J2,3 = 4.8 Hz, 1H,
H2), 8.43 (d, J3,4 = 7.9 Hz, 1H, H4), 7.65-7.62 (m, 2H, NH, H3),
7.17 (d, J2',3' = 7.5 Hz, 2H, H3'), 7.01 (d, J2',3' = 7.5 Hz, 2H, H2'),
2.62 (t, J5',6' = 7.1 Hz, 2H, H5'), 1.69-1.59 (m, H6'), 1.31-1.26 (m,
22H, H7'-H17'), 0.88 (t, J17',18' = 7.2 Hz, 2H, H18'); 13C NMR
(125 MHz, CDCl3) δ ppm 180.3 (C5), 176.0 (C8), 155.5 (C2),
148.6 (C8a), 141.4 (C4'), 134.9 (C4), 134.7 (C1'), 128.6 (C3'),
127.0 (C3), 126.9 (C4a), 124.6 (C2'), 35.6 (C5'), 32.1 (C6'), 31.5,
29.9, 29.8, 29.8, 29.8, 29.7, 29.6, 29.5, 22.8 (C7'-C17'), 14.3
(C18'); HRMS-ESI (m/z) calcd. for [C29H37ClN2O2+H]+:
481.2616, obsd.: 481.2616.
4.1.29. 6-Chloro-7-(4-heptylphenyl)amino-quinoline-5,8-dione
(24a). By subjecting dichloroQQ 8 (136 mg, 0.60 mmol) and 4-
heptylaniline (0.15 mL, 0.72 mmol) to the general procedure for
the synthesis of substituted QQs, the title compound was isolated
as red crystals (92 mg, 40%); Rf = 0.23 (petroleum ether/EtOAc,
1/1, v/v); m.p.: 150.5 °C; IR (υmax): 2915, 2849, 1690, 1636,
1589, 1577, 1559, 1555, 1513, 1481, 1470, 1452, 1322, 1311,
1302, 1277, 1248, 1217, 1180, 1152, 1067, 856, 844, 725, 623,
1
567 cm-1; UV–vis (toluene) λmax (log ε): 505 (2.69) nm; H NMR
(500 MHz, CDCl3) δ ppm 8.98 (d, J2,3 = 4.7 Hz, 1H, H2), 8.51 (d,
J3,4 = 7.9 Hz, 1H, H4), 7.84 (br. s, 1H, NH), 7.70 (dd, J3,4 = 7.7
Hz, J2,3 = 4.7 Hz, 1H, H3), 7.16, (d, J2',3' = 7.6 Hz, 2H, H3'), 7.02
(d, J2',3' = 7.6 Hz, 2H, H2'), 2.62 (t, J5',6' = 7.7 Hz, 2H, H5'), 1.65-
1.59 (m, 2H, H6'), 1.32-1.27 (m, 8H, H7'- H10'), 0.88 (t, J10',11'
=
6.1 Hz, 3H, H11'); 13C NMR (125 MHz, CDCl3) δ ppm 179.2
(C8), 176.5 (C5), 153.9 (C2), 146.3 (C8a), 142.2 (C6), 141.4
(C4'), 135.1 (C4), 134.6 (C1'), 130.2 (C4a), 128.6 (C3), 128.5
(C3'), 124.7 (C2'), 113.5 (C7), 35.6 (C5'), 31.9 (C9'), 31.5 (C6'),
29.3 (C7'), 29.3 (C8'), 22.8 (C10'), 14.2 (C11'); HRMS(ESI) m/z
calcd. for [C22H23ClN2O2+H]+: 383.1521, obsd.: 358.1520.
4.1.33. 6-Chloro-7-(4-methoxylbenzyl)amino-quinoline-5,8-
dione (26a). By subjecting dichloroQQ 8 (144 mg, 0.63 mmol)
and methoxybenzylamine (0.10 mL, 0.76 mmol) to the general
procedure for the synthesis of substituted QQs, the title
compound was isolated as red crystals (167 mg, 67%); Rf = 0.29
(CH2Cl2/EtOAc, 5/1, v/v); m.p.: 179.3 °C; IR (υmax): 3308, 1698,
1595, 1560, 1509, 1447, 1359, 1302, 1246, 1181, 1149, 1089,
1036, 809, 724, 580, 545, 517, 445, 410 cm-1; UV-vis (DMF)
4.1.30. 7-Chloro-6-(4-heptylphenyl)amino-quinoline-5,8-dione
(24b). By subjecting dichloroQQ 8 (136 mg, 0.60 mmol) and 4-
heptylaniline (0.15 mL, 0.72 mmol) to the general procedure for

1
λmax (log ε): 465 (3.53) nm; H NMR (500 MHz, CDCl3) δ ppm
M. tuberculosis strain mc26230 (ΔRD1 ΔpanCD) was grown
in Middlebrook 7H9-oleic acid-albumin-dextrose-catalase
(OADC)- tyloxapol (0.2% glycerol, oleic acid, albumin, dextrose,
catalase) and plated on solid 7H11-OADC at 5% CO2 and 20%
O2. These media were supplemented with 50 μg/mL
pantothenate.43-45 Cultures were grown at 37°C while shaking
(160 rpm). Strain mc26230 is an avirulent auxotrophic M.
tuberculosis mutant that behaves identically to wild-type M.
tuberculosis when grown in pantothenate-supplemented medium
but is incapable of causing disease even in SCID mice.46
8.91 (d, J2,3 = 4.8 Hz, 1H, H2), 8.46 (d, J3,4 = 7.8 Hz, 1H, H4),
7.64 (dd, J3,4 = 7.9 Hz J2,3 = 4.6 Hz, 1H, H3), 7.25 (d, Jo-CH,m-CH
=
8.1 Hz, 2H, o-PhCH), 6.90 (d, Jo-CH,m-CH = 8.1 Hz, 2H, m-PhCH),
6.30 (br s, 1H, NH), 5.00 (d, JCH2,NH = 5.1 Hz, 2H, CH2) 3.79 (s,
3H, O-CH3); 13C NMR (125 MHz, CDCl3) δ ppm 179.0 (C8),
175.6 (C5), 159.7 (Cq-OCH3), 153.6 (C2), 146.1 (C8a), 144.4
(C7), 134.9 (C4), 129.9 (C4a), 128.6 (C3), 129.3 (o-PhCH),
114.5 (m-PhCH), 55.5 (OCH3); HRMS-ESI (m/z) calcd. for
[C17H13ClN2O2+H]+: 329.0887, obsd.: 328.0688.
4.3.2. Samples.
Each compound was dissolved in sterile DMSO to make 10
mM stock solutions.
4.1.34. 7-Chloro-6-(4-methoxylbenzyl)amino-quinoline-5,8-
dione (26b). By subjecting dichloroQQ 8 (144 mg, 0.63 mmol)
and methoxybenzylamine (0.10 mL, 0.76 mmol) to the general
procedure for the synthesis of substituted QQs, the title
compound was isolated as orange crystals (53 mg, 21%); Rf =
0.20 (CH2Cl2/EtOAc, 5/1, v/v); IR (υmax): 3310, 1699, 1603,
1576, 1516, 1350, 1235, 1100, 1024, 800, 725, 678, 511 cm-1;
4.3.3. Obtaining MIC values.
In clear-bottomed 96-well plates (Nunc), two-fold serial
dilutions of each compound were added to volumes of 100 µL of
7H9 medium. The last column of each plate did not contain any
compound and served as a negative control. Previously prepared
M. tuberculosis mc26230 inoculum was diluted with medium to
achieve a final OD600 of 0.05. The inoculum was then added to
each well and the plates incubated at 37 °C for five days. After
incubation, 30 µL of 0.02% resazurin was added to the wells, and
the plates incubated at 37 °C for 24 hours. The minimal
inhibitory concentration was determined by the compound
concentration well that remained blue (non-viable cells) and has
not changed to pink (viable cells).
1
UV-vis (DMF) λmax (log ε): 460 (2.03) nm; H NMR (500 MHz,
CDCl3) δ ppm 8.92 (d, J2,3 = 4.6 Hz, 1H, H2), 8.43 (d, J3,4 = 7.8
Hz, 1H, H4), 7.68 – 7.62 (m, 1H, H3), 7.24 (d, Jo-CH,m-CH = 8.7
Hz, 2H, o-PhCH), 6.91 (d, Jo-CH,m-CH = 8.1 Hz, 2H, m-PhCH),
5.86 (br s, 1H, NH), 4.33 (d, JCH2,NH = 5.5 Hz, 2H, CH2) 3.81 (s,
3H, O-CH3); 13C NMR (125 MHz, CDCl3) δ ppm 181.6 (C8),
175.5 (C5), 159.5 (Cq-OCH3), 153.4 (C2), 146.0 (C8a), 144.5
(C6), 134.7 (C4), 129.9 (C4a), 128.4 (C3), 129.3 (o-PhCH),
114.4 (m-PhCH), 55.3 (OCH3); HRMS-ESI (m/z) calcd. for
[C17H13ClN2O2+H]+: 329.0887, obsd.: 328.0688.
4.3.4. Measuring oxygen consumption rates
4.1.35.
6-Chloro-7-(4-methoxybenzyl)amino-2-methyl-
M. smegmatis inverted membrane vesicles (IMVs) were prepared
as previously described.47 The rate of oxygen consumption of
NADH (0.5 mM final concentration)-energized IMVs was
determined using an Oroboros O2k fluorespirometer as
previously described.48 The experiments were performed in
biological triplicate.
quinoline-5,8-dione (27a). By subjecting dichloroQQ 9 (212 mg,
0.88 mmol) and methoxybenzylamine (0.14 mL, 1.05 mmol) to
the general procedure for the synthesis of substituted QQs, the
title compound was isolated as orange crystals (148 mg, 49%); Rf
= 0.39 (CH2Cl2/EtOAc, 9/1, v/v); m.p.: 169.3 °C; IR (υmax): 3315,
1699, 1600, 1576, 1557, 1506, 1436, 1357, 1323, 1239, 1177,
1153, 1106, 1094, 1034, 818, 801, 738, 678, 599, 562, 518, 472,
417 cm-1; UV–vis (toluene) λmax (log ε): 485 (2.20), 320 (2.51)
1
nm; H NMR (500 MHz, CDCl3): δ ppm 8.29 (d, J3,4 = 8.1 Hz,
Acknowledgments
1H, H4), 7.47 (d, J3,4 = 8.0 Hz, 1H, H3), 7.24 (d, Jo-CH,m-CH = 8.1
Hz, 2H, o-PhCH), 6.87 (d, Jo-CH,m-CH = 8.1 Hz, 2H, m-PhCH),
6.23 (br s, 1H, NH), 4.97 (d, JNH,CH2 = 6.0 Hz, 2H, CH2-Ph), 3.77
(s, 3H, O-CH3), 2.69 (s, 3H, CH3); 13C NMR (125 MHz, CDCl3):
δ ppm 179.1 (C8), 176.0 (C5), 163.6 (C2), 159.5 (Cq-OCH3),
145.5 (C8a), 144.3 (C7), 134.9 (C4), 129.6 (Cq-CH2), 129.2 (o-
PhCH), 128.4 (C3), 127.7 (C4a), 114.4 (m-PhCH), 55.3 (O-CH3),
50.53, 48.7 (CH2), 25.0 (CH3); HRMS-ESI (m/z) calcd. for
[C18H15ClN2O2+H]+: 343.0844, obsd.: 343.0846.
The authors would like to thank the Maurice Wilkins Centre
for Molecular Biodiscovery for financial support for this work
and Prof. Martyn P. Coles for obtaining XRD data for
compounds 10b, 21b, and 22a.
Supplementary Material
Supplementary data associated with this article can be found,
in the online version, at:
4.2. Cyclic voltammetry
References
The electrochemical measurements were conducted at ambient
room temperature (~20 °C) using a PGSTAT128N potentiostat-
galvanostat (Metrohm Autolab Instruments, Switzerland),
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respectively, and a silver wire was used for a reference electrode.
For all samples the QQ concentration was approximately 1 mM
and the electrolyte concentration (C2H5)4N(PF6) was 50 mM in a
30 mL solution of acetonitrile. All the CVs were recorded at 100
mV/s.
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