Structural Simplification of Bedaquiline: the Discovery of 3-(4-(N,N-Dimethylaminomethyl)phenyl)quinoline-Derived Antitubercular Lead Compounds

Article abstract of DOI:10.1002/cmdc.201600441

Bedaquiline (BDQ) is a novel and highly potent last-line antituberculosis drug that was approved by the US FDA in 2013. Owing to its stereo-structural complexity, chemical synthesis and compound optimization are rather difficult and expensive. This study

Full text of DOI:10.1002/cmdc.201600441

DOI: 10.1002/cmdc.201600441
Full Papers
Structural Simplification of Bedaquiline: the Discovery of
3-(4-(N,N-Dimethylaminomethyl)phenyl)quinoline-Derived
Antitubercular Lead Compounds
Chunxian He,[a, b] Laura Preiss,[c] Bin Wang,[d] Lei Fu,[d] Hui Wen,[b] Xiang Zhang,[b]
Huaqing Cui,*[b] Thomas Meier,*[c, e] and Dali Yin*[a]
Bedaquiline (BDQ) is a novel and highly potent last-line antitu-
berculosis drug that was approved by the US FDA in 2013.
Owing to its stereo-structural complexity, chemical synthesis
and compound optimization are rather difficult and expensive.
This study describes the structural simplification of bedaquiline
while preserving antitubercular activity. The compound’s struc-
ture was split into fragments and reassembled in various com-
binations while replacing the two chiral carbon atoms with an
achiral linkage instead. Four series of analogues were de-
signed; these candidates retained their potent antitubercular
activity at sub-microgram per mL concentrations against both
sensitive and multidrug-resistant (MDR) Mycobacterium tuber-
culosis strains. Six out of the top nine MIC-ranked candidates
were found to inhibit mycobacterial ATP synthesis activity with
IC50 values between 20 and 40 mm, one had IC50 >66 mm, and
two showed no inhibition, despite their antitubercular activity.
These results provide a basis for the development of chemical-
ly less complex, lower-cost bedaquiline derivatives and de-
scribe the identification of two derivatives with antitubercular
activity against non-ATP synthase related targets.
Introduction
Tuberculosis (TB) is a serious threat to human health,[1–3] caus-
ing 1.5 million deaths in 2013.[4,5] The emergence and transmis-
sion of multidrug-resistant (MDR) and extensively drug-resist-
ant (XDR) TB strains is a particular challenge for global TB pre-
vention and treatment.[3] Bedaquiline (1) is the first novel US
Food and Drug Administration (FDA)-approved anti-TB drug
for the treatment of MDR-TB cases in the past 40 years.[6–11] In
vitro studies demonstrated potent inhibition of mycobacterial
growth by bedaquiline, against both drug-sensitive and drug-
resistant mycobacteria, with a minimum inhibitory concentra-
tion (MIC) of 0.06 mgmLÀ1.[9] Bedaquiline also exhibits excellent
clinical efficacy for the treatment of TB patients, particularly
those with MDR-TB infections.[9] It has a remarkably long half-
life, which was attributed to a high logP value (7.52) and cat-
ionic, amphiphilic properties resulting in tissue accumula-
tion.[8,12] Adverse side effects of bedaquiline, such as phospholi-
pidosis and cardiovascular risks, may relate to these molecular
features. In particular, an N-desmethyl metabolite (“M2”) was
reported to be more toxic but less bactericidal.[8,13] At the mo-
lecular level the compound was shown to inhibit the mycobac-
terial F1Fo ATP synthase by binding to its membrane-embed-
ded Fo rotor ring, a ring-shaped assembly of identical c-subunit
copies.[6,14] Here, the half-maximal inhibitory concentration
(IC50) of bedaquiline, efficiently inhibiting the mycobacterial
ATP synthase, was reported to be remarkably low (25 nm). Fur-
thermore, the mode of action of bedaquiline is highly target
specific,[14] as the IC50 values for human, bovine, and mouse mi-
tochondrial ATP synthases were found to be 20000-fold
higher.[10,14,15]
[a] Dr. C. He, Prof. D. Yin
State Key Laboratory of Bioactive Substances and Function ofNatural Medi-
cine, Institute of Materia Medica, Peking Union Medical College andChinese
Academy of Medical Sciences, Beijing, 100050 (China)
E-mail: yindali@imm.ac.cn
[b] Dr. C. He, H. Wen, X. Zhang, Dr. H. Cui
Beijing Key Laboratory of Active Substances Discovery and Drugability-
Evaluation, Institute of Materia Medica, Peking Union Medical College and-
Chinese Academy of Medical Sciences, Beijing, 100050 (China)
E-mail: hcui@imm.ac.cn
Besides these obvious assets of bedaquiline, its chemical
complexity in harboring two adjacent chiral centers, makes the
chemical synthesis of this new anti-TB drug laborious and
costly in the production process.[11,16] Many ongoing research
programs are focused on the optimization of bedaquiline to
decrease its structural complexity while maintaining its antitu-
bercular activity.[17–24] Still, new bedaquiline analogues are re-
quired to deliver potential new leads.
[c] Dr. L. Preiss, Prof. T. Meier
Department of Structural Biology, Max Planck Institute of Biophysics,
Max-von-Laue-Str. 3, 60438 Frankfurt am Main (Germany)
[d] B. Wang, L. Fu
Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor-
Research Institute, Beijing Chest Hospital, Capital Medical University, 97 Ma
Chang Street, Beijing 101149 (China)
[e] Prof. T. Meier
Department of Life Sciences, Imperial College London, Exhibition Road,
London SW7 2AZ (UK)
E-mail: t.meier@imperial.ac.uk
The aim of this study was therefore to simplify the chemical
synthesis of bedaquiline to work toward new, alternative leads.
Once these simplified scaffolds are achieved, they will be used
to improve pharmacokinetic properties to decrease the ad-
Supporting information for this article can be found under http://
dx.doi.org/10.1002/cmdc.201600441: methodology for ATP synthesis
assays, antitubercular assays, cytotoxicity assays, and chemistry.
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verse side effects of bedaquiline. Based on the previously re-
ported relationship of structure and antitubercular activity of
various diarylquinoline analogues,[9] we dissected bedaquiline
into various fragments and reorganized them to obtain novel
antitubercular agents with simplified scaffolds. The MIC values
of the new compounds were determined, and the best nine
candidates were tested for their inhibitory activities against
ATP synthesis inhibition in mycobacteria.
its analogue 2 suggested that the naphthylmethyl group can
be replaced with a substituted benzyl ring.[9] Thus, in our
chemical optimization, we also used the substituted benzyl
ring instead of a naphthylmethyl group to design some new
compounds. In addition, the minor bromo and hydroxy groups
were added to the final compounds, as desired.
In series 1, fragments A and C were attached to the tertiary
carbon atom at the 3-position of the quinoline moiety, and
fragment B was attached to fragment A. In series 2, fragment-
s A and C were attached to the tertiary carbon at the 3-posi-
tion, while fragment B was attached to fragment C. In series 3,
fragments A and B were attached to the tertiary carbon at the
3-position, while fragment C was moved down to the 2-oxyl
position. Finally, in series 4 fragment A was attached to the 3-
position of the quinoline moiety, fragment B was attached to
fragment A, and fragment C was moved down to the 2-oxyl
position. From series 1 to 4, we systematically simplified the
structure of bedaquiline to remove the two chiral carbons and
to understand the structure antimycobacterial activity relation-
ship of these new analogues.
Results and Discussion
Design strategy
Bedaquiline (1) contains two adjacent chiral carbon atoms that
bridge three aryl rings and a dimethylaminoethyl moiety
(Figure 1). The structure and antitubercular activity relationship
of diarylquinoline analogues as well as the importance and
contribution of each fragment of bedaquiline to its antituber-
cular activity have been quantitatively evaluated.[9] It was
shown that the activity of bedaquiline is closely related to the
spatial distribution of its segments. Some fragments, such as
the quinolino and dimethylamino groups, are necessary to
maintain its activity, whereas other groups such as the bromo
and hydroxy groups are less important. Therefore, we split be-
daquiline into the core quinoline moiety, three major frag-
ments (phenyl ring, naphthylmethyl, and dimethylaminoethyl),
and two minor fragments (bromo and hydroxy) (Figure 1). We
then reassembled the quinoline core with three major frag-
ments to design four new series of scaffolds. Notably, previous
structure–activity relationship (SAR) studies of bedaquiline and
First round of optimization
Compounds of series 1
The synthesis of compound 6 (Scheme 1) began with a nucleo-
philic addition of (3-fluorobenzyl)magnesium bromide to 2-me-
thoxyquinoline-3-carbaldehyde to give 4. Intermediate 4 was
oxidized with Dess–Martin periodinane to produce 5,[25] which
was reacted with an appropriate Grignard reagent to give 6.
Figure 1. Strategy of bedaquiline simplification. Bedaquiline was split into the core quinoline moiety, three major and two minor fragments (bromo and hy-
droxy groups). The major fragments comprise the phenyl ring (fragment A), the side chain dimethylaminoethyl (fragment B), and the naphthylmethyl ring
(fragment C). These major fragments were reattached to the core quinoline moiety to design four series of new analogues while gradually replacing the
chiral linkage.
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In series 1 (Table 1), we designed compounds, in which frag-
ment B was attached to fragment A. In total, eight compounds
were synthesized, which provided primary information about
the SAR of the compounds in series 1. An antitubercular activi-
ty screening revealed that compound 6a has the most potent
antitubercular activity (1 mgmLÀ1) in this series of compounds,
while the growth of mammalian cells was inhibited with
CC50 >64 mgmLÀ1. An identical molecule, 10a, harboring a bro-
mide, is less active, suggesting that it is not required to pre-
serve antitubercular activity. In addition, relative to compound
10a, compound 10b has an additional methylene unit exten-
sion between fragment C and the other segments. However,
compound 10b shows less potency against the growth of my-
cobacterium. Thus, the greater distance between fragment C
and the main scaffold likely disfavors its antitubercular activity.
Other analogues from this series with similar structures exhibit-
ed only weak activity against mycobacteria, indicating that the
arrangement of the fragments in series 1 is not suitable to ach-
ieve the desired antimycobacterial activity. Note that all candi-
dates of this series still contain one chiral carbon, and racemic
mixtures were used to generate CC50 and MIC values.
Scheme 1. Synthesis of compound 6. Reagents and conditions: a) (3-fluoro-
benzyl)magnesium bromide, THF, RT, 2 h, 66.5%; b) Dess–Martin periodinane,
CH2Cl2, RT, 3 h, 94.8%; c) substituted phenylmagnesium bromide, THF, RT,
2 h, 56.1–86.9%.
Compounds of series 2
Aniline (11) reacted with hydrocinnamoyl chloride to afford 12,
which was then treated with phosphoryl chloride and DMF at
1008C to provide 13 (Scheme 3). The reaction of 13 with
sodium methoxide produced 14 via a SN2 reaction. Next, 14
was activated by N-bromosuccinimide (NBS) to make 15. The
intermediate 15 was treated with substituted aniline and po-
tassium carbonate at room temperature, or followed by a reac-
tion with various aminoalkyl bromides to produce 16. The syn-
thesis of the derivatives required minor modifications (Sup-
porting Information).
Scheme 2. Synthesis of compound 10. Reagents and conditions: a) (2-((dime-
thylamino)methyl)phenyl)magnesium bromide, THF, RT, 2 h, 72.1–83.8%;
b) TBAP/NMO, 1,4-dioxane, RT, 15 h, 77.2–87.5%; c) Grignard reagent, THF,
RT, 2 h, 38.1–56.2%.
Compound 10 (Scheme 2) was obtained by reacting 2-methox-
yquinoline-3-carbaldehyde with (2-((dimethylamino)methyl)-
phenyl)magnesium bromide to produce intermediate 8. Oxidiz-
ing 8 with TBAP/NMO in 1,4-dioxane afforded 9,[26] which was
then treated with a Grignard reagent to give 10.
In series 2 (Table 2), fragment B was attached to fragment C.
The nitrogen or oxygen atoms located close to fragment C
were placed to mimic the hydroxy group of bedaquiline. A
total of six compounds were synthesized in this series. The ac-
tivity screening revealed that most of the compounds in
Scheme 3. Synthesis of N-linked compounds 16. Reagents and conditions: a) hydrocinnamoyl chloride, Et3N, CH2Cl2, RT, 5 h, 93.6–98.2%; b) POCl3, DMF, 1008C,
16 h, 46.0–82.2%; c) NaOMe/MeOH, reflux, 6 h, 98.2–99.3%; d) NBS/CCl4, reflux, 3 h; e) 1. substituted aniline, K2CO3, DMF, RT, 2 h, or 2. multistep (see Support-
ing Information for details).
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Table 1. In vitro antitubercular activity of series 1 compounds.[a]
[b]
Compd
6a
R1
R2
R3
H
MIC
CC50
mgmLÀ1
mm
mgmLÀ1
>64
mm
1.0
2.3
>148.8
6b
H
6.8
15.8
7.6
17.6
6c
H
H
>32
>32
16
>85.8
>67.8
31.5
26
>64
>64
59
69.7
>135.6
>126.0
117.0
6d
10a
10b
Br
Br
>32
>63.4
10c
10d
Br
>32
>32
>61.4
>67.8
1.4
2.7
OCH3
>64
>135.6
[a] Reference compound: bedaquiline MIC=0.060 mgmLÀ1 (0.1 mm). [b] Concentration at which the growth of Vero cells is inhibited by 50%.
series 2 exhibit moderate antitubercular activity. Compound
16e, however, was nearly inactive, which might have been
caused by the very short distance between the terminal amine
and fragment C of the molecule. In addition, we can also con-
clude from series 2 that the bromide is not important to retain
the antitubercular activity of this compound type. Further-
more, there is one chiral carbon left in the structures of all can-
didates in this series, and the racemic mixtures were used to
generate CC50 and MIC values. As none of the compounds
from series 2 exhibited sufficient antimycobacterial activity in
the very low-micromolar range, these compounds were not
chosen for further chemical optimization.
with Dess–Martin periodinane produced 19, which was then
reacted with 1-naphthol to give 20. The synthesis of 22 was
completed by the condensation of 20 with hydroxylamine hy-
drochloride, and dimethylaminoethyl chloride successively. The
treatment of 20 with (3-(dimethylamino)propyl)magnesium
chloride gave 23. Compound 24 was obtained by heating 23
under acidic conditions (25% w/w hydrochloric acid in alco-
hol).
In series 3 (Table 3) fragments A and B were joined with
a methylene linker forming a planar configuration. In addition
fragment C was added to the quinoline core by an ether bond.
This structure allowed us to remove the two chiral carbons. Ac-
cording to this strategy, we synthesized compounds 22 and
24. Compound 23 was synthesized for structure–activity com-
parison. An antitubercular evaluation showed that all three
compounds (22–24) from this series exert a reasonably potent
activity against mycobacteria. This suggests that placing frag-
ment C in the 2-methoxyl position maintains the antitubercular
activity. The comparison of compounds 23 and 24 further re-
Compounds of series 3
The preparation of compounds 22–24 (Scheme 4) started from
2-chloroquinoline-3-carbaldehyde (17) with methylmagnesium
iodide or phenylmagnesium bromide to provide secondary al-
cohol intermediates 18. The oxidation of two 18 analogues
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veals that the planar configuration between frag-
ments A and B does not affect the antitubercular ac-
tivity. It also indicates that the hydroxy group is not
important for the antitubercular activity of this new
scaffold. Moreover, none of the compounds from
series 3 contains the bromide. Hence it does not
affect the antitubercular activity of this series of com-
pounds, in agreement with the SAR information from
series 1 and 2.
Table 2. In vitro antitubercular activity of series 2 compounds.[a]
[b]
Compd
R1
R2
MIC
mgmLÀ1
CC50
mgmLÀ1
mm
mm
16a
H
7.7
6.4
17.0
14
12
30.9
Compounds of series 4
The design of series 4 compounds was based on the
finding that the planar configuration of compound
24 (series 3) showed no negative effect on the antitu-
bercular activity. Thus, we moved the phenyl ring
(fragment A) to the double bond position between
the quinoline and basic amino groups, but kept frag-
ment C attached to the 2-position of the quinoline.
The synthesis of 3-aromatic analogues 30 is shown in
Scheme 5. The synthesis of key substituted quinoline
intermediates 26 started from substituted quinoline
25. The reaction of 25 and N-iodosuccinimide gave
3-iodoquinoline 26, which was then treated with
meta-chloroperoxybenzoic acid (mCPBA) to produce
27, and chlorinated with phosphoryl chloride to give
2-chloro-3-iodoquinoline 28. Target compounds 30
were prepared via Suzuki–Miyaura coupling of com-
pound 28 with the corresponding substituted boric
acid or boronic acid pinacol cyclic ester to obtain
29.[27] Subsequently, the chloro moiety was ex-
changed with benzyl alcohol, aromatic alcohol,
phenol, thiophenol, or aromatic amine by a nucleo-
philic substitution to obtain 30.
16b
H
13.7
25.7
16c
16d
H
3.8
4.2
8.9
8.3
8.9
20.8
59.3
Br
30
16e
16 f
Br
Br
>32
>67.5
>64
>135.0
2.0
4.0
9.2
18.4
[a] Reference compound: bedaquiline MIC=0.060 mgmLÀ1 (0.1 mm). [b] Concentration
at which the growth of Vero cells is inhibited by 50%.
In total, 14 compounds were synthesized for
series 4 (30a–30n; Table 4), all of which contain no
Scheme 4. Synthesis of series 3 compounds. Reagents and conditions: (a) methylmagnesium iodide or phenylmagnesium bromide, THF, 08C, 76.4–78.5%;
b) Dess–Martin periodinane, CH2Cl2, RT, 92.7–95.5%; c) 1-naphthol, K2CO3, DMSO, 1008C, 86.9–92.9%; d) hydroxylamine hydrochloride, Et3N, EtOH, RT, 84.6%;
e) 2-dimethylaminoethyl chloride hydrochloride, NaH, THF, 66.8%; f) (3-(dimethylamino)propyl)magnesium chloride, 95.7%; g) HCl/EtOH, reflux, 72.7%.
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average. Comparison of the structures and antituber-
cular activities of series 4 compounds shows that the
length of the terminal amine chain can be 1–2 car-
bons (compounds 30a, 30b) while retaining antitu-
bercular activity. Further, the presence of the terminal
basic nitrogen atom was essential to sustain the anti-
tubercular activity (compounds 30h, 30m), whereas
the bromo group was not (compounds 30e, 30 f).
Scheme 5. Synthesis of series 4 compounds. Reagents and conditions: a) N-iodosuccini-
mide, AcOH, 1008C, 28 h, 47.4–46.9%; b) mCPBA, CHCl3, 3 h, RT, 90.6–92.7%; c) POCl3,
CHCl3, 3 h, reflux, 72.9–85.7%; d) 4-(dimethylamino)methylphenylboronic acid, Pd(PPh3)4,
Na2CO3, toluene/H2O, 14 h, 76.3–91.5%; e) benzyl alcohol/phenol/thiophenol, NaH, THF,
RT, 6 h, 68.0–99.3%.
Second round of optimization
Based on the results obtained from series 4, we ex-
plored the effect of 2-aryl substituents and the
spacer length of the terminal amine group in our
new scaffold of 2-aryl-3-(dimethylamino-substituted)-
phenylquinoline on antitubercular activity (Figure 2).
Table 3. In vitro antitubercular activity of series 3 compounds.[a]
In the first group of compounds (Table 5), we investigated
the position at which the basic nitrogen containing side chain
was attached to the phenyl ring as well as the lateral chain
length. We assembled a small library of 6-bromo-2-((naphth-1-
yl)methyl)oxy-3-substituted phenylquinoline analogues (32).
The synthetic route is outlined in Scheme 6. The antitubercular
screening assay showed that: 1) the para-substituted N,N-di-
methylaminomethylphenyl ring has the most potent antituber-
cular activity for this scaffold, and 2) the terminal nitrogen
atom is necessary for antitubercular activity. Other substituents
decreased the antitubercular activity of this scaffold significant-
ly. Compounds 32a, 32d, and 32e showed antitubercular ac-
tivities (MIC) of 0.43, 0.47, and 0.44 mgmLÀ1, and cytotoxicity
(CC50) against mammalian cells of 13, 12, and 3.9 mgmLÀ1, re-
spectively.
[b]
Compd
R
MIC
mgmLÀ1
CC50
mgmLÀ1
mm
mm
22
4.0
2.0
10.0
11
27.5
23
24
4.3
4.1
4.4
9.5
Next, we substituted the naphthalen-1-ylmethanol ring with
various aryl groups that have different physicochemical proper-
ties, while keeping 4-(N,N-dimethylaminomethyl)phenyl group
as the 3-substituent. A small group of analogues 34 were syn-
thesized (Scheme 7). Antitubercular screening showed activity
of several derivatives with MIC~0.4 mgmLÀ1 (Table 6). The aryl-
methyloxy group at C2 of the quinolone was substituted with
a variety of aromatic groups having different physicochemical
properties, such as a para-chlorophen-1-ylmethanol ring (34i,
1.8
10
22.5
[a] Reference compound: bedaquiline MIC=0.060 mgmLÀ1 (0.1 mm).
[b] Concentration at which the growth of Vero cells is inhibited by 50%.
more chiral centers. Intriguingly, series 4 compounds were gen-
erally potent against mycobacteria with MIC values of
~1 mgmLÀ1, whereas their CC50 values were 10-fold higher on
MIC=0.55 mgmLÀ1
MIC=0.43 mgmLÀ1). These substituents maintain the antituber-
) or a pyridin-4-ylmethanol ring (34m,
Figure 2. Scheme for the second round of compound optimization. Starting from bedaquiline, both chiral carbon atoms in the first round of optimization
were removed, and a new scaffold of 2-oxy-3-phenyl-6-bromoquinoline with potent anti-TB activity was obtained. In the second round of optimization, the
substituents of this new scaffold were changed to improve the anti-TB activity of these new compounds.
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Table 4. In vitro antitubercular activity of series 4 compounds.[a]
[b]
Compd
R1
R2
R3
Br
MIC
CC50
mgmLÀ1
mm
mgmLÀ1
mm
30a
1.0
2.0
10
20.1
30b
30c
30d
Br
Br
Br
2.0
1.8
1.6
3.9
3.5
3.3
3.8
7.4
23.4
51.9
12
25
30e
30 f
30g
30h
OMe
1.8
2.0
4.0
4.9
12
15
26.7
37.1
H
H
>32
>32
76.5
>64
>64
>153.1
>150.2
Br
>75.1
30i
Br
>32
>73.7
>64
>147.5
30j
Br
Br
Br
Br
1.6
1.9
3.3
4.0
4.4
9.2
23.6
30k
30l
11
1.0
2.2
11
23.6
30m
>32
>63.8
>64
>127.8
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Table 4. (Continued)
[b]
Compd
R1
R2
R3
Br
MIC
CC50
mgmLÀ1
>32
mm
mgmLÀ1
mm
30n
>67.5
3.9
8.2
[a] Reference compound: bedaquiline MIC=0.060 mgmLÀ1 (0.1 mm). [b] Concentration at which the growth of Vero cells is inhibited by 50%.
was compound 34m with an IC50 value of 20.3Æ
1 mm (Figure 3C) and an improved logP of 5.55
(Table S1), which may also be beneficial from a phar-
macokinetic point of view and which may help de-
crease some of the adverse side effects of bedaqui-
line.[8,12] Remarkably, two compounds (32d and 32p)
did not affect ATP synthesis at all, while still display-
ing potent antimycobacterial activity (MIC90: 0.47 and
0.51 mgmLÀ1, respectively; Figure S2). As a control, in-
hibition by bedaquiline was assayed, exhibiting an
IC50 value <10 nm (Figure S1).
Scheme 6. Synthesis of compound 32. Reagents and conditions: a) 1-naphthalenemetha-
nol, NaH, THF, RT, 6 h, 93.4%; b) for boric acid: Pd(PPh3)4, Na2CO3, toluene/H2O, 14 h, for
boronic acid pinacol cyclic ester: Pd(dppf)Cl2·CH2Cl2, Na2CO3, toluene/H2O, 14 h, 41.4–
86.8%.
All seven tested compounds, which inhibited ATP
synthesis activity, share a structural feature with be-
daquiline, that is, the presence of a dimethylamino
(DMA) moiety. This structural part of bedaquiline rep-
resents the most important structural feature in the
interaction with the ATP synthase c-ring and is hence
Scheme 7. Synthesis of compound 34. Reagents and conditions: a) (4-((dimethylamino)-
methyl)phenyl)boronic acid, Pd(PPh3)4, Na2CO3, toluene/H2O, 14 h, 81.5–85.8%; b) NaH,
THF, RT, 6 h, 34.4–91.3%.
a
decisive element of the molecule’s inhibitory
power.[14] In the lead compounds described herein,
the DMA moieties are all attached to longer aryl side
chains than the ethyl chain present in bedaquiline.
cular activity, and may provide a method for optimizing the
physicochemical properties of the final compounds.
Therefore, the subtle but exact structural placement of this
critical moiety is impaired, which explains the higher IC50
values measured for these derivatives. In agreement with that
notion are the two candidates (32d and 32p), which show no
influence on ATP synthesis activity and lack this structural ele-
ment completely. The fact that these compounds still show
specific killing activity on mycobacteria (Table S1) implies that
they target and affect other cellular processes or proteins in
mycobacterial cells. Future work needs to be carried out to
identify these potentially interesting targets.
Inhibition of ATP synthesis activity by selected compounds
in mycobacteria
The design of the new antimycobacterial lead compounds was
inspired by bedaquiline, which is known to inhibit mycobacte-
rial ATP synthase with an IC50 value in the low nanomolar
range (Supporting Information Figure S1).[14] To determine if
the new compounds share this property, nine candidates with
MIC values in the sub-microgram per mL range were selected
(Table S1) and tested for their ability to inhibit the ATP synthe-
sis activity of Mycobacterium phlei inverted membrane vesicles
(IMVs) (Figure 3A). A concentration range of 0–100 mm was as-
sayed for each compound. The calculated activities were used
to determine an IC50 value for each of the candidates (Fig-
ure 3B). Six of the compounds (34m, 32h, 34a, 34 f, 32e, and
32o) inhibited ATP synthesis with IC50 values between 20 and
40 mm (Figure S2). One candidate (34i) showed a slight inhibi-
tory effect; however, the IC50 value could not be calculated
due to the low solubility of the compound. The best candidate
In vitro anti-TB activities against drug-resistant clinical
isolates of M. tuberculosis
To further explore the effect of selected compounds on drug-
resistant clinical isolates of M. tuberculosis and compare it with
the effect on the drug-sensitive H37Rv strain, we performed
MIC determinations with two representative compounds that
showed ATP synthesis inhibitory activity (34m and 32e) and
two candidates that showed only marginal and no effect on
the ATP synthase, 34i and 32d, respectively (Figure 3C). The in
vitro inhibitory activities of these four compounds were
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screened against two drug-resistant clinical isolates
(isolates 12513 and 6133), which are both resistant to
isoniazid (INH) and rifampicin (RFP).[28] The MIC values
against the drug-sensitive H37Rv strain of M. tubercu-
losis were also determined again (Table 7). Com-
pounds 34m and 32e exhibited similar MIC values
for both the drug-resistant and drug-sensitive strains.
Interestingly, for compound 34i that had only mar-
ginal effects on ATP synthesis, the MICs for the drug-
resistant strains 6133 and 12153 were 5.4- and 7.9-
fold higher. A similar effect was observed for com-
pound 32d, which had no measureable impact on
ATP synthesis: the MIC was found to be 7.4-fold
higher for strain 6133 than for the drug-sensitive
H37Rv strain. The measured effects for 34i and 32d
indicate that these compounds target alternative
sites or processes in the mycobacterial cell; these re-
sults encourage future work to identify these novel
targets and to validate them in greater detail as po-
tential new sites for mycobacterial inhibitors.
Table 5. In vitro antitubercular activity of compounds from the second round of opti-
mization.[a]
[b]
Compd
32a
R
MIC
mgmLÀ1
CC50
mgmLÀ1
mm
mm
0.43
1.9
0.87
13
26.1
32b
3.7
6.3
12.3
7.6
32c
32d
1.7
3.2
4.1
0.47
0.87
12
22.3
Conclusions
32e
32 f
0.44
2.2
0.73
3.9
3.9
4.8
6.6
8.6
In this study we describe the chemical simplification
of bedaquiline, while largely retaining the potent an-
titubercular activity. Inspired by the SAR of bedaqui-
line, we designed a set of new lead compounds
using a fragment-based approach. The bedaquiline
molecule was first split into its various functional
groups and recombined in a way that decreased or
completely removed the initial stereochemical com-
plexity. The approach promises to significantly de-
crease production costs and make it accessible for
a broader variety of chemical laboratories and clinics.
Initially, four series of compounds were designed,
synthesized, and evaluated for their antitubercular
activity. Among the initial four series of compounds,
series 4, incorporating a 2-aryl moiety and a 3-(4-
(N,N-dimethylamino)methyl)phenyl group, was found
to contain the most potent analogues with MIC
values <1 mgmLÀ1. Further optimization of this scaf-
fold, modifying the C2 and C6 positions of the quino-
line, yielded several potent inhibitors with MIC<
0.6 mgmLÀ1. The most potent candidates were select-
ed and assayed for their capacity to inhibit ATP syn-
thesis activity in mycobacterial membranes. Our bio-
chemical analysis reveals that some of the newly syn-
thesized compounds showed a direct impact on my-
cobacterial ATP synthesis, with IC50 values between
20 and 40 mm, while others did not affect ATP synthe-
sis itself. The latter compounds are promising new
candidates that are able to target other cellular pro-
cesses in mycobacterial cells. This study provides the
basis for the development of novel, chemically sim-
plified, low-cost bedaquiline derivatives to fight
drug-resistant M. tuberculosis strains.
32g
32h
1.5
2.3
>64
>101.9
0.61
3.4
1.0
6.3
4.6
3.8
7.5
32i
32j
7.0
10
15.6
36
56.3
32k
0.73
1.2
53
87.9
32l
0.84
1.4
1.6
2.7
40
14
77.7
27.1
32m
32n
0.79
1.5
3.7
7.0
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the mixture was extracted with CH2Cl2 (3ꢁ10 mL), dried
with Na2SO4 and concentrated. The residue was purified
by flash column chromatography with petroleum ether/
ethyl acetate/triethylamine (40:15:1) to afford 32a as
a white solid (87 mg, 87.3%); mp: 85–868C. 1H NMR
(400 MHz, [D6]acetone): d=8.23 (d, J=8.2 Hz, 1H), 8.18
(s, 1H), 8.11 (s, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.88 (d, J=
8.4 Hz, 1H), 7.85 (d, J=8.9 Hz, 1H), 7.78 (dd, J=8.8,
1.6 Hz, 1H), 7.72 (d, J=6.9 Hz, 1H), 7.61–7.56 (m, 3H),
7.54 (t, J=6.8 Hz, 1H), 7.46 (t, J=7.6 Hz, 1H), 7.29 (d, J=
7.9 Hz, 2H), 6.07 (s, 2H), 3.38 (s, 2H), 2.17 ppm (s, 6H);
13C NMR (100 MHz, [D6]acetone): d=160.22, 145.21,
140.31, 138.10, 135.47, 134.74, 133.66, 133.26, 132.68,
130.60, 130.07, 129.66, 129.64, 129.43, 129.33, 128.30,
128.11, 128.00, 127.13, 126.73, 126.15, 124.94, 117.89,
67.02, 64.33, 45.56 ppm; HRMS (ESI-TOF, m/z): calcd for
C29H26ON2Br [M+H]+ 497.1223, found: 497.1223.
Table 5. (Continued)
[b]
Compd
R
MIC
mgmLÀ1
CC50
mgmLÀ1
mm
mm
32o
32p
0.67
0.51
1.3
12
13
22.7
0.94
24.1
32.7
32q
32r
1.1
3.1
2.1
5.7
17
6-Bromo-3-(4-(4-methylpiperazin-1-yl)phenyl)-2-(naph-
thalen-1-ylmethoxy)quinoline (32d): The procedure
used to synthesize 32a was repeated using 31 and (4-(4-
methylpiperazin-1-yl)phenyl)boronic acid to afford com-
pound 32d as a white solid in 79.1% yield; mp: 132–
1338C. 1H NMR (400 MHz, [D6]acetone): d=8.26 (d, J=
8.5 Hz, 1H), 8.14 (s, 1H), 8.10 (d, J=2.2 Hz, 1H), 7.96 (d,
J=7.6 Hz, 1H), 7.91 (d, J=8.3 Hz, 1H), 7.84 (d, J=8.9 Hz,
1H), 7.80–7.71 (m, 2H), 7.65–7.59 (m, 1H), 7.59–7.52 (m,
3H), 7.49 (dd, J=8.2, 7.1 Hz, 1H), 6.95–6.85 (m, 2H), 6.09
(s, 2H), 3.24–3.13 (m, 4H),2.51–2.41 (m, 4H), 2.24 ppm (s,
3H); 13C NMR (100 MHz, [D6]acetone): d=160.43, 152.09,
144.80, 136.96, 134.77, 133.80, 132.80, 132.73, 131.02,
130.39, 129.62, 129.61, 129.46, 128.44, 128.25, 128.15,
127.19, 126.81, 126.75, 126.22, 124.95, 117.79, 115.59,
66.92, 55.79, 48.99, 46.39 ppm; HRMS (ESI-TOF, m/z):
calcd for C31H29ON3Br [M+H]+ 538.1485, found
538.1482.
>64
>118.7
>124.5
32s
32t
32u
32v
>32
>62.3
>64
>64
>64
44
>32
>32
>32
>60.9
>62.9
>59.8
>121.9
>125.7
82.2
[a] Reference compound: bedaquiline MIC=0.060 mgmLÀ1 (0.1 mm). [b] Concentration
6-Bromo-3-(4-((4-(2-(dimethylamino)ethyl)piperazin-1-
yl)methyl)phenyl)-2-(naphthalen-1-ylmethoxy)quino-
line (32h): The procedure used to synthesize 32a was
repeated using 31 and (4-((4-(2-(dimethylamino)ethyl)pi-
at which the growth of Vero cells is inhibited by 50%.
Experimental Section
perazin-1-yl)methyl)phenyl)boronic acid to afford compound 32h
as a yellow wax-like solid in 67.2% yield; mp: 95–968C. 1H NMR
(400 MHz, [D6]acetone): d=8.24 (d, J=8.2 Hz, 1H), 8.20 (s, 1H),
8.12 (s, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.89 (d, J=8.3 Hz, 1H), 7.86 (d,
J=9.0 Hz, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.73 (d, J=6.9 Hz, 1H),
7.66–7.50 (m, 4H), 7.47 (t, J=7.7 Hz, 1H), 7.30 (d, J=7.9 Hz, 2H),
6.08 (s, 2H), 3.45 (s, 2H), 2.63–2.27 (m, 12H), 2.16 ppm (s, 6H);
13C NMR (150 MHz, [D6]acetone): d=160.26, 145.24, 139.71, 138.14,
135.50, 134.77, 133.68, 133.30, 132.71, 130.62, 130.11, 129.69,
129.68, 129.45, 128.35, 128.15, 128.03, 127.15, 126.76, 126.18,
124.99, 117.92, 67.05, 63.11, 58.02, 57.42, 54.47, 54.03, 46.09 ppm;
HRMS (ESI-TOF, m/z): calcd for C35H38ON481Br [M+H]+ 611.2203,
found 611.2185.
Chemistry: All reagents and anhydrous solvents are commercially
available and were used without further purification. Temperatures
are given in degrees Celsius (8C). NMR spectra were recorded on
Bruker AVIIIHD spectrometers using TMS as internal standard.
Chemical shifts (d) are reported in ppm, and coupling constants (J)
are given in hertz (Hz). The following multiplicity abbreviations are
used: (s) singlet, (d) doublet, (t) triplet, (q) quartet, (m) multiplet,
and (br) broad. ESI-HRMS data were measured on a Thermo Exac-
tive Orbitrap Plus spectrometer. All reactions were monitored by
TLC. Column chromatography was carried out with silica gel (200–
300 mesh size). Flash column chromatography was performed on
a Biotage Isolera One instrument. Purity was determined by LC–MS
and NMR spectroscopy. All final compounds are >95% pure. See
the Supporting Information for detailed synthesis and characteriza-
tion of all intermediates and final compounds.
6-Bromo-3-(4-(((3s,5s,7s)-adamantan-1-ylamino)methyl)phenyl)-
2-(naphthalen-1-ylmethoxy)quinoline (32k): The procedure used
to synthesize 32a was repeated using 31 and (4-(((3s,5s,7s)-ada-
mantan-1-ylamino)methyl)phenyl)boronic acid to afford compound
32k as a yellow solid in 55.1% yield; mp: 72–738C. 1H NMR
(400 MHz, [D6]acetone): d=8.25 (d, J=8.1 Hz, 1H), 8.18 (s, 1H),
8.12 (d, J=1.6 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.90 (d, J=8.4 Hz,
1H), 7.86 (d, J=8.9 Hz, 1H), 7.78 (dd, J=8.8, 1.8 Hz, 1H), 7.74 (d,
J=6.8 Hz, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.58–7.51 (m, 3H), 7.48 (t,
J=7.6 Hz, 1H), 7.34 (d, J=7.9 Hz, 2H), 6.08 (s, 2H), 3.74 (s, 2H), 2.77
6-Bromo-3-(4-((dimethylamino)methyl)phenyl)-2-(naphthalen-1-
ylmethoxy)quinoline (32a): A mixture of 6-bromo-3-iodo-2-(naph-
thalen-1-ylmethoxy)quinoline 31 (100 mg, 0.20 mmol), tetrakis(tri-
phenylphosphine)palladium (12 mg, 0.01 mmol), Na2CO3 (43 mg,
0.41 mmol) and 3-((dimethylamino)methyl)phenylboronic acid
(39 mg, 0.22 mmol) in the mixture of toluene (4 mL) and water
(2 mL) was stirred at 808C for 10 h. Water (10 mL) was added and
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(brs, 1H), 1.92–1.45 ppm (m, 15H); 13C NMR (150 MHz,
[D6]acetone): d=160.33, 145.20, 143.69, 138.07, 134.90,
134.79, 133.70, 133.24, 132.76, 130.60, 129.97, 129.70,
129.69, 129.47, 128.64, 128.50, 128.26, 128.06, 127.20,
126.78, 126.21, 124.98, 117.90, 67.07, 51.12, 45.09, 43.65,
37.56, 30.59 ppm; HRMS (ESI-TOF, m/z): calcd for
C37H36ON281Br [M+H]+ 605.1985, found 605.1.992
Table 6. In vitro antitubercular activity of compounds from the second round of opti-
mization.[a]
[b]
Compd
R1
R2
H
MIC
mgmLÀ1
CC50
6-Bromo-3-(4-((dimethylamino)methyl)-3-fluorophen-
yl)-2-(naphthalen-1-ylmethoxy)quinoline (32l): The
procedure used to synthesize 32b was repeated using
31 and (4-((dimethylamino)methyl)-3-fluorophenyl)bor-
onic acid pinacol ester to afford compound 32l as
a white solid in 71.4% yield; mp: 106–1078C. 1H NMR
(400 MHz, [D6]acetone): d=8.30–8.21 (m, 2H), 8.14 (s,
1H), 7.96 (d, J=7.8 Hz, 1H), 7.91 (d, J=8.3 Hz, 1H), 7.88
(d, J=9.2 Hz, 1H), 7.82 (d, J=8.9 Hz, 1H), 7.75 (d, J=
6.9 Hz, 1H), 7.60 (t, J=6.9 Hz, 1H), 7.55 (t, J=6.9 Hz, 1H),
7.51–7.44 (m, 2H), 7.43–7.34 (m, 2H), 6.10 (s, 2H), 3.44 (s,
2H), 2.19 ppm (s, 6H); 13C NMR (150 MHz, [D6]acetone):
d=162.47, 160.85, 159.97, 145.43, 138.56, 137.69, 137.63,
134.80, 133.65, 133.56, 132.76, 131.95, 131.92, 130.77,
129.79, 129.72, 129.48, 128.33, 127.88, 127.26, 126.97,
126.96, 126.79, 126.53, 126.43, 126.18, 125.88, 125.86,
124.94, 118.05, 117.01, 116.85, 67.20, 56.63, 56.62,
45.45 ppm; HRMS (ESI-TOF, m/z): calcd for C29H25ON281BrF
[M+H]+ 517.1108, found 517.1117.
mm
mgmLÀ1
mm
34a
0.62
1.6
1.5
4.0
9.6
34b
Br
3.7
11
25.4
34c
34d
34e
Br
Br
Br
2.5
5.6
4.3
1.7
7.8
17.4
26.0
12.9
2.0
12
6-Bromo-3-(4-((dimethylamino)methyl)-3-methoxy-
0.81
6.2
4.4
phenyl)-2-(naphthalen-1-ylmethoxy)quinoline
(32n):
The procedure used to synthesize 32b was repeated
using 31 and (4-((dimethylamino)methyl)-3-methoxyphe-
nyl)boronic acid pinacol ester to afford compound 32n
34 f
34g
34h
34i
Br
Br
Br
Br
0.58
5.2
1.2
10.9
1.5
9.2
11.7
15.9
22.9
1
as a white solid in 78.5% yield; mp: 106–1078C. H NMR
(600 MHz, [D6]acetone): d=8.26 (s, 1H), 8.23 (d, J=
8.3 Hz, 1H), 8.14 (d, J=2.2 Hz, 1H), 7.97 (d, J=7.5 Hz,
1H), 7.93 (d, J=8.3 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.80
(dd, J=8.8, 2.3 Hz, 1H), 7.75 (d, J=6.8 Hz, 1H), 7.62–7.57
(m, 1H), 7.57–7.53 (m, 1H), 7.49 (dd, J=8.2, 7.0 Hz, 1H),
7.34 (d, J=7.6 Hz, 1H), 7.22–7.15 (m, 2H), 6.06 (s, 2H),
3.35 (s, 2H), 3.27 (s, 3H), 2.16 ppm (s, 6H); 13C NMR
(150 MHz, [D6]acetone): d=160.26, 157.97, 145.24,
138.11, 136.43, 134.82, 133.66, 133.33, 132.91, 130.67,
130.46, 129.90, 129.69, 129.53, 128.70, 128.21, 128.07,
128.04, 127.44, 126.80, 126.27, 124.92, 121.98, 117.92,
112.64, 67.25, 57.55, 55.24, 45.74 ppm; HRMS (ESI-TOF,
m/z): calcd for C30H28O2N2Br [M+H]+ 527.1329, found
527.1323.
5.6
7.4
0.72
0.55
1.1
11
6-Bromo-3-(4-((dimethylamino)methyl)-2-methoxy-
phenyl)-2-(naphthalen-1-ylmethoxy)quinoline
(32o):
34j
Br
Br
1.5
3.1
1.7
4.2
8.7
The procedure used to synthesize 32b was repeated
using 31 and (4-((dimethylamino)methyl)-2-methoxyphe-
nyl)boronic acid pinacol ester to afford compound 32o
1
as a yellow solid in 71.8% yield; mp: 65–668C. H NMR
(600 MHz, [D6]acetone): d=8.12 (dd, J=8.0, 1.0 Hz, 1H),
8.08 (d, J=2.2 Hz, 1H), 8.04 (s, 1H), 7.91 (dd, J=7.5,
1.9 Hz, 1H), 7.85 (d, J=6.1 Hz, 1H), 7.84 (d, J=6.7 Hz,
1H), 7.77 (dd, J=8.9, 2.3 Hz, 1H), 7.63 (dd, J=6.9, 0.6 Hz,
1H), 7.57–7.49 (m, 2H), 7.42 (dd, J=8.2, 7.1 Hz, 1H), 7.23
(d, J=7.5 Hz, 1H), 6.98 (s, 1H), 6.92–6.86 (m, 1H), 3.56 (s,
3H), 3.39 (s, 2H), 2.19 ppm (s, 6H); 13C NMR (150 MHz,
[D6]acetone): d=161.08, 158.17, 145.43, 142.42, 138.88,
134.66, 133.89, 133.09, 132.58, 131.46, 130.44, 129.72,
129.36, 129.33, 127.76, 127.42, 127.06, 126.62, 126.50,
34k
0.89
14
26.8
34l
Br
0.79
1.5
5.0
9.3
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126.12, 124.88, 124.83, 121.30, 117.64, 111.83, 66.56,
64.71, 55.65, 45.62 ppm; HRMS (ESI-TOF, m/z): calcd for
C30H28O2N2Br [M+H]+ 527.1329, found 527.1325.
Table 6. (Continued)
6-Bromo-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-2-
(naphthalen-1-ylmethoxy)quinoline (32p): The proce-
dure used to synthesize 32b was repeated using 31 and
(6-(4-methylpiperazin-1-yl)pyridin-3-yl)boronic acid pina-
col ester to afford compound 32p as a white solid in
81.2% yield; mp: 130–1318C. 1H NMR (400 MHz,
[D6]acetone): d=8.42 (d, J=1.8 Hz, 1H), 8.23 (d, J=
8.2 Hz, 1H), 8.18 (s, 1H), 8.10 (d, J=1.8 Hz, 1H), 7.96 (d,
J=7.8 Hz, 1H), 7.91 (d, J=8.3 Hz, 1H), 7.87–7.79 (m, 2H),
7.79–7.70 (m, 2H), 7.64–7.52 (m, 2H), 7.49 (t, J=7.6 Hz,
1H), 6.70 (d, J=8.9 Hz, 1H), 6.09 (s, 2H), 3.53 (t, J=5.0 Hz,
4H), 2.39 (t, J=5.0 Hz, 4H), 2.23 ppm (s, 3H); 13C NMR
(150 MHz, [D6]acetone): d=160.38, 159.64, 149.00, 144.96,
139.05, 136.75, 134.79, 133.67, 133.01, 132.78, 130.44,
129.76, 129.66, 129.50, 128.32, 128.18, 127.28, 126.79,
126.24, 125.84, 124.85, 121.44, 117.92, 106.54, 67.06, 55.58,
46.43, 45.55 ppm; HRMS (ESI-TOF, m/z): calcd for
C30H2881BrN4O [M+H]+ 541.1421, found 541.1427.
[b]
Compd
R1
R2
Br
MIC
mgmLÀ1
CC50
mgmLÀ1
mm
mm
34m
0.43
0.71
0.95
3.0
9.7
6.7
34n
Br
1.5
3.9
20.9
34o
34p
Br
Br
1.6
5.9
12
29.4
45.8
15.9
17
3-(4-((Dimethylamino)methyl)phenyl)-2-(naphthalen-1-
ylmethoxy)quinoline (34a): To a solution of 2-chloro-3-
[a] Reference compound: bedaquiline MIC=0.060 mgmLÀ1 (0.1 mm). [b] Concentration
at which the growth of Vero cells is inhibited by 50%.
(4-((dimethylamino)methyl)phenyl)quinoline
(100 mg,
Figure 3. Inhibition of ATP synthesis in mycobacteria by selected lead compounds. The top nine candidates, selected by their MIC values, were tested for
their ATP synthesis inhibitory activity using Mycobacterium phlei inverted membrane vesicles. The corresponding IC50 values were determined in a concentra-
tion-dependent series of inhibition measurements. A) ATP synthesis activities were recorded using a luminescence-based activity assay.[14] The increasing lumi-
nescence signal, indicating continuous ATP synthesis at various concentrations (shown in different colors) of compound 34m, is shown exemplarily. As a con-
trol, the uncoupler carbonyl cyanide m-chlorophenyl hydrazone (CCCP) is plotted (purple trace). B) Concentration-dependent inhibition of ATP synthesis and
determination of IC50 for 34m. The rates for ATP synthesis were calculated and plotted versus the concentration of compound 34m to determine the concen-
tration required to inhibit 50% of remaining activity (IC50). Error bars represent the standard deviation of at least three biological replicates. C) IC50 values de-
termined for the tested compounds. Whereas six compounds showed inhibition of ATP synthesis activity with IC50 values between 20 and 40 mm (34m, 32h,
34a, 34 f, 32e, and 32o) and one >66 mm (34i), two compounds (32d and 32p) showed no measurable effect up to 100 mm.
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Table 7. In vitro antitubercular activities (MIC values) against drug-resistant clinical isolates of M. tuberculosis.
Compd:
34m
mgmLÀ1
32e
mgmLÀ1
34i
mgmLÀ1
32d
mgmLÀ1
INH
RFP
mgmLÀ1
mm
mm
mm
mm
mgmLÀ1
mm
mm
2.56
>48
0.06
12153[a]
6133[a]
H37RV
0.48
0.55
0.43
1.07
1.22
0.95
0.94
0.69
0.44
1.57
1.15
0.73
2.62
1.83
0.33
5.45
3.81
0.68
0.51
3.42
0.46
0.94
6.35
0.85
>40
>40
0.05
>291
>291
2.11
>40
0.36
0.05
[a] Strain number of in vitro cultured clinical isolate of MDR M. tuberculosis.
0.34 mmol) and 1-naphthalenemethanol (68 mg, 0.43 mmol) in
4 mL DMF was added Cs2CO3 (140 mg, 0.43 mmol). After stirring at
808C for 8 h, water (20 mL) was added, and the mixture was ex-
tracted with CH2Cl2 (3ꢁ10 mL), dried with Na2SO4 and concentrat-
ed. The residue was purified by flash column chromatography with
petroleum ether/ethyl acetate/triethylamine (40:15:1) to afford
34a as a white solid (128.9 mg, 91.2%); mp: 93–958C. 1H NMR
(600 MHz, [D6]acetone): d=8.25 (d, J=8.4 Hz, 1H), 8.21 (s, 1H),
7.98–7.89 (m, 3H), 7.88 (d, J=8.3 Hz, 1H), 7.74 (d, J=6.9 Hz, 1H),
7.69 (t, J=7.6 Hz, 1H), 7.65–7.58 (m, 3H), 7.55 (t, J=7.4 Hz, 1H),
7.46 (t, J=7.6 Hz, 2H), 7.29 (d, J=7.9 Hz, 2H), 6.09 (s, 2H), 3.39 (s,
2H), 2.17 ppm (s, 6H); 13C NMR (150 MHz, [D6]acetone): d=159.80,
146.56, 139.94, 139.07, 136.01, 134.76, 133.94, 132.73, 130.31,
130.09, 129.56, 129.43, 129.32, 128.62, 128.04, 127.65, 127.22,
127.11, 126.72, 126.70, 126.18, 125.30, 124.99, 66.77, 64.35,
45.55 ppm; HRMS (ESI-TOF, m/z): calcd for C29H27N2O [M+H]+
419.2118, found 419.2110.
(m, 2H), 7.43 (d, J=8.3 Hz, 2H), 7.39 (td, J=7.9, 5.9 Hz, 1H), 7.33
(d, J=7.7 Hz, 1H), 7.30–7.24 (m, 1H), 7.09–7.01 (m, 1H), 5.62 (s,
2H), 3.46 (s, 2H), 2.22 ppm (s, 6H); 13C NMR (150 MHz, [D6]acetone):
d=164.48, 162.86, 160.04, 145.14, 141.25, 141.20, 140.52, 138.17,
135.50, 133.33, 131.10, 131.04, 130.63, 130.13, 129.62, 129.48,
128.21, 128.04, 124.33, 124.31, 118.00, 115.27, 115.19, 115.12,
115.05, 67.79, 67.78, 64.42, 45.60 ppm; HRMS (ESI-TOF, m/z): calcd
for C25H23BrFN2O [M+H]+ 465.0972, found 465.0974.
6-Bromo-2-((4-chlorobenzyl)oxy)-3-(4-((dimethylamino)methyl)-
phenyl)quinoline (34i): The procedure used to synthesize 34a was
repeated using 33a and 4-chlorobenzyl alcohol to afford com-
pound 34i as a yellow solid in 82.4% yield; mp: 120–1218C.
1H NMR (600 MHz, [D6]acetone): d=8.21 (s, 1H), 8.12 (d, J=2.0 Hz,
1H), 7.79 (d, J=8.8 Hz, 1H), 7.76 (dd, J=8.9, 2.1 Hz, 1H), 7.70–7.64
(m, 2H), 7.56–7.52 (m, 2H), 7.42 (d, J=8.2 Hz, 2H), 7.40–7.35 (m,
2H), 5.59 (s, 2H), 3.45 (s, 2H), 2.22 ppm (s, 6H); 13C NMR (150 MHz,
[D6]acetone): d=160.08, 145.14, 140.53, 138.16, 137.29, 135.50,
133.83, 133.32, 130.63, 130.55, 130.11, 129.61, 129.48, 129.25,
128.19, 128.03, 117.97, 67.83, 64.43, 45.63 ppm; HRMS (ESI-TOF, m/
z): calcd for C25H2381BrClN2O [M+H]+ 483.0656, found 483.0639.
6-Bromo-3-(4-((dimethylamino)methyl)phenyl)-2-((2-methoxy-
benzyl)oxy)quinoline (34e): The procedure used to synthesize
34a was repeated using 33a and 2-methoxybenzyl alcohol to
afford compound 34e as a yellow wax-like solid in 81.5% yield;
2-([1,1’-Biphenyl]-4-ylmethoxy)-6-bromo-3-(4-((dimethylamino)-
methyl)phenyl)quinoline (34k): The procedure used to synthesize
34a was repeated using 33a and [1,1’-biphenyl]-4-ylmethanol to
afford compound 34k as a yellow solid in 89.8% yield; mp: 96–
1
mp: 96–978C. H NMR (600 MHz, [D6]acetone): d=8.20 (s, 1H), 8.11
(d, J=2.2 Hz, 1H), 7.81 (d, J=8.8 Hz, 1H), 7.76 (dd, J=8.9, 2.2 Hz,
1H), 7.73–7.64 (m, 2H), 7.44 (dd, J=7.5, 1.4 Hz, 1H), 7.40 (d, J=
8.2 Hz, 2H), 7.29 (td, J=8.2, 1.7 Hz, 1H), 7.03 (d, J=8.1 Hz, 1H),
6.90 (td, J=7.4, 0.7 Hz, 1H), 5.60 (s, 2H), 3.91 (s, 3H), 3.44 (s, 2H),
2.21 ppm (s, 6H); 13C NMR (150 MHz, [D6]acetone): d=160.48,
158.37, 145.31, 140.42, 137.92, 135.64, 133.20, 130.59, 130.14,
129.93, 129.87, 129.64, 129.41, 128.28, 127.97, 126.10, 121.04,
117.77, 111.32, 64.49, 64.44, 55.81, 45.61 ppm; HRMS (ESI-TOF, m/z):
calcd for C26H26BrN2O2 [M+H]+ 477.1172, found 477.1166.
1
978C. H NMR (600 MHz, [D6]acetone): d=8.22 (s, 1H), 8.13 (d, J=
2.2 Hz, 1H), 7.82 (d, J=8.9 Hz, 1H), 7.77 (dd, J=8.9, 2.2 Hz, 1H),
7.70 (d, J=8.2 Hz, 2H), 7.68–7.63 (m, 4H), 7.61 (d, J=8.3 Hz, 2H),
7.48–7.43 (t, J=7.8 Hz, 2H), 7.42 (d, J=8.2 Hz, 2H), 7.35 (t, J=
7.4 Hz, 1H), 5.66 (s, 2H), 3.45 (s, 2H), 2.21 ppm (s, 6H); 13C NMR
(150 MHz, [D6]acetone): d=160.27, 145.22, 141.46, 141.26, 140.48,
138.11, 137.44, 135.59, 133.28, 130.62, 130.14, 129.70, 129.63,
129.47, 129.38, 128.25, 128.21, 128.02, 127.71, 127.69, 117.89, 68.36,
64.44, 45.62 ppm; HRMS (ESI-TOF, m/z): calcd for C31H28ON2Br [M+
H]+ 523.1380, found 523.1389.
6-Bromo-3-(4-((dimethylamino)methyl)phenyl)-2-((3-methoxy-
benzyl)oxy)quinoline (34 f): The procedure used to synthesize
34a was repeated using 33a and 3-methoxybenzyl alcohol to
afford compound 34 f as a colorless wax-like solid in 92.4% yield;
2-(4-(Benzyloxy)phenoxy)-6-bromo-3-(4-((dimethylamino)me-
thyl)phenyl)quinoline (34l): The procedure used to synthesize
34a was repeated using 33a and 4-(benzyloxy)phenol to afford
compound 34l as a yellow solid in 79.9% yield; mp: 103–1048C.
1H NMR (600 MHz, [D6]acetone): d=8.31 (s, 1H), 8.15 (s, 1H), 7.77
(d, J=7.8 Hz, 2H), 7.71 (dd, J=8.9, 1.3 Hz, 1H), 7.55 (d, J=8.9 Hz,
1H), 7.51 (d, J=7.6 Hz, 2H), 7.46 (d, J=7.9 Hz, 2H), 7.41 (t, J=
7.5 Hz, 2H), 7.34 (t, J=7.3 Hz, 1H), 7.20 (d, J=8.8 Hz, 2H), 7.08 (d,
J=8.8 Hz, 2H), 5.14 (s, 2H), 3.47 (s, 2H), 2.22 ppm (s, 6H); 13C NMR
(150 MHz, [D6]acetone): d=160.75, 156.90, 148.20, 144.98, 140.61,
138.87, 138.41, 135.53, 133.41, 130.58, 130.17, 129.79, 129.61,
129.29, 128.65, 128.49, 128.36, 123.79, 118.44, 116.20, 70.85, 64.43,
45.64 ppm; HRMS (ESI-TOF, m/z): calcd for C31H28BrN2O2 [M+H]+
539.1329, found 539.1334.
1
mp: 52–538C. H NMR (600 MHz, [D6]acetone): d=8.20 (s, 1H), 8.11
(d, J=2.1 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.76 (dd, J=8.9, 2.2 Hz,
1H), 7.69 (d, J=8.2 Hz, 2H), 7.42 (d, J=8.2 Hz, 2H), 7.26 (t, J=
7.9 Hz, 1H), 7.09 (d, J=1.7 Hz, 1H), 7.06 (d, J=7.5 Hz, 1H), 6.84
(dd, J=8.1, 2.4 Hz, 1H), 5.58 (s, 2H), 3.76 (s, 3H), 3.45 (s, 2H),
2.22 ppm (s, 6H); 13C NMR (150 MHz, [D6]acetone): d=160.75,
160.22, 145.22, 140.45, 139.79, 138.06, 135.60, 133.26, 130.60,
130.20, 130.14, 129.61, 129.46, 128.24, 127.98, 120.55, 117.88,
114.23, 113.68, 68.46, 64.42, 55.45, 45.61 ppm; HRMS (ESI-TOF, m/z):
calcd for C26H26BrN2O2 [M+H]+ 477.1172, found 477.1167.
6-Bromo-3-(4-((dimethylamino)methyl)phenyl)-2-((3-fluoro-
benzyl)oxy)quinoline (34h): The procedure used to synthesize
34a was repeated using 33a and 3-fluorobenzyl alcohol to afford
compound 34h as a yellow solid in 85.4% yield; mp: 82–838C.
1H NMR (600 MHz, [D6]acetone): d=8.21 (s, 1H), 8.12 (d, J=2.1 Hz,
1H), 7.79 (d, J=8.8 Hz, 1H), 7.76 (dd, J=8.9, 2.1 Hz, 1H), 7.71–7.65
6-Bromo-3-(4-((dimethylamino)methyl)phenyl)-2-(pyridin-4-ylme-
thoxy)quinoline (34m): The procedure used to synthesize 34a
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was repeated using 33a and 4-pyridylcarbinol to afford compound
34m as a white solid in 84.7% yield; mp: 86–878C. 1H NMR
(600 MHz, [D6]acetone): d=8.54 (dd, J=4.4, 1.5 Hz, 2H), 8.24 (s,
1H), 8.13 (s, 1H), 7.76 (d, J=1.3 Hz, 2H), 7.71 (d, J=8.2 Hz, 2H),
7.47 (d, J=8.0 Hz, 2H), 7.44 (d, J=5.9 Hz, 2H), 5.65 (s, 2H), 3.49 (s,
2H), 2.24 ppm (s, 6H); 13C NMR (150 MHz, [D6]acetone): d=159.83,
150.65, 147.16, 145.07, 140.45, 138.30, 135.47, 133.38, 130.65,
130.16, 129.62, 129.58, 128.17, 128.09, 122.65, 118.11, 66.97, 64.37,
45.55 ppm; HRMS (ESI-TOF, m/z): calcd for C24H23BrN3O [M+H]+
448.1019, found 448.1016.
2-(Benzylthio)-6-bromo-3-(4-((dimethylamino)methyl)phenyl)qui-
noline (34n): The procedure used to synthesize 34a was repeated
using 33a and benzyl mercaptan to afford compound 34n as
a yellow solid in 71.4% yield; mp: 67–688C. 1H NMR (600 MHz,
[D6]acetone): d=8.13 (s, 1H), 7.98 (d, J=8.9 Hz, 1H), 7.96 (s, 1H),
7.83 (d, J=8.9 Hz, 1H), 7.49 (d, J=7.8 Hz, 2H), 7.47 (d, J=8.0 Hz,
2H), 7.43 (d, J=7.9 Hz, 2H), 7.28 (t, J=7.5 Hz, 2H), 7.20 (t, J=
7.3 Hz, 1H), 4.56 (s, 2H), 3.46 (s, 2H), 2.21 ppm (s, 6H); 13C NMR
(150 MHz, [D6]acetone): d=160.10, 146.51, 141.09, 139.18, 136.75,
136.21, 135.16, 133.62, 130.81, 130.39, 130.21, 130.04, 129.67,
129.19, 128.33, 127.81, 119.27, 64.41, 45.64, 35.22 ppm; HRMS (ESI-
TOF, m/z): calcd for C25H24BrN2S [M+H]+ 463.0844, found 463.0844.
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(20 mm Tricine/KOH pH 7.5, 0.1m NaCl, 5 mm KPi, 5 mm MgCl2),
50 mm ADP, 50 ng luciferase (Roche), 166 mm luciferin, and 2 mL
DMSO to a total volume of 300 mL. The addition of inhibitors was
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Acknowledgements
The research leading to these results was funded by the National
Science and Technology Major Projects for “Major New Drugs In-
novation and Development” (China) (2015ZX09102007-016-003),
the National High-tech R&D Program (China) (2012AA020302a),
and the Wellcome Trust (UK) (WT110068/Z/15/Z).
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Keywords: ATP synthase · bedaquiline · multidrug resistance ·
Mycobacterium tuberculosis · pulmonary tuberculosis
[1] F. S. Branco, A. C. Pinto, N. Boechat, Curr. Top. Med. Chem. 2013, 13,
2808–2849.
Received: August 26, 2016
[2] L. G. Dover, G. D. Coxon, J. Med. Chem. 2011, 54, 6157–6165.
Published online on && &&, 0000
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FULL PAPERS
C. He, L. Preiss, B. Wang, L. Fu, H. Wen,
X. Zhang, H. Cui,* T. Meier,* D. Yin*
&& – &&
Structural Simplification of
Bedaquiline: the Discovery of 3-(4-
(N,N-
Dimethylaminomethyl)phenyl)quino-
line-Derived Antitubercular Lead
Compounds
Anti-TB streamlining: Synthesis of the
new antituberculosis antibiotic bedaqui-
line is expensive and time consuming.
To overcome difficulties met in the syn-
thesis of bedaquiline, a fragment-based
strategy was used to create a new
simpler structures and no chiral centers.
While these new lead compounds main-
tain their potent antitubercular activities
toward Mycobacterium tuberculosis, they
are less potent at inhibition of the mo-
lecular target of bedaquiline: the ATP
synthase.
series of lead compounds with much
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