Identification and synthesis of novel inhibitors of mycobacterium ATP synthase

Article abstract of DOI:10.1016/j.bmcl.2017.05.081

A non-diaryl quinoline scaffold 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one was identified by screening of diverse set of compounds against M. smegmatis ATP synthase. Herein, we disclose our efforts to develop the structure activity relationship against Mycob

Full text of DOI:10.1016/j.bmcl.2017.05.081

Accepted Manuscript
Identification and Synthesis of Novel Inhibitors of Mycobacterium ATP Syn-
thase
Yogesh B. Surase, Kirandeep Samby, Sagar R. Amale, Ruchi Sood, Kedar P.
Puranpatre, Pawan K. Pareek, Biswajit Das, Kamna Nanda, Subodh Kumar,
Ashwani K. Verma
PII:
S0960-894X(17)30579-6
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.05.081
BMCL 25026
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
8 March 2017
24 April 2017
26 May 2017
Please cite this article as: Surase, Y.B., Samby, K., Amale, S.R., Sood, R., Puranpatre, K.P., Pareek, P.K., Das, B.,
Nanda, K., Kumar, S., Verma, A.K., Identification and Synthesis of Novel Inhibitors of Mycobacterium ATP
Synthase, Bioorganic & Medicinal Chemistry Letters (2017), doi: http://dx.doi.org/10.1016/j.bmcl.2017.05.081
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Identification and Synthesis of Novel Inhibitors of
Mycobacterium ATP Synthase
Yogesh B. Surasea*, Kirandeep Sambya, Sagar R. Amalea, Ruchi Sooda, Kedar P.
Puranpatrea, Pawan K. Pareeka, Biswajit Dasa,, Kamna Nandaa, Subodh Kumarb, and
Ashwani K. Vermaa
a New Drug Discovery Research, Ranbaxy Research Laboratories(Now Sun Pharmaceutical Industries LTD.) , Plot-20,
Sector-18, Udyog Vihar, Gurgaon 122001, India
a Daiichi Sankyo Life Science Research Centre in India, Daiichi Sankyo India Pharma Pvt. Ltd., Village Sarhaul, Sector-18,
Udyog Vihar Industrial Area, Gurgaon – 122 015, India (Current Address)
b Department of Chemistry, Guru Nanak Dev University, Amritsar-143005, India
Email: ybsurase_2@rediffmail.com
Abstract—A non-diaryl quinoline scaffold 6,7-Dihydropyrazolo[1, 5-a]pyrazin-4-one was identified by screening of diverse set of
compounds against M.smegmatis ATP synthase. Herein, we disclose our efforts to develop the structure activity relationship against
Mycobacterium tuberculosis (Mtb. H37Rv strain) around the identified hit 1. A scaffold hopping approach was used to identify
compounds 14a, 14b and 24a with improved activity against MTb.H37Rv.
Tuberculosis (TB) is a disease of antiquity which is
thought to have evolved sometime between the seventh
and sixth millennia BC.1 According to World Health
Organization (WHO) there were 9.6 million incident cases
of TB and 1.5 million deaths in 2014 making TB a global
public health issue.2 The global health impact of Mtb. is
further aggravated in AIDS patients whose immune
system is compromised.3. Comorbidity with HIV and
the emergence of multidrug resistant (MDR) TB;
extensively drug-resistant (XDR) TB or totally drug-
resistant (TDR) TB has worsened the TB treatment.4,5,6,7
New drugs are needed to tackle the growing global
problem of multidrug-resistant and extensively drug-
resistant tuberculosis.8 Patients with MDR TB need a
combination of second-line and third-line anti-
tuberculosis drugs,,9,10 which are much more expensive
and more toxic compared to standard drug treatment
regimen, and treatment may last much longer.
infections with antibiotics that target biosynthetic
processes; thus in recent years people have targeted
bacterial membrane and enzymes involved in anaerobic
respiration. This emerging concept involving disruption
of energy metabolism in dormant bacteria is
exemplified by the efficacy of Bedaquiline, which
inhibits membrane-bound ATP synthase. 11 Bedaquiline
(Fumarate){also known as TMC-207, diarylquinoline
(DARQ)} was the first novel anti-tubercular drug
approved by the US Food and Drug Administration
(FDA) specifically for the treatment of MDR-TB in the
past 40 years.12-17 It is found effective against all states of
Mycobacterium tuberculosis like active, dormant,
replicating,
non-replicating,
intracellular
and
extracellular.12,18,19 Although, Bedaquiline has been
launched, the drug possesses serious adverse effects
13,20
such as cardiac arrhythmias, phospholipidosis.
There were more deaths in the Bedaquiline group than
In recent years, persistent efforts in this direction have
led to several lead molecules progressing to clinical
trials which exhibited promising activities against drug-
sensitive and drug-resistant strains of the causative
organism Mtb.. It is hard to treat the persistent
in the placebo group with no causal pattern evident .21
1

O
Benzylic region
Amide region
HOOC
OH
Cl
Cl
O
N
COOH
O
N
Cl
Cl
N
O
N
Br
N
N
N
Compound 1
Central Scaffold
N
N
O
N
Bedaquiline (fumarate)
Compound 1
O
O
O
Figure 1: Structures of Bedaquiline (Fumarate) and Hit obtained from
screening campaign
*
*
*
N
N
N
*
*
*
N
N
N
N
N
Scaffold B
5,6,7,8-Tetrahydro-4H-pyrazolo
[1,5-a][1,4]diazepin-4-one
Scaffold A
3,4-Dihydropyrrolo[1,2-a]
pyrazin-1(2H)-one
Scaffold C
Pyrazolo[1,5-a]
pyrazin-4(5H)-one
Adverse
effects
of
bedaquiline,
such
as
phospholipidosis and cardiovascular risks, may be
related to molecular features like cationic, amphiphilic
properties and high logP (7.52).15,22 Especially, an N-
desmethyl metabolite (“M2”) was reported to be more
toxic.15,23 These observed adverse effects of Bedaquiline
suggests the necessity of new chemical entities as
selective ATP Synthase inhibitors without any potential
adverse effects. It is expected that new class of
compounds may have a different toxicological profile.
Therefore, screening of a chemically diverse small
molecule library against M. smegmatis ATP synthase
was carried out.
O
O
*
N
*
N
*
N
N
N
*
N
OH
Scaffold D
7-hydroxy 6,7-dihydropyrazolo
[1,5-a]pyrazin-4-one
Scaffold E
Imidazo[1,2-a]
pyrazin-8(7H)-one
Figure 3: Derivatization strategy for Hit obtained from screening
campaign
Initially our focus was to develop an SAR around the
benzylic and amidic region. The strategy for the
synthesis of of N-substituted 6, 7-dihydropyrazolo [1,
5-a] pyrazin-4-one (Z=N) derivatives 7a-7l is
summarized in synthetic scheme 1. The alkylation of
An automated screening of 10,000 compounds was
performed using Tecan Robot.
commercially
available
diethyl
pyrazole-3,5-
dicarboxylate followed by transformation to azide 4.
Reduction of azide 4 using Staudinger reaction25
furnished the ring closure to lactum 5 as reported in
literature.26,27 This intermediate 5 was converted to 6
by the trimethylaluminium mediated amidation reaction.
The compounds 1 and 7a-7n were synthesized either by
alkylation with different benzyl bromides or by
Buchwald-Hartwig cross coupling reaction.28,29 Diverse
amide derivatives 9a-9h were synthesized using similar
reaction sequence.
Figure 2: Signal Background (S: B) ratio of ATP synthase screening –
Assay
Using this assay, compounds were screened at a single
inhibitor concentration of 10 μM and 151 potential
actives – (hit rate: 1.51 %) were identified. Dose-
response curves, using phosphate assays, led to
identification of 24 hits (hit rate: 0.24%). This effort
led to the identification of hit from a non-DARQ
template which exhibited activity of 0.27M in
biochemical assay and 16 g/mL against Mtb. H37Rv.
Based on the activity in biochemical, whole cell and
cytotoxicity assays compound 1 was identified as a hit
for further optimization. Compounds from this series
were screened using the procedure reported by Koul et.
al. 24
O
O
O
O
O
O
O
O
O
O
a
b
c
HN
N
N
z
O
z
O
z
Br
n
N3
n
2a: Z = N
2b: Z = CH
3a: Z = N; n = 1
3b: Z = CH; n = 1
3c: Z = N; n = 2
4a: Z = N; n = 1
4b: Z = CH; n = 1
4c: Z = N; n = 2
O
O
O
O
d
R1
N
O
N
O
N
HN
HN
e
N
z
N
z
N
z
O
n
n
n
5a: Z = N; n = 1
5b: Z = CH; n = 1
5c: Z = N; n = 2
6a: Z = N; n = 1
6b: Z = CH; n = 1
6c: Z = N; n = 2
1, 7a-7l: Z = N; n = 1
7m: Z = CH; n = 1
7n: Z = N; n = 2
O
O
N
O
To generate the structure activity relationship we
divided compound 1 in three regions viz benzylic
region, amide region and the central scaffold (Fig. 3).
O
N
N
f
g
5a
N
N
N
N
O
Cl
R'
Cl
Cl
R'
Cl
9a-9h
8
Scheme 1: Synthesis of 6, 7-dihydropyrazolo [1, 5-a] pyrazin-4-one, 3,4-
Dihydropyrrolo[1,2-a]pyrazin-1(2H)-one and 5,6,7,8-Tetrahydro-4H-
pyrazolo[1,5-a][1,4]diazepin-4-one. Reagent and conditions: (a) K2CO3,
1,2-dibomoethane/1,3-dibromopropane, ACN, reflux, 90 min, 67-97%;
0
(b) NaN3, DMF, 40 C, 82-98%; (c) TPP, THF-H2O, reflux, 57-97%; (d)
piperidine, (AlMe3)2, THF, reflux, 27-85%; (e) i) NaH, R1X, DMF, RT,
67-90%; or ii) R1X, BINAP, Pd2(dba)3, Cs2CO3, 1,4-dioxane, reflux,
2

O
O
63%; f) NaH, 3,4-dichlorobenzyl bromide, RT, 76%; g) NHR’2; (AlMe3)2,
THF, reflux, 45-77%.
O
O
O
O
O
b
O
O
N
O
a
HN
Si
HN
HN
Si
N
N
N
N
N
N
After establishing an initial SAR, scaffold hopping30,31
was done around “6, 7-dihydropyrazolo [1, 5-a]
pyrazin-4-one” as shown in figure 3. We explored five
scaffolds viz. 3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-
one (scaffold A), 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-
a][1,4]diazepin-4-one (scaffold B), pyrazolo[1,5-
a]pyrazin-4(5H)-one core (scaffold C), 7-hydroxy 6,7-
dihydropyrazolo[1,5-a]pyrazin-4-one core (scaffold D)
and imidazo[1,2-a]pyrazin-8(7H)-one (scaffold E).
OH
16
15
11
O
O
N
N
N
N
d
c
N
N
N
N
O
O
X
X
O
OH
18a-18b
Si
17a-17b
Scheme 3: Synthesis of 7-hydroxy-6,7-dihydropyrazolo[1,5-a]pyrazin-
4(5H)-ones. Reagent and conditions: a) TBDMSCl, imidazole, DMAP,
DCM, 48%; b) Piperidine; (AlMe3)2, THF, 68%; c) NaH, XBnBr, THF-
DMF, RT, 75-77%; d) TBAF, THF, 46-51%.
Scaffold A and Scaffold B: Following similar reaction
sequence,
the
amide
derivatives
of
3,4-
dihydropyrrolo[1,2-a]pyrazin-1(2H)-one and 5,6,7,8-
tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one (7m
and 7n respectively) were synthesized as outlined in
synthetic scheme 1.
Scaffold E: The synthesis of amides 24a-24b of
imidazo[1,2-a]pyrazin-8(7H)-one scaffold
achieved using commercially available
was
2,3
dichloropyrazine in five steps (scheme 4). Intermediate
22 was synthesized following similar procedure
reported by Ager et.al.32 Trimethylaluminium mediated
amidation with piperidine followed by N-benzylation
Scaffold C: The amide derivatives of pyrazolo[1,5-
a]pyrazin-4(5H)-one core 14a-14b, were prepared from
commercially
dicarboxylate over five steps as outlined in synthetic
scheme 2. Trimethylaluminium mediated
available
diethyl
pyrazole-3,5-
afforded the amides 24a-24b.
Cl
Cl
O
Cl
NH2
N
Cl
a
NH2
O
O
N
O
c
N+
Br
b
N
HN
N
monoamidation followed by treatment with p-TSA
afforded the cyclized product 11. De-hydration using
methane sulphonic acid yielded compound 12 which
upon reaction with trimethylaluminium and piperidine
afforded piperidinyl amide 13 in good yield. Reaction of
amide 13 using sodium hydride as a base and
substituted benzyl bromides furnished the final
compounds 14a-14b.
N
N
N
O
19
20
O
21
22
O
O
d
N
N
N
N
e
N
HN
X
N
N
O
O
24a-24b
23
Scheme 4: Synthesis of Imidazo[1,2-a]pyrazin-8(7H)-one . Reagent and
conditions: (a) aq. ammonia, THF, 90%; (b) ethyl bromopyruvate, 1,4-
dioxane, RT, 56%; (c) ethanol, reflux, 80%; (d) Piperidine; (AlMe3)2,
O
O
O
O
HN
O
O
HN
O
O
O
c
a
b
O
N
N
HN
O
HN
2a
N
N
THF, 67%; (e) NaH, XBnCH2Br, THF-DMF, RT, 36-45%.
OH
O
10
11
The compounds were screened in biochemical assay to
confirm the MOA and in whole cell screens for activity
against Mtb H37Rv. Three regions of the hit (compound
1) viz. benzylic region, amide region and the central
scaffold were explored. To understand the SAR at
benzylic region of 6, 7-dihydropyrazolo [1, 5-a]
pyrazin-4-one core; a set of diverse compounds with
cycloalkyl, aryl or substituted-benzyl were explored by
fixing the piperidinyl group at amide region. Except for
appropriately substituted benzyl substitution, all other
substitutions led to loss in ATP synthase activity (7a-
7d; table 1). The substitution at ortho position (7i) of
benzyl group led to loss in activity in biochemical
assays. Different electron withdrawing and neutral
groups were tolerated at meta and para position of the
benzyl ring. However, the substitution at meta position
(7e, 7h, 7j) was preferred over para substitution. These
compounds had a modest whole cell activity of 8g/mL
against M. tuberculosis H37Rv and activity results are
summarized in Table 1. Any modification at amide
O
O
O
O
e
d
N
O
HN
N
O
N
HN
X
N
N
N
O
N
N
N
12
14a-14b
13
Scheme 2: Synthesis of pyrazolo[1,5-a]pyrazin-4(5H)-ones. Reagent and
conditions: (a) aminoacetaldehyde dimethyl acetal, (AlMe3)2, THF,
reflux, 50%; (b) p-TSA, acetone-H2O, reflux, 67%; (c) methane sulphonic
acid, RT, 72h, 41%; (d) piperidine; (AlMe3)2, THF, RT, 2h, 79%; (e)
NaH, XBnCH2Br, DMF, RT, 78-80%.
Scaffold D: Further derivatives of 7-hydroxy 6,7-
dihydropyrazolo[1,5-a]pyrazin-4-one
core
were
synthesized using synthetic scheme 3. The hydroxyl
group of cyclized product 11 was protected using
TBDMS group and then it was converted to amides
17a-17b using similar reaction conditions. The TBDMS
deprotection using TBAF afforded compounds 18a-18b.
3

region led to loss in activity in the biochemical assays
and thus confirmed the necessity of piperidin-1-yl
amide at this position (Results can be referred in
supplementary data).
Although we identified compounds with potent ATP
synthase inhibitory activity, they showed modest whole
cell activity. The SAR around the benzylic region and
amide region was very narrow hence we shifted our
focus to modify the central core by scaffold hopping
approach. The derivatives of 3,4-dihydropyrrolo[1,2-
*
1.05
>10
0.02
8
Cl
Cl
>100
7k
7l
Cl
>32
0.25
*
#
#
Bedaquiline (racemic)
#: Not determined
a]pyrazin-1(2H)-one;
pyrazolo[1,5-a][1,4]diazepin-4-one;
a]pyrazin-4(5H)-one and imidazo[1,2-a]pyrazin-8(7H)-
one cores (7m, 7n, 14a, 14b, 18a, 18b, 24a and 24b)
were evaluated in biochemical and whole cell assays.
5,6,7,8-tetrahydro-4H-
pyrazolo[1,5-
Removal of one nitrogen from central scaffold (pyrazole
to pyrrole) showed loss in enzyme activity (1 vs. 7m)
whereas insertion of saturated methylene in the
dihydropyrazinone scaffold retained enzyme as well as
the anti-TB whole cell activity (1 vs. 7n). Introduction
of unsaturation in the central scaffold {i.e pyrazolo[1,5-
a]pyrazin-4(5H)-one} retained the ATP synthase
enzyme activity, and showed improved cell based anti-
TB activity of 2-4 g/mL (1 and 7g vs. 14a and 14b).
Introduction of hydroxyl group on the 6,7-
dihydropyrazolo [1,5-a]pyrazin-4-one core was not
tolerated and resulted in loss of ATP synthase activity
(compound 18a and 18b). Modifying the central
scaffold as imidazo[1,2-a]pyrazin-8(7H)-one scaffold
retained ATP synthase enzyme activity and exhibited
better anti-TB cell based activity for compound 24a
however it showed loss in anti-TB activity for
compound 24b.
Table 1: Variations at benzylic region
O
R1
O
N
N
N
N
Compd.
No
R1
IC50
(µM)
MIC
Cytotoxicity
(µg/mL)
(g/mL)
Cl
Cl
1
0.27
>10
16
>100
#
*
7a
CH3
>32
*
7b
7c
7d
7e
>10
>32
>32
>32
16
#
Table 2: Variation at the central core by scaffold hopping
Cl
Cl
*
X
O
>10
#
Central
Core
R2
Y
N
*
>10
#
Cytotoxicity
(g/mL)
Comp
No
Central
Core
MIC
(µg/mL)
R2
IC50 (µM)
*
0.042
>100
O
Cl
Cl
*
*
N
1
0.27
1.55
0.29
16
8
>100
>100
>100
*
N
N
*
O
Cl
Cl
7f
0.52
0.29
0.046
8
8
8
>100
>100
>100
*
*
N
7m
7n
*
N
O
Cl
Cl
*
*
N
*
*
8
7g *
7h
N
N
O
*
Cl
Cl
N
*
18a
18b
1.054
32
16
>100
>100
N
N
OH
O
*
*
N
7i
7j
>10
>32
8
#
Cl
3.3M
N
N
OH
Cl
O
Cl
Cl
*
*
*
*
0.11
N
N
14a
14b
0.81
0.28
4
2
>100
31.96
4
*
*
>100
N
N
N
N
O
*

class of compounds could be a good starting point for
the anti-tubercular drug discovery.
O
O
Cl
Cl
*
*
*
N
N
N
N
24a
24b
0.52
4
>100
*
*
N
N
Acknowledgements
*
4.7
>32
>100
#
We thank Department of Biotechnology India for
funding
(BT/PR/7854/MED/14/1139/2006)
and
Bedaquiline (racemic)
0.02
0.25
Pharmacokinetic and Metabolism department for phys
chem and CYP profiling.
#: Not determined
Supplementary data
Since it is expected that any newly developed anti-TB drug
will be administered as a part of multidrug regimen, the
identification of potential DDI liabilities is important. As a
step to understand the liabilities with potent compounds,
the inhibitory effects to cytochrome P450 (CYP) in human
liver microsomes (HLM) were studied. The logD,
solubility and CYP inhibition profile of selected
compounds is summarized in table 3. All the potent
compounds did not show CYP liability @ 10 M
(<50% inhibition). Methylene insertion in the
dihydropyrazinone scaffold (7n) not only lowered the
distribution coefficient (logD: 2.1) but also improved
the solubility from 7.2 g/mL to 109 g/mL.
References and notes
1. Manchester K. Tuberculosis and leprosy in antiquity: an
interpretation. Medical History, 1984, 28:162-173.
2.
WHO.
Global
Tuberculosis
Report
2015.
http://www.who.int/tb/publications/global_report/en/.
3. CDC. Reported Tuberculosis in the United States, 2011.
http://www.cdc.gov/tb/statistics/reports/2011/default.htm
(accessed Feb 5, 2015).
4. World Health Organization. Multidrug-resistant
tuberculosis
http://www.who.int/tb/challenges/mdr/en/ (accessed Feb 5,
2015).
(MDR-TB).
Table 3: LogD, solubility and CYP inhibition of potent molecules
5. WHO Global Tuberculosis Report, 2015. 1–115.
Comp No.
logD
Solubility CYP % inhibition
pH 6.8
(@10uM_HLM)
6. Velayati AA, Masjedi MR, Farnia P, et al.
Emergence of new forms of totally drug-resistant
tuberculosis bacilli: super extensively drug-resistant
tuberculosis or totally drug-resistant strains in iran.
Chest. 2009; 136: 420–425.
1A2, 2C9, 2C19, 2D6, 3A4
(g/mL)
1
3.8
4.0
7.2
54
13, 11, 0, 0, 16
17, 19, 0, 0, 0
7g
7n
2.1
3.1
3.0
3.5
3.7
3.6
4.1
109
<1.0
40.0
<1.0
<1.0
1.2
13, 13, 0, 0, 0
1, 24, 31, 21, 0
0, 29, 4, 48, 0
0, 28, 11, 30, 0
0, 46, 31, 14, 0
3, 0, 6, 0, 0
18a
18b
14a
14b
24a
24b
7. Udwadia ZF, Amale RA, Ajbani KK, Rodrigues C.
Totally drug-resistant tuberculosis in India. Clin Infect
Dis. 2012; 54:579–581.
8. Abubakar I.; Zignol M, Falzon D.; Raviglione M.; Ditiu
L.; Masham S.; Adetifa I.; Ford N.; Cox H.; Lawn
SD.; Marais
M.; Lipman M.; Zijenah L.; Logan S.; McNerney
R.; Zumla A.; Sarda K.; Nahid P.; Hoelscher
BJ.; McHugh
TD.; Mwaba
P.; Bates
2.7
0, 2, 0, 6, 0
*
M.; Pletschette M.; Memish ZA.; Kim P.; Hafner R.; Cole
S.; Migliori GB.; Maeurer M.; Schito M.; Zumla A. Drug-
resistant tuberculosis: time for visionary political
leadership. Lancet Infect Dis 2013; 13: 529–39.
Novel scaffold 6,7-dihydropyrazolo[1, 5-a]pyrazin-4-
one was identified by screening of chemically diverse
compounds (10,000 compounds) from the corporate
compound library using Mycobacterium Smegmatis
ATP synthase enzyme. Compounds 14a, 14b and 24a
showed potent ATP synthase inhibitory activity and
MIC of 2-4g/mL). Compound 7n shows improved
logD and solubility as compared to parent hit 1. These
compounds do not significantly inhibit the activity of
any of the CYP450 enzymes (1A2, 2C9, 2C19, 2D6,
3A4) tested at 10 µM concentration. Therefore, this
9. ZumLa A.; Raviglione M.; Hafner R.; von Reyn CF.
Tuberculosis. N Engl J Med 2013; 368: 745–55.
10. ZumLa A.; Nahid P.; Cole ST. Advances in the
development of new tuberculosis drugs and treatment
regimens. Nat Rev Drug Discov 2013; 12: 388–404.
11. Hurdle J.G.;. O’Neill A. J.; Chopra I.; and Lee R. E.
Targeting bacterial membrane function: an underexploited
5

mechanism for treating persistent infections. Nat Rev
Microbiol. 2011; 9(1): 62–75.
22. van Heeswijk R. P.; Dannemann B.; Hoetelmans R. M..
Bedaquiline: a review of human pharmacokinetics and
drug-drug interactions. J. Antimicrob. Chemother. 2014,
69, 2310–2318.
12. Andries, K.; Verhasselt, P.; Guillemont, J.; Göhlmann,
H.W.; Neefs, J.M.; Winkler, H.; van Gestel, J.;
Timmerman, P.; Zhu, M.; Lee, E.; et al. A diarylquinoline
drug active on the ATP synthase of Mycobacterium
tuberculosis. Science 2005, 307, 223–227.
23. Lakshmanan M.; Xavier A. S.. Bedaquiline - The first
ATP synthase inhibitor against multi drug resistant
tuberculosis. J. Young Pharm. 2013, 5, 112–115.
13. Cohen, J. Infectious disease. Approval of novel TB
drug celebrated–with restraint. Science 2013, 339 (6116),
130.
24. Koul A.; Dendouga N.; Vergauwen K.; Molenberghs
B.; Vranckx L.; Willebrords R.; Ristic Z.; Lill H.; Dorange
I.; Guillemont J.; Bald D.; Andries K. Diarylquinolines
target subunit c of mycobacterial ATP synthase. Nat Chem
Biol. 2007;3:323–324.
14. Diacon A. H.; Pym A.; Grobusch M.; Patientia R.;
Rustomjee R.; Page- Shipp L.; Pistorius C.; Krause R.;
Bogoshi M.; Churchyard G.; Venter A.; Allen J.; Palomino
J. C.; De Marez T.; van Heeswijk R. P.; Lounis N.;
Meyvisch P.; Verbeeck J.; Parys W.; de Beule K.; Andries
K.; Mc Neeley D. F.. The Diarylquinoline TMC207 for
Multidrug-Resistant Tuberculosis, N. Engl. J. Med. 2009,
360, 2397–2405.
25. Gololobov Y. G.; Zhmurova I. N.; Kasukhin, L. F..
Sixty years of staudinger reaction. Tetrahedron, 1981,
37(3), 437-472.
26. Blackburn C.; Barrett C.; Brunson M.; Chin J.;
England D.; Garcia K.; Gigstad K.; Gould A.; Gutierrez J.;
Hoar K.; Rowland R. S.; Tsu C.; Ringeling J.; Wager K.;
Xu H.. Histone deacetylase inhibitors derived from 1,2,3,4-
tetrahydropyrrolo[1,2-a]pyrazine and related heterocycles
selective for the HDAC6 isoform. Bioorg. Med. Chem.
Letters, 2014, 24(23), 5450-5454.
15. Fox G. J.; Menzies D.. A view of the evidence for
using Bedaquiline (TMC207) to treat multi-drug resistant
tuberculosis Infect. Dis. Ther. 2013, 2, 123–144.
16. Guillemont J.; Meyer C.; Poncelet A.; Bourdrez X.;
Andries K.. Diarylquinolines, synthesis pathways and
quantitative structure--activity relationship studies leading
to the discovery of TMC207. Future Med. Chem. 2011, 3,
1345–1360.
27. Blackburn C.; Chin J.; Gigstad K. M.; Xu H..
Preparation of substituted hydroxamic acids as inhibitors
of HDAC6. U.S. Pat. Appl. Publ. 2011, US 20110251184
A1.
28. Louie,J.; Hartwig, J.F. "Palladium-catalyzed synthesis
of arylamines from aryl halides. Mechanistic studies lead
to coupling in the absence of tin reagents", Tetrahedron
Letters, 1995, 36 (21): 3609–3612.
17. Koul A.; Dendouga N.; Vergauwen K.; Molenberghs
B.; Vranckx L.; Willebrords R.; Ristic Z.; Lill H.; Dorange
I.; Guillemont J.; Bald D.; Andries K.. Diarylquinolines
target subunit c of mycobacterial ATP synthase Nat. Chem.
Biol. 2007, 3, 323–324.
29. Guram, A.S.; Rennels, R.A.; Buchwald, S.L. "A
Simple Catalytic Method for the Conversion of Aryl
Bromides to Arylamines", Angew Chem, Int Ed. 1995,
34 (12): 1348–1350.
18. Matteelli, A.; Carvalho, A. C.; Dooley, K. E.; Kritski,
A.. TMC207: the first compound of a new class of potent
anti-tuberculosis drugs. Future Microbiol. 2010, 5, 849-
858.
30. Schneider G.; Neidhart W.; Giller T.; Schmid G.
“Scaffold-Hopping” by topological pharmacophore search:
a contribution to virtual screening. Angew Chem, Int Ed.
1999; 38(19):2894–2896.
19. Koul A, Vranckx L, Dendouga N, Balemans W, Van
den Wyngaert I, Vergauwen K, et al. Diarylquinolines are
bactericidal for dormant mycobacteria as a result of
disturbed ATP homeostasis. J Biol Chem 2008;283:25273–
80.
31. Martin YC.; Kofron JL.; Traphagen LM. Do
structurally similar molecules have similar biological
activity? J Med Chem. 2002; 45 (19):4350–4358.
20. Anti-Infective Drugs Advisory Committee Meeting
Report. The U.S. Food and Drug Administration.,
November 28, 2012.
32. Ager IR.; Barnes AC.; Danswan GW.; Hairsine PW;
Kay DP.; Kennewell PD.; Matharu SS.; Miller P.; Robson
P.; Rowlands DA; Tully WR.; Westwood R.. J Med
Chem 1988, 31(6): 1098 – 1115.
21. Diacon, A. H.; Pym, A.; Grobusch, M. P.; de los Rios,
J. M.; Gotuzzo, E.; Vasilyeva, I.; Leimane, V.; Andries,
K.; Bakare, N.; De Marez, T.; Haxaire-Theeuwes, M.;
Lounis, N.; Meyvisch, P.; De Paepe, E.; van Heeswijk, R.
P. G.; Dannemann, B. Multidrug-resistant tuberculosis and
culture conversion with bedaquiline. N. Engl. J. Med. 2014,
371 (8), 723−732.
6

Graphical Abstract
Novel series of non-DARQ (DiARyl Quinoline)
template as ATP synthase inhibitor have been
identified and scaffold hopping approach led to
compound 14b, with potent ATP synthase
activity and MIC against MTb.H37Rv.
O
O
N
N
N
N
14b
ATP Synthase IC50 : 0.280 M
Mtb. (H37Rv) MIC : 2 g/mL
7