Synthesis and evaluation of analogues of the tuberculosis drug bedaquiline containing heterocyclic B-ring units

Article abstract of DOI:10.1016/j.bmcl.2017.10.042

Analogues of bedaquiline where the phenyl B-unit was replaced with monocyclic heterocycles of widely differing lipophilicity (thiophenes, furans, pyridines) were synthesised and evaluated. While there was an expected broad positive correlation between lipophilicity and anti-TB activity, the 4-pyridyl derivatives appeared to have an additional contribution to antibacterial potency. The majority of the compounds were (desirably) more polar and had higher rates of clearance than bedaquiline, and showed acceptable oral bioavailability, but there was only limited (and unpredictable) improvement in their hERG liability.

Full text of DOI:10.1016/j.bmcl.2017.10.042

Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and evaluation of analogues of the tuberculosis drug
bedaquiline containing heterocyclic B-ring units
Peter J. Choi a, Hamish S. Sutherland a, Amy S.T. Tong a, Adrian Blaser a, Scott G. Franzblau c,
Christopher B. Cooper d, Manisha U. Lotlikar d, Anna M. Upton d, Jerome Guillemont e, Magali Motte e,
a,b
Laurence Queguiner e, Koen Andries f, Walter Van den Broeck f, William A. Denny a,b, , Brian D. Palmer
⇑
a Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
b Maurice Wilkins Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
c Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA
d Global Alliance for TB Drug Development, 40 Wall St, New York 10005, USA
e Medicinal Chemistry Department (Infectious Diseases), Janssen Pharmaceuticals, Campus de Maigremont, BP315, 27106 Val de Reuil Cedex, France
f Janssen Infectious Diseases BVBA, Beerse, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Analogues of bedaquiline where the phenyl B-unit was replaced with monocyclic heterocycles of widely
differing lipophilicity (thiophenes, furans, pyridines) were synthesised and evaluated. While there was an
expected broad positive correlation between lipophilicity and anti-TB activity, the 4-pyridyl derivatives
appeared to have an additional contribution to antibacterial potency. The majority of the compounds
were (desirably) more polar and had higher rates of clearance than bedaquiline, and showed acceptable
oral bioavailability, but there was only limited (and unpredictable) improvement in their hERG liability.
Ó 2017 Published by Elsevier Ltd.
Received 7 September 2017
Revised 6 October 2017
Accepted 19 October 2017
Available online xxxx
Keywords:
Bedaquiline
Bedaquiline analogues
Tuberculosis
Drug development
The often late detection of tuberculosis (TB),1 coupled with the
need to use long and complex multi-drug treatment regimens, has
led to an alarming increase in cases that are resistant to the stan-
dard front-line drugs (multi-drug-resistant; MDR). In 2016, about
580,000 new cases (3.9% of new cases and 21% of recurrent cases)
were classified globally as MDR-TB, and this proportion has been
rising rapidly.2
Thus the discovery of bedaquiline (TMC207, Sirturo, Janssen
Pharmaceuticals; Fig. 1; 1), a new TB drug, that, due to a novel
mechanism of action (inhibition of the mycobacterial ATP syn-
thase3) is useful against drug-resistant tuberculosis (MDR-TB),
has been of great significance. When added to standard back-
ground therapy used for MDR-TB, it demonstrated more rapid bac-
tericidal activity than background therapy alone,4 and was
approved by the US Food and Drug Administration in 2012 for
the treatment of MDR-TB. However it is very lipophilic (measured
logP 7.25),5 which likely contributes to its long terminal half-life of
5–6 months.6 The resultant potential for over-proportional accu-
mulation in tissue has limited the full exploration of its potential
dose range.7 More generally, highly lipophilic drugs also have a
propensity for liver toxicity.8 Bedaquiline also shows inhibition
of the hERG (human Ether-à-go-go-Related Gene; KCNH2) cardiac
potassium channel, with the concomitant risk of delayed ventricu-
lar repolarization (QTc interval),6 and this is a point to be consid-
ered in the planning of combination regimens with other TB
drugs with similar effects (e.g. fluoroquinolones, clofazimine).9
Thus bedaquiline analogues of comparable antibacterial activity
but with lower clogP and less potent inhibition of the hERG potas-
sium channel, but similar in anti-Mtb potency to bedaquiline,
would be of substantial interest. We have previously10 explored
the effects of a range of more polar 6-substituents on the quinoline
ring and showed that, on balance, a 6-CN group offered a signifi-
cant reduction in overall lipophilicity over the standard 6-Br group
(about 1.25 logP units) with the least deleterious effect on antibac-
terial potency.
In the current paper we explore the effects of replacing the phe-
nyl B-ring unit of bedaquiline with heterocycles of differing
lipophilicity. One example of such a heterocyclic analogue, the
⇑
Corresponding author at: Auckland Cancer Society Research Centre, School of
Medical Sciences, The University of Auckland, New Zealand.
E-mail address: b.denny@auckland.ac.nz (W.A. Denny).
https://doi.org/10.1016/j.bmcl.2017.10.042
0960-894X/Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Choi P.J., et al. Bioorg. Med. Chem. Lett. (2017), https://doi.org/10.1016/j.bmcl.2017.10.042

2
P.J. Choi et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
In Scheme 2, the 2-furyl analogues 15–21 were prepared by the
O
B
same procedure as in Scheme 1, reacting 51 and 2-furylaldehye
(65) to give alcohol 66, which was deoxygenated to give A/B-unit
67. Condensation of this with the appropriate Mannich bases
(selected from 55a–55j) gave compounds 15–21. The 3-furyl ana-
logues 22–28 were synthesized by preparation of the boronic acid
68 (from 51) and Suzuki coupling of this and 3-(bromomethyl)fu-
ran 69 to give A/B-unit 70, and subsequent condensation with the
appropriate Mannich base as above (see Supplementary Material
for further details).
OH
OH
D
6
Br
NMe2
Br
NMe2
A
N
O
N
O
C
1
2
Fig. 1. Structure of bedaquiline (1) and a furan analogue (2).
Schemes 3 and 4 outline the syntheses of the B-ring unit pyridyl
compounds 29–50. In Scheme 3, Suzuki coupling of boronic acid 68
and 2-(chloromethyl)-6-methoxypyridine (71) gave A/B-unit 72,
which was condensed with Mannich bases 55a, 55b and 55f and
55l to give compounds 29, 30 and 33 of Table 1. Similar reaction
of 68 with bromides 82 and 83 gave respectively A/B-units 84
and 85, which yielded compounds 38 and 39 of Table 1. Compound
35 was prepared by Suzuki coupling of quinoline 51 with aldehyde
73 to give the resulting hydroxyl intermediate 74. Mesylation fol-
lowed by reduction of 74 afforded the A/B-unit 75. Likewise, com-
pounds 36 and 37 were prepared by Suzuki coupling of quinoline
51 with aldehydes 76 and 77 to give the resulting hydroxy inter-
mediates 78 and 79. Lewis acid mediated deoxygenation of these
gave A/B-units 79 and 80 respectively. All of these A/B-units were
3-furan 2 also with a smaller (phenyl) C-ring unit, (Fig. 1) has
already been reported to show significant activity in M. smegmatis,
with the separated racemic diastereomer pairs (configurations not
assigned) having values of 1.57 and 0.06 mg/mL.11
The bedaquiline analogues were synthesized from appropriate
benzylquinoline A/B-units and 3-(dimethylamino)-1-arylpropan-
1-one C/D-units, following
a
route described previously.7,10
Scheme 1 shows the synthesis of the thienyl A/B-units 54, 58, 61
and 64 by base-catalysed condensation (LiTMP) of quinoline 51
and the appropriate thiophene aldehydes12,13 52,14 56, 59 and 62
to give the intermediate alcohols 53, 57, 60 and 63 in acceptable
yields (ꢀ55%). These were then deoxygenated by Et3SiH under acid
conditions in good yields to the A/B-units 54, 58, 61 and 64 (see
Supplementary Material for further details).
S
S
O
NMe2
Br
iii
OH
S
NMe2
Br
Br
i
X
2
+
R
+
R
3
N
O
N
O
N
O
CHO
4
Compounds
51
52
53
: X=OH (56%)
55a: 3-CN
55b: R=2,3-diOMe
3 (19%)
ii
54: X=H (89%)
4
5
(23%)
(37%)
55c
: R=2-aza, 3-OMe
55d: R=3-aza, 5-Me
55e: R=3-aza, 2-OMe
6 (48%)
8
(27%) of Table 1
S
OH
S
O
NMe2
iii
NMe2
F
Br
Br
X
S
i
+
51
+
N
O
N
O
F
CHO
56
57
58
: X=OH (58%)
: X=H (31%)
Compound 9 (40%) of Table 1
55f
ii
S
S
OH
Br
NMe2
Br
X
+
55e
55f
51
+
S
iii
R
i
N
O
N
O
CHO
Compounds
59
60: X=OH (55%)
61: X=H (79%)
11 (41%)
ii
12 (35%) of Table 1
OMe
OMe
S
S
OMe
S
OH
Br
NMe2
Br
iii
55e
55f
X
+
51
i
R
+
O
N
N
O
CHO
Compounds
13 (27%)
62
63: X=OH (53%)
64: X=H (69%)
ii
14
(35%) of Table 1
Scheme 1. Classes A–D (compounds 3–14). Reagents and conditions: (i) LiTMP, THF, ꢁ75 °C, 1.5 h then appropriate aldehyde, ꢁ75 °C, 4 h; (ii) Et3SiH, TFA, DCM, 20 °C; (iii)
LDA or LiTMP, THF, ꢁ75 °C, 1.5 h then 55a–55f, ꢁ75 °C, 4 h.
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P.J. Choi et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
3
O
X
O
NMe2
iii
Br
Compounds
2
i
O
+
15-21 of Table 1
51
R
+
3
N
O
4
CHO
55f
15
: R=3-F
55h: R=3-OCF3
55e
(80%)
17 (79%)
18
66: X=OH (65%)
67: X=H (62%)
65
ii
: R=2,3-diOMe
55i: R=2,3-OCH2O- 19 (75%)
55j 20
(69%)
: R=2-aza
55a: R=3-CN
(55%)
21 (64%)
O
+
O
NMe2
Br
B(OH)2
Br
O
iii
i
2
Compounds
+
iv
51
R
22 28
-
of Table 1
N
O
3
O
N
4
68 (94%)
69
Br
70
(31%)
55f: R=3-F
55g
55h: R=3-OCF3
22 (55%)
: R=2-aza, 3-F
24
25
(28%)
(45%)
55e: R=2,3-diOMe
: R=2,3-OCH2O-
55j: R=2-aza
26 (50%)
55i
27
28
(50%)
(37%)
Scheme 2. Classes E and F (compounds 15–28). Reagents and conditions: (i) LiTMP, B(OiPr)3; (ii) Et3SiH, TFA, DCM, 20 °C, 1 h; (iii) LDA, THF, ꢁ75 °C, 1.5 h then appropriate
ketone 55, ꢁ75 °C, 4 h; (iv) Pd(PPh3)4, Cs2CO3, toluene/DMF, 90 °C, 5 h.
N
O
NMe2
ii
MeO
N
N
Br
68
2
+
i
29 30
,
Compounds
-
+
R
MeO
32, 33 of Table 1
3
OMe
(74%)
4
Cl
71
55f:
55l:
R=3-F
29 (30%)
72
R=3-Me
30
32
(66%)
(18%)
55b: R= 2,3-diOMe
55a:
R= 3-CN
33 (70%)
N
O
NMe2
Me2N
N
N
35
Br
Compound
ii
iii
X
51
+
+
(43%) of Table 1
Me2N
OMe
F
O
73
55f
74: X=OH (56%)
75: X=H (76%)
iv
R
N
O
NMe2
ii
R
iii
+
51
Compounds
i
Br
N
+
36
37
X
(38%)
(37%) of Table 1
F
OHC
76
N
OMe
: X=OH, R=NMe2 (79%)
79: X=OH, R=NEt2 (57%)
80
55f
78
: R=NMe2
77: R-NEt2
v
: X=H, R=NMe2 (70%)
81: X=H, R=NEt2 (76%)
R
N
O
NMe2
ii
R
i
i
Compounds
Br
68
+
N
+
38 (45%)
F
39
(82%) of Table 1
N
O
Cl
55f
82: R=SMe
84: R=SMe (59%)
85: R=SEt (62%)
83
: R=SEt
Scheme 3. Class G (compounds 29–39). Reagents and conditions: (i) Pd(PPh3)4, Cs2CO3, toluene/DMF, reflux; (ii) LDA, THF, ꢁ75 °C, 1.5 h then the appropriate ketone 55, ꢁ75
°C, 4 h; (iii) LiTMP, THF, ꢁ75 °C, 1.5 h then appropriate aldehyde, ꢁ75 °C, 4 h; (iv) MsCl, Et3N, DMF, then NaBH4; (v) NaBH4, AlCl3.
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4
P.J. Choi et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
Me
Me
N
N
O
NMe2
ii
i
+
Compounds 40-
42
+
68
Br
of Table 1
Cl
R
86
N
OMe
55k
40 (20%)
41 (82%)
: R=OMe
87
(39%)
55a: R=CN
55f:
42
(94%)
R=F
OMe
N
MeO
OMe
N
O
NMe2
ii
MeO
i
+
Compound 43
(20%) of Table 1
68
+
Br
F
Cl
N
OMe
88
55f
89 (69%)
MeO
MeO
N
MeO
MeO
N
O
NMe2
ii
Compounds 44-
i
+
68
2
3
+
Br
45 47 50
of
,
-
R
Cl
90
Table 1
N
OMe
55f
: R=F
55l: R=Me
55k
44 (29%)
45 (37%)
47 (75%)
48 (30%)
49 (38%)
50 (24%)
91 (66%)
: R=OMe
55m: R=OCF2H
55a
: R=CN
55b: R=2,3-diOMe
Scheme 4. Classes G and H (compounds 40–45 and 47–50). Reagents and conditions: (i) Pd(PPh3)4, Cs2CO3, toluene/DMF, reflux, 5 h (72%); (ii) LDA, THF, ꢁ75 °C, 1.5 h then
the appropriate ketone 55, ꢁ75 °C, 4 h.
condensed with Mannich base 55f to give the target compounds
(see Supplementary Material for further details).
HPLC at BioDuro LLC (Beijing). The coupling yields for classes E–
H appear to be higher than classes A–D, although this comparison
is complicated by the small sample sizes in classes B, C and D.
Moreover, in some cases, the coupling reaction proceeded in high
conversion, but due to difficulty in purifying the product from
impurities the final yield was reduced. There is however, an appar-
ent correlation between the electron density at the benzylic posi-
tion of the A/B-unit and the yield of the reaction. The best
coupling unit (E) is a 2-substituted furan which exerts a strong
electron donating effect towards the benzylic position. While the
second best unit (G) is a more electron withdrawing pyridine,
the 2 or 4-substituted electron donating substituent contributes
some electron density towards the benzylic position. Unit H has
a 4-aza atom which renders the benzylic position less electron rich,
despite a 2-methoxy substituent, and the average coupling yield is
even lower. These observations suggest that the lithium anion
formed at the benzylic position could be more nucleophilic with
a higher electron donation from the B-ring, making the A/B-unit
more reactive and favouring the coupling reaction.
The compounds were evaluated for their inhibition of growth
(measured as MIC90 values in mg/mL) against M.tb (strain H37Rv)
under both replicating (MABA)16 or non-replicating (LORA)17 con-
ditions. Under these conditions bedaquiline (1) is a potent inhibitor
of both (MICs 0.05 and 0.08 mM respectively). In a previous struc-
ture-activity relationship (SAR) study of bedaquiline analogues7
it was shown that electron-withdrawing groups, especially F or
Cl at the 3- and 4-positions on the phenyl B-ring unit (Fig. 1) pro-
vided compounds with better MICs against M. smegmatis, but at the
expense of even higher overall lipophilicity. In a search for less
lipophilic analogues, we prepared and evaluated compounds
where this phenyl B-ring unit was replaced with different
In Scheme 4, similar Suzuki coupling of boronic acid 68 with
chlorides 86, 88 and 90 gave A/B-units 87, 89 and 91. These were
condensed with the appropriate Mannich bases to give compounds
40–45 and 47–50 of Table 1 (see Supplementary Material for fur-
ther details).
Some of the C/D-unit Mannich bases required have been previ-
ously reported.10,15 New analogues were prepared either via the
Mannich reaction from the corresponding acetophenones or the
Grignard reaction from the corresponding Weinreb amides as
shown in Scheme 5 (see Supplementary Material for further
details).
For comparison of 6-Br and 6-CN substituents in the A-unit, sev-
eral Br analogues (6, 9, 15, 22, 30, 33, 45) were converted directly
to the corresponding CN compounds (7, 10, 16, 23, 31, 34, 46)
(Scheme 6). We have previously shown10 that the optimum condi-
tions for this reaction are aryl bromide (1 equiv), zinc (0.1 equiv),
zinc (II) cyanide (0.55 equiv), tris(dibenzylideneacetone)dipalla-
dium(0) (Pd2(dba)3 (0.1 equiv), and tri(o-tolyl) phosphine (0.2
equiv).
Reaction of the A/B units prepared in Schemes 1 and 2 with
in situ-prepared LDA, (lithium diisopropylamide) or LiTMP (lithium
tetramethylpiperidide) at ꢁ78 °C for 60–90 min) followed by addi-
tion of the appropriate Mannich bases 55a–j (ꢁ78 °C, 3–4 h, then
AcOH) under previously-reported7,1 conditions gave required
diarylquinolines 3–6, 8, 9 and 11–14 of Table 1, as a racemic mix-
ture of two diastereomers (see Supplementary Material for further
details). This mixture was purified by column chromatography to
>95% purity in-house, and the desired RS, SR enantiomer was then
separated from the mixture by preparative super-critical fluid
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P.J. Choi et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
5
Table 1
Bedaquiline analogues containing heterocyclic ring units.
MeO
D:
Me
C:
Me
B:
Me
Me
X (Class)
S
=
Me
A:
S
S
S
X
OH
R
NMe2
2
Z
4
Z
5
O
N
Y
N
O
Me
5
H:
F:
G:
2
3
2
E:
N
3
O
4
No
R
X (Class)
Y
MIC90 (mg/mL)a
clogPb
MABA
LORA
1
3
4
5
6
7
8
9
Br
Br
Br
Br
Br
CN
Br
Br
CN
Br
Br
Br
CN
Br
CN
Br
Br
Br
Br
Br
Br
CN
Br
Br
Br
Br
Br
Br
Br
CN
Br
Br
CN
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
CN
Br
Br
Br
Br
Phenyl
2,3-Benz
3-CN
2,3-DiOMe
2-Aza, 3-OMe
3-Aza, 5-Me
3-Aza, 5-Me
3-Aza, 2-OMe
3-F
0.05
0.12
0.50
0.12
0.58
1.94
0.12
0.06
0.05
0.47d
0.22
0.24
0.70d
0.74d
1.79d
0.76d
0.71d
0.69d
1.95d
1.96d
0.74d
1.08d
0.68d
0.76d
1.16d
0.90d
1.80d
0.12d
0.13
0.30
0.24d
0.34
0.38
0.18
0.08
0.02
0.14
0.14
1.9
0.08
0.12
0.27
0.15
0.30
1.10
0.20
0.11
0.20
7.25
6.10
6.33
5.99
5.67
4.24
5.99
6.81
4.67
5.01
5.55
5.09
4.55
5.40
4.02
7.51
6.14
6.45
4.98
4.69
5.40
4.04
5.00
7.30
5.93
6.23
4.77
5.14
5.50
4.16
4.66
4.43
3.07
5.44
5.44
6.49
5.86
6.39
5.00
4.51
5.22
5.59
5.19
5.55
4.19
5.00
5.41
4.48
4.71
A
A
A
A
A
A
B
B
C
C
D
D
E
E
E
E
E
E
E
F
10
11c
12
13
14c
15c
16c
17c
18c
19c
20c
21c
22c
23c
24c
25c
26c
27c
28c
29c
30
31
32c
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
3-F
3-F
3-Aza, 2-OMe
3-Aza, 2-OMe
3-F
3-F
3-F
3-OCF3
2,3-DiOMe
2,3-OCH2O-
2-Aza
3-CN
3-F
0.52
0.53
F
F
F
F
F
F
3-F
2-Aza, 3-F
3-OCF3
2,3-DiOMe
2,3-OCH2O–
2-Aza
3-F
3-Me
3-Me
2,3-DiOMe
3-CN
3-CN
3-F
3-F
3-F
3-F
3-F
3-OMe
3-CN
3-F
G; Z = 2-OMe
G; Z = 2-OMe
G; Z = 2-OMe
G; Z = 2-OMe
G; Z = 2-OMe
G; Z = 2-OMe
G; Z = 2-NMe2
G; Z = 4-NMe2
G; Z = 4-NEt2
G; Z = 4-SMe
G; Z = 4-SEt
0.25
0.15
0.75
0.82
0.20
0.15
0.02
0.37
0.15
2.2
3.38
0.97
0.54
0.07
0.04
0.14
<0.02
<0.02
0.21
G; Z = 5-Me
G; Z = 5-Me
G; Z = 5-Me
1.32
0.53
0.47
0.02
0.02
0.15
<0.02
<0.02
0.13
0.21d
G; Z = 4,5-diOMe
H; Z = 2,3-diOMe
H; Z = 2,3-diOMe
H; Z = 2,3-diOMe
H; Z = 2,3-diOMe
H; Z = 2,3-diOMe
H; Z = 2,3-diOMe
H; Z = 2,3-diOMe
3-F
3-F
3-Me
3-Me
3-OMe
3-OCF2H
3-CN
2,3-DiOMe
a
MIC90 (lg/mL); minimum inhibitory concentration for 90% inhibition of growth of M.tb strain H37Rv, determined under aerobic (replicating; MABA) (Ref. 16) or non-
replicating (LORA) (Ref. 17) conditions, determined at the Institute for Tuberculosis Research, University of Illinois at Chicago. Each value is the mean of at least two
independent determinations.
b
clogP calculated by ChemDraw Ultra v12.0.2. (CambridgeSoft).
RS/SR racemic mixture.
MICs determined at Tibotec (Mechelen, Belgium).
c
d
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6
P.J. Choi et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
Route A
heterocycles of varying lipophilicity (Table 1). A representative
D
subset of compounds were also evaluated for a number of pharma-
cological properties, and compared against bedaquiline (1)
(Table 2).
O
NMe2
O
i
2
6
C
Compounds 3–10 explore the use of dimethylthiophene B-ring
units. While these are slightly more lipophilic than benzene, the
set of compounds prepared had clogP values lower than bedaqui-
line (between 6.33 and 4.24) and MABA MICs between 0.05 and
0.58 mg/mL. The exception was the much less lipophilic CN deriva-
tive 7 (clogP 4.24), which was less active. The 2,3-dimethylthio-
phene 9, bearing a more lipophilic 3-F C-unit substituent, had
comparable activity to 1 and its cyano counterpart 10, with a much
lower clogP (4.67) was equally potent. The 2-Me and 2-OMe thio-
phenes 12 and 13 were also effective inhibitors, despite clogP val-
ues of around 5.
Given that good activity had been reported for furan 2 (albeit in
M. smegmatis),11 we evaluated a series of both 2- and 3-furyl ana-
logues bearing different C-unit substituents. For the whole dataset
(49 compounds, including 1), despite a wide variation in structure
and some MICs being determined using a slightly different protocol
(see Table 1), there was a modest positive correlation between
potency and lipophilicity (Eq. (1)), as was shown previously for
both bedaquiline derivatives10 and other classes of M.tb
inhibitors.18
3
5
4
X
X
Route B
D
O
N
O
OH
O
NMe2
O
ii
2
6
iii
C
3
X
5
4
X
X
No
55a
X
Route(ref)
% yield
i or ii/iii
3-CN
A16
A8
B
55b
55c
55d
55e
55f
2,3-diOMe
2-aza,3-OMe
3-aza,5-Me
3-aza,2-OMe
3-F
92/69
80/93
61/95
B
B
A8
B
55g
55h
55i
2-aza,3-F
3-OCF3
67/100
A8
A
2,3-OCH2O-
2-aza
28
42/97
82
log MIC ¼ ꢁ0:53c log P þ 1:96
ð1Þ
55j
B
n ¼ 46; R ¼ 0:48; p ¼ 0:04; F ¼ 5:1
55k
55l
3-OMe
A
3-Me
A8
A
The 2-furyl (15–21) and 3-furyl (22–28) compounds had a rel-
atively narrow range of potencies (MICs 0.68–1.96 mg/mL), despite
a wide lipophilicity range (clogPs from 7.51 to 4.02). For this sub-
group of similar compounds, high lipophilicity (clogP) correlated
with higher potency (MIC) (Eq. (1)). Compounds 29–43 of Table 1
55m
3-OCF2H
25
Scheme 5. Preparation of C/D-unit Mannich bases. Footnotes for Scheme 5: (i)
CH2O, Me2NꢂHCl, cꢂHCl, EtOH, 90 °C, 18 h; (ii) (COCl)2, cat. DMF, DCM, then MeNH
(OMe)ꢂHCl, pyridine; (iii) vinylMgBr, THF, then Me2NH, H2O.
X
X
OH
OH
Zn / Zn(CN)2
Pd2(dba)3 / P(o-tol)3
NC
NMe2
Br
NMe2
DMF / 50 o
C
N
O
N
O
6
9
15
22
30
33
45
7
(66%)
(80%)
Y
Y
10
16 (84%)
23
(43%)
31 (81%)
34
(68%)
46 (51%)
Scheme 6. Preparation of cyano analogues.
Table 2
Comparative activity and pharmacologic data for selected representative analogues.
CYPa
hERGb
Clint
HLM t1/2d
F(%)e
clogPf
c
No
1
9
>50
10
>50
>10
10
0.37
0.88
3
231
60
15
18
64
12
19
52
61
37
70
48
7.25
6.81
3.08
5.44
6.39
5.22
5.59
5.55
4.19
4.48
12
45
38
11
56
36
13
11
19
35
36
39
42
43
45
48
49
0.89
0.46
45
30
24
36
40
4.6
>10
>10
>10
>10
1.9
0.53
68
a
b
c
d
e
f
IC50 (mM) for inhibition of CYP 3A4 (20 min exposure).
IC50 (mM) for inhibition of the hERG channel; studies conducted by Wuxi AppTec (Ref. 18).
Clint (mL/min/mg/protein) in human liver microsomes after 60 min exposure to 1 mg/mL of drug.
Half-life (min) on exposure to human liver microsomes; studies conducted by BioDuro LLC.
Oral bioavailability (%) in rats; studies conducted by BioDuro LLC.
See Table 1.
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P.J. Choi et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
7
explored a variety of 3-pyridyl B-ring units. The clogP values of
Acknowledgements
these again ranged quite widely (from 6.49 to 3.07) but as a class
they were more potent than the other B-unit heterocycle com-
pounds, with the majority having MICs < 0.5 mg/mL in both MABA
and LORA assays. Finally, the small cohort of 4-pyridyl analogues
(44–50) appeared even more potent, with MICs < 0.05 mg/mL in
both assays yet with clogP values around 5 (significantly better
than that of 1). Thus it is possible to go against the overall trend
of a positive correlation between MIC and lipophilicity with com-
pounds such as 47 and 48, which retain the potency of 1 yet have
a clogP lower by 2.25 units. This was shown earlier10 by studying
compounds with varying 6-substituents in the A-ring unit quino-
line, where the polar CN substituent lowered overall clogP by
1.38 log units with only an average twofold increase in MIC. In
the present study, the seven Br/CN pairs 6/7, 9/10, 15/16, 22/23,
30/31, 33/38 and 45/46, covering a wide range of B-ring units che-
mistries, likewise showed only an average 2.2-fold increase in MIC.
Table 2 shows that, for both 1 and selected analogues, IC50 val-
ues for cytotoxicity in mammalian cells (VERO green monkey kid-
ney epithelial cells) were all >10 mg/mL,19 and (in the majority of
cases) the IC50 values for inhibition of the common CYP3A4 metab-
olizing enzyme were ꢃ10 mM. The potency of 1 for inhibition of the
hERG calcium channel (IC50 0.37 mM)20 is seen as a potential liabil-
ity (cardiovascular toxicity) and changes that attenuated this effect
would be beneficial. However, for the compounds tested there was
only modest (at best 5-fold; compound 43) and unpredictable
improvement in this parameter. Compound 1 has quite low clear-
ance in human liver microsomes, as reflected in its Clint and t1/2
values in Table 2, with all of the other analogues having signifi-
cantly higher rates of clearance. Finally, compound 49 showed an
oral bioavailability comparable to that of 1, despite its significantly
lower lipophilicity. Indeed, all of the compounds in Table 2 had
acceptable bioavailability.
This work was supported by the Bill and Melinda Gates Founda-
tion, Seattle, United States (#OPP1017459), the U.S. Agency for
International Development (USAID), Ronald Reagan Building
Washington, DC, United States (GHS-A-00-08-00012-00), the U.K.
Department for International Development (DFID), 22 Whitehall,
London, England, and Irish Aid, 23-27 Henry Street, Limerick, Eire.
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.bmcl.2017.10.042.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
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Conclusions
This work, part of a study10 exploring analogues of 1 with an
altered profile of biological properties, has focused on the effects
of replacing the phenyl B-ring unit of bedaquiline with heterocy-
cles of differing lipophilicity, in compounds with a smaller C-ring
unit; thiophene-, furan- and pyridyl-based B-ring units were stud-
ied. In addition to the expected broad positive correlation between
lipophilicity and anti-TB potency (Eq. (1)), the 3-pyridyl and espe-
cially the 4-pyridyl compounds did seem to have an additional
measure of potency, suggesting that further exploration of the
B-unit region might be fruitful.
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InfectiveDrugsAdvisoryCommittee/UCM329258.pdf>; Accessed 30th August
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Please cite this article in press as: Choi P.J., et al. Bioorg. Med. Chem. Lett. (2017), https://doi.org/10.1016/j.bmcl.2017.10.042