Spirocyclic and Bicyclic 8-Nitrobenzothiazinones for Tuberculosis with Improved Physicochemical and Pharmacokinetic Properties

Article abstract of DOI:10.1021/acsmedchemlett.8b00634

8-Nitrobenzothiazinones (BTZs) typified by the second-generation analogue PBTZ169 are a new class of antitubercular agents. The activity of BTZs and lipophilicity are tightly coupled since the molecular target DprE1 is located in the mycobacterial cell envelope. A series of analogues was designed to address the notorious insolubility of the BTZs while preserving the required lipophilicity. This was accomplished by decreasing the molecular planarity and symmetry through bioisosteric replacement of the piperazine moiety of PBTZ169 with spirocyclic and bicyclic diamines. Several promising compounds with improved aqueous solubilities were identified with potent antitubercular activity. Compound 5 was identified as the most promising candidate based on its excellent antitubercular activity (MIC of 32 nM), more than 1000-fold improvement in solubility, 2-fold lower clearance in mouse and human microsomes relative to PBTZ169, and promising pharmacokinetic parameters.

Full text of DOI:10.1021/acsmedchemlett.8b00634

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Letter
Spirocyclic and Bicyclic 8-Nitrobenzothiazinone for Tuberculosis
with Improved Physicochemical and Pharmacokinetic Properties
Gang Zhang, Michael Howe, and Courtney C. Aldrich
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.8b00634 • Publication Date (Web): 23 Feb 2019
Downloaded from http://pubs.acs.org on February 24, 2019
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ACS Medicinal Chemistry Letters
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Spirocyclic and Bicyclic 8-Nitrobenzothiazinones for
Tuberculosis with Improved Physicochemical and
Pharmacokinetic Properties
†
‡
†, ‡,*
Gang Zhang , Michael Howe and Courtney C. Aldrich
†
State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Peking Union
Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China
Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States
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‡
O
O
S
F3C
F3C
N
N
S
N
N
NO2
N
NO2
N
H
PBTZ169
*comparable MIC
improved aqueous solubility
*improved metabolic and PK profile
*
Supporting Information Placeholder
ABSTRACT: 8-Nitrobenzothiazinones (BTZs) typified by the second-generation analogue PBTZ169 are a new class of
antitubercular agents. The activity of BTZs and lipophilicity are tightly coupled since the molecular target DprE1 is located in the
mycobacterial cell envelope. A series of analogues was designed to address the notorious insolubility of the BTZs while preserving
the required lipophilicity. This was accomplished by decreasing the molecular planarity and symmetry through bioisosteric
replacement of the piperazine moiety of PBTZ169 with spirocyclic and bicyclic diamines. Several promising compounds with
improved aqueous solubilities were identified with potent antitubercular activity. Compound 5 was identified as the most promising
candidate based on its excellent antitubercular activity (MIC of 32 nM), more than 1000-fold improvement in solubility, 2-fold
lower clearance in mouse and human microsomes relative to PBTZ169, and promising pharmacokinetic parameters.
Keywords: benzothiazinone, tuberculosis, antitubercular, spirocyclic
Tuberculosis (TB) is an infectious disease mainly caused by
members of Mycobacterium tuberculosis (Mtb) complex. In
017, more than 10 million people were actively infected by
TB and approximately 1.6 succumbed to the disease. The
current treatment regimen for drug-susceptible TB involves 6–
possesses extraordinary whole-cell activity with a minimum
inhibitory concentration (MIC) of ~ 1 nM against drug-
sensitive (DS) and drug-resistant (DR) Mtb strains, displays
strong synergism with other TB drugs, is potently bactericidal,
and significantly shortens therapy in a TB mouse relapse
1
2
5
9
months of the first-line TB drugs isoniazid, rifampicin,
model. While impressive, PBTZ169 does have liabilities
ethambutol, and pyrazinamide. The lengthy treatment course
is necessary to eliminate the various bacterial subpopulations
that exhibit differential drug sensitivity including dormant
bacilli which are phenotypically drug resistant. Consequently,
the emergence of drug resistance TB (DR-TB) caused by
either multidrug or extensively drug resistant Mtb strains
represents a global health crisis.
emanating from its extremely poor solubility (<0.01 µg/mL at
pH 7.4 in 1× PBS buffer at 37 °C) that portend poor
membrane penetration. This may affect oral bioavailability (F)
and volume of distribution (V ), neither of which have been
d
reported.
The 8-nitrobenzothiazinones (BTZs) represent an entirely new
class of compounds with a fascinating history and mechanism
of action first identified by Ute Möllmann as
biotransformation products of dithiocarbamates, which in turn
2, 3
had been initially synthesized by Vadim Makarov.
The
benzothiazinones are mechanism-based inhibitors of the
flavoenzyme DprE1 and are bioactivated by the dihydroflavin
cofactor FADH through reduction of the C-8 nitro group to a
2
nitroso intermediate that covalently reacts with Cys387 in the
enzyme active site to form a semi-mercaptal enzyme-inhibitor
4
adduct (Figure 1). With support from the NM4TB
Figure 1. Binding mode of PBTZ169 to the target DprE1
consortium led by Stewart Cole, Makarov developed a concise
synthesis of the BTZs and carried out an extensive SAR
campaign culminating in the synthesis of the second-
(
PDB code: 4NCR).
The structure-activity relationships (SAR) of the
benzothiazinones reveal a strong positive correlation between
5
generation candidate PBTZ169. This promising compound
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lipophilicity and activity, consistent with location of the target
Scheme 1. Representative Synthesis of Analog 1.
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6
DprE1, which is found in the periplasmic space of the
mycobacterial cell wall. Consequently, introduction of polar
6
functional groups to modulate solubility is unlikely to be
successful without adversely impacting potency. Disruption of
molecular symmetry and planarity is an alternate strategy to
7
,8
improve aqueous solubility.
The 6-trifluormethyl-8-
nitrobenzothiazinone heterocycle must be strictly maintained
and even subtle alterations obliterate activity providing limited
opportunities to disrupt planarity in this portion of the
molecule. On the other hand the piperazine substituent appears
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0
substantially more tolerant to modification. Indeed, many
structural modifications at position 2 of BTZ core have been
For compound 2 and 5 we employed an alternate synthetic
route due to low yields in the final cyclization step with 17. Boc-
4
,5,9-18
reported.
Based on these SAR requirements, we initially
3
,6-diazabicyclo[3.1.1]heptane 13 was elaborated to 18 via
elected to replace the central piperazine moiety with a wide
variety of bioisosteric spirocyclic and bicyclic diamines that
preserve the overall lipophilicity, but disrupt the molecular
symmetry and/or planarity of PBTZ169 (Figure 2).
2
reaction with carbon disulfide in aqueous NaOH. Nucleophilic
aromatic substation of 18 with 17 followed by cyclization
smoothly provided 19. TFA-mediated deprotection of the Boc
group furnished 20 and reduction amination with cyclohexane
carboxaldehyde yielded 2 in 81% yield. Spirocyclic analogue 2
was recrystallized (mp 122–124 °C) from EtOH–EtOAc (1:1, v/v).
Analogue 5 was prepared analogously as described in the
Supporting Information.
Scheme 2. Representative Synthesis of Piperazine Analog 2.
Figure 2. Proposed analogues in this study containing
bioisosteric replacements of the piperazine moiety.
We initially conceived of a series of closely related bicyclic
and spirocyclic analogues to reduce planarity. A representative
synthesis is illustrated in Scheme 1 for compound 1. Reductive
1
9
amination of Boc-3,6-diazabicyclo[3.1.1]heptane 13 and
cyclohexane carboxaldehyde with NaBH(OAc) afforded 14
All compounds were evaluated for whole-cell activity against
M. tuberculosis strains H37Rv, CDC1551, and Erdrman in 7H9
medium to determine minimum inhibitory concentrations (MICs)
that resulted in complete inhibition of observable growth. The
MICs were nearly identical for all M. tuberculosis strains and
MIC data for strain H37Rv are shown in Table 1 (MICs for
CDC1551 and Erdman were equal to or 4-fold lower than H37Rv,
Table S2). The MICs ranged by nearly two-orders of magnitude
from 16–1024 nM. To track physicochemical properties, we
calculated the lipophilic ligand efficiency (LLE) and logP of each
analogue. Spirocycle 12 is the most potent analogue with an MIC
of 16 nM followed by compounds 5 and 9 with MICs of 32 nM
and compound 7 whose MIC is 64 nM. Among these analogues,
only 12 has an improved LLE relative to PBTZ169 due to an
overall decrease in clogP, whereas 5, 7, and 9 all have lower LLEs
primarily attributed to their decreased activity. Examination of the
structure–activity relationships (SAR) reveal analogues containing
conservative modifications to the piperazine nucleus are generally
better tolerated, whereas more extreme modifications resulted in
substantial decrease in activity. Thus, the 4,4- 4,6- 5,5-, 5,6- and
3
that was subsequently deprotected by trifluoroacetic acid to
furnish 15. Reaction with carbon disulfide in aqueous NaOH
20
yielded 16. Nucleophilic aromatic substitution of 16 with 2-
chlorobenzamide derivative 17 followed by intramolecular
cyclization provided 1 in 80% yield that was purified by silica
1
3
gel chromatography. Consistent with a decrease in planarity,
the melting point of 1 (mp 126–128 °C) was significantly
5
decreased compared to PBTZ169 (mp 176–178 °C).
Compounds 3–4 and 6–12 were prepared in analogous fashion
as described in the Supporting Information.
6
,6-spirocycles in 3, 4, 6, 8, 10 and 11 were poorly tolerated
resulting in nearly 64–512-fold losses in potencies compared to
PBTZ169. Based on the outstanding whole-cell activities, we
selected compounds 5, 7, 9 and 12 for further evaluation.
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We performed in vitro metabolic stability studies for
Table 1. MIC90 and clogP of 1–12.ꢀꢀ
1
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5
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7
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compounds 5, 7, 9 and 12 in parallel with PBTZ169, using
both mouse and human liver microsomes (MLM and HLM).
The results are shown in Table 3. Compound 5 has the lowest
intrinsic clearance in both MLM and HLM that is nearly 2-
fold lower than PBTZ169 while 9 behaves similarly to
PBTZ169. However, compounds 7 and 12 were rapidly
metabolized in MLMs, but displayed improved stability in
HLMs relative to PBTZ169. We also measured plasma protein
binding (PPB) and showed all compounds exhibited nearly
quantitative PPB with compound 5 having a slightly improved
free fraction of 0.5% versus 0.1% for PBTZ169. Given the
high PPB, it was not surprising that all compounds exhibited
high plasma stability. Based on these results, we selected
MIC
a
b
Compounds
R
clogP
LLE
(
nM)
PBTZ169
2
4.6
4.4
4.4
4.3
4.3
4.1
4.1
2.5
2.5
1.7
2.0
3.4
1
1
1
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1
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5
5
5
5
5
5
5
5
5
5
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0
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0
1
2
3
4
5
128
128
1024
512
32
compound
5
for evaluation of vivo pharmacokinetic
parameters in ICR mice.
Table 3. Microsomal stability, plasma protein binding and
plasma stability of compounds 5, 7, 9, 12 and PBTZ169.
t
1/2
Clint
(µL·min ·mg )
HLM MLM HLM
Plasma
Stability
(%)
-1
-1 PPB
(
min)
(%)
6
256
4.7
1.9
MLM
34.4
65.2
7.05
27.3
8.33
PBTZ169
43.0
76.6
26.6
30.6
43.0
20.1
10.6
98.4
25.4
83.3
16.5 99.9
9.05 99.5
26.1 99.6
22.7 99.9
16.1 99.4
88.7
91.4
81.9
102
7
8
9
64
256
32
4.4
3.9
5.0
2.8
2.7
2.5
5
7
9
1
2
93.3
1
0
128
1024
16
4.9
5.4
3.2
2.0
0.6
4.6
The in vivo PK profile of compound 5 was evaluated in ICR
mice after intravenous (i.v.) (2 mg/kg) and oral (p.o.) (10
mg/kg) administration (Table 4). Compound 5 displays a
useful PK profile with a 27% oral bioavailability and a high
11
1
2
volume of distribution (V ) that is offset by moderate-to-high
d
a
Calculated log10P (clogP) was determined by ChemDraw Professional
version 16.0; Lipophilic ligand efficiency (LLE) was calculated from the
equation: LLE= log10MIC-clog10P.
clearance resulting in a terminal elimination half life of 2.5 h.
Makarov and co-workers only dosed PBTZ169 orally at 25
mg/kg and observed similar exposure as measured by the area-
under-the curve (AUC) assuming linear PK and a slightly
b
The objectives of our study were to improve aqueous
solubility, thus selected compounds 5, 7, 9 and 12 were
examined for their kinetic solubility in phosphate-buffered
saline pH 7.4 by LC-MS/MS and the results are shown in
Table 2 along with the experimentally determined melting
points (mp) and total polar surface areas (tPSA). Compound 7
displayed the highest solubility (14.6 µg/mL) that was 1600-
fold greater than PBTZ169 while 5, 9, and 12 also showed
marked improvements in solubility. The solubility did not
show obvious correlation with the molecular descriptor tPSA
or melting points.
5
shorter terminal elimination half-life.
Table 4. Pharmacokinetic parameters for compound 5 in ICR
mice following intravenous (2 mg/kg) and oral (10 mg/kg)
administration.
Compound 5
PK parametersa
p.o.
i.v.
-
1
C
max (ng·mL )
195 ± 61
2.19 ± 0.29
3.09 ± 0.09
791 ± 338
-
483 ± 143
2.53 ± 0.25
2.24 ± 0.23
576 ± 54
58.2 ± 5.7
12.8 ± 2.5
-
t
1/2 (h)
MRT (h)
AUC (ng·h·mL )
Table 2. Solubility, melting points and tPSA of 5,7,9 and 12.ꢀꢀ
-1
-1
-1
Compounds
Solubility (µg/mL)
mp (°C)
183–185
110–112
>250
tPSA
87.7
96.5
87.7
87.7
84.5
Clint (mL·min ·kg )
-
2
-1
PBTZ169
< 1 × 10
Vd (L·kg )
-
5
7
9
4.8 ± 0
F (%)
27.4 ± 11.7
a
14.6 ± 0.1
C
max
:
maximum concentration of drug in blood plasma;
elimination half-life of drug; MRT: mean residence time; AUC: area
under the curve; Clint hepatic clearance; apparent volume of
distribution; F: oral bioavailability.
1/2
t : the
-
2
< 2.9 × 10
0.30 ± 0.02
209–211
192–194
:
d
V :
1
2
*
tPSA was calculated by Chembiodraw Ultra version 15.0.
In conclusion, we designed and synthesized a series of
benzothiazinones with spirocyclic and bicyclic isosteres of the
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piperazine to improve physicochemical properties by
Page 4 of 5
(5) Makarov, V.; Lechartier, B.; Zhang, M.; Neres, J.; van der
Sar, A.M.; Raadsen, S.A.S.A.; Hartkoorn, R.C.; Ryabova,
O.B.; Vocat, A.; Decosterd, L.A.; Widmer, N.; Buclin, T.;
Bitter, W.; Andries, K.; Pojer, F.; Dyson, P.J.; Cole, S.T.,
Towards a new combination therapy for tuberculosis with
next generation benzothiazinones. EMBO Mol. Med. 2014, 6,
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disruption of molecular planarity. Compound 5 containing the
azabicyclo[3.1.0]hexan-3-amine emerged as the most
promising analogue based on its improved solubility,
enhanced microsomal stability, and lower PPB compared to
PBTZ169. In addition, compound 5 had a respectable
pharmacokinetic profile with an oral bioavailability of 27%
and high volume of distribution.
3
72–383.
(
6) Brecik, M.; Centárová, I.; Mukherjee, R.; Kolly, G.S.;
Huszár, S.; Bobovská, A.; Kilacsková, E.; Mokošová, V.;
Svetlíková, Z.; Šarkan, M.; Neres, J.; Korduláková, J.; Cole,
ASSOCIATED CONTENT
Supporting Information
S.T.; Mikušová, K., DprE1 is a vulnerable tuberculosis drug
target due to its cell wall localization. ACS Chem. Biol. 2015,
10, 1631–1636.
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The Supporting Information is available free of charge on the
ACS Publications website.
(7) Ishikawa, M.; Hashimoto, Y., Improvement in aqueous
solubility in small molecule drug discovery programs by
disruption of molecular planarity and symmetry. J. Med.
Chem. 2011, 54, 1539–1554.
Experimental procedure, biochemical methods, LC-MS/MS
1
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method, and H and C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
(8) Degorce, S.L.; Bodnarchuk, M.S.; Cumming, I.A.; Scott,
J.S., Lowering lipophilicity by Adding Carbon: One-Carbon
Bridges of Morpholines and Piperazines. J. Med. Chem.
2018, 61, 8934–8943.
*
E-mail: ccaldrich@imm.ac.cn; aldri015@umn.edu
(
9) Lv, K.; You, X.; Wang, B.; Wei, Z.; Chai, Y.; Wang, B.;
Wang, A.; Huang, G.; Liu, M.; Lu, Y., Identification of
better pharmacokinetic benzothiazinone derivatives as new
antitubercular agents. ACS Med. Chem. Lett., 2017, 8, 636–
641.
Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the
manuscript.
(10) Piton, J.; Vocat, A.; Lupien, A.; Foo, C.; Riabova, O.;
Makarov, V.; Cole, S.T., Structure-based drug design and
characterization of sulfonyl-piperazine benzothiazinone
inhibitors of DprE1 from Mycobacterium tuberculosis.
Antimicrob. Agents Chemother. 2018, 62, e00681-18.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
(
11) Gao, C.; Ye, T.-H.; Wang, N.-Y.; Zeng, X.-X.; Zhang, L.-D.;
Xiong, Y.; You, X.-Y.; Xia, Y.; Xu, Y.; Peng, C.-T.; Zuo,
W.-Q.; Wei, Y.; Yu, L.-T., Synthesis and structure-activity
relationships evaluation of benzothiazinone derivatives as
potential anti-tubercular agents. Bioorg. Med. Chem. Lett.
This work was financially supported by a grant from the CAMS
Innovation Fund for Medical Sciences (CAMS-2017-I2M-1-011).
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