Design and syntheses of anti-tuberculosis agents inspired by BTZ043 using a scaffold simplification strategy

Article abstract of DOI:10.1021/ml500039g

Tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (Mtb), is a global public health concern because of the emergence of various resistant strains. Benzothiazin-4-ones (BTZs), represented by BTZ043, are a promising new class of agents for the treatment of tuberculosis and have been shown to kill Mtb in vitro, ex vivo, and in mouse models of TB. Herein we report the design and syntheses of nitroaromatic sulfonamide, reverse-amide, and ester classes of anti-TB agents using a scaffold simplification strategy based on BTZ043. The presented work explores the effect of functional groups such as sulfonamides, reverse-amides, and esters that are attached to the nitroaromatic rings on their anti-TB activity. The in vitro activity of the compounds evaluated against the H37Rv strain of Mtb show that nitroaromatic sulfonamides and nitrobenzoic acid esters with two nitro substituents were most active and highlights the importance of the electronic character (electron deficient aromatic ring) of the nitroaromatic ring as a central theme in these types of nitroaromatic anti-TB agents.

Full text of DOI:10.1021/ml500039g

Letter
pubs.acs.org/acsmedchemlett
Design and Syntheses of Anti-Tuberculosis Agents Inspired by
BTZ043 Using a Scaffold Simplification Strategy
Rohit Tiwari,† Ute Mollmann,‡ Sanghyun Cho,§ Scott G. Franzblau,§ Patricia A. Miller,†
̈
and Marvin J. Miller*,†
†Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
‡Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoll Institute, Beutenbergstrasse 11a, 07745 Jena,
̈
Germany
§Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois
60612, United States
S
* Supporting Information
ABSTRACT: Tuberculosis (TB), a disease caused by
Mycobacterium tuberculosis (Mtb), is a global public health
concern because of the emergence of various resistant strains.
Benzothiazin-4-ones (BTZs), represented by BTZ043, are a
promising new class of agents for the treatment of tuberculosis
and have been shown to kill Mtb in vitro, ex vivo, and in mouse
models of TB. Herein we report the design and syntheses of
nitroaromatic sulfonamide, reverse-amide, and ester classes of
anti-TB agents using a scaffold simplification strategy based on
BTZ043. The presented work explores the effect of functional
groups such as sulfonamides, reverse-amides, and esters that
are attached to the nitroaromatic rings on their anti-TB
activity. The in vitro activity of the compounds evaluated against the H37Rv strain of Mtb show that nitroaromatic sulfonamides
and nitrobenzoic acid esters with two nitro substituents were most active and highlights the importance of the electronic
character (electron deficient aromatic ring) of the nitroaromatic ring as a central theme in these types of nitroaromatic anti-TB
agents.
KEYWORDS: Mycobacterium tuberculosis, scaffold simplification strategy, BTZ043, nitroaromatics, DprE1
1), have been shown to kill Mtb in vitro, ex vivo, and in mouse
models of TB. The minimum inhibitory concentration (MIC)
uberculosis (TB), is a disease caused by Mycobacterium
Ttuberculosis (Mtb). Approximately 2 billion people are
infected by TB worldwide, and it accounts for approximately 2
million deaths every year. TB is considered a global public
health concern because of the emergence of multidrug resistant
(MDR), extensively drug resistant (XDR), and, recently, totally
drug resistant forms.1,2 Coinfection with human immunodefi-
ciency virus (HIV) causes both TB and HIV to progress more
rapidly. An estimated 1.3 million deaths occurred among HIV
negative TB cases in 2009, whereas 0.4 million deaths occurred
in HIV cases with TB coinfection the same year.1,3
Recently, TMC207 (bedaquiline) was the first new anti-TB
agent to be approved in over 40 years.4 Still, the current anti-
TB treatment regimen suffers from poor patient compliance
due to the required simultaneous and long-term administration
of multiple drugs, side effects, and treatment costs. This
noncompliance also has contributed to the emergence of MDR
and XDR strains. Therefore, there is a growing demand for new
agents that are effective against TB.5,6
Figure 1. Structures of a representative 1,3-benzothiazinone anti-TB
agent, BTZ043, and other recently developed nitroaromatic amide
anti-TB agents.
of BTZ043 was found to be 1 ng/mL against Mtb, which is
extraordinary relative to existing drugs, such as isoniazid and
ethambutol.7,8 More recently, additional structure−activity
relationship (SAR) studies led to the development of pBTZ,
Recently, 1,3-benzothiazin-4-ones (BTZs) were discovered
and found to be promising new agents for the treatment of
tuberculosis.7,8 BTZs, especially BTZ043 (compound 1, Figure
Received: January 29, 2014
Accepted: March 3, 2014
© XXXX American Chemical Society
A
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ACS Medicinal Chemistry Letters
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which is reported to have efficacy in mouse and zebrafish
models of tuberculosis.9
Mycobacteria possess a thick, impermeable hydrophobic cell
wall. This cell wall includes peptidoglycan and D-arabinofur-
anose, containing arabinogalactan, arabinomannan polysacchar-
ides, mannans, glucans, mycolic acids, lipids, glycolipids, poly
glutamate-glutamine polymers, and proteins.9,10 D-Arabinofur-
anose, a component of arabinogalactan and arabinomannan is
biosynthesized in a process catalyzed by decaprenyl-phospho-
ribose-2′-epimerase (DprE1).10,11 BTZ043 was shown to be a
suicide inhibitor of DprE1, a key enzyme of the cell wall
assembly for mycobacteria.7,9,13
Figure 2. Design of anti-TB agents inspired by BTZ043. The
molecular fragments of BTZ043 considered for the design are colored
in purple.
A long-standing goal of our lab and many others is to
develop effective syntheses of anti-TB agents. Herein we report
design and syntheses of simplified anti-TB agents based on the
molecular mode of action of BTZ043.
further simplified to facilitate syntheses while exploring the
SAR.
The SAR studies carried out by Makarov et al.7 and the
detailed mechanistic studies carried out by Trefzer et al.9,13 and
our group,12 indicate that the anti-TB activity of BTZs depends
on the electron deficient nitroaromatic core; whereas
substitution of the (S)-2-methyl-1,4-dioxa-8-azaspiro[4.5]-
decane group of 1 by either its enantiomer or by variety of
functional groups, including substituted piperazines,7,14 is not
as influential.
This modification was inspired by recent X-ray crystallo-
graphic studies by Neres et al.15 on a covalently bound
BTZ043-derived nitroso semimercaptal adduct with DprE1.
This crystal structure revealed only a complementary weak
hydrophobic interaction of the side chain leucine with the
piperidine ring of BTZ043, whereas the dioxa-spirocycle is
exposed without any noticeable interaction with DprE1.
In order to validate our scaffold simplification strategy by
computational docking, a representative dinitro compound
from each of the presented classes was docked into the crystal
structure of DprE1 (PDB code 4F4Q)15 using Glide.16,17 Since
compound 1 was crystallized as a covalent adduct with DprE1,
it was necessary to optimize the docking protocol. This was
achieved by docking the nitroso intermediate of 1 into DprE1
(see Supporting Information). Therefore, the S−N covalent
bond of the semimercaptal adduct in the crystal structure was
deleted, and the resulting ligand was converted into its nitroso
intermediate (see Supporting Information for complete details)
and docked. As can be seen from Figure 3A, the nitroso
intermediate of BTZ043 was docked in the same binding
pocket formed by the semimercaptal adduct.
Next, we repeated the docking with compounds 9, 19, and
24 to explore and compare their binding with that of
semimercaptal adduct in DprE1. Our docking study indicated
that the dinitroaromatic portion present in all these compounds
binds essentially in the same pocket as that of 1 (Figure 3B).
Thus, this observed docking pattern of sulfonamides, reverse
amide, and nitrobenzoic acid ester class of compounds further
justified our design strategy of these classes using a scaffold
simplification strategy.
As shown in Scheme 1, preparation of the first sulfonamide
subset of compounds (8−10) only required reactions between
appropriately substituted aryl sulfonyl chlorides with (S)-2-
methyl-1,4-dioxa-8-azaspiro [4.5]decane (7) in the presence of
triethylamine. The aryl sulfonyl chloride precursors were
obtained from commercial sources or prepared by diazotization
of the corresponding 1,3-disubstituted anilines with sodium
nitrite followed by reaction with sulfur dioxide gas in the
presence of Cu(I)Cl.18 The phenyl-substituted analogue 11 was
synthesized in 69% yield by the Suzuki coupling of 10 with
phenyl boronic acid in the presence of CsF.19
The effect on the anti-TB activity by the replacement of the
nitro groups of aryl sulfonamides by pyridyl or pyridyl-N-oxides
was also investigated. The pyridyl-N-oxide 12 was synthesized
in 38% yield from 10 by utilizing the coupling procedure
described by Fagnou et al.20,21 The pyridine analogue 13 was
However, the mechanistic details related to the reductive
activation of BTZ043 to its nitroso intermediate are yet to be
completely understood.9,12,13 It was hypothesized that the
cofactor FADH2 was responsible for the reduction of the nitro
group of BTZ043 to its nitroso intermediate, which in turn
reacts with the cysteine at the active site of DprE1 to form a
covalent semimercaptal adduct.
Our recent work further demonstrated that BTZ043 and
other nitroaromatic compounds such as nitrobenzamides and
nitroaromatic-BTZ hybrids undergo similar chemistry and
metabolic transformations and thus may have common
activating and metabolizing targets. In particular, our work
suggests that these related nitroaromatic anti-TB agents can
undergo cine addition reactions with either nucleophilic
thiolates present in the active site of the enzyme (DprE1 in
the case of BTZ043) or by a hydride from cofactor (FADH2).
Activation initiated by cine addition to the nitroaromatic
prodrugs initiates conversion to the corresponding target-active
nitroso intermediates thereby causing the subsequent suicide
inhibition of the enzyme (DprE1 in the case of BTZ043).12
Therefore, for the design and syntheses of BTZ043-based
analogues, we retained the reactive nitroaromatic core and
envisioned the simplification (defragmentation) of the BTZ043
scaffold based on electron withdrawing 1,3,5-substituents
(namely, the trifluoromethyl, nitro, and carbonyl highlighted
in purple in Figure 2) into three easily synthesized and cost-
effective nitroaromatic analogues, namely, the sulfonamide
based, the aniline based, and finally the benzyl ester based
scaffolds shown in Figure 2.
The sulfonamide derivatives were designed as bioisosteres of
the carbonyl fragment colored in purple (Figure 2), whereas the
aniline derivatives are termed reverse-amides to reflect that they
were designed to explore SAR by variation of previously
reported substituted nitro benzamides.3 The sulfonamide and
the reverse-amide based versions retained the dioxa-8-
azaspiro[4.5]decane group from BTZ043 in order to keep
their molecular surface areas similar to that of BTZ043, whereas
the design of the ester based class of nitroaromatic agents was
B
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ACS Medicinal Chemistry Letters
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Scheme 1. Synthesis of BTZ043 Inspired Sulfonamide Based
a
Nitroaromatics
a
Reagents and conditions: (a) (i) NaNO2, HCl, CH3COOH; (ii) SO2,
CH3COOH; (b) 7, Et3N, DCM, rt; (c) phenyl boronic acid,
Pd(PPh3)4, CsF, 1,4-dioxane, reflux, 69%; (d) pyridine-N-oxide,
PtBu3·HBF4, Pd(OAc)2, K2CO3, toluene, 110 °C, 38%; (e) iron
dust, 0.1 M CH3COOH.
Table 1. In Vitro Activity of the Analogues Inspired by
BTZ043 against the H37Rv Strain of Mtb in 7H12 and GAS
a
Media (MIC in μM)
MABA: 7H12
MABA: GAS
R1
R2
(μM)
(μM)
8
CF3
NO2
6.99
1.53
>10
>64
>64
10.2
2.05
nd
9
NO2 NO2
10
11
12
CF3
CF3
CF3
Br
Ph
17.4
>64
pyridine-N-
oxide
Figure 3. (A) Overlay of the docking nitroso intermediate of BTZ043
(carbons are purple) on the crystallized semimercaptal adduct
(carbons are cyan). (B) Overlay of the docked structures of
compounds 9 (carbons are pink), 19 (carbons are blue), and 24
(carbons are colored white) on the crystallized semimercaptal adduct
(carbons are cyan).
13
CF3
CF3
CF3
pyridine
H
>50
49.3
17.9
18.4
22.6
2.03
0.27
<0.02
17
>50
18
NO2
23.0
47.9
>50
19
NO2 NO2
CF3 NO2
NO2 NO2
23
24
13.03
<0.02
then synthesized by the reduction of compound 12 with Fe/
CH3COOH.
BTZ043
a
MABA, microplate alamar blue assay; GAS, glycerol-alanine-salts
The in vitro activity of compounds 8−10 and 11−13 in two
different mycobacterial growth media (7H12 and GAS)22−24
are summarized in Table 1. As can be seen from Table 1, only
compounds 8 and 9 showed significant activity against the
H37Rv strain of Mtb, while others were less active. The SAR
studies further highlighted the importance of the nitro group
for the anti-TB activity of these compounds. It is probable that
the sulfonamide class, in general, is still not as electron deficient
as the 1,3-benzothiazinones. Therefore, the nitroaromatic ring
present in 8 is still not as electron deficient as in dinitro-
substituted compound 9, which is consistent with the difference
in anti-TB activity (see Table 2). Additionally, compound 9 did
medium; 7H12, 7H9 medium plus casitone, palmitic acid, albumin,
and catalase.
not show any toxicity in the VERO assay, whereas compound 8
was found to be toxic (see Supporting Information for VERO
and LORA activities). Both compounds 8 and 9 were only
weakly active against nonreplicating Mtb (LORA).
Syntheses of the anilines or reverse-amide compounds (17−
19, Scheme 2) required prior ketalization of commercially
available 4-oxo-ethyl-cyclohexane carboxylate (14) with (S)-2-
methyl-2,2-propandiol in the presence of catalytic pTsOH to
C
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ACS Medicinal Chemistry Letters
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a
Table 2. Mulliken Charges on the Indicated Positions
Calculated by AM1 Methods for Representative
Dinitroaromatic Scaffolds
Scheme 3. Synthesis of Benzyl Esters of Nitrobenzoic Acids
a
a
Reagent and conditions: (a) oxalyl chloride, cat. DMF; (b) Et3N,
CH2Cl2, DMAP, 80−90%.
Mulliken charges
9
19
24
1
2
3
0.24
0.26
0.26
0.17
0.10
0.11
0.22
0.22
0.22
Overall, the SAR pattern displayed by this class of
compounds was similar to both sulfonamides and reverse-
amides (Table 1). Briefly, the m-dinitrobenzoate esters
displayed more potent activity than the corresponding m-
trifluoromethyl-m-nitro benzoates.
Surprisingly, this class of compounds displayed much weaker
activity in the 7H12 media and displayed notable activity in the
GAS media (Table 1).
a
The Mulliken charges are shown only for the numbered atoms for
comparison purposes.
a
Scheme 2. Syntheses of Reverse-Amide Nitroaromatics
In conclusion, from Table 1, it is clear that simple
sulfonamides and nitrobenzoic acid ester analogues with dinitro
substituents (compounds 9 and 24) were more active though
not at the level of BTZ043 itself. The reverse-amide
functionality drastically affected the in vitro anti-TB activity
of the studied nitroaromatic scaffold. Table 2 shows the
Mulliken charges25 calculated using AM1 method26 on
dinitroaromatic 9, 19, and 24. It is evident from Table 2 that
the nitroaromatic scaffold present in 9 is more electron
deficient than 24, which in turn is more electron deficient than
19. As shown in Figure 3, the docking pattern for 9, 19, and 24
with DprE1 is similar; however, there is a marked difference in
the electronic nature of the nitroaromatic rings brought about
by the introduction of the sulfonamide, reverse-amide, and
ester functionality. This difference is reflected in their anti-TB
activity. Therefore, this work highlights the importance of the
electronic character (electron deficient aromatic ring) of the
nitroaromatic ring as a central theme in these nitroaromatic
anti-TB agents.
a
Reagent and conditions: (a) pTsOH, benzene, reflux; (b) LiOH,
THF/water; (c) (i) oxalyl chloride, DMF, CH2Cl2, 4 h; (ii) Et3N,
CH2Cl2, 12 h.
obtain 15. Compound 15 was then saponified to afford the free
carboxylic acid, which was coupled with m,m-disubstituted
electron deficient anilines by reaction of the acid chloride of 15
in the presence of triethylamine to obtain compounds 17−19.
On the basis of the earlier results with the sulfonamide class of
analogues, other substitutions such as phenyl, pyridyl, or
pyridyl-N-oxide for this class of analogues were not explored.
The in vitro activities of compounds 17−19 in two different
mycobacterial growth media (7H12 and GAS) are also included
in Table 1.
The change in the electronic character of the nitroaromatic
ring brought by the reverse-amide functionality became evident
by in vitro activities. The nitro aromatic ring in this class of
compounds (17−19) is not as electron deficient as in the
sulfonamides, and hence, this class of compounds is virtually
devoid of any appreciable activity (see Table 2 for the Mulliken
charges calculated for 19). Notably, unlike the previous class
the dinitro compound (19) was found to be less active than the
mononitro one (18).
ASSOCIATED CONTENT
* Supporting Information
■
S
Complete experimental details along with the characterizations
of the synthesized compound. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*(M.J.M.) Tel: +1-574-631-7571. Fax: 1-574-631-6652. E-mail:
mmiller1@nd.edu.
Funding
This research was supported in part by grant 2R01AI054193
from the National Institutes of Health (NIH).
Notes
The authors declare no competing financial interest.
The nitrobenzoic acid esters 23−24 (Scheme 3) were
synthesized in 80−90% yields by coupling of the appropriately
substituted nitrobenzoic acids, 20−21 with the various
commercially available benzyl alcohol, 22 in the presence of
triethylamine and a catalytic amount of DMAP. Both m-dinitro
benzoic acids and m-trifluoromethyl-m-nitro benzoic acid esters
were synthesized.
ACKNOWLEDGMENTS
■
We thank the University of Notre Dame, especially the Mass
Spectrometry and Proteomics Facility (Bill Boggess, Michelle
Joyce, and Nonka Sevova), which is supported by Grant CHE-
0741793 from the National Science Foundation (NSF).
D
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ACS Medicinal Chemistry Letters
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ABBREVIATIONS
■
DMF, N,N-dimethyl formamide; DprE1, decaprenylphosphor-
yl-β-D-ribose 2′ oxidase; MDR, multidrug resistant; M.
tuberculosis, Mycobacterium tuberculosis; XDR, extensively drug
resistant; TB, tuberculosis
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rapid, accurate docking and scoring. 2. Enrichment factors in database
screening. J. Med. Chem. 2004, 47, 1750−1759.
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