Identification of N-(2-Phenoxyethyl)imidazo[1,2-a]pyridine-3-carboxamides as New Antituberculosis Agents

Article abstract of DOI:10.1021/acsmedchemlett.6b00330

A series of imidazo[1,2-a]pyridine carboxamides (IPAs) bearing an N-(2-phenoxyethyl) moiety was designed and synthesized as new antitubercular agents. Seven 2,6-dimethyl IPAs demonstrated excellent in vitro activity (MIC: 0.025-0.054 μg/mL) against the drug susceptive H37Rv strain and two clinically isolated multidrug-resistant Mycobacterium tuberculosisstrains. Compound 10j displayed acceptable safety and pharmacokinetic properties, opening a new direction for further development.

Full text of DOI:10.1021/acsmedchemlett.6b00330

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Letter
Identification of N-(2-Phenoxyethyl)imidazo[1,2-
a]pyridine-3-carboxamides as New Anti-tuberculosis Agents
zhaoyang Wu, Yu Lu, Linhu Li, Rui Zhao, Bing Wang, Kai Lv, Mingliang Liu, and Xue-Fu You
ACS Med. Chem. Lett., Just Accepted Manuscript • Publication Date (Web): 11 Oct 2016
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Identification of N-(2-Phenoxyethyl)imidazo[1,2-a]pyridine-3-
carboxamides as New Anti-tuberculosis Agents
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⊥
⊥
Zhaoyang Wu, †, Yu Lu, ‡, Linhu Li, † Rui Zhao, † Bin Wang, ‡ Kai Lv, †, § Mingliang Liu, *, † Xuefu
You *, †
†Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing
100050, China
‡Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Department of Pharmacology, Beijing Tuberculosis and
Thoracic Tumor Research Institute, Beijing ChestHospital, Capital Medical University, Beijing 101149, China
§Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA.
KEYWORDS Antitubercular agents, MTB H37Rv, multidrug resistantꢀMTB, Nꢀ(2ꢀphenoxyethyl) imidazo [1,2ꢀa] pyridine
carboxamides, structure−activity relationship
ABSTRACT: A series of imidazo [1,2ꢀa] pyridine carboxamides (IPAs) bearing an Nꢀ(2ꢀphenoxyethyl) moiety were designed and
synthesized as new antitubercular agents. Seven 2,6ꢀdimethyl IPAs demonstrated excellent in vitro activity (MIC: 0.025ꢀ0.054
ꢁg/mL) against the drug susceptive H37Rv strain and two clinically isolated multidrugꢀresistant Mycobacterium tuberculosisstrains.
Compound 10j displayed acceptable safety and pharmacokinetic properties, opening a new direction for further development.
Tuberculosis (TB) remains one of the world’s deadliest
pandemic diseases with over 9 million new cases and 1.5 milꢀ
lion deaths estimated by the World Health Organization
(WHO) in 2014.1 The spread of multidrugꢀresistant tuberculoꢀ
sis (MDRꢀTB) and the emergence of extensively drugꢀ
resistant tuberculosis (XDRꢀTB) have reinvigorated drug disꢀ
covery efforts in search of novel drugs.2ꢀ4 Encouragingly, beꢀ
daquiline (an ATP synthase inhibitor) was, for the first time in
at least 40 years, approved by the US FDA for clinical manꢀ
agement of MDRꢀTB in 2012.5 However, considering the high
attrition rate in clinical trials, it is still highly valuable to idenꢀ
tify new molecules with alternative scaffolds as effective antiꢀ
TB drug candidates.
SAR study was also explored to facilitate the further developꢀ
ment of IPAs.
Imidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxamides (IPAs) as TB antiꢀ
biotics have garnered great interest recently. Structure–activity
relationship (SAR) studies of IPAs have demonstrated that the
carboxamide linker with the Nꢀbenzylic group is critical for
antimycobacterial activity.6 Two candidates, Q203 (Figure
1)6,7 and ND09759 (Figure 1), 8,9 targeting the Mycobacterium
tuberculosis (MTB) QcrB7,10 were found to have excellent
inhibitory potency against drugꢀsensitive, MDR and XDR
strains. DNB1 (Figure 1), a dinitrobenzamide targeting
DprE1/DprE2, was reported to be highly active against MTB,
including XDR strains.11 Given that all three candidates beꢀ
long to aromatic carboxamides, we intended to make structural
modifications on Q203 and ND09759 by peripheral modificaꢀ
tion. Thus, a series of 2,6ꢀ/2,7ꢀdimethyl IPAs (10a-m, 11a-n)
were designed as new antiꢀTB agents in which Nꢀ(2ꢀ
phenoxy)ethyl groups were introduced at first in this study
(Figure 1). Our primary objective was to identify alternative
linkers with potent antimycobacterial activity. A preliminary
Figure 1. Design of the new molecules
The synthetic route for target compounds 10a-m and 11a-n
is outlined in Scheme 1. Commercially unavailable 2ꢀ
phenoxyethanamines 3a-n were first prepared from different
phenols
1a-n
via
the
reaction
with
Nꢀ(2ꢀ
hydroxyethyl)phthalimide in the presence ofazodicarboxylate
(DEAD) and PPh3 in THF at 0ꢀ5°C, and then the resulting
condensates 2a-nwere treated with hydrazine hydrate in ethaꢀ
nol at 50°C.12
Condensations of 2ꢀaminopyridines 4, 5 with ethyl 2ꢀ
chloroacetoacetate in the presence of Et3N provided ethyl imꢀ
idazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylates 6,7.13 Hydrolysis of the
esters 6,7 in a LiOHꢀH2OꢀC2H5OH system yielded compounds
8,9. The target compounds 10a-m and 11a-n were obtained by
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amidation of the acids 8,9 with the amines 3a-n in the presꢀ type MTB H37Rv, suggesting their promising potential for
1
2
3
4
5
6
ence of 1ꢀ(3ꢀdimethylaminopropyl)ꢀ3ꢀethylcarbodiimide hyꢀ
drochloride (EDCI) and 1ꢀHydroxybenzotriazole (HOBT). In
addition, compound 14 withthe aminoethyl linker was also
synthesized from the amine 13, which can be easily prepared
through the nucleophilic substitution of 4ꢀbromoaniline 12 and
2ꢀbromoethanꢀ1ꢀamine hydrobromide (Scheme 1).
both drugꢀsensitive and resistant MTB strains (Table2).
Table 1.Structures and in vitro activity of 10, 11, and 14
against MTB H37Rv
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8
9
Scheme 1.Synthesis of target compounds 10a-n, 11a-m and
14
10
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12
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Compd.
10a
10b
10c
10d
10e
10f
X
MIC (ꢁg/mL)
0.054
0.038
0.029
0.204
0.401
0.030
0.031
0.146
0.030
0.027
0.303
0.245
0.390
0.935
0.231
0.329
0.673
2
H
2ꢀCH3
3ꢀCH3
4ꢀCH3
2ꢀOCH3
3ꢀOCH3
4ꢀOCH3
4ꢀF
10g
10h
10i
Reagents and conditions: (i) Nꢀ(2ꢀhydroxyethyl) phthalimide,
DEAD, PPh3, THF, 0ꢀ5°C; (ii) hydrazine hydrate, EtOH,
50°C; (iii) ethyl 2ꢀchloroacetoacetate, Et3N, MeCN, reflux;
(iv) LiOH, H2O, EtOH, rt, and then HCl; (v) EDCl, HOBT,
CH2Cl2, rt; (vi) toluene, reflux, then NaOH, rt
4ꢀCl
10j
4ꢀBr
10k
10l
2ꢀNO2
4ꢀNO2
4ꢀC6H5
H
The synthesized compounds 10a-n, 11a-m, and 14 were iniꢀ
tially screened for in vitro activity against MTB H37Rv ATCC
27294 strain (MTBꢀ1) using the Microplate Alamar Blue Asꢀ
say (MABA).14,15 The minimum inhibitory concentration
(MIC) is defined as the lowest concentration effecting a reducꢀ
tion in fluorescence of > 90% relative to the mean of replicate
bacteriumꢀonly controls. The MIC values of the compounds
along with isoniazid (INH) andrifampicin (RFP)for compariꢀ
son are presented in Table 1.
10m
11a
11b
11c
11d
11e
11f
2ꢀCH3
3ꢀCH3
4ꢀCH3
2ꢀOCH3
3ꢀOCH3
4ꢀOCH3
4ꢀF
The data revealed that most of the target compounds had poꢀ
tent activity against this strain (MIC: < 1 ꢁg/mL). 2,6ꢀ
Dimethyl IPAs were found to be much more active than the
corresponding 2,7ꢀdimethyl IPAs (10a-m vs 11a-m). Among
2,6ꢀdimethyl IPAs, 10a-c, 10f, 10g, 10i, and 10j showed exꢀ
cellent activity (MIC: 0.027ꢀ0.054 ꢁg/mL). The nature and
position of the substituent (X) on the benzene ring of comꢀ
pounds 10a-m influenced activity. With a few exceptions
(10d, 10e, 10h), the presence of an electronꢀdonating group
(methyl, methoxyl) or a halogen atom on the ring was found to
be favorable, but introduction of an electronꢀwithdrawing (niꢀ
tro) or a bulkier (phenyl) group resulted in decreased activity.
0.254
2
11g
11h
11i
2
4ꢀCl
2
11j
4ꢀBr
0.463
0.5
11k
11l
2ꢀNO2
4ꢀNO2
4ꢀC6H5
3ꢀNO2
/
4
11m
11n
14
0.518
0.5
In further modifications, the oxyethyl linker was replaced
by the isostereaminoethyl moiety. Compound 14 demonstrated
weaker activity (MIC: 0.25 ꢁg/mL) than 10j (MIC: 0.027
ꢁg/mL) against MTB H37Rv strain. The result revealed that
the oxyethyl moiety seems to be preferred over the aminoethyl
one.
0.25
INH
RFP
/
0.049
0.05
/
Moreover, the compounds 10a-m, 11a-n, and 14 were evalꢀ
uated for their in vitro antibacterial activity against representaꢀ
tive strains using standard techniques.16 MIC is defined as the
concentration of the compound required to give complete inꢀ
hibition of bacterial growth. It was found that none of the
compounds had activity (MIC: >32 ꢁg/mL) against any of the
tested gramꢀnegative (E. coli ATCC 25922, K. pneumoniae12ꢀ
Encouraged by their strong potency against the drugꢀ
sensitive MTB H37Rv strain, compounds 10a-c, 10f, 10g, 10i,
and 10j were further evaluated against two clinical isolated
11168 (MTBꢀ2) and 9160 (MTBꢀ3) MDR strains resistant to
both of INH and RFP. It was shown that all of the compounds
displayed excellent activity against these two strains with
similar MIC values (0.025ꢀ0.051 ꢁg/mL) to that of the wildꢀ
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1, P. aeruginosa 12ꢀ12) orgramꢀpositive strains (S. aureus
AUC0ꢀ∞ of 288.22±126.06 h.ng/mL, T1/2 of 1.50±0.43 h, Vd/F
of 185975.1±137163.90 mL/kg, and CL/F of
1
2
3
4
5
6
7
8
ATCC25923, methicillinꢀsensitive S. aureus 12ꢀ1, methicillinꢀ
resistant S. aureus 12ꢀ2, methicillinꢀsensitive S. epidermidis
12ꢀ1, methicillinꢀresistant S. epidermidis 12ꢀ6, S. pneumoniae
ATCC 49619). This indicated that the target compounds are
remarkably selective, since they had potent activity against
MTB. Pethe K and his colleagues have also confirmed that
this class of compounds is not active against other Gramꢀ
negative and Gramꢀpositive strains.7
86284.81±51685.89 mL/h/kg. Compound 10ahad a high Cmax
of 654.86 ± 311.87 ng/mL and an AUC0ꢀ∞ of 453.24 ± 254.13
h.ng/mL, but a short T1/2 of 0.43 ± 0.09 h and a poor Vd/F of
33806.34 ± 13481.74 mL/kg. The results suggestedthat the
presence of a substituent at the paraꢀposition of the benzene
ring is favorable for the PK profiles of 2,6ꢀdimethyl IPAs.
9
Table 4. Pharmacokinetic parameters of 10a, 10f, and 10j
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Table 2.In vitro activity of10a-c, 10f, 10g, 10i, and 10j
againstMDR strains resistant to both of INH and RFP
dosed orally in rats at 25 mg/kg（mean ± SD, n = 6）
Compd.
Cmax(ng/mL)
Tmax (h)
10a
10f
10j
MIC (ꢁg/mL)
Compd.
654.86 ±
311.87
351.16 ±
127.23
225.33±200.7
1
MDRꢀMTB
11168
MDRꢀMTB
9160
0.33 ± 0.16
0.17 ± 0.09
0.50±0.25
10a
10b
10c
10f
0.030
0.036
0.026
0.029
0.026
0.025
0.036
>40
0.047
0.050
0.033
0.035
0.034
0.028
0.051
>40
AUC0ꢀ∞（
h.ng/mL）
453.24 ±
254.13
214.46 ±
89.20
288.22±126.0
6
T1/2 (h)
0.43 ± 0.09
0.61 ± 0.20
1.12 ± 0.38
0.71 ± 0.15
1.50±0.43
1.60±0.45
MRT (h)
10g
10i
185975.1±
137163.90
33806.34 ± 188349.28 ±
Vd/F (mL/kg)
13481.74
114024.43
10j
116573.23 ±
67837.38
86284.81±
51685.89
CL/F
(mL/h/kg)
55158.14 ±
24763.45
INH
RFP
36.889
38.647
In conclusion, a series of novel IPA derivatives bearing an
Nꢀ(2ꢀphenoxy)ethyl moiety were designed as new antitubercuꢀ
lar agents by using a scaffold hopping strategy. Many 2,6ꢀ
dimethyl IPAs exhibited excellent in vitro inhibitory activity
against both drugꢀsensitive MTB strain H37Rv and drugꢀ
resistant clinical isolates. Compound 10j displayed acceptable
safety and PK properties and it may serve as a new and promꢀ
ising lead compound for further antitubercular drug discovery.
Also, compound 14, with its considerable activity (MIC: 0.25
ꢁg/mL) against MTB H37Rv strain, arouses our great interest
in exploring SAR of Nꢀ(2ꢀphenylamino)ethyl IPAs. Further
modifications of Nꢀ(2ꢀphenoxy) and Nꢀ(2ꢀphenylamino)ethyl
IPAs are in progress, and the study results will be reported in
due course.
Based on the measured activity levels against all of the testꢀ
ed strains, the three most active compoundswith structural
diversity, 10a, 10f, and 10j, were further tested for in vivo
tolerability by recording the number of survivors after a single
intravenous dose in mice of 50 and 100 mg/kg, or an oral dose
in rats of 500 and 1000 mg/kg, followed by a 7ꢀday observaꢀ
tion. As shown in Table 3, all three compounds showed good
tolerance in mice at 100 mg/kg (i.v.) or in rats at 500 mg/kg
(p.o.).Compound 10j displayed the lowest oral acute lethal
toxicity, followed by 10f and then 10a.
Table 3. Acute Toxicity Study of 10a, 10f, and 10j
ASSOCIATED CONTENT
Supporting Information
no. of animals that surꢀ
dose（mg/kg）
vived/total no. of aniꢀ
mals
Compd.
The Supporting Informationisavailableonthe ACS Publications
web site.
i.v. (mice)
50
p.o. (rats)
500
i.v. (mice)
5/5
p.o. (rats)
5/5
10a
10f
10j
Experimental procedures and analytical data forcompounds
10a-m 11a-n, 14.
100
50
1000
500
5/5
2/5
5/5
5/5
100
50
1000
500
5/5
4/5
AUTHOR INFORMATION
Corresponding Author
5/5
5/5
100
1000
5/5
5/5
*Tel: 010ꢀ63030965. Fax: 010ꢀ63036965.
*Eꢀmail: lmllyx@126.com.
The in vivo pharmacokinetic (PK) profiles of 10a, 10f, and
10jwere evaluated in rats after a single oral administration of
25 mg/kg. As shown in Table 4, compound10j, with a bromo
atom at the paraꢀposition of the benzene ring, displayed relaꢀ
tively good PK properties, with Cmax of 225.33±200.71 ng/mL,
Eꢀmail: xuefuyou116@yahoo.cn.
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of new and old agents. Nat. Rev. Drug Dis.2013, 12, 175ꢀ
Present Addresses
1
2
176.
†No 1, TiantanXili, Beijing 100050, P.R.China
(5) Cohen, J. Infectious disease. Approval of novel TB drug
celebrated–with restraint. Science 2013, 339, 130.
(6) Kang, S.; Kim, R. Y.; Seo, M. J.; Lee, S.; Kim, Y. M.;
Seo, M.; Seo, J. J.; Ko, Y.; Choi, I.; Jang, J.; Nam, J.;
Park, S.; Kang, H.; Kim, H. J.; Kim, J.; Ahn, S.; Pethe,
3
4
5
6
7
8
9
Author Contributions
⊥These authors contributed equally to this work.
Funding Sources
This work is supported by the National S&T Major Special
Project on Major New Drug Innovations (2014ZX09507009ꢀ
003, 2015ZX09102007ꢀ008), NSFC (81373267, 21502237),
National key research and development program
(2016YFA0201500) and Beijing Municipal Administration of
Hospitals Clinical Medicine Development of Special Funding
Support (ZYLX201304).
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K.; Nam, K.; No, Z.; Kim, J. Lead optimization of a novel
series of imidazo[1,2ꢀa]pyridine amides leading to a clinꢀ
ical candidate (Q203) as a multiꢀ and extensivelyꢀdrugꢀ
resistant antiꢀtuberculosis agent. J. Med. Chem. 2014, 57,
5293−5305.
Notes
(7) Pethe, K.; Bifani, P.; Jang, J.; Kang, S.; Park, S.; Ahn, S.;
Jiricek, J.; Jung, J.; Jeon, H. K.; Cechetto, J.; Christophe,
T.; Lee, H.; Kempf, M.; Jackson, M.; Lenaerts, A. J.;
Pham, H.; Jones, V.; Seo, M. J.; Kim, Y. M.; Seo, M.;
Seo, J. J.; Park, D.; Ko, Y.; Choi, I.; Kim, R.; Kim, S. Y.;
Lim, S.; Yim, S. A.; Nam, J.; Kang, H.; Kwon, H.; Oh, C.
T.; Cho, Y.; Jang, Y.; Kim, J.; Chua, A.; Tan, B. H.;
Nanjundappa, M. B.; Rao, S. P. S.; Barnes, W. S.;
Wintjens, R.; Walker, J. R.; Alonso, S.; Lee, S.; Kim, J.;
Oh, S.; Oh, T.; Nehrbass, U.; Han, S.ꢀJ.; No, Z.; Lee, J.;
Brodin, P.; Cho, S.ꢀN.; Nam, K.; Kim, J. Discovery of
Q203, a potent clinical candidate for the treatment of tuꢀ
berculosis. Nat. Med. 2013, 19, 1157−1160.
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank Accdon for its linguistic assistance during the
preparation of this manuscript.
ABBREVIATIONS
IPAs, imidazo [1,2ꢀa] pyridine carboxamides; MTB, Mycobacꢀ
terium tuberculosis; MDRꢀTB, multidrugꢀresistant tuberculosis ;
XDRꢀTB, extensively drugꢀresistant tuberculosis; EDCI, 1ꢀ(3ꢀ
dimethylaminopropyl)ꢀ3ꢀethylcarbodiimide
hydrochloride;
HOBT, 1ꢀHydroxybenzotriazole; MIC, the minimum inhibitory
concentration; MABA, Microplate Alamar Blue Assay; Cmax, the
maximum concentration; Tmax, the time to maximum concentraꢀ
tion; AUC0ꢀ∞, area under curve from time zero to infinity; t1/2, the
plasma elimination halfꢀlife; MRT, mean residence time; Cl,
Clearance; Vz, volume of distribution; F, bioavailability.
(8) Cheng, Y.; Moraski, G. C.; Cramer, J.; Miller, M. J.;
Schorey, J. S. Bactericidal activity of an imidazo[1, 2ꢀ
a]pyridine using a mouse M. tuberculosis infection modꢀ
el. PloS one. 2014, 9, e87483.
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(15) Lu, Y.; Zheng, M. Q.; Wang B.; Fu, L.; Zhao, W. J.; Li,
P.; Xu, J.; Zhu, H.; Jin, H. X.; Yin, D. L.; Huang, H. H.;
Upton, A. M.; Ma, Z. K. Clofazimine analogs with efficaꢀ
cy against experimental tuberculosis and reduced potenꢀ
tial for accumulation, Antimicrob. Agents Chemother.
2011, 55, 5185ꢀ5193.
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(12) Lv, K.; Sun, Y. X; Sun, L. Y.; Wei, Z.; Guo, H. Y.; Wu,
J. W; Liu, M. L. Design, synthesis and in vitroantibacteriꢀ
al activity of fluoroquinolone derivatives containing a chiꢀ
ral 3ꢀ(alkoxyimino)ꢀ2ꢀ(aminomethyl)azetidine moiety.
ChemMedChem, 2012, 7, 1230ꢀ1236.
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(16) MIC values were determined as described by the NCCLS
(see: National Committee for Clinical Laboratory Standꢀ
ards, Performance Standards for Antimicrobial Susceptiꢀ
bility Testing: 11th Informational Supplement, Vol. 21;
NCCLS: Wayne, PA, USA, 2001, M100ꢀS11). MIC was
defined as the lowest concentration of each compound
that inhibits visible growth of bacteria after incubation at
35 °C for 18–24 h.
(13) Li, L. H.; Wu, Z. Y.; Liu, M. L.; Li, Z. R; Guo, H. Y.;
Zhang Q. R. Microwave assisted synthesis ofdisubstitꢀ
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nol. Heterocycles, 2015, 91, 2087ꢀ2095.
(14) Collins, L.; Franzblau, S. G. Microplate alamar blue assay
versus BACTEC 460 system for highꢀ
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ACS Medicinal Chemistry Letters
Page 6 of 6
A series of novel IPA derivatives bearing an Nꢀ(2ꢀphenoxy) ethyl moiety were designed as new antitubercular agents by using a
scaffold hopping strategy. Many 2,6ꢀdimethyl IPAs exhibited excellent in vitro inhibitory activity against both drugꢀsensitive MTB
strain H37Rv and drugꢀresistant clinical isolates.
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