Nitrofuranyl Methyl Piperazines as New Anti-TB Agents: Identification, Validation, Medicinal Chemistry, and PK Studies

Article abstract of DOI:10.1021/acsmedchemlett.5b00141

Whole-cell screening of 20,000 drug-like small molecules led to the identification of nitrofuranyl methylpiperazines as potent anti-TB agents. In the present study, validation followed by medicinal chemistry has been used to explore the structure-activity relationship. Ten compounds demonstrated potent MIC in the range of 0.17-0.0072 μM against H₃₇Rv Mycobacterium tuberculosis (MTB) and were further investigated against nonreplicating and resistant (Rif^R and MDR) strains of MTB. These compounds were also tested for cytotoxicity. Among the 10 tested compounds, five showed submicromolar to nanomolar potency against nonreplicating and resistant (Rif^R and MDR) strains of MTB along with a good safety index. Based on their overall in vitro profiles, the solubility and pharmacokinetic properties of five potent compounds were studied, and two analogues, 14f and 16g, were found to have comparatively better solubility than others tested and acceptable pharmacokinetic properties. This study presents the rediscovery of a nitrofuranyl class of compounds with improved aqueous solubility and acceptable oral PK properties, opening a new direction for further development.

Full text of DOI:10.1021/acsmedchemlett.5b00141

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Letter
Nitrofuranyl Methyl Piperazines as New Anti-TB agents:
Identification, Validation, Medicinal Chemistry and PK Studies
Kushalava Reddy Yempalla, Gurunadham Munagala, Samsher Singh, Asmita
Magotra, Sunil Kumar, Vikrant Singh Rajput, Sonali S. Bharate, Manoj Tikoo,
G. D. Singh, Inshad Ali Khan, Ram A. Vishwakarma, and Parvinder Pal Singh
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.5b00141 • Publication Date (Web): 31 Aug 2015
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Nitrofuranyl Methyl Piperazines as New Anti-TB agents: Identifica-
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Kushalava Reddy Yempalla,1,5,⊥ Gurunadham Munagala,1,5,⊥ Samsher Singh,2,5,⊥ Asmita Magotra,3,5
Sunil Kumar,2,5 Vikrant Singh Rajput,2,5 Sonali S. Bharate,4 Manoj Tikoo,3 G. D. Singh,3 Inshad Ali
Khan,2,5,* Ram A. Vishwakarma1,5,* and Parvinder Pal Singh1,5,*
1Medicinal Chemistry Division,2 Clinical Microbiology Division,3 PKꢀPD and Toxicology Division,4 Preꢀformulation Laboraꢀ
tory,5Academy of Scientific and Innovative Research, CSIRꢀIndian Institute of Integrative Medicine, Canal Road, Jammu
180 001, India
KEYWORDS: Mycobacterium tuberculosis, MTB H37Rv, Multidrug resistant-TB, 6-nitro-2,3-dihydroimidazooxazole, Struc-
ture activity relationship.
ABSTRACT: Wholeꢀcell screening of 20,000 drugꢀlike small molecules led to the identification of nitrofuranyl methylpiperazines
as potent antiꢀTB agents. In the present study, validation followed by medicinal chemistry has been used to explore the structureꢀ
activity relationship. Ten compounds demonstrated potent MIC in the range of 0.17 – 0.0072 µM against H37Rv Mycobacterium
tuberculosis (MTB) and were further investigated against nonꢀreplicating and resistant (RifR and MDR) strains of MTB. These
compounds were also tested for cytotoxicity. Among the 10 tested compounds, five showed subꢀmicromolar to nanomolar potency
against nonꢀreplicating and resistant (RifR and MDR) strains of MTB along with a good safety index. Based on their overall in vitro
profiles, the solubility and pharmacokinetic properties of five potent compounds were studied, and two analogs, 14f and 16g, were
found to have comparatively better solubility than others tested and acceptable pharmacokinetic properties. This study presents the
reꢀdiscovery of a nitrofuranyl class of compounds with improved aqueous solubility and acceptable oral PK properties, opening a
new direction for further development.
The emergence of resistant tuberculosis has been a
serious concern worldwide that has reinvigorated drug discovꢀ
ery efforts in search of novel candidates that are effective
against both susceptible and resistant strains as well as safe
and potentially fasterꢀacting, with the aim of shortening
lengthy TB treatments.1ꢀ3 Whole cell screening is an attractive
approach to the fast identification of novel compounds active
against TB.4 The success of the whole cell screeningꢀdriven
approach to tuberculosis is best illustrated by the discovery of
bedaquiline (TMC207, diarylquinoline derivative).5,6 Similar
success has been shown by the discovery of other preꢀclinical
candidates such as benzothiazoles TCAꢀ17 and imidazꢀ
opyridine amides Qꢀ203.8 Considering the high attrition rate in
clinical trials, further enrichment of the clinical pipeline is
greatly needed.
compounds yielded 233 molecules with ≤ 8 µg/ml MIC
against sensitive and resistant strains of MTB. The chemical
clustering of these hits revealed nitrofuranyl methylpiperazine
as one of the most potent scaffolds (Fig 1). The identified niꢀ
trofuranyl methylpiperazine cluster included six compounds
1a-f with a MIC in the range of 0.2 – 25.3 µM against H37Rv
and RifR strains of MTB (Fig. 1).
A literature survey revealed that nitrofuran containꢀ
ing compounds are known to possess antiꢀTB potential. Lee
and coꢀworkers10ꢀ16 have extensively studied nitrofuranylaꢀ
mides 2 and also generated several leads {3 (Leeꢀ562), 4 (Leeꢀ
878) and 5 (Leeꢀ1106)} as shown in Fig. 2. Despite excellent
in vitro profiles, these molecules possessed poor in vivo effiꢀ
cacy because of their low oral bioꢀavailability and aqueous
solubility, indicating that further effort is needed to utilize
these compounds effectively. Our wholeꢀcell screening proꢀ
gram resulted in the identification of nitrofuranyl methyl piꢀ
perazine 1, wherein a nitrofuranyl ring is directly attached to a
piperizine ring through a methylene instead of an amide linkꢀ
age. The high potency of these compounds, along with their
comparatively simpler structure and likeliness of increased
aqueous solubility indicated the need for further investigation.
A medicinal chemistry program was initiated on nitrofuranyl
methyl piperazine 1 using the strategy shown in Fig. 3.
To discover novel and potent antiꢀTB agents, a
wholeꢀcell screening approach was adapted and 20,000 small
drugꢀlike compounds were procured and screened.9 The aim of
this approach was to find drugꢀlike compounds in this collecꢀ
tion and then to chemically modify these compounds to imꢀ
prove their PK/PD behaviors. The library was initially
screened against sensitive (H37Rv) and rifampicin resistantꢀ
(RifR) strains of MTB at the concentration of 16 µg/ml, and
707 molecules demonstrated >90% growth inhibition. A minꢀ
imum inhibitory concentration (MIC) determination for these
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Fig 2: Nitrofuranyl containing antiꢀTB molecules
.
Fig 1: Schematic representation of wholeꢀcell screening of 20,000
molecules
Fig 3: Medicinal chemistry approach
Results and Discussion:
Scheme 1: Synthesis of identified hit 1a
Chemistry:
Initially, the potent hit 1a was prepared by the reducꢀ
tive amination of 5ꢀnitrofuraldehyde 6 with 4ꢀphenyl piperaꢀ
zine 7 (Scheme 1). Next, to ascertain the role of the nitro
group, the desꢀnitro derivative 13 was prepared using the synꢀ
thetic strategy shown in Scheme 2. The role of the furan ring
was also investigated by synthesizing analogs 14a-c, in which
the furan ring was replaced with a thiophene ring using the
same synthetic strategy. The effect of ring C was also studied,
and analogs 14d-l were synthesized with varying substituents.
Through further modification, analogs 16a-h were prepared by
replacing the phenyl ring (ring C) with alkyl/aryl sulfonyl
groups as per the synthetic strategy shown in Scheme 3. In
another modification, the piperazine ring (ring B) was reꢀ
placed with piperidine and morpholine rings using the synthetꢀ
ic scheme shown in Scheme 4.
Biological evaluation:
The synthesized analogs 1a, 13, 14a-l, 15, 16a-g and
18a-b were screened for in vitro activity against MTB H37Rv
(ATCC27294 strain) using the microbroth dilution method.
The MIC was determined as the minimum concentration of the
compound required to inhibit 90% of bacterial growth. The
MIC values of all of the synthesized compounds are summaꢀ
rized in Table 1.
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Scheme 2: Synthesis of ring A and C modified nitrofuranyl methyl piperazines
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Scheme 3: Synthesis of alkyl/aryl sulfonyl groups containing nitrofuranyl methyl piperazines
ly better MIC values of 0.0072 and 0.02 µM against H37Rv
Scheme 4: Synthesis of nitrofuranyl analogs
strain of MTB, respectively. Among the metaꢀgroups, comꢀ
pounds with methoxy group 14j and cyano group 14k demonꢀ
strated the most potent MIC values of 0.047 and 0.019 µM,
respectively (Table 1). The activity results suggested that both
the nature and position of substituents influenced activity, and
the presence of bulkier groups at the paraꢀposition and smaller
groups at the metaꢀposition led to enhanced potency.
In further modifications, the phenyl ring (ring C) was
replaced by alkyl/aryl sulfonyl groups. Compound 16a, with a
methane sulfonyl group on the piperazine ring, demonstrated
decreased activity. However, nitrofuranyl methyl piperazines
with un/substituted phenyl sulfonyl groups 16b-h showed
good to excellent activity (Table 1). Moreover, due to the
presence of a sulfonyl group between ring B and ring C, anaꢀ
logs with an even smaller group at the paraꢀposition of ring C
exhibited good activity. Overall, these results suggest that
replacement of the phenyl ring with an arylsulfonyl moiety is
acceptable. The replacement of the piperazine ring with piperꢀ
idine in compound 18a led to a MIC of 0.59 µM, but replaceꢀ
ment with morpholine in compound 18b led to a complete loss
of activity. These results indicate that the piperazine ring is
preferred over piperidine or morpholine rings. A brief sumꢀ
mary of SAR is shown in Fig. 4.
Synthesized compound 1a exhibited an MIC value of
0.2 µM against the H37Rv strain of MTB, similar to that obꢀ
served during the library screen. The removal of nitro group
destroyed the activity of the compound 13, which revealed that
the presence of the nitro group is essential. The replacement of
furan with a thiophene ring was also unfavorable, and none of
the thiophene ringꢀcontaining analogs 14a-c demonstrated any
inhibition at concentrations up to 10 µM. The results suggestꢀ
ed that the nitroꢀfuran moiety is essential for activity.
The effect of ring C and its substituents were also inꢀ
vestigated. The nature and position of the substituents greatly
influenced activity. The presence of substituents at paraꢀ and
metaꢀpositions on ring C was found to be favorable. Among
the different paraꢀgroups, compounds with bulkier groups 14f
(4-terꢀbutyl), 14 h (4ꢀmorpholinyl) demonstrated comparativeꢀ
Among all of the tested compounds, the 10 most acꢀ
tive nitrofuranyl methyl piperazine analogs with activities of
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≤0.2 µM (Table 1) were further screened against nonꢀ
Table 2: Activity against non-replicating and resistant
strains of MTB, and cytotoxicity studiesa
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replicating (streptomycin starved M. tuberculosis 18b) and
resistant (RifR & MDR) strains of MTB. The cytotoxic potenꢀ
tial of these compounds was also investigated in a HepG2 cell
line. The results are shown in Table 2. Five analogs viz., 14f,
14h, 14k, 15 and 16 g demonstrated potent MIC values against
nonꢀreplicating and resistant strains of MTB. None of the testꢀ
ed compounds were toxic in HepG2 cell lines, and all have
acceptable safety indices.
9
Table 1: In vitro activity of all synthesized compoundsa
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MIC (H37Rv)
(ꢀM)
MIC (H37Rv)
(ꢀM)
Compound
Compound
13
15
16a
>16.5
>13.1
0.004 ± 0
23.07 ± 7.9
0.17 ± 0
14a
14b
14c
14d
14e
14f
14g
14h
14i
16b
>11.8
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>11.5
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0.0072 ± 0.03
0.37 ± 0.18
0.02 ± 0
0.31 ± 0
16e
0.15 ± 0
16f
0.5 ± 0.1
0.08 ± 0
16g
Among the five tested compounds, three compounds
14f, 15 and 16g possess promising PK properties, with Cmax
values of 2352.11, 3806.90 and 3263.51 nM, respectively and
AUC0ꢀt values of 2994.63, 2709.06 and 4221.42 nM*h, respecꢀ
tively. The half lives of 14f, 15 and 16 g were calculated to be
4.04, 1.69 and 1.46 h, respectively. Compound 14h had a high
Cmax of 5342.18 and an AUC0ꢀt of 4512.72, but a comparatively
short elimination half life. Although compound 14k demonꢀ
strated good aqueous solubility, it was not detected in an in
vivo oral PK experiment. This result might be due to the posiꢀ
tion and nature of the substituents present on ring C. The presꢀ
ence of substituents at the paraꢀposition provides stability and
prevents the compound from being metabolized quickly.18 In
14k, a cyano group is present at the metaꢀposition, while in the
other four compounds (14f, 14h, 15 and 16g), substituents are
present at the paraꢀposition. Thus, compound 14k may underꢀ
go fast metabolism, preventing its detection. The PK results
obtained suggest that compounds 14f and 16g demonstrate
good in vivo exposure and half lives.
1.3 ± 0
16h
0.3 ± 0.1
0.047 ± 0
0.019 ± 0.006
25.2 ± 7.6
0.59 ± 0.2
31.4 ± 10.8
0.07 ± 0.03
18a
14j
18b
14k
14l
Rifampicin
aValues reported are the average of three individual measurements ± SD.
Table 3: Solubility and PK profiles of potent compounds
PKb
Cmax
(nM)
Solubility( M)a
Compound
AUC0-t
(nM*h)
t1/2 (h)
Tmax (h)
water PBS
SGF
SIF
Fig 4: Brief SAR of nitrofuranyl methylpiperzine series
14f
14h
14k
15
116.5 58.2
2994.63
4512.72
nd
1165.5 2.9
0.25
0.25
nd
4.04
0.88
nd
2352.11
5342.18
nd
Based on the measured activity levels against all of
the tested strains, the five most active compounds, 14f, 14h,
14k, 15 and 16g were further tested for solubility and pharmaꢀ
cokinetic activity. Previous studies have reported that nitrofuꢀ
ran based compounds suffer from poor absorption, which
might be caused by their poor aqueous solubility. We studied
the solubility of potent compounds in water and in other media
(basic and acidic), and all of the tested compounds except 14h
possess good to excellent aqueous solubility. The oral in vivo
pharmacokinetic properties of these compounds were also
studied in mice at a dose of 10 mg/kg, and the results are
summarized in Table 3 (detail given in SI).
2.68
--
--
--
256.3 256.3
1285.5 2571.1
108.3 54.1
2563.1
32
2709.06
4221.42
2571.1 2571.1
2167.6 13.5
0.25
0.25
1.69
1.46
3806.90
3263.51
16g
aSolubility data were the average of three determinations (SD values <1%). bOral dose at 10
mg/kg and the data were average of five determinations. *nd: not detected
In conclusion, we have reꢀdiscovered nitrofuranyl
methyl piperazine as a potent scaffold for compounds effective
against sensitive and resistant strains of MTB. The present
study demonstrates the promise of the nitrofuranylꢀbased class
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strains of MTB. The reported compounds have optimal PK
properties and comparatively better aqueous solubility than
other reported analogs in this class. Studies to determine the in
vivo efficacy of these compounds are currently underway.
ASSOCIATED CONTENT
Supporting Information
Full experimental details for the compounds syntheꢀ
sized, along with NMR and MS spectra and descriptions of bioꢀ
logical assays, are provided. This material is available free of
charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
Tel.: +91ꢀ191ꢀ2569111, Fax: +91ꢀ191ꢀ2569333; Eꢀmail:
ppsingh@iiim.res.in, ram@iiim.res.in and iakhan@iiim.res.in
Author Contributions
⊥
KRY, GM and S Singh have equally contributed to
this work. KR and GM performed the chemical syntheses. SS, SK
and VSR performed biological screening. AM, MT and GDS
performed in vivo PK. SSB performed the solubility study. PPS,
IAK and RAV participated in the design and execution of this
study.
Funding Sources
This work was supported by the Council of Scientific
and Industrial Research (CSIR)ꢀNew Delhi with research grant #
HCP 0001. This work is assigned the IIIM Publicaꢀ
tion No: IIIM/1761/2015.
ACKNOWLEDGMENTS
KRY, GM, S Singh, AM, and VSR thank CSIR, and SK
thanks UGC for a fellowship.
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Nitrofuranyl Methyl Piperazines as New Anti-TB agents: Identifica-
tion, Validation, Medicinal Chemistry and PK Studies
Kushalava Reddy Yempalla,1,5,⊥ Gurunadham Munagala,1,5,⊥ Samsher Singh,2,5,⊥ Asmita Maꢀ
gotra,3,5 Sunil Kumar,2,5 Vikrant Singh Rajput,2,5 Sonali S. Bharate,4 Manoj Tikoo,3 G. D.
Singh,3 Inshad Ali Khan,2,5,* Ram A. Vishwakarma1,5,* and Parvinder Pal Singh1,5,*
6
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