Synthesis, 3D-QSAR analysis and biological evaluation of quinoxaline 1,4-di-N-oxide derivatives as antituberculosis agents

Article abstract of DOI:10.1016/j.bmcl.2016.01.066

A series of quinoxaline 1,4-di-N-oxide derivatives variously substituted at C-2 position were synthesized and evaluated for in vitro antimycobacterial activity. Seventeen compounds exhibited potential activity (MIC ?6.25?μg/mL) against Mycobacterium tuber

Full text of DOI:10.1016/j.bmcl.2016.01.066

Accepted Manuscript
Synthesis, 3D-QSAR analysis and biological evaluation of Quinoxaline 1,4-di-
N-oxide derivatives as antituberculosis agents
Yuanhu Pan, Panpan Li, Shuyu Xie, Yanfei Tao, Dongmei Chen, Menghong
Dai, Haihong Hao, Lingli Huang, Yulian Wang, Liye Wang, Zhenli Liu,
Zonghui Yuan
PII:
S0960-894X(16)30065-8
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.01.066
BMCL 23531
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 September 2015
11 January 2016
22 January 2016
Please cite this article as: Pan, Y., Li, P., Xie, S., Tao, Y., Chen, D., Dai, M., Hao, H., Huang, L., Wang, Y., Wang,
L., Liu, Z., Yuan, Z., Synthesis, 3D-QSAR analysis and biological evaluation of Quinoxaline 1,4-di-N-oxide
derivatives as antituberculosis agents, Bioorganic & Medicinal Chemistry Letters (2016), doi: http://dx.doi.org/
10.1016/j.bmcl.2016.01.066
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Synthesis, 3D-QSAR analysis and biological evaluation of
Quinoxaline 1,4-di-N-oxide derivatives as antituberculosis agents
Yuanhu Pan a, Panpan Li a, Shuyu Xie a, Yanfei Tao a, Dongmei Chen a, Menghong
Dai b, Haihong Hao b, Lingli Huang b, Yulian Wang b, Liye Wang a, Zhenli Liu b,
Zonghui Yuan a, b,
*
a National Reference Laboratory of Veterinary Drug Residues (HZAU) and MOA Key
Laboratory for the Detection of Veterinary Drug Residues, b MOA Laboratory for
Assessment of Quality and Safety of Livestock and Pourtry Products, Huazhong
Agricultural University, Wuhan, Hubei 430070,China
*Correspondence to Dr. Zonghui Yuan, Tel.: 0086-27-87287186; Fax:
0086-27-87672232, E-mail address: yuan5802@mail.hzau.edu.cn
1

Abstract
A series of quinoxaline 1,4-di-N-oxide derivatives variously substituted at C-2
position were synthesized and evaluated for in vitro antimycobacterial activity.
Seventeen compounds exhibited potential activity (MIC ≤ 6.25 μg/mL) against
Mycobacterium tuberculosis (H37Rv), in particular the compounds 3d and 3j having
an MIC value of 0.39 μg/mL. None of the compounds exhibited cytotoxicity when
using an MTT assay in VERO cells.
CoMFA (q2 = 0.507, r2 = 0.923) and CoMSIA (q2 =0.665, r2 = 0.977)
models
antimycobacterial activity
The
3D-QSAR study of these compounds can provide useful information for further
rational design of novel quinoxaline 1,4-di-N-oxides for treatment of tuberculosis.
Key words: Quinoxaline 1,4-di-N-oxide;Tuberculosis;Antimycobacterial activity;
3D-QSAR;CoMFA;CoMSIA
2

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major
global health problem and ranks as the second leading cause of death from an
infectious disease worldwide. According to the latest report of World Health
Organization (WHO), there were 9.0 million new TB cases in 2013 and 1.5 million
TB deaths.1 The standard treatment for TB is generally comprised of several effective
anti-TB drugs such as isoniazid, rifampicin, ethambutol, and pyrazinamide.2,3
However, the emergence of new Mtb strains as like multi drug resistant (MDR) and
extensively drug resistant (XDR) TB severely threatens tuberculosis control.4,5 So it
becomes necessary to discover newer anti-TB agents which can target a novel
pathway so as to be effective against Mtb-resistant strains.6-8
Quinoxaline-1,4-di-N-oxide derivatives have attracted continuing interest over the
years because of their varied biological activities, including antibacterial, antiviral,
antifungal, antiprotozoal, 9-12 anticancer and hypoxia-selective properties. 13-18
Recently, a wide range of quinoxaline-1,4-di-N-oxide derivatives with variable
substituents at different positions and their anti-TB activities have been reported and
many of these compounds possess excellent anti-TB activity.19–27
the antimycobacterial activity of the synthesized compounds
significantly depends on the presence of the two N-oxide groups. The presence of
electronegative group such as chlorine or fluorine atom as well as trifluoromethyl
group at C-6 or C-7 posotion on the quinoxaline ring was
antimycobacterial activity against Mtb H 37Rv.11,21 In addition,
quinoxaline-1,4-di-N-oxide derivatives with different C-2 substituents displayed
distinct antimycobacterial activity suggested that C-2 position substituent play a
crucial role in their antimycobacterial activities. For example, a series of
quinoxaline-1,4-di-N-oxide derivatives bearing ester groups at C-2 position exhibited
3

significant antimycobacterial activity (MIC 0.10 – 6.25 μg/ml), 22 while the analogs
with amide groups at C-2 position exhibited weak activities.24
O
N
O
N
O
N
O
O
O
N
O
Br
v, vi
S
ii
NH2
i
O
N
O
2
N
N
N
O
O
3
BFO
1
iv
vii
iii
O
O
O
O
N
O
O
R
S
N
N
R
N
R
H
N
N
N
O
O
O
4a~4l
3a~3j
2a~2j
2a, R= -N(CH2CH3)2
3a, R= -S-(CH2)2-OH
3b, R= -S-(C6H5)
3c, R= -S-(4'-Me-C6H5)
3d, R= -S-(4'-F-C6H5)
3e, R= -S-(4'-OMe-C6H5)
3f, R= 2'-S-benzoxazole
3g, R= 2'-S-benzimidazole
3h, R= 2' -S-benzothiazole
3i, R= 2'-S-thiazole
4a, R = acetyl
4b, R = benzoyl
4c, R = 4'-F-benzoyl
4d, R = 4'-methoxyl-benzoyl
4e, R = 3',4',5'-trimethoxyl-benzoyl
4f, R = cyclohexanecarbonyl
4g, R = isonicotinoyl
4h, R = thenoyl
4i, R = naphthoyl
4j, R = L-valyl
4k, R = L-tyrosyl
4l, R = L-tryptophanyl
2b, R= -N(CH3)(C6H5)
2c, R= -N(CH3)(4'-Me-C6H5)
2d, R= -N(CH3)(4'-F-C6H5)
2e, R= -N(CH3)(-CH2-C6H5)
2f, R= -Piperidyl
2g, R= -N(CH3)(C6H11
2h, R= 4'-methyl-1'-piperazinyl
2i, R= 2'-NH-thiazole
)
2j, R= 2'-NH-benzimidazole
3j, R= 3'-S-(1'H)-1',2',4'-triazole
Scheme 1. Reagents and conditions: (i) Acetylacetone , CH2Cl2, TEA, 25 oC, 12 h, 80%; (ii) Br2,
glacial acetic acid, 60 oC, 8 h, 62%; (iii) RNH-, EtOAc, TEA, 25 oC, 1 h, 65-82%; (iv) R-SH,
DMF, 25 oC, 1 h, 82-92%; (v) N-(Boc)-2-aminoethanethiol, DMF, TEA, 25 oC, 1h, 90%; (vi) HCl,
EtOAc, 4h, 84%; (vii) 4a~4i: RCOCl, CH2Cl2, 0~25 oC, 1h, 80-92%; 4j~4l: a: N-(Boc)-amino
acid, DCC/ NHS, DMAP, CH2Cl2, 25 oC, 12 h, 70%; b: TFA, EtOAc, 4h, 80%.
In this study, aim to optimization of the structure at C-2 position of the quinoxaline
ring, a series of new Quinoxaline 1,4-di-N-oxide derivatives were synthesized and
subjected to preliminary screening for their anti-TB activity against Mtb H37Rv strain
in order to discover potential anti-TB agents. Scheme 1 depicts the synthetic route of
new quinoxaline-1,4-di-N-oxide derivatives. Compound 1 was synthesized by treating
4

benzofuroxane with acetyl acetone as previously described.21 Bromination of 1 with
bromine in glacial acetic acid to yield the key intermidiates compound 2,
2-bromoacetyl-3-methylquinoxaline-1,4-di-N-oxide. Then compounds 2a~2j were
obtained by the nucleophilic substitution reaction of 2 and the corresponding amino
derivatives. Similarly, various mercapto compounds were allowed to react with the
intermediate 2 in DMF to give compounds 3b~3j with excellent yields ranged from
82% to 92 %. For the synthesis of compoumds 4a~4l, the intermediate 2 was
converted into 3 by reaction with N-(Boc)-2-aminoethanethiol and deprotection of
Boc group with hydrochloric acid in ethyl acetate. After that, 4a~4i were obtained by
reacting 3 with various acyl chloride in dichloromethane. 4j~4l were synthesized via
two steps including coupling of 3 with different N-protected amino acids by using
dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) and then
deprotetion of Boc group with trifluoroactic acid in ethyl acetate. All the compounds
were chemically characterized by LC-MS, melting point, infrared (IR) and nuclear
magnetic resonance (1H-NMR) spectra, as well as element analysis.
The newly synthesized quinoxaline-1,4-di-N-oxide derivatives were evaluated for
their antimycobacterial activity against Mtb H37Rv strain using the Microplate
Alamar Blue Assay (MABA) with isoniazid as the positive control. The theoretical
lipophilicity (ClogP) of the compounds were calculated by SYBYL-X 2.0 (Tripos,
inc.) and compared with their anti-TB activity as shown in Table 1. Compounds
2a-2j , bearing amino substituents at C-2 position showed little antimycobacterial
activity (MIC > 6.25 μg/mL) against Mtb H37Rv strain except 2d, which exhibited an
MIC value of 6.25 μg/mL. Aliphatic amines attached at C-2 side chain were less
active than aromatic amines substituents, such as 2a, 2e, 2g and 2h, exhibited no
activity (MIC = 50 μg/mL). Compounds 3b-3j displayed promising antimycobacterial
5

activity (MIC ≤ 6.25 μg/mL) against Mtb H37Rv, among then componds 3d and 3j
exhibited most potent anti-TB activity (MIC = 0.39 μg/mL). It seemed that thioether
substituents of 3b-3h are responsible for their higher lipophilicity and significantly
enhance their antimycobacterial activities. When an amino or hydroxyethyl group was
attached to sulfur, such as compound 3 and 3a (ClogP = -1.84 and -1.90), the
antimycobacterial activity was strongly reduced (MIC > 50 μg/mL). It was worth
noting that compounds 3i and 3j also exhibited good anti-TB potency, whereas they
have a lower lipophilicity (ClogP < 0). This result indicated that the steric and
electrostatic effect, as well as hydrogen bond of the side chain at C2 position may also
play an important role in its antimycobacterial activity. Compounds 4a-4l which also
contain a thioether group at C-2 position but have a longer alkyl chain than 3a-3j
exhibited moderate antimycobacterial activity. Compound 4c, containing
4-fluorobenzamide moiety, exhibited MIC value of 1.56 μg/mL. It seemed that
4-fluorophenyl substituents of 2d, 3d and 4c were favourable for their
antimycobacterial activity, which may due to the increased lipophilicity and enhanced
permeability into cell membrane. When amino acid was introduced into the C-2 side
chian, the antimycobacterial activity was impaired. For example, compounds 4j-4l,
containing L-valyl, L-tyrosyl and L-tryptophanyl moiety, exhibited MIC of 25, 25 and
6.25 μg/mL respectively.
Table 1 Chemical structure, ClogP, in vitro antituberculosis activity, cytotoxicity and
SI of compounds 2a-2j, 3a-3j, 3 and 4a-4l against M. tuberculosis H37Rv strain.
O
O
O
O
R
R
N
S
N
N
H
N
N
O
O
2a-2j; 3; 3a-3j
4a-4l
c
MIC b
(μg/mL)
CC50
(μg/mL)
SI d
(CC50/MIC)
Compd.
R
ClogP a
6

-0.35
0.48
50
25
-
-
-
-
2a
2b
N
N
N
0.98
25
-
-
2c
2d
2e
2f
N
F
0.80
6.25
50
> 100
> 16
N
0.43
-
-
-
-
-
-
-
-
N
-0.10
-0.63
-2.19
-0.94
25
N
50
2g
2h
2i
N
N
50
S
N
N
50
-
-
H
H
N
HN
0.18
12.5
-
2j
N
OH
-1.90
0.77
50
-
-
3a
3b
S
S
1.56
50
32
S
S
S
1.27
0.97
0.72
0.78
0.39
0.78
50
50
50
64
3c
3d
3e
F
128
64
OCH3
O
N
S
1.33
0.77
3.13
6.25
50
16
16
3f
H
N
S
S
S
S
100
3g
N
S
1.30
1.56
3.13
0.39
50
50
50
32
3h
3i
N
S
-0.29
-1.05
16
N
N
NH
128
3j
N
NH2
-1.84
-1.95
50
50
-
-
-
-
3
S
4a
O
-0.24
6.25
> 100
> 16
4b
O
7

F
0.10
1.56
3.13
> 100
> 100
> 128
> 32
4c
O
OCH3
-0.04
4d
O
OCH3
OCH3
OCH3
-0.76
0.08
25
-
-
-
-
4e
4f
O
O
12.5
N
-1.00
-0.41
0.93
6.25
6.25
6.25
50
64
4g
4h
4i
O
S
> 100
> 100
> 16
> 16
O
O
O
-1.24
-1.42
25
25
-
-
-
-
4j
NH2
O
4k
NH2
OH
O
-0.76
6.25
0.2
> 100
> 16
4l
NH2
N
H
Isoniazide
a calculated by SYBYL-X 2.0 (Tripos, inc.)
b Actual minimum inhibitory concentration (MABA assay).
c Measurement of cytotoxicity in VERO cells.
d Selectivity index.
(-): Not tested.
The compounds which exhibited promising antimycobacterial activity against Mtb
H37Rv (MIC ≤ 6.25 μg/mL) were tested for in vitro cytotoxicity by MTT
(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay against VERO
cell line. The IC50 and the selectivity index (SI =/CC50/MIC) was calculated and list in
8

Table 1. The compounds showed less toxicity against VERO cells (SI > 10).
In order to better understand the structure activity relationship, CoMFA and CoMSIA
models were establishedbased on the antimycobacterial activity data of the newly
synthesized quinoxaline-1,4-di-N-oxide derivatives. In this study, the MIC values
were converted to pMIC values according to the following formula:
pMIC = - lg(MIC×10-3) / (molecular weight)
pMIC values were used as dependent variables in the CoMFA and CoMSIA analysis.
Table 2 PLS statistics of CoMFA and CoMSIA 3D-QSAR models
Statistical parameters
CoMFA
CoMSIA
0.665
6
q2 a
ONC b
r2 c
0.507
4
0.923
0.977
0.117
164.021
SE d
0.201
e
Fratio
74.466
Field Contribution (%)
Steric
0.523
0.114
0.230
0.272
0.146
0.239
Electrostatic
Hydrophobic
H-bond donor
H-bond acceptor
0.477
-
-
-
a Cross-validated correlation coefficient after the leave-one-out procedure.
b Optimum number of components.
c Non-cross-validated correlation coefficient.
d Standard error of estimate.
e F-test value.
All the molecular modeling calculations were performed using SYBYL-X2.0 installed
on DELL GPCJ4X1 workstation running under the Windows XP. Energy
minimizations were performed using the Tripos force field with the Powell conjugate
gradient minimization algorithm and a convergence criterion of 0.05 kcal/ mol*Å.
9

Charges were calculated by the Gasteiger-hücker method in the software. Alignment
of molecules was performed using 2-carbonyl-quinoxaline-1,4-di-N-oxide nucleus as
a template, and compound 3d, one of the most active molecules, was chosen as the
template molecule and all the other molecules were aligned to it using the database
alignment method in SYBYL (Fig. 1).
Fig. 1. Alignment
molecules
The PLS statistic results of CoMFA and CoMSIA models were summarized in
Table 2. For CoMFA model, the q2 and r2 was 0.507 and 0.923, while for CoMSIA
model was 0.665 and 0.977. The standard errors of estimate of CoMFA and CoMSIA
models were also reasonably low amounting to 0.201 and 0.117. Fisher test results
were 74.466 and 164.021 for CoMFA and CoMSIA models, respectively. The
contributions of steric, electrostatic fields in CoMFA model were 52.3% and 47.7%,
while the contributions of steric, electrostatic, hydrophobic, hydrogen bond donor and
acceptor fields of CoMSIA model were 11.4%, 23.0%, 27.2%, 14.6%, and 23.9%,
respectively. The predicted versus the experiment pIC50 values are listed in Table 3
and are depicted graphically in Fig. 2. It seemed that the CoMSIA 3D-QSAR model
10

performed better than the CoMFA model for less residues between the predicated and
experimental pMIC values were found.
6.5
CoMFA Model
R2 = 0.9224
6
5.5
5
4.5
4
3.5
3.5
4
4.5
5
5.5
6
6.5
Experimental pMIC
6.5
6
CoMSIA Model
R2 = 0.977
5.5
5
4.5
4
3.5
3.5
4
4.5
5
5.5
6
6.5
Experimental pMIC
Fig. 2. Graphs of predicted versus experimental pMIC of the 33 molecules for
CoMFA and for CoMSIA 3D QSAR models.
11

Table 3 Experimental and predicted antituberculosis activities against M. tuberculosis
H37Rv strain (pMIC) of the compounds for CoMFA and CoMSIA models.
Comp.
no.
MIC pMIC exp
CoMFA
CoMSIA
pMIC pred. Residual
pMIC pred. Residual
2a
50
25
3.76
4.11
4.12
4.73
3.82
4.08
3.81
3.80
3.80
4.45
3.77
3.77
5.32
5.64
5.95
5.66
5.07
4.77
5.39
5.03
5.91
4.73
4.80
5.73
5.44
4.29
4.51
4.80
4.81
4.85
4.20
4.26
4.88
3.854
4.271
4.183
4.495
3.759
3.986
4.105
3.777
3.876
4.439
4.296
3.680
5.477
5.540
5.827
6.060
5.189
4.977
5.285
4.951
5.698
4.485
4.683
5.445
5.394
4.137
4.651
4.783
4.602
4.844
4.494
4.419
4.746
-0.094
-0.161
-0.063
0.235
0.061
0.094
-0.295
0.023
-0.076
0.011
-0.526
0.090
-0.157
0.100
0.123
-0.400
-0.119
-0.207
0.105
0.079
0.212
0.245
0.117
0.285
0.046
0.153
-0.141
0.017
0.208
0.006
-0.294
-0.159
0.134
3.906
4.178
4.094
4.404
3.814
4.145
4.057
3.688
3.822
4.452
3.774
3.896
5.572
5.654
5.752
5.711
5.054
4.666
5.191
5.071
5.852
4.758
4.675
5.753
5.484
4.311
4.531
4.829
4.753
4.862
4.213
4.328
4.926
-0.146
-0.068
0.026
2b
2c
2d
2e
2f
25
6.25
50
0.326
0.006
25
-0.065
-0.247
0.112
2g
2h
2i
50
50
50
-0.022
-0.002
-0.004
-0.126
-0.252
-0.014
0.198
2j
12.5
50
3
3a
3b
3c
3d
3e
3f
50
1.56
0.78
0.39
0.78
3.13
6.25
1.56
3.13
0.39
50
-0.051
0.016
3g
3h
3i
0.104
0.199
-0.041
0.058
3j
4a
4b
4c
4d
4e
4f
-0.028
0.125
6.25
1.56
3.13
25
-0.023
-0.044
-0.021
-0.021
-0.029
0.057
12.5
6.25
6.25
6.25
25
4g
4h
4i
-0.012
-0.013
-0.068
-0.046
4j
4k
4l
25
6.25
The CoMFA contour map of steric field is shown in Fig. 3. One big green contour
was observed near the terminal of the side chain on C-2 position of the quinoxaline,
12

which indicated a favorable sterically bulky group at this region. Conversely, the
sterically unfavorable regions indicated by yellow contours were spotted in front of
the quinoxaline plane, which may explain why compounds 4e, 4i and 4j were less
potent than others. In CoMFA contour map of the electrostatic field in Fig. 4, several
small red contours were found around the methyl group at C3 position and the
aromatic ring substituent of the side chain. This can explain the fact that the
compounds with methyl group at C-3 together with a phenyl ring like 3b-3e, or with a
heteroaromatic ring like 3f and 3h-3j were more active than others, while in
compound 3g the substituent aromatic ring was far away from the red contour and
hence is less active. Furthermore, compound 2d, in which a fluorine atom attached on
p-position of benzene ring, was the most potent one in series 2, and same fact was
found on 3d and 4c. On the other hand, a big blue contour was found cover across the
region between quinoxaline and the substituent aromatic ring which may explain the
fact that when thioether linkage in componnd 3d was replaced by methylamino group
(2d), the activity decreased dramatically.
Fig. 3. CoMFA Steric contour around the compound 3d: green contour favours steric
or bulky group and yellow contour denotes disfavored region.
13

Fig. 4. CoMFA electrostatic contour around the compound 3d: blue contour indicates
electropositive charge and red contour electronegative charge.
Fig. 5. CoMSIA steric contour maps based on compound 3d: green contour favours
steric or bulky group and yellow contour denotes disfavored region.
Fig. 6. CoMSIA electrostatic contour maps based on compound 3d: blue contour
indicates electropositive charge and red contour electronegative charge.
14

The CoMSIA steric (Fig. 5) and electrostatic contours (Fig. 6) are similar to those
of CoMFA. The hydrophobic contour map of CoMSIA model was displayed in Fig. 7.
A yellow contour was found between the quinoxaline ring and the white contour, and
the thioether linkage to aromatic ring was buried in yellow contour. This explained
why compounds 3b-3i with a thioether moiety have higher potency than compounds
2a-2j with a amino groups, and why compounds 3 and 3a, which contain a
hydrophilic substitution of amino and hydroxy group respectively, have no activity.
A big white contour around the aromatic ring of the side-chain indicated that
hydrophilic property of this substituent was beneficial to the activity. This is in
agreement with the fact that compounds 4b-4d, 4g and 4h which contain an amide
group attached to aromatic heterocycle could also exhibit moderate activity.
Fig. 7. CoMSIA hydrophobic contour maps based on compound 3d: yellow contours
represent regions where hydrophobic groups increase activity, while white contours
highlight regions that would favour hydrophilic groups.
15

Fig. 8. CoMSIA hydrogen bond donor and acceptor contour maps based on
compound 3d: cyan and purple contours represent favorable and unfavorable
hydrogen bond donor regions, respectively; magenta and red contours represent
favorable and unfavorable hydrogen bond acceptor regions, respectively.
In the hydrogen bond donor and acceptor contour maps of CoMSIA model (Fig. 8),
two cyan contours were observed near the N-O group at C-4 position and aromatic
side chain suggested that hydrogen bond donor would be favored there. However, one
purple contour found close to the C1’ position of the aromatic ring of the side chain
may explain the fact that when amino acid were introduced into the side chain (4i, 4j
and 4k), the analogs exhibited less activity. One big magenta contour located between
the methyl group at C3 and the aromatic ring of the side chain, which indicated that
the oxygen of the carbonyl group at C2 lay near to the red contour and hence, these
analogs exhibited good anti-TB activity. Conversely, the unfavorable red contour
around the C2 and the methylene group indicated that when the oxygen of the
carbonyl group directed toward this direction the anti-TB activity was decreased.
In summery, thirty-three quinoxaline-1,4-di-N-oxide derivatives bearing flexible
substituted groups at C2-position have been synthesized and screened for their in vitro
antimicrobial activity. Seventeen of them exhibited promising in vitro
16

antimycobacterial activities when tested against Mtb H37Rv (MIC ≤ 6.25 μg/mL), and
displayed no cytotoxicity against VERO cells when tested using an MTT assay. The
CoMFA and CoMSIA models revealed that variations in substitutions at C-2 position
could have a significant impact on the activity, especially compounds bearing a
thioether linkage side chain and a sterically bulky aromatic group at the terminal of
the side chain at C-2 position of quinoxaline ring was essential for the anti-TB activity.
The 3D-QSAR studies can provide useful information for the further rational design
of novel quinoxaline 1,4-di-N-oxides for treatment of tuberculosis.
Acknowledgement
This work was supported by grants from the National High Technology Research and
Development Program of China (grant number 2011AA10A214) and the Special
Fund for Agro-scientific Research in the Public Interest (201203040).
Supplementary data
Supplementary data (biological assay, experimental procedure and copies of the 1H
and 13C NMR spectra for some of the important compounds) associated with this
article can be found.
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Graphical abstract
Design, synthesis and 3D-QSAR analysis of Quinoxaline 1,4-di-N-oxide
derivatives as antituberculosis agents
Yuanhu Pan a, Panpan Li a, Shuyu Xie a, Yanfei Tao a, Dongmei Chen a, Menghong Dai b,
Haihong Haob, Lingli Huang b, Yulian Wang b, Liye Wang a, Zhenli Liu b, Zonghui Yuan a, b
National Reference Laboratory of Veterinary Drug Residues (HZAU) and MOA Key Laboratory
b
for the Detection of Veterinary Drug Residues, MOA Laboratory for Assessment of Quality and
Safety of Livestock and Pourtry Products, Huazhong Agricultural University, Wuhan, Hubei
430070,China
O
O
O
O
S
N
N
R
R
CoMFA and CoSIA
N
N
O
O
3d: R= 4-FBn
screen for in vitro antimycobacterial activity
3j: R= 1H-1,2,4-triazole-3-yl
MIC = 0.39 μg/mL
against M. tuberculosis H37Rv
20