Synthesis and SAR study of simple aryl oximes and nitrofuranyl derivatives with potent activity against Mycobacterium tuberculosis

Article abstract of DOI:10.2174/1570180816666181227115738

Background: Oximes and nitrofuranyl derivatives are particularly important compounds in medicinal chemistry. Thus, many researchers have been reported to possess antibacterial, antiparasitic, insecticidal and fungicidal activities. Methods: In this work, we report the synthesis and the biological activity against Mycobacterium tuberculosis H₃₇RV of a series of fifty aryl oximes, ArCH=N-OH, I, and eight nitrofuranyl compounds, 2-nitrofuranyl-X, II. Results: Among the oximes, I: Ar = 2-OH-4-OH, 42, and I: Ar = 5-nitrofuranyl, 46, possessed the best activity at 3.74 and 32.0 μM, respectively. Also, 46, the nitrofuran compounds, II; X = MeO, 55, and II: X = NHCH₂Ph, 58, (14.6 and 12.6 μM, respectively), exhibited excellent biological activities and were non-cytotoxic. Conclusion: The compound 55 showed a selectivity index of 9.85. Further antibacterial tests were performed with compound 55 which was inactive against Enterococcus faecalis, Klebisiella pneumonae, Pseudomonas aeruginosa, Staphylococcus aureus, Salmonella typhymurium and Shigel-la flexneri. This study adds important information to the rational design of new lead anti-TB drugs. Structure-activity Relationship (SAR) is reported.

Full text of DOI:10.2174/1570180816666181227115738

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Letters in Drug Design & Discovery, 2020, 17, 12-20
RESEARCH ARTICLE
ISSN: 1570-1808
eISSN: 1875-628X
Synthesis and SAR Study of Simple Aryl Oximes and Nitrofuranyl
Derivatives with Potent Activity Against Mycobacterium tuberculosis
Impact
Factor:
0.953
Cristiane França da Costa1,2, Marcus Vinicius Nora de Souza1,*, Maria Cristina da Silva Lourenço3,
Elaine Soares Coimbra4, Guilherme da Silva Lourenço Carvalho3, James Wardell1,5, Stephane Lima
Calixto4 and Juliana da Trindade Granato4
1Instituto de Tecnologia em Fármacos Farmanguinhos, FIOCRUZ Fundação Oswaldo Cruz, Rio de Janeiro, Brazil;
3
2Centro de Desenvolvimento Tecnológico em Saúde-CDTS, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil; Instituto
de Pesquisas Clínicas Evandro Chagas, Departament of Bacteriology, FIOCRUZ Fundação Oswaldo Cruz, Rio de Ja-
4
neiro, Brazil; Instituto de Ciências Biológicas, Universidade Federal de Juiz de Fora, Juiz de Fora-MG, Brazil;
5CHEMSOL, 1 Harcourt Road, Aberdeen, AB15 5NY, Scotland, UK
Abstract: Background: Oximes and nitrofuranyl derivatives are particularly important compounds
in medicinal chemistry. Thus, many researchers have been reported to possess antibacterial,
antiparasitic, insecticidal and fungicidal activities.
Methods: In this work, we report the synthesis and the biological activity against Mycobacterium
tuberculosis H37RV of a series of fifty aryl oximes, ArCH=N-OH, I, and eight nitrofuranyl com-
pounds, 2-nitrofuranyl-X, II.
A R T I C L E H I S T O R Y
Received: August 21, 2018
Results: Among the oximes, I: Ar = 2-OH-4-OH, 42, and I: Ar = 5-nitrofuranyl, 46, possessed the
Revised: November 15, 2018
best activity at 3.74 and 32.0 µM, respectively. Also, 46, the nitrofuran compounds, II; X = MeO,
Accepted: December 12, 2018
55, and II: X = NHCH2Ph, 58, (14.6 and 12.6 µM, respectively), exhibited excellent biological activ-
ities and were non-cytotoxic.
DOI:
10.2174/1570180816666181227115738
ꢀ
Conclusion: The compound 55 showed a selectivity index of 9.85. Further antibacterial tests were
performed with compound 55 which was inactive against Enterococcus faecalis, Klebisiella
pneumonae, Pseudomonas aeruginosa, Staphylococcus aureus, Salmonella typhymurium and Shigel-
la flexneri. This study adds important information to the rational design of new lead anti-TB drugs.
Structure-activity Relationship (SAR) is reported.
Keywords: Tuberculosis, aryl oximes, nitrofuranyl derivatives, Mycobacterium tuberculosis, cytotoxicity, Staphylococcus aureus.
1. INTRODUCTION
The first line of treatment adopted by the WHO consists
of a combination of four drugs, including isoniazid and pyra-
zinamide, both having simple structures (Fig. 1) [2].
(TB), caused by Mycobacterium tuberculosis, is a seri-
ous infectious disease that mainly affects the lungs (pulmo-
nary TB), which is responsible for more than 75 percent of
cases, but it may also affect different parts of the body, such
as the brain, stomach, bones, skin, intestine, liver, kidneys,
spinal cord and breasts. The TB persists as a major global
public health problem, with recent reports estimating approx-
imately 10 million new cases and 2 million deaths annually
[1, 2]. Currently, about a third of the world’s population is
infected with Mycobacterium, so its control and prevention
represent a major challenge [3, 4].
ꢀ
Fig. (1). First line drugs used to treat tuberculosis.
*Address correspondence to this author at the Department of Drugs Synthe-
sis, Farmanguinhos-Fiocruz, Sizenando Nabuco 100, Manguinhos, 21041-
250, Rio de Janeiro, Brazil; Tel/Fax: (+55) 213977-2404;
E-mail: mvndesouza@gmail.com
The HIV-TB co-infection and the increase of multidrug-
resistant bacteria, arising from the indiscriminate use of anti-
biotics, contribute to the increased number of new cases of
1875-628X/20 $65.00+.00
©2020 Bentham Science Publishers

Synthesis and SAR Study of Simple Aryl Oximes and Nitrofuranyl Derivatives
Letters in Drug Design & Discovery, 2020, Vol. 17, No. 1 13
TB [5-7]. For the first time in nearly 50 years, two new com-
pounds bedaquiline and delamanid have been approved for
the treatment of MDR-TB. These compounds are indicated
for use when an effective treatment regimen is not otherwise
available [8]. Thus, it is urgent to develop new, potent, less
toxic and cheaper drugs, with new mechanisms of action [9].
tained in a 77% yield from 5-nitrofuran-2-carboxylic acid,
54, and methanol in the presence of H2SO4 under reflux for 5
h, followed by extraction with ethyl acetate/water [21].
Compounds, 57 and 58, were prepared from 5-nitrofuran-2-
carbonyl chloride with propylamine and phenylamine, re-
spectively, were purified by recrystallization in methanol and
were obtained in 55 and 67% yields, respectively (Scheme 1)
[22]. Compounds, 52-54 and 56, were commercial samples
obtained from Sigma-Aldrich (Supplementary Material).
Oximes and nitrofuranyl derivatives are particularly im-
portant compounds in medicinal chemistry [10, 11]. Various
oximes and nitrofuran have been reported to possess antibac-
terial, antiparasitic, insecticidal and fungicidal activities
[12-14]. With this in mind, we initiated a study of the an-
titubercular activity of a number of oximes and nitrofuranyl
derivatives, and as we now report we have found significant
activity. As are isoniazide and pyrazinamide, important in
TB treatment, these compounds are very simple compounds,
but no testing has been previously reported in the literature
against Mycobacterium tuberculosis. A Structure-Activity
Relationship (SAR) is reported.
2.3. In Vitro Evaluation
The antimycobacterial activities of compounds 1-58 have
been assessed against M. tuberculosis ATTC 27294 using
the Micro plate Alamar Blue Assay (MABA) [23]. This
methodology is nontoxic, uses a thermally-stable reagent and
shows good correlation with proportional and BACTEC ra-
diometric methods [24, 25]. The method is described as fol-
lows: 200 mL of sterile deionized water was added to all
outer-perimeter wells of 96 sterile well plates (falcon, 3072:
Becton Dickinson, Lincoln Park, NJ) to minimize evapora-
tion of the medium in the test wells during incubation. The
96 plates received 100mL of the Middlebrook 7H9 broth
(Difco Laboratories, Detroit, MI, USA) and successive dilu-
tion of the compounds 1-58 was made directly on the plate.
The final drug concentrations tested were 0.01 to
100.0μg/mL. Plates were covered and sealed with parafilm
and incubated at 37oC for five days. 25 mL of a freshly pre-
pared 1:1 mixture of Alamar Blue (Accumed International,
Westlake Ohio) reagent and 10% tween 80 was then added
to the plate and incubated for 24 h. A blue color in the well
was interpreted as no bacterial growth, and a pink color was
scored as growth [4, 5]. The Minimal Inhibition Concentra-
tion (MIC) was defined as the lowest drug concentration,
which prevented a color change from blue to pink. MIC val-
ues represent means of three separate experiments and the
variation coefficient of the method is 9.8 %.
2. EXPERIMENTAL
2.1. General Procedures
The majority of the compounds used in this study have
been previously reported, but all were fully characterized in
this study by mass spectrometry, 1H and 13C NMR spectroscopy
and melting point: where appropriate, our data were compared
with those in the literature. NMR spectra were obtained using a
Bruker Avance spectrometer operating at 400 or 500 MHz (1H)
and 100 or 125 MHz (13C) [15-19]. Mass spectra (ESI) were
obtained on a ZQ electrospray spectrometer simple quadrupole.
Melting points were determined on an MQAPF-301 digital
melting point Microquimica. Apparatus [3].
2.4. Cytotoxicity in Mammalian Cells
Murine peritoneal macrophages were used for this assay and
the viability of cells was determined by the colorimetric 3-(4, 5-
dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT -
Sigma Chemical Co., St. Louis, MO, USA) method [26].
Peritoneal macrophages were obtained from BALB/c
mice previously inoculated with 3% thioglycollate medium
(Sigma Chemical Co., St. Louis, MO, USA). The macro-
phages were used for the cytotoxicity assay in a concentra-
tion of 2x106 cells/mL (2x105cells/well) in 96-well culture
plates in RPMI 1640 medium supplemented with 10% inac-
tivated fetal bovine serum, at 33ºC and 5% CO2 atmosphere.
After 24 hours, the adherent macrophages were incubated
with several concentrations of the compounds (0.15-150.0
µM), for 72 hours at 37°C in 5% CO2. Then, the cells were
incubated with 10 µL of a 5 mg/ml solution of MTT for two
hours at 37°C in 5% CO2. The reaction was stopped by add-
ing 100 µL of acid isopropanol and the absorbance was
measured at 570 nm (Multiskan MS microplate reader, Lab-
Systems Oy, Helsink, Finland). The 50% cytotoxic concen-
tration (CC50) was defined as the compound concentration
required to reduce cell viability by 50%. The CC50 values
were obtained from three independent experiments per-
formed in duplicate using Probit version 5.0 software.
Scheme (1). a) NH2OH.HCl, K2CO3, H2O, reflux, 1-2 hs;
b) CH3OH, H2SO4, reflux, 5hs; c) 5-nitrofuran-2-carbonyl chloride,
NH2(CH2)2CH3/ NH2CH2Ph, CH2Cl2, room temperature, 20 hs.
2.2. Chemicals
The oximes were prepared using a similar methodology
to that described by Liu et al. [20]. The oximes, 1-51, were
obtained in 15-98% yields by the treatment of aldehydes
hydroxylamine hydrochloride and potassium carbonate in
water under reflux for 1-2 h. They were purified by recrystal-
lization from methanol solutions. Compound 55 was ob-

14 Letters in Drug Design & Discovery, 2020, Vol. 17, No. 1
França da Costa et al.
Table 1. In vitro antitubercular activities of aromatic oximes 1-45.
ꢀ
MIC (M. tuberculosis ATTC 27294)
Compound
R
Yield (%)
M. P. (ºC)
M. P. (ºC) Lit. [28]
µg/mL
µMa
1
-
62
98
92
75
91
56
89
83
77
83
56
91
57
41
64
91
82
68
98
97
46
85
98
86
90
42
15
35
32
60
95
92
-
-
64.5-65
-
Resistant
Resistant
Resistant
Resistant
Resistant
Resistant
Resistant
Resistant
Resistant
Resistant
Resistant
Resistant
12.5
Resistant
Resistant
Resistant
Resistant
Resistant
Resistant
Resistant
Resistant
Resistant
Resistant
Resistant
Resistant
91.2
2
2-F
63-64
3
3-F
66-68
4
4-F
85-87
85-87
72-73
68-69
117
5
2-Cl
69-71
6
3-Cl
64-65
7
4-Cl
114-117
101-103
70-72
8
2-Br
102-104
80
9
3-Br
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
4-Br
109-110
130-131
181-183
54-55
109-111
130-132
174-176
55
3-CN
4-CN
2-OH
3-OH
60-62
-
Resistant
Resistant
Resistant
Resistant
Resistant
Resistant
Resistant
Resistant
Resistant
Resistant
Resistant
Resistant
Resistant
50
Resistant
Resistant
Resistant
Resistant
Resistant
Resistant
Resistant
Resistant
Resistant
Resistant
Resistant
Resistant
Resistant
326.7
4-OH
112-115
91-92
114-115
89-91
-
2-OMe
3-OMe
4-OMe
2-NO2
3-NO2
4-NO2
3-OEt
4-OEt
4-N(CH3)2
4-Me
-
162-164
96-97
-
96
119-121
123-124
59-60
-
128
60-61
-
72-74
149-151
73-75
74-75
2,4-di-OH
2,5-di-OH
3,4-di-OH
2,3-di-OH
2,3-di-Cl
2,4-di-Cl
3,4-di-Cl
178-180
132-134
178-180
162-164
120-122
136-138
118-120
-
129-131
-
Resistant
50
Resistant
326.7
114-115
-
100
529.2
134-136
116-119
Resistant
Resistant
Resistant
Resistant
32
(Table 1) contd….

Synthesis and SAR Study of Simple Aryl Oximes and Nitrofuranyl Derivatives
Letters in Drug Design & Discovery, 2020, Vol. 17, No. 1 15
MIC (M. tuberculosis ATTC 27294)
Compound
R
Yield (%)
M. P. (ºC)
M. P. (ºC) Lit. [28]
µg/mL
µMa
33
34
35
36
37
38
39
40
41
42
43
44
45
2,6-di-Cl
2,3-di-OMe
98
70
93
80
91
93
99
72
62
77
66
94
72
144-146
96-97
-
Resistant
Resistant
Resistant
Resistant
Resistant
Resistant
12.5
Resistant
Resistant
Resistant
Resistant
Resistant
Resistant
75.7
96
2,4-di-OMe
99-101
87-89
104-105
3,4-di-OMe
-
2,5-di-OMe
98-99
103-104
2,6-di-OMe
111-113
105-106
ND
-
2-OH, 4-Me
2-Cl, 3-OH
-
-
Resistant
12.5
Resistant
74.8
2-OH, 3-OMe
2-OH, 4-OMe
2-OH, 5-NO2
2,3,4- tri-OMe
2-Cl, 3-OH, 4-OMe
122-123
137-138
288 (d)b
79-80
120-121
-
6.25
37.4
175-178
25
137.3
-
-
Resistant
Resistant
Resistant
Resistant
304(d)
a µM= µg/mL x 1000/FW; b(d) Decomposition.
Table 2. In vitro antitubercular activities of oximes derived from heteroaromatic aldehydes 46-49 and compounds containing
5-nitrofuran 52-58.
MIC (M. tuberculosis
M. P. (ºC) Lit.
ATTC 27294)
µg/mL
Compound
Structure
Yield (%)
M. P. (ºC)
[29]
µMa
46
47
51
85
121-122
130-132
121
5.0
32.0
130-133
Resistant
Resistant
145.2
48
98
158-160
156-157
25
49
50
76
91
129-131
111-113
130-133
110-112
Resistant
Resistant
Resistant
Resistant
51
52
92
-
133-135
-
-
-
Resistant
Resistant
Resistant
Resistant
(Table 2) Contd….

16 Letters in Drug Design & Discovery, 2020, Vol. 17, No. 1
França da Costa et al.
MIC (M. tuberculosis
ATTC 27294)
µg/mL
M. P. (ºC) Lit.
[29]
Compound
Structure
Yield (%)
M. P. (ºC)
µMa
53
54
-
-
-
-
-
-
3.12
21.8
Resistant
Resistant
55
56
57
77
-
77-79
-
77-80
-
2.5
6.25
50
14.6
47.3
55
96-98
103
252.4
58
67
63-65
-
3.12
12.6
a µM= µg/mL x 1000/FW.
Table 3. In vitro antitubercular activity, toxicity and selectivity index of compounds that showed more activity against Mycobacte-
rium tuberculosis.
MIC (M. tuberculosis
CC50 (µM)a
Selectivity Indexb
ATTC 27294)
Compound
µg/mL
12.5
50
µM
91.2
326.7
75.7
74.8
37.4
137.3
32.0
145.2
21.8
14.6
47.3
252.4
12.6
13
27
39
41
42
43
46
48
53
55
56
57
58
> 150.00
> 150.00
> 150.00
> 150.00
> 150.00
76.43
> 1.64
> 0.46
> 1.98
> 2.00
> 4.01
0.56
12.5
12.5
6.25
25
5.0
112.91
31.22
3.53
25
0.21
3.12
2.5
22.41
1.03
143.76
78.07
9.85
6.25
50
1.80
31.48
0.12
3.12
97.01
7.70
aCC50 50% cytotoxicity concentration on macrophages; b IS = CC50/ MIC.

Synthesis and SAR Study of Simple Aryl Oximes and Nitrofuranyl Derivatives
Letters in Drug Design & Discovery, 2020, Vol. 17, No. 1 17
All procedures performed in this assay were approved by the
Ethics Committee for Animal Handling (013/2015-CEUA)
of the Federal University of Juiz de Fora [27].
respectively. The amide, 58, containing a benzyl group with
MIC= 12.6 µM, is more active than that having a propyl
group, 57, (MIC = 252.4 µM) which indicates that substitu-
ents in the amido group are also critical for biological activi-
ty (Fig. 3).
3. RESULTS AND DISCUSSION
All compounds were tested in vitro against M. tuberculo-
sis ATTC 27294. Tables 1 and 2, list the compounds studied,
along with their preparative yields, melting points and com-
parison with the literature values, and the biological activi-
ties.
Critical position
N - Inactive
S - Decrease biological activity
O - Increase biological activity
O2N
X
For oximes of monosubstituted benzaldehydes, com-
pounds 1-25, only compound 13 exhibited activity against
M. tuberculosis (MIC=91.2 µM). Compound 13 has an ortho
hydroxyl group (Table 1). For di-and poly-substituted com-
pounds activity is only shown by compounds containing an
ortho hydroxyl group, with the additional substituents having
a significant effect on the activity (Fig. 2). Of some interest,
additional hydroxyl groups drastically reduce the activity
compared to that of 13, as shown by the decreased biological
activity of compounds, 27 (2,5-di-OH) and 29 (2,5-di-OH),
and especially by the non-activity of compound 28 (2,3-di-
OH) (Table 1). As clearly illustrated in Table 1, the effect of
other additional groups depends on the substituents: for ex-
ample, compound 42 (2-OH, 4-OMe) has a greater activity,
compounds 39 (2-OH, 4-Me) and 41 (2-OH, 3-OMe) have
similar activities, and compound, 43 (2-OH, 5-NO2) has re-
duced activity compared to that of compound 13 (2-OH).
The trend in activities seems to follow broadly the electron
releasing ability of the additional substituents.
R
R= CH2OH < CHNOH < CHO < CHONHCH2Ph < CO2Me
Increase the biological activity
ꢀ
Fig. (3). Structure-activity relationship of the heteroaromatics ox-
imes and nitro-furan analogs tested against M. tuberculosis.
The cytotoxic effects and the selectivity indices were
evaluated for all compounds having displayed better activity,
Table 3. In general, the compounds did not show the
cytotoxic effect on macrophages at the maximum concentra-
tion tested (IC50 > 150.0 μM) or showed low toxic effect
(IC50 > 50.0 μM). The cytotoxicity sequence was 55 < 46 <
58 < 56 < 43, with IC50 values of 143.76, 112.91, 97.01,
78.07 and 76.43 µM, respectively. Compounds, 13, 27, 39,
41 and 42, had non-toxic effects on macrophages at the max-
imum concentration tested (IC50 > 150.0 μM).
The selective index (SI) - which represents the ratio be-
tween the CC50 and MIC values, and thus the in vitro safety
– were calculated for 55 and 58, the compounds having bet-
ter activity against Mycobacterium tuberculosis, and were
found to be 9.85 and 7.70, respectively. The selective index
(IE) measures how much the compound is active against the
mycobacterium without damaging the cells [28, 29].
In other antibacterial tests, 55, was found to be inactive
against Enterococcus faecalis ATCC 29212, Klebisiella
pneumonae TP7962/CLT0182, Pseudomonas aeruginosa
ATCC 27853, Staphylococcus aureus ATCC 29213, Salmo-
nella typhymurium ATCC 14028 and Shigella flexneri
ATCC 120120. This result suggests that the compound 55 is
selective in its spectrum of antibacterial activity.
ꢀ
CONCLUSION
Fig. (2). Structure-activity relationship of the oximes tested against
M. tuberculosis.
The antitubercular activity of aryl oximes, ArCH=N-OH,
I, and nitrofuranyl compounds, 2-nitrofuranyl-X, II, de-
scribed in this study, indicates a selectivity against M. tuber-
culosis. The presence of an ortho hydroxyl group in the ben-
zaldehyde oxime is a requirement for antitubercular activity.
Additional substituents significantly affect the activities,
with the most active compound being compound 2-hydroxy-
4-methoxybenzaldehye oxime, 42. The most promising het-
eroaryl oxime, 46, exhibited an activity of 32.0 µM. Howev-
er, more active nitrofuran derivatives were compounds, 55,
(5-nitrofuranyl-CO2Me), and 58 (5-nitrofuranyl-NHCH2Ph),
at 14.6 µM and 12.6 µM, respectively, both having excellent
selectivity indices of 9.85 and 7.70, respectively.
The biological activities of the heteroaromatic oximes,
46-50, indicate strongly the importance of nitrofuranyl
group, Table 2. Thus, it was decided to further test other
nitrofuranyl compounds, 52-58, containing different func-
tional groups. 2-Nitrofuran 52 was not active, which pointed
to the necessity of having another functional group in the
nitro-furanyl ring. When compared with the oxime 46
(MIC=32.0 µM), the acid 54 was inactive, but the corre-
sponding alcohol, 56, aldehyde, 53, and ester, 55, displayed
good to excellent results with MIC=43.7, 21.8 and 14.6 µM,

18 Letters in Drug Design & Discovery, 2020, Vol. 17, No. 1
França da Costa et al.
[PMID:
[http://dx.doi.org/10.1016/j.ejmech.2011.01.004]
21295888]
Compound 55 was inactive against other bacteria, sug-
gesting a selectivity against Mycobacterium tuberculosis.
This study provides important additional information in the
quest to discover new anti-TB drugs.
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CONSENT FOR PUBLICATION
Not applicable.
[8]
[9]
AVAILABILITY OF DATA AND MATERIALS
The authors confirm that the data supporting the findings
of this research are available within this manuscript and its
supplementary material.
FUNDING
[10]
[11]
The authors thank Farmanguinhos, INI, CDTS, Univer-
sidade Federal de Juiz de for the financial support of the re-
search. Fellowships granted to E.S.C. and M.V.N.S. by
CNPq. Fellowships granted to C.F.C. by Fiotec. Fellowships
granted to S.L.C. and J.T.C. by CAPES.
[http://dx.doi.org/10.2174/156802607780059772]
17346196]
[PMID:
Souza, J.L.S.; Nedel, F.; Ritter, M.; Carvalho, P.H.; Pereira, C.M.;
Lund, R.G. Antifungal susceptibility, exoenzyme production and
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Ma, J.; Ma, M.; Sun, L.; Zeng, Z.; Jiang, H. Synthesis, herbicidal
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ime ether derivatives. J. Chem., 2015, 2015, 1-8.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
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[13]
ACKNOWLEDGEMENTS
[http://dx.doi.org/10.1155/2015/435219]
Rakesh, D.B.; Bruhn, M.; Madhura, R.B.; Maddox, Lee, Trivedi,
A.; Yang, L.; Scherman, M.S.; Gilliland, J.C.; Gruppo, V.; McNeil,
M.R.; Lenaerts, A.J.; Meibohm, B.; Lee, R.E. Antitubercular nitro-
furan isoxazolines with improved pharmacokinetic properties.
Bioorg. Med. Chem., 2012, 20, 6063-6072.
Declared none.
SUPPLEMENTARY MATERIAL
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Tawari, N.R.; Degani, M.S.; Chem, T. Pharmacophore modeling
and density functional theory analysis for a series of nitroimidazole
compounds with antitubercular activity. Chem. Biol. Drug Des.,
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web site along with the published article.
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