Discovery and modification of sulfur-containing heterocyclic pyrazoline derivatives as potential novel class of β-ketoacyl-acyl carrier protein synthase III (FabH) inhibitors

Article abstract of DOI:10.1016/j.bmcl.2012.05.091

A series of sulfur-containing heterocyclic pyrazoline derivatives (C1-C18; D1-D9) have been synthesized and purified (all are new except one) to screen for FabH inhibitory activity. Compound C14 showed the most potent biological activity against Escherich

Full text of DOI:10.1016/j.bmcl.2012.05.091

Bioorganic & Medicinal Chemistry Letters 22 (2012) 4619–4624
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery and modification of sulfur-containing heterocyclic pyrazoline
derivatives as potential novel class of b-ketoacyl-acyl carrier protein synthase
III (FabH) inhibitors
Yu-Shun Yang a, Fei Zhang a, Chao Gao a, Yan-Bin Zhang a, Xiao-Liang Wang a, Jian-Feng Tang a, Jian Sun a,
a,
Hai-Bin Gong b, , Hai-Liang Zhu
⇑
⇑
a State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China
b Xuzhou Central Hospital, Xuzhou 221009, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of sulfur-containing heterocyclic pyrazoline derivatives (C1–C18; D1–D9) have been synthesized
and purified (all are new except one) to be screened for FabH inhibitory activity. Compound C14 showed
the most potent biological activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus
Received 21 March 2012
Revised 14 May 2012
Accepted 28 May 2012
Available online 5 June 2012
and Bacillus subtilis (MIC values: 1.56–3.13
performed the best in the thiazolidinone series (MIC values: 3.13–6.25
strong broad-spectrum antimicrobial activity. Compounds C14 and D6 exhibited the most potent E. coli
FabH inhibitory activity with IC50 of 4.6 and 8.4 M, respectively, comparable with the positive control
DDCP (IC50 = 2.8 M). Docking simulation was performed to position compound C14 and D6 into the
l
g/mL), being comparable with the positive control, while D6
lg/mL). They also demonstrated
Keywords:
Thiazole
Thiazolidinone
Pyrazoline
Antibacterial activity
FabH
l
l
E. coli FabH structure active site to determine the probable binding model. The structurally modification
of previous compounds and the attempt in innovative target have brought a positive progress.
Ó 2012 Elsevier Ltd. All rights reserved.
Being resistant to known therapies and showing reduced
susceptibility to our most trusted antibiotics, bacteria become a
greater threat to us human beings. Therefore the research of new
antibacterial agents with novel target or the re-exploitation of
foregone drugs plays a great role.1
ubiquitous structure of FabH have guaranteed that FabH inhibitors
are potent antibiotics with broad-spectrum activity. Thus, over one
hundred FabH inhibitors have been screened by enzymatic assays
and subsequently optimized using structure guided drug design
methods.11–14
Fatty acid biosynthesis (FAB), which is an essential metabolic
process for prokaryotic organisms and is required for cell viability
and growth, seems to be an attractive target.2 While fatty acid
synthesis occurs in homodimeric multifunctional enzyme in
humans,3,4 in bacteria the pathway is composed of various discrete
enzymes. The considerable differences ensured the possibility for
the type II FAS pathway to be a potential target. b-Ketoacyl-acyl
carrier protein (ACP) synthase III, also known as FabH or KAS III,
initiates the fatty acid elongation cycles (Fig. 1),5 and participates
in the feedback regulation of the biosynthetic pathway via product
inhibition.6 Although FabB (KAS I) and FabF (KAS II) are condensing
enzymes performing the chain elongation reactions in subsequent
cycles leading to longchain acyl ACP products as well,7,8 FabH is
structurally distinct. The three-dimensional structure of FabH is
highly conserved across a variety of Gram-positive and Gram-neg-
ative bacteria.9 In spite of the denial necessity of FabB (KAS I) and
FabF (KAS II) for Gram-positive bacteria,10 the key role and
The pyrazoline motif makes up the core structure of numerous
biologically active compounds. Thus, many pyrazoline derivatives
exhibit a wide range of bioactivities such as antibacterial,15–17 fun-
gistatic,18 anti-viral/anti-tumor,19,20 anti-inflamatory,21 analge-
sic,22 and anti-hyperglycemic.23 However, the synthesis and FabH
inhibitory activity of 4,5-dihydro-(1H)-pyrazole derivatives is
O
S
CoA
CO2+CoA-SH
FabH
O
O
Acetyl-CoA
R
S
Acp
β -Ketoacyl-Acp
O
O
Ac
HO S
Malonyl-CoA
⇑
Corresponding authors. Tel./fax: +86 25 8359 2672.
E-mail addresses: ghbxzh@yahoo.com.cn (H.-B. Gong), zhuhl@nju.edu.cn (H.-L.
Zhu).
Figure 1. FabH accomplishes the initial condensation step in FASII.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.05.091

4620
Y.-S. Yang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4619–4624
O
X
O
CHO
X
R1
i
R1
A
R2
S
R2
NH2
N
N
X
ii
R1
B
R2
iv
iii
R3
O
S
S
N
N
N
N
N
X
N
X
R1
R1
R2
R2
D1-D9
C1-C18
Compound R1
R2
R3
H
H
H
H
H
OCH3
OCH3
OCH3
OCH3
OCH3
H
X
Compound R1
R2
R3
X
C1
F
H
H
Cl
H
H
H
H
Cl
H
H
H
H
Cl
H
S
S
S
S
S
S
S
S
S
S
O
O
O
O
C15
C16
C17
C18
F
H
H
Cl
H
OCH3
O
O
O
O
C2
Br
Br
Cl
CH3
OCH3
OCH3
OCH3
C3
Cl
C4
C5
C6
CH3
OCH3
F
D1
D2
D3
D4
D5
D6
D7
D8
D9
F
Br
Cl
CH3
OCH3
F
Br
Cl
CH3
H
H
Cl
H
H
H
H
Cl
H
/
/
/
/
/
/
/
/
/
S
S
S
S
C7
Br
C8
Cl
C9
CH3
OCH3
F
Br
Cl
C10
C11
C12
C13
C14
S
O
O
O
O
H
H
H
CH3
Scheme 1. General synthesis of compounds (C1–C18; D1–D9). Reagents and conditions: (i) EtOH, 40% NaOH, reflux, 30 min; (ii) EtOH, thiosemicarbazide, NaOH, 80 °C, 5 h;
(iii) EtOH, bromoacetophenone, 80 °C, 5 h, H2O; (iv) EtOH, Ethyl bromoacetate, NaOAc, 80 °C, 5 h.

Y.-S. Yang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4619–4624
4621
Table 1
Antimicrobial activity of the synthesized compounds (C1–C18, D1–D9)
O
S
N
S
N
N
N
N
N
H3C
H3C
D0
C0
Compound
Minimum inhibitory concentrations (
P. aeruginosa
l
g/mL)
Gram-negative
Gram-positive
E. coli
S. aureus
B. subtilis
C1
C2
C3
C4
C5
C6
C7
C8
12.5
6.25
50
3.13
6.25
12.5
6.25
50
12.5
12.5
12.5
1.56
50
12.5
12.5
12.5
12.5
12.5
12.5
3.13
>50
1.56
6.25
6.25
>50
3.13
>50
6.25
12.5
6.25
>50
6.25
12.5
12.5
6.25
12.5
12.5
1.56
12.5
12.5
>50
1.56
6.25
12.5
12.5
50
50
6.25
12.5
3.13
12.5
12.5
12.5
12.5
6.25
50
C9
6.25
12.5
6.25
3.13
12.5
1.56
6.25
6.25
50
3.13
6.25
6.25
12.5
6.25
12.5
3.13
6.25
12.5
3.13
6.25
12.5
1.56
12.5
12.5
6.25
1.56
12.5
1.56
12.5
12.5
12.5
6.25
12.5
12.5
12.5
3.13
12.5
3.13
6.25
6.25
6.25
12.5
6.25
3.13
C10
C11
C12
C13
C14
C15
C16
C17
C18
D1
D2
D3
D4
D5
D6
D7
D8
D9
50
3.13
12.5
3.13
12.5
6.25
>50
6.25
12.5
12.5
>50
6.25
50
3.13
12.5
12.5
3.13
12.5
12.5
3.13
C0
D0
Kanamycin B
suffering
modification.
a
stasis for the lack of innovation in structural
Twenty-seven sulfur-containing heterocyclic pyrazoline deriva-
tives were synthesized to screen for the antibacterial activity. All of
them were synthesized for the first time in spite of C14 (the struc-
ture but not its bio-activity).28 The synthesis of compounds C1–
C18; D1–D9 followed the general pathway outlined in Scheme 1.
They are both prepared in three steps. Firstly, the different substi-
tuted acetophenone on treatment with thiophene-2-carbaldehyde
(or furan-2-carbaldehyde) in presence of 40% NaOH yielded
different analogues of chalcones. Secondly, the cyclization of the
obtained shiny powder by subjoining thiosemicarbazide led to
3,5-diaryl-4,5-dihydro-1H-pyrazole-1-carbothioamides (intermedi
ates). Then the corresponding target compounds C1–C18 (2-(3,5-
diaryl-4,5-dihydro-1H-pyrazol-1-yl)-4-arylthiazole) were produc
ed after another cyclization with bromoacetophenone while com-
pounds D1–D9 (2-(3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl)thia-
zol-4(5H)-one) were manufactured with the participation of Ethyl
bromoacetate and NaOAc. The refined compounds were finally ob-
tained by subsequent purification with recrystallisation. All of the
In continuation to extend the research on antibacterial com-
pounds with FabH inhibitory activity,24,25 we report in the present
work the synthesis and structure–activity relationships of a series
of sulfur-containing heterocyclic pyrazoline derivatives. Introduc-
ing the structure of thiazole or thiazolidinone leads to a positive re-
sult as initially designed by CADD (computer assistant drug
design). One considerable reason is the reported antibacterial
activity of thiazole and thiazolidinone,26,27 while the other is the
reinforcement of the combination between our compounds and
the receptor. Moreover, we conduct another attempt to enhance
the molecular interaction with an addition of thiophene or furan,
for this kind of structure can also contribute to the formation of
hydrogen bonds. Biological evaluation indicated that some of the
synthesized compounds were potent inhibitors of FabH and the
modification brought about a positive consequence as a result of
possible enhancement of the ligand–receptor interactions.

4622
Y.-S. Yang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4619–4624
Table 2
bacteria, which was similar to the positive control, broad-spectrum
antibiotic kanamycin B with corresponding MIC values between
1.56 and 3.13 g/mL. Meanwhile, the data suggested their broad-
spectrum antibacterial activity as well. D6 (3.13–6.25 g/mL) dem-
E. coli FabH inhibitory activity of the selected compounds
l
Compounds
E. coli FabH
IC50 M)
Hemolysis
(
l
LC30a (mg/mL)
l
onstrated a relatively better activity among D1–D9 and also was
comparable with kanamycin B. Further, C14 and D6 showed lower
MIC values than C0 and D0 (MIC: D6 < D9 < D0), respectively, indi-
cating the favorable effect of the introduction of a heterocyclic ring.
Subsequently preliminary SAR studies were performed to
deduce how the structure variation and modification could affect
the antimicrobial activity. Firstly, the compounds of C series sug-
gested a slightly better antibacterial activity than the compounds
of D with the same substituent groups on the phenyl ring and
the same heterocyclic. For example, C5 and C10 showed MIC values
C2
C3
C4
C5
23.3 0.31
>150
10.9 0.07
30.6 0.28
>150
22.3 0.11
9.7 0.05
4.6 0.03
19.7 0.40
15.7 0.22
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
C8
C11
C12
C14
C16
C18
D2
D4
D5
D6
D9
DDCP
27.1 0.48
13.6 0.25
89.9 1.21
8.4 0.10
18.4 0.33
2.8
>10
>10
>10
>10
>10
>10
of 6.25–50
lg/mL and 6.25–50
lg/mL while D5 showed MIC values
of 12.5– >50
lg/mL. For the others the inference was also correct
basically. Secondly, the introduction of the electron-donating
group (here it was –OCH3) at the position of R3 weakened the anti-
a
microbial effect in the C series. For example, C4 (1.56–3.13
lg/mL)
Lytic concentration 30%.
suggested lower MIC values than C9 (6.25–12.5 g/mL) against all
l
four kinds of bacteria. Thirdly, when we controlled R1, R2 and R3,
the results in Table 1 inferred that the modification with a furan
structure made a greater success than that with a thiophene struc-
synthetic compounds gave satisfactory analytical and spectroscopic
data, which were in full accordance with their depicted structures.
All the synthesized compounds C1–C18, D1–D9 were evaluated
for their antimicrobial activities against two Gram-negative bacte-
rial strains: Escherichia coli and Pseudomonas aeruginosa and two
Gram-positive bacterial strains: Bacillus subtilis and Staphylococcus
aureus by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazo-
lium bromide) method. The MIC (minimum inhibitory concentra-
tions) values of those compounds against these bacteria were
presented in Table 1. Standard antibacterial agent kanamycin B
was also screened under identical conditions for comparison.
Meanwhile, we took C0 and D0 as the other two comparisons. They
were two previous compounds, which have been used as EGFR
(Epidermal Growth Factor Receptor) inhibitors and this time
screened out from compounds with the same backbone but differ-
ent substituents using a pre-experiment of the same method. The
results revealed that most of the synthetic compounds exhibited
significant antibacterial activities and the structurally modification
contributed to obvious progress in bioactivities.
ture in the thiazole series. For example, C12 (1.56–3.13
lg/mL)
performed superior activity than C2 (6.25–12.5 g/mL). However,
l
when it came to the thiazolidinone series, the influence of hetero-
cyclic structure seemed to be less important (despite D1 and D6).
For example, D2 (6.25–12.5
sion of bacteria with D7 (6.25–12.5
l
g/mL) declared equivalent suppres-
g/mL). Finally, we attempted
l
to address the influence of the substituent groups on the phenyl
ring. As a first experiment, we only synthesized the target com-
pounds with relatively good activities after being screened by com-
puter assistant drug design, avoiding the redundant work while
simplifying the situation. The spatial configuration and the influ-
ence of heterocyclic structure might make the effect of the substit-
uents insignificant, yet we could still perceive the trend in C series
that –CH3 > –Br > –OCH3 > –F. For example, C4 (3.13–6.25
mL) > C2 (6.25–12.5 g/mL) > C5 (6.25–50 g/mL) > C1 (12.5–50
g/mL). In D series the result was a bit different with the probable
order that –CH3 > –Br > –F > –OCH3. For example, D4 (3.13–6.25
/mL) > D2 (6.25–12.5 g/mL) > D1 (6.25– >50 g/mL) > D5(12.5–
>50 g/mL). However, D6 was the only unusual compound which
did not meet the trend. Moreover, the order of these compounds
lg/
l
l
l
lg
l
l
Out of the 27 sulfur-containing heterocyclic pyrazoline deriva-
tives, compounds C14 displayed most potent activity with MIC
values between 1.56 and 3.13 lg/mL against all four kinds of
l
Figure 2. (A) 2D molecular docking modeling of compound C14 with 1HNJ. (B) 3D model of the interaction between compound C14 and 1HNJ bonding site. The one H-bond
(green line) is displayed as dotted lines and the amino acid it acts on is labeled in green. The four
with their corresponding amino acids labeled in yellow.
p–cation interactions and one p–sigma interaction are shown as orange lines

Y.-S. Yang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4619–4624
4623
Figure 3. (C) 2D molecular docking modeling of compound D6 with 1HNJ. (D) 3D model of the interaction between compound D6 and 1HNJ bonding site. The two H-bonds
(green lines) are displayed as dotted lines and the amino acids they act on are labeled in green. The one
amino acid labeled in yellow.
p–cation interaction is shown as orange line with its corresponding
also implied another inference that groups with weaker electron-
withdrawing or electron-donating ability induced higher antibac-
terial activity to some extent. Further, the gloomy results of com-
pounds with substituents of 3,4-dichloro called our attentions
and indicated that multi-substituent compounds might not be a
potential direction of future research.
with a p–cation interaction. This ensures the binding affinity and
results in an increased antibacterial activity. A remarkable hydro-
gen bond is formed by the oxygen atom of the thiazolidinone ring
and the hydrogen atom of ARG249 (OÁ Á ÁH–N: 1.86 Å, 164.464°)
while the other is a familiar one formed by the oxygen atom of fur-
an and the hydrogen atom of ASN210 (OÁ Á ÁH–N: 2.47 Å, 105.568°).
In addition, we selected the top 12 compounds and the bottom
3 compounds of the antibacterial activity according to their MIC
values to test their activity as E. coli FabH inhibitors. The results
were summarized in Table 2. As shown, all the bottom compounds
showed little E. coli FabH inhibitory while most of the top com-
pounds displayed potent E. coli FabH inhibitory. Among them,
C14 showed the most potent inhibitory activity with IC50 of
Further, the p–cation interaction is conducted by the furan ring
with the end amino cation of ARG36 (distance: 6.70 Å). The binding
model inferred that the introduction of furan or thiophene en-
hanced the binding affinity with greater possibility to form hydro-
gen bond or
p–cation interaction. Besides, the absence of one
benzene ring and the substitute of thiazole with thiazolidinone
made the ligand easier to conduct hydrogen bond but more diffi-
cult to form p–sigma interaction. However, we could not ignore
4.6
with IC50 of 2.8
inhibitory activity with IC50 of 8.4
Other tested top compounds displayed moderate inhibitory activ-
ity with IC50 ranging from 9.7 to 30.6 M. The results of E. coli FabH
l
M which were comparable to the positive control DDCP29
M. D6, besides, suggested a relatively potent
M, being top of the D series.
l
the advantage of D series when they are bound to receptors with
tighter active sites in the future research. The docking calculation
of all the compounds was also depicted in Table 3. The CDocker En-
ergy (energy of the ligand–receptor complexes) agreed with the
FabH inhibitory trend for all the synthesized compounds.
To conclude, two series of compounds, C1–C18 (2-(3,5-diaryl-
4,5-dihydro-1H-pyrazol-1-yl)-4-arylthiazole) and D1–D9 (2-(3,5-
diaryl-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one) have been
synthesized and evaluated for their antibacterial activities.
Compound C14 showed the most potent biological activity against
E. coli, P. aeruginosa, S. aureus and B. subtilis with MIC values of
l
l
inhibitory activity of the tested compounds were basically corre-
sponding to the structure relationships (SAR) of their antibacterial
activities. This indicated that the potent antibacterial activities of
the synthetic compounds were probably correlated to their FabH
inhibitory activities. Besides, it was obvious from Table 2 that all
selected compounds displayed low hemolytic inhibitory activity.
In an effort to make the possible mechanism by which the title
compounds can induce antibacterial activity easier to understand
and guide further SAR studies, the molecular docking of all the
compounds with E. coli FabH was performed on the binding model
based on the E. coli FabH-CoA complex structure (1HNJ.pdb).30 The
binding modes of potent inhibitor C14 and D6 with 1HNJ were de-
picted in Figures 2 and 3, respectively.
In the binding model, compound C14 is nicely bound to 1HNJ
via one hydrogen bond, four p–cation interactions and one p–sig-
ma interaction. The oxygen atom of furan contributes to the hydro-
gen bonding interaction (OÁ Á ÁH–N: 2.37 Å, 156.562°) with the
backbone amino hydrogen atom of ASN247. Further, the benzene
ring (connecting directly to the pyrazoline) of compound C14
1.56–3.13 lg/mL, being comparable with the positive control,
Table 3
The docking calculation of the synthesized compounds (C1-C18, D1-D9)
Compounds
CDocker Energy
Gb (kcal/mol)
Compounds
CDocker Energy
Gb (kcal/mol)
D
D
C1
C2
C3
C4
C5
C6
C7
C8
À12.52
À15.17
À7.19
C15
C16
C17
C18
À14.30
À16.61
À9.74
À18.52
À15.10
À12.07
À15.05
À9.19
À16.86
D1
D2
D3
D4
D5
D6
D7
D8
D9
À14.37
À15.80
À11.91
À16.98
À10.89
À17.10
À14.90
À13.34
À16.37
forms two
p–cation interactions with the end amino cation of
ARG36 (distance: 3.21 Å and 5.14 Å) and ARG249 (distance:
3.21 Å and 5.18 Å) each. Moreover, the thiazole ring of compound
C9
À14.77
À12.17
À15.77
À18.99
À12.71
À20.47
C10
C11
C12
C13
C14
C14 engenders a
p–sigma interaction with GLY209 (distance:
2.75 Å), enhancing the binding action between receptor 1HNJ and
ligand compound C14 as well. As for compound D6, it also per-
forms a nice bonding situation via two hydrogen bonds together

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Y.-S. Yang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4619–4624
11. Lee, P. J.; Bhonsle, J. B.; Gaona, H. W.; Huddler, D. P.; Heady, T. N.; Kreishman-
Deitrick, M.; Bhattacharjee, A.; McCalmont, W. F.; Gerena, L.; Lopez-Sanchez,
M.; Roncal, N. E.; Hudson, T. H.; Johnson, J. D.; Prigge, S. T.; Waters, N. C. J. Med.
Chem. 2009, 52, 952.
12. Nie, Z.; Perretta, C.; Lu, J.; Su, Y.; Margosiak, S.; Gajiwala, K. S.; Cortez, J.;
Nikulin, V.; Yager, K. M.; Appelt, K.; Chu, S. J. Med. Chem. 2005, 48, 1596.
13. Daines, R. A.; Pendrak, I.; Sham, K.; Aller, G. S. V.; Konstantinidis, A. K.;
Lonsdale, J. T.; Janson, C. A.; Qiu, X.; Brandt, M.; Khandekar, S. S.; Silverman, C.;
Head, M. S. J. Med. Chem. 2003, 46, 5.
while D6 performed the best in the thiazolidinone series with MIC
values of 3.13–6.25 g/mL. These new sulfur-containing heterocy-
clic pirazoline derivatives demonstrated strong broad-spectrum
antimicrobial activity. Compounds C14 and D6 also exhibited the
most potent E. coli FabH inhibitory activity with IC50 of 4.6 and
l
8.4 lM, respectively. Docking simulation was performed to posi-
tion compound C14 and D6 into the E. coli FabH structure active
site to determine the probable binding model. The introduction
of heterocyclic ring (furan or thiophene) reinforced the combina-
tion of our compounds and the receptor, while the thiazole series
and thiazolidinone series displayed their own advantages each
other. The innovative attempt to use previous EGFR inhibitors in
the research of E. coli FabH inhibitory activity also led to a gratify-
ing result.
14. Singh, S.; Soni, L. K.; Gupta, M. K.; Prabhakar, Y. S.; Kaskhedikar, S. G. Eur. J. Med.
Chem. 2008, 1071, 43.
15. Tanitame, A.; Oyamada, Y.; Ofuji, K.; Fujimoto, M.; Iwai, N.; Hiyama, Y.; Suzuki,
K.; Ito, H.; Wachi, M.; Yamagishi, J. J. Med. Chem. 2004, 47, 3693.
16. Genin, M. J.; Allwine, D. A.; Anderson, D. J.; Barbachyn, M. R.; Emmert, D. E.;
Garmon, S. A.; Graber, D. R.; Grega, K. C.; Hester, J. B.; Hutchinson, D. K.; Morris,
J.; Reischer, R. J.; Ford, C. W.; Zurenko, G. E.; Hamel, J. C.; Schaadt, R. D.; Stapert,
D.; Yagi, B. H. J. Med. Chem. 2000, 43, 953.
17. Bekhit, A. A.; Fahmy, H. T. Y.; Rostom, S. A. F.; Baraka, A. M. Eur. J. Med. Chem.
2003, 38, 27.
18. Sridhar, R.; Perumal, P. T.; Etti, S.; Shanmugam, G.; Ponnuswamy, M. N.;
Prabavathy, V. R.; Mathivanan, N. Bioorg. Med. Chem. Lett. 2004, 14, 6035.
19. Manfredini, S.; Bazzanini, R.; Baraldi, P. G.; Bonora, M.; Marangoni, M.; Simoni,
D.; Pani, A.; Scintu, F.; Pinna, E. Anti-Cancer. Drug. Des. 1996, 11, 193.
20. Park, H.-A.; Lee, K.; Park, S.-J.; Ahn, B.; Lee, J.-C.; Cho, H. Y.; Lee, K.-I. Bioorg. Med.
Chem. Lett. 2005, 15, 3307.
21. Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins, P. W.; Docter,
S.; Graneto, M. J.; Lee, L. F.; Malecha, J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier,
D. J.; Yu, S. S.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.;
Koboldt, C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.;
Isakson, P. C. J. Med. Chem. 1997, 40, 1347.
Acknowledgments
The work was financed by National Natural Science Foundation
of China (No. J1103512) and Agricultural Research Project (NO.
NY1002).
Supplementary data
22. Menozzi, G.; Mosti, L.; Fossa, P.; Mattioli, F.; Ghia, M. J. Heterocycl. Chem. 1997,
34, 963.
23. Bebernitz, G. R.; Argentieri, G.; Battle, B.; Brennan, C.; Balkan, B.; Burkey, B. F.;
Eckhardt, M.; Gao, J.; Kapa, P.; Strohschein, R. J.; Schuster, H. F.; Wilson, M.; Xu,
D. D. J. Med. Chem. 2001, 44, 2601.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.05.
091.
24. Li, H.-Q.; Shi, L.; Li, Q.-S.; Liu, P.-G.; Luo, Y.; Zhao, J.; Zhu, H.-L. Bioorg. Med.
Chem. 2009, 17, 6264.
References and notes
25. Lv, P.-C.; Wang, K.-R.; Yang, Y.; Mao, W.-J.; Chen, J.; Xiong, J.; Zhu, H.-L. Bioorg.
Med. Chem. Lett. 2009, 19, 6750.
1. Leeb, M. Nature 2004, 431, 892.
26. Chimenti, F.; Bizzarri, B.; Bolasco, A.; Secci, D.; Chimenti, P.; Granese, A.;
Carradori, S.; D’Ascenzio, M.; Lilli, D.; Rivanera, D. Eur. J. Med. Chem. 2011, 46,
378.
27. Lv, P.-C.; Zhou, C.-F.; Chen, J.; Liu, P.-G.; Wang, K.-R.; Mao, W.-J.; Li, H.-Q.; Yang,
Y.; Xiong, J.; Zhu, H.-L. Bioorg. Med. Chem. 2010, 18, 314.
28. Sahin, Z. S.; Isik, S.; Salgin-Goksen, U.; Gokhan-Kelekci, N. Chin. J. Struct. Chem.
2010, 29, 700.
29. He, X.; Anne, M. R.; Umesh, R. D.; Glen, E. K.; Kevin, A. R. Antimicrob. Agents
Chemother. 2004, 48, 3093.
2. Lee, J.-Y.; Jeong, K.-W.; Lee, J.-U.; Kang, D.-I.; Kim, Y. Bioorg. Med. Chem. 2009,
17, 1506.
3. Lu, Y. J.; Zhang, Y. M.; Rock, C. O. Biochem. Cell Biol. 2004, 82, 145.
4. Lai, C. Y.; Cronan, J. E. J. Biol. Chem. 2003, 19, 51494.
5. Ali, A.; Seung, J. C. Bioorg. Med. Chem. 2006, 14, 1474.
6. Heath, R. J.; Rock, C. O. J. Biol. Chem. 1833, 1996, 271.
7. White, S. W.; Zheng, J.; Zhang, Y. M.; Rock, C. O. Annu. Rev. Biochem. 2005, 74,
791.
8. Veyron-Churlet, R.; Guerrini, O.; Mourey, L.; Daffé, M.; Zerbib, D. Mol. Microbiol.
2004, 54, 1161.
9. Puupponen-Pimiä, R.; Nohynek, L.; Meier, C.; Kähkönen, M.; Heinonen, A. H. J.
Appl. Microbiol. 2001, 90, 494.
30. Qiu, X.; Janson, C. A.; Smith, W. W.; Head, M.; Lonsdale, J.; Konstantinidis, A. K.
J. Mol. Biol. 2001, 307, 341.
10. Brinster, S.; Lamberet, G.; Staels, B.; Trieu-Cout, P.; Gruss, A.; Poyart, C. Nature
Lett. 2009, 458, 83.