Design and synthesis of novel 2-pyridone peptidomimetic falcipain 2/3 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2008.05.068

The structure-based design, chemical synthesis and in vitro activity evaluation of various falcipain inhibitors derived from 2-pyridone are reported. These compounds contain a peptidomimetic binding determinant and a Michael acceptor terminal moiety capable of deactivating the cysteine protease active site.

Full text of DOI:10.1016/j.bmcl.2008.05.068

Bioorganic & Medicinal Chemistry Letters 18 (2008) 4210–4214
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and synthesis of novel 2-pyridone peptidomimetic falcipain
2/3 inhibitors
Edite Verissimo a,b, Neil Berry b, Peter Gibbons b, M. Lurdes S. Cristiano a, Philip J. Rosenthal c, Jiri Gut c,
Stephen A. Ward d, Paul M. O’Neill b,
*
a Department of Chemistry, Biochemistry and Pharmacy, and CCMAR, University of the Algarve, Campus de Gambelas, Faro 8005-039, Portugal
b Department of Chemistry, University of Liverpool, PO Box 147, Liverpool L69 3BX, UK
c Department of Medicine, San Francisco General Hospital, University of California, San Francisco, CA 94143-0811, USA
d Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The structure-based design, chemical synthesis and in vitro activity evaluation of various falcipain inhib-
itors derived from 2-pyridone are reported. These compounds contain a peptidomimetic binding deter-
minant and a Michael acceptor terminal moiety capable of deactivating the cysteine protease active site.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 8 March 2008
Revised 15 May 2008
Accepted 16 May 2008
Available online 20 May 2008
Keywords:
Malaria
Plasmodium falciparum
Cysteine protease
Falcipain-2
Peptidomimetic
Due to increasing resistance to existing antimalarials1 develop-
ment of new safe and effective antimalarial drugs remains an
important goal toward achieving control of malaria. Among poten-
tial new targets for antimalarial chemotherapy are cysteine prote-
ases, enzymes that cleave small peptide substrates by the action of
a nucleophilic cysteine thiol group and that in malaria parasites
play important physiological roles.2 The differences in nature of
parasitic cysteine proteases and its human orthologues have
prompted interest in this class of proteases.2 Also, it has been
shown that cysteine protease inhibitors arrested the erythrocytic
life cycle of Plasmodium falciparum, the most virulent human ma-
laria parasite, by blocking the hydrolysis of the host hemoglobin,
causing abnormally swollen food vacuoles3 and moreover, some
of these molecules have led to cure of malaria in mice.4,5 P. falcipa-
rum parasites contain four typical papain family cysteine proteases
known as falcipains.6 The importance of the role of falcipain-1
(FP1) is yet not clear,6 and the biological role of falcipain-20
(FP20), biochemically very similar to falcipain-2 (FP2), is still uncer-
tain too.7 Better known proteases are falcipain-28,9 and falcipain-3
(FP3),9,10 expressed in trophozoites, localized in the food vacuole
and able to degrade hemoglobin, therefore suggesting to be major
hemoglobinases and targets for cysteine protease inhibitors.
Initial studies with generic peptide cysteine protease inhibitors
like leupeptin and E64 were followed by the finding of more spe-
cific ones and several peptide-based falcipain inhibitors have since
been identified, including carbonyl-containing11 and vinyl sulfone-
containing inhibitors 1a,b (Fig. 1).12 These compounds act by irre-
versible alkylation of the cysteine residue13–15 at the active site via
either 1,2-addition16 in the case of aldehydes17 or conjugate addi-
tion in the case of vinyl sulfones. Consistent structural features
leading to achieve maximal FP2 and FP3 inhibition by the peptidyl
analogues appear to include a leucine residue at the P2 posi-
tion8,10,18 and the unnatural amino-acid homophenylalanine at
the P1 position.16,18 Also, conformationally constrained vinyl sulf-
ones 2 (Fig. 1) have been prepared and demonstrate high FP2 inhi-
bition.19 However, peptidyl inhibitors may have a limited utility as
therapeutic agents since they have some theoretical disadvantages,
including relatively poor pharmacokinetic profiles as their amide
bonds are susceptible to cleavage by other proteases,20 and also be-
cause they can be relatively non-selective and thus promote host
toxicity.21
The incorporation of a non-peptidic scaffold that can constrain
the amino-acid backbone has potential advantages, such as
increasing selectivity by stabilizing a biologically active conforma-
tion and decreasing toxicity to the human host. Examples of
success in the field of peptidomimetics active against cysteine
proteases include the discovery of novel peptide-based ICE
* Corresponding author.
E-mail address: P.M.oneill01@liv.ac.uk (P.M. O’Neill).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.05.068

E. Verissimo et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4210–4214
4211
P2 site
O
O
O O
S
O O
S
H
N
H
N
N
N
H
Ph
Ph
O
N
H
Ph
O
O
O
Ph
Ph
1b
1a
P1 site
O
O
Ph
Ph
Ph
O
HN
Ph
N
S
O O
2
N
O
Ph
CO2H
OMe
Ph
OAc
O
O
O
O
N
N
Ph
O
N
H
N
H
Ph
O
N
H
N
CO2Me
H
O
O
4
3
Figure 1. Potent small molecule cysteine protease inhibitors of peptidic and peptidomimetic nature.
(interleukin-1b-converting enzyme) inhibitors 3 (Fig. 1)22 and no-
vel human rhinoviruses inhibitors.23 More significantly, studies by
Lin et al. at the Walter Reed Army Institute of research showed that
peptidomimetic analogues 4 (Fig. 1) can be designed with potent
antimalarial activity in vitro.21 In all these studies, the pyridone
ring core was found to be a suitable surrogate for a portion of
the peptide.
As the bioactive conformation of the inhibitors (e.g. 1b) are not
known, we undertook a modeling study to verify that the proposed
inhibitors 6a and 6c could adopt similar low energy conformations
to the known inhibitor 1b. Similarity between 1b and 6c was as-
sessed using FieldTemplater, a tool for comparing molecules using
their electrostatic and hydrophobic fields.24 Each conformation of
one molecule was aligned to each conformation of the other mol-
ecule to identify the most similar compound on the basis of field
similarity and volume of steric overlap. As can be seen from Figure
2, the most similar conformations of the proposed inhibitor 6c and
the known inhibitor 1b possessed a high degree of similarity (Field
Similarity 0.789, Volume Similarity 0.863). There were many other
‘good’ matches of conformation between these two molecules indi-
cating that these molecules could adopt similar low energy confor-
mations. The proposed molecule 6a was assessed for its similarity
urated methyl ester analogue (Field Similarity 0.800, Volume Sim-
ilarity 0.846), with many other ‘good’ matches of low energy
conformers.
The synthesis of cysteine protease inhibitors described in this
study involves incorporation of a 2-pyridone ring and different
P1 fragments for recognition and binding to the enzyme and of dif-
ferent Michael acceptor groups capable of reacting with the nucle-
ophilic thiol of the cysteine residue. In this communication, we
focus on conformationally restricted peptidomimetic inhibitors
5a,b and 6a–c of P. falciparum cysteine proteases and the assess-
ment of their antimalarial activity.
Our original synthesis of peptidomimetics was developed in or-
der to achieve target molecules unsubstituted at the P1 position
(Lin’s approach), by direct use of methylbromoacetate as one of
the building blocks (R1 = H). Later on we introduced a substituent
at this position by working from commercially available protected
D
-phenylalanine
and
D
-homophenylalanine
(R1 = CH2Ph,
R1 = C2H4Ph).
Preparation of the key intermediate 12 (Fig. 3) was achieved by
coupling an amino-protected pyridone ring with a moiety contain-
ing the desired substituent at the P1 position and an ester function,
to allow subsequent chemical transformations. Pyridonyl-alde-
hydes 5, themselves target molecules in this synthesis, were ob-
tained directly from 12, and the remaining target molecules 6a–c
to the
a
,b unsaturated methyl ester analogue of 1b. Pleasingly,
,b unsat-
there was a high degree of similarity between 6a and the
a
Figure 2. Pairwise molecular alignment from FieldTemplater of 1b (green) with 6c (red) and the 1b
a,b unsaturated methyl ester analogue (yellow) with 6a (blue).
(Hydrogens omitted for clarity. Pictures generated using PyMol25.) The template structure presented in Figure 3 (6a–c), designed on the basis of the considerations described
above and of molecular modeling studies, represents our target peptidomimetic malarial cysteine protease inhibitor.

4212
E. Verissimo et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4210–4214
The P1 block 11 was obtained from commercially available Boc-
-phenylalanine and Boc- -homophenylalanine (Scheme 2). Boc-
deprotection followed by nitrous deamination afforded -hydrox-
P2 recognition
element
D
D
A
a
electrophilic group for
enzyme alkylation
yacid intermediates 9a and 9b. Esterification under acidic condi-
tions gave the corresponding methyl esters 10a and 10b, which
were then converted into the more reactive triflates 11a and 11b.
The triflates 11a–b were then condensed with the pyridone
fragment 8 to give intermediates 12a–b (Scheme 3) in good yield.
After purification on silica gel, the esters were quantitatively re-
duced to the primary alcohols 13a–b, which were selectively oxi-
dized to the corresponding aldehydes 5a–b27 (Scheme 3), via a
Dess–Martin periodinane oxidation or, more successfully, using
Swern conditions. Olefination of the aldehyde using Wittig– or
Horner–Emmons–Wadsworth methodologies afforded target mol-
ecules 6a–c (Scheme 3).28 This is an approach widely applied to the
E
Z
N
N
H
O
R1
P3 site
P1 recognition
element
Potential for
H-bonding
O
B
Z
N
Z
N
E
N
N
H
H
O
R1
a
,b unsaturated esters29,30 and aryl or alkyl vinyl
O
R1
synthesis of
sulfones.18,31,32
R1 = H; CH2Ph; C2H4Ph
E = CO2Me; SO2Ph
6a-c
5a,b
The antimalarial activity of the target molecules prepared was
measured in red blood cell-based assays. Efficacy was monitored
by parasite {3H}-hypoxanthine incorporation using parasite-in-
fected human erythrocytes.33,34 We have assayed compounds in
triplicate against the chloroquine-resistant parasite strain TM6
and against the chloroquine-sensitive parasite strain 3D7 (Table
1). The screening of our three best peptidomimetics against puri-
fied recombinant FP2 and FP3 (prepared as previously de-
scribed8,10) was performed as previously described by Shenai
et al.18
SN2
with inversion
O
O
TfO
Z
N
Z
NH
O
N
O
+
N
H
H
R1
11
O
R1
O
12
8
Figure 3. (A) Structure of peptidomimetic template and (B) retrosynthetic analysis
for analogues 6a–6c.
All our new peptidomimetic derivatives displayed measurable
in vitro antimalarial inhibition, with IC50 ranging from 6 to
40
with no measurable antimalarial activity). Compound 6c was the
best inhibitor of this series, followed by the ,b unsaturated methyl
ester 6a, with very close activity to the one presented by aldehyde
5b. As seen previously, the vinyl sulfone 6b and the aldehyde 5a,
bearing a phenylalanine substituent at P2 position, were less active
than their counterparts bearing the longer unnatural segment of
l
M (initial synthetic approach with R1 = afforded compounds
were obtained via a Wittig-type strategy. The synthetic transfor-
mations employed followed previously reported preparations of
related peptidyl and peptidomimetic inhibitors.23,26 The pyridone
8 was obtained from commercially available 3-nitropyrid-2-one,
by selective reduction of the nitro group and subsequent protec-
tion of the primary amine 7 as a carbamate (Scheme 1).
a
O
(i)
(ii)
NH
NH
NH
Ph
O
N
O2N
H2N
H
O
O
O
7, 98%
8, 50%
Scheme 1. Reagents and conditions: (i) H2, 10% Pd–C, EtOH, 8 h, rt.
R1
O
O
O
(i)
(ii)
HO
HO
O
OH
O
N
H
O
R1
OH
R1
9a R1= CH2Ph, 64%
9b R1= C2H4Ph, 69%
10a R1= CH2Ph, 100%
10b R1= C2H4Ph, 100%
(iii)
O
O
O
R1
F3C S
O
O
11a R1= CH2Ph, 59%
11b R1= C2H4Ph, 53%
Scheme 2. Reagents and conditions: (i) HCl, dioxane, hexane, then H2SO4 and NaNO2 aq; (ii) HCl, MeOH, overnight, rt; (iii) 2,6-lutidine, trifluoromethane sulfonic anhydride,
neat, 0 °C, 1 h.

E. Verissimo et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4210–4214
4213
O
(i)
(ii)
OH
R1
Cbz
N
8
11a,b
Cbz
N
+
O
N
H
N
H
R1
O
O
12a R1= CH2Ph, 76%
13a R1= CH2Ph, quant.
13b R1= C2H4Ph,quant.
12b R1= C2H4Ph, 67%
(iii)
O
Cbz
N
O
N
H
(iv)
(v)
O
R1
O
Cbz
N
6a R1= C2H4Ph, 91%.
N
H
R1
O
5a R1= CH2Ph, 72%
5b R1= C2H4Ph, 78%
O
S
Cbz
N
Ph
N
H
O
O
R1
6b R1= CH2Ph, 63%
6c R1= C2H4Ph, 98%
Scheme 3. Reagents and conditions: (i) NaH, THF, rt, 2 h; (ii) NaBH4, CaCl2, EtOH, ꢀ5 °C; (iii) a—DMP, CH2Cl2, 1 h, rt; b—DMSO, CH2Cl2, then (COCl)2 and Et3N; (iv)
Ph3P@CO2Me, THF, reflux, 1 h; (v) NaH, diethyl(phenylsulfonyl)methylphosphonate, THF, ꢀ10 °C to rt, 1 h, 30 min.
Table 1
Antimalarial activities of peptidomimetic compounds (R1 ¼ H) versus Plasmodium falciparum parasites and recombinant enzymes FP2 and FP3
Cbz
N
R2
R1
N
H
O
a
Compound
R1
R2
IC50 (lM)
3D7c parasite strain
TM6c parasite strain
Rec FP2
Rec FP3
5a
5b
CH2Ph
C2H4Ph
CHO
CHO
37.3
31.0
36.0
22.7
—
10.9
—
>25.0
COOMe
SO2Ph
SO2Ph
6a(E:Z 9:1)
6b (E)
C2H4Ph
CH2Ph
C2H4Ph
27.9
35.7
5.7
35.3
36.0
9.0
19.0
>25.0
—
—
b
b
6c (E:Z 1:1)
0.003d
0.0029
0.0219
SO2Ph
1a
C2H4Ph
Chloroquine
15 nM
150 nM
a
Parasites were maintained in continuous culture, according to the method described by Trager and Jensen.33 IC50 values were measured according to the method
described by Desjardins et al.34
b
Precipitation of the compound occurred in this case, not allowing reliable analysis.
c
3D7 is a chloroquine-sensitive strain of the parasite P. falciparum, and TM6 is a chloroquine-resistant strain of the parasite.
d
Compound tested against Itg2 strain of P. falciparum parasites.12
homophenylalanine. These results are supportive with the fact that
a longer chain is a more suitable substituent to have in the P1 rec-
ognition site of FP2 inhibitors. Though molecular modeling studies
showed excellent match of conformations between both our pepti-
domimetic 6a and 6c and their peptidic counterparts, antimalarial
activity is more significant with the vinyl sulfonyl analogue, indi-
cating that this electrophilic moiety may be more reactive toward
the nucleophilic thionyl group of the target enzyme. Also, we can
see from our activity results that reversible aldehyde inhibitors
show slightly higher activity against the chloroquine-resistant
strain TM6. Activity of our three best peptidomimetics against puri-
fied recombinant enzymes FP2 and FP3 was found to be week
against parasite enzymes.35 It is noteworthy that compound 5b
shows both higher antiplasmodial activity and enzymatic inhibi-
tion when compared to compound 6a; however, the solubility
problems encountered for compound 6c under the experimental
conditions used in this assay have not permitted, until the current
time, to obtain a clear correlation between the antiparasitic and
enzymatic inhibitory activities, which would strengthen the
hypothesized mode of action for this class of compounds.
In summary, a new class of peptidomimetics have been synthe-
sized, following a short and optimized synthetic route and incorpo-
rating a new pyridone ring scaffold as a replacement for the
peptidic leucine residue, at the P2 position, within the inhibitor’s
framework. From analysis of the work described in this paper, it
seems that though conformational restriction is reported to be a
(IC50 > 10
lM), with higher activity against FP2 than FP3, in line
with previous reports of the selectivity of these types of compounds

4214
E. Verissimo et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4210–4214
requirement for inhibitors to be recognized by many proteases,36,37
and despite our results being comparable and consistent to others
for peptidomimetic cysteine protease inhibitors reported in the lit-
erature,38 the rigid pyridine moiety chosen here is not a suitable
backbone modification, as structurally comparable unconstrained
peptidyl aldehydes and vinyl sulfones display higher activity.5,12,18
10H, Ar), 6.87 ((dd, J = 6.8 Hz, J = 1.2 Hz, 1H), 6.15 (t, J = 7.2 Hz, 1H), 5.18 (s, 2H),
4.90 (br s, 1H), 3.92 (br s, CHO), 3.16 (m, 2H, CH2). 13C NMR (100 MHz, CDCl3) d
158.1, 153.7, 137.4, 136.4, 129.8, 129.1, 129.0, 128.7, 128.5, 128.3, 127.3, 120.5,
107.1, 67.4, 63.9. MS found [M+Na+CH3OH]+ 431.1577, C23H24N2O523Na
requires 431.1583. Procedure for the synthesis of compound 5b: this product
was prepared in 78% as a yellow oil. The product was purified by flash column
chromatography using 45% EtOAc in hexane as the eluent system. ½a D22
ꢀ184°
ꢁ
(c 0.8, CH2Cl2). mmax (neat)/cmꢀ1 3386, 1732, 1649, 1597, 1564, 1512, 1454,
1381, 1360, 1261, 1199, 1160, 1066. 1H NMR (400 MHz, CDCl3) dH 9.60 (s, 1H,
CHO), 8.08 (d, J = 7.2 Hz, 1H), 7.82 (s, 1H), 7.40–7.14 (m, 10H, Ar), 6.75 (dd,
J = 7.2 Hz, J = 1.6 Hz, 1H), 6.30 (t, J = 7.2 Hz, 1H), 5.21 (s, 2H), 4.75 (dd, J = 9.6 Hz,
J = 4.0 Hz, 1H), 2.70–2.58 (m, 3H), 2.34–2.22 (m, 1H). 13C NMR (100 MHz,
CDCl3) dC 195.7, 157.1, 153.3, 139.7, 135.9, 129.9, 128.7, 128.6,128.4, 128.1,
128.1, 126.6, 120.5, 107.3, 67.4, 67.2, 29.7, 29.4, 30,0. MS found [M+H]+
391.1663, C23H23N2O4 requires 391.1658.
Acknowledgments
The authors thank the Biotechnology and Biological Sciences
Research Council (BBSRC, S.A.W., P.O.N., P.G. Grant BB/C006321/
1) and the FCT (Fundação para a Ciência e Tecnologia in Portugal,
Ph.D. Grant: SFRH/6176/2001), and the National Institute of
Health, Portugal for funding this work.
28. Procedure for the synthesis of peptidomimetic pyridone vinyl ester 6a: Precursor
aldehyde (0.59 mmol) was dissolved in dry tetrahydrofuran (8.7 ml), and
(methoxycarbonylmethylene)–triphenylphosphorane (0.83 mmol) added. The
reaction mixture was refluxed for 1 h then left stirring at room temperature,
overnight. The crude mixture obtained was purified by flash chromatography,
using 40% EtOAc in hexane as the eluent system, affording the pure product as
a viscous yellow oil (91%). mmax (neat)/cmꢀ1 3377, 1728, 1649, 1601, 1512,
1454, 1437, 1389, 1356, 1263, 1198, 1066. 1H NMR (400 MHz, CDCl3) dH 8.02
(d, J = 7.2 Hz, 1H), 7.91 (s, 1H, NH), 7.41–7.10 (m, 10H, Ar), 6.99 (dd, J = 15.6 Hz,
J = 5.2 Hz, 1H, vinyl H), 6.85 (dd, J = 7.2 Hz, J = 2.0 Hz, 1H), 6.29 (t, J = 7.2 Hz,
1H), 5.82 (dd, J = 15.6 Hz, J = 2.0 Hz, 1H, vinyl H), 5.77 (m, 1H), 5.21 (s, 2H),
3.72 (s, 3H), 2.68–2.60 (m, 1H), 2.56–2.49 (m, 1H), 2.29–2.12 (m, 2H). 13C NMR
(100 MHz, CDCl3) dC 166.0, 157.1, 153.4, 145.1, 140.1, 136.0, 129.6, 128.6,
128.3, 128.3, 128.1, 126.4, 125.2, 123.2, 119.5, 107.3, 67.1, 55.8, 51.8, 34.7,
32.0, 30.9. MS found [M+Na]+ 469.1722, C26H26N2O523Na requires 469.1739.
Procedure for the synthesis of peptidomimetic pyridone vinyl phenyl sulfones 6b,c:
References and notes
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To
a solution of diethyl (phenylsulfonyl)methyl phosphonate previously
prepared (0.30 mmol) in THF (3 ml), at ꢀ10 °C, was added sodium hydride
(0.32 mmol). After gas evolution had ceased (approx. 30 min), a solution of the
aldehyde precursor (0.24 mmol) in THF (3 ml), at 0 °C, was added under
nitrogen and with stirring. The reaction mixture was allowed to warm to 25 °C,
with continuous stirring. After 1 h 30 min the reaction mixture was diluted
with diethyl ether (15 ml) and then poured into brine (10 ml). The layers were
separated, and the organic portion was dried over magnesium sulphate,
filtered, and the filtrate concentrated under reduced pressure. The products
were purified by flash column chromatography, using a 35% EtOAc in hexane
solvent system. Compound 6b was obtained as a pink oil (63%, analysis shown
for the E product): ½a D22
ꢁ
ꢀ32° (c 1.0, CH2Cl2). mmax (neat)/cmꢀ1 3377, 3063,
2925, 1729, 1648, 1599, 1559, 1507, 1447, 1387, 1357, 1306, 1198, 1148, 1086,
1069, 745, 688. 1H NMR (400 MHz, CDCl3) dH 7.86 (m, 2H), 7.73–6.98 (m, 16H),
6.74 (dd, J = 7.2 Hz, J = 1.6 Hz, 1H), 6.18 (dd, J = 15.0 Hz, J = 2.0 Hz, 1H, vinyl),
6.15 (t, J = 7.2 Hz, 1H), 5.90–5.85 (m, 1H), 5.10 (s, 2H), 3.17–3.03 (m, 2H). 13C
NMR (100 MHz, CDCl3) dC 157.1, 153.6, 140.0, 134.0, 133.5, 129.9-127.7,
125.84, 120.0, 107.6, 73.3, 68.4, 67.5, 61.6, 57.6, 53.8, 44.8, 39.6, 32.0, 30.1,
25.7. Found [M+Na]+ 537.1453, C29H26N2O5S23Na requires 537.1460 and
[M+K]+ 553.1220, C29H26N2O5S39
K requires 553.1200. Compound 6c was
obtained as a colorless oil (98%, analysis shown for the E/Z product mixture):
½
a 2D2
ꢁ
ꢀ137° (c 0.3, CH2Cl2). mmax (neat)/cmꢀ1 3375, 1728, 1649, 1604, 1512,
1504, 1446, 1358, 1308, 1252, 1199, 1145, 1084, 902., 872. 1H NMR (400 MHz,
CDCl3) dH 8.05–7.01 (m), 6.66 (dd, J = 7.2 Hz, J = 2.0 Hz), 6.36 (dd0, J = 6.8 Hz,
J = 2.0 Hz), 6.19 (t, J = 7.2 Hz), 6.12 (t0, J = 6.8 Hz), 5.73 (dd0, J = 10.8 Hz, J =
5.2 Hz), 5.55 (t, J = 8.4 Hz), 5.21 (s, 2H), 5.20 (s0, 2H), 3.83 (d, J = 8.4 Hz, 2H),
3.66 (m, 2H), 3.48 (dd0, J = 14.4 Hz, J = 10.8 Hz), 3.05 (s), 2.80–2.72 (m), 2.67 (t,
J = 8.4 Hz, 2H), 2.43 (t0, J = 7.6 Hz, 2H). 13C NMR (100 MHz, CDCl3)dC 156.3,
155.8, 153.3, 153.2, 149.3, 146.7, 139.8, 139.7, 138.6, 138.6, 135.9, 135.8, 134.1,
133.9, 133.6, 129.5, 129.3, 128.6, 128.5, 128.3, 128.2, 128.1, 127.3, 126.4, 120.2,
120.1, 116.9, 114.7, 106.5, 106.5, 67.1, 55.3, 55.1, 44.4, 36.1, 32.4, 32.40, 31.6,
30.6, 25.3. Found [M+H]+ 551.1601, C30H28N2SO5 23Na requires 551.1617.
29. Dragovich, P. S.; Webber, S. E.; Binford, S. L.; Babine, R. E.; Lee, B. J., et al J. Med.
Chem. 1998, 41, 2806.
26. Warner, P.; Green, R. C.; Gomes, B.; Strimpler, A. M. J. Med. Chem. 1994, 37,
3090.
27. Procedure for the synthesis of peptidomimetic pyridone aldehydes 5a,b: DMSO
(3.02 mmol) was added to a solution of oxalyl chloride (1.81 mmol) in DCM
(0.55 ml) at ꢀ78 °C, and stirred for 5 min. The alcohol (1.01 mmol) dissolved in
DCM (15 ml) was then added, and the mixture was stirred for 15 min still at
ꢀ78 °C, after which triethylamine (7.05 mmol) was added. The reaction
mixture was allowed to warm up to 0 °C and kept at that temperature until
TLC analysis indicated consumption of the starting material. The reaction
mixture was then diluted with water, washed with brine and saturated aq
NaHCO3. The organic layer was dried over MgSO4, evaporated and purified by
flash column chromatography. Procedure for the synthesis of compound 5a: This
product was prepared in 72% as a clear yellow oil. The product was purified by
flash column chromatography using 45% EtOAc in hexane as the eluent system.
30. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
31. Enders, D.; Von Berg, S.; Jendeleit, B. Org. Synt. 1995, 78, 169.
32. Carretero, J. C.; Demillequand, M.; Ghosez, L. Tetrahedron 1987, 43, 5125.
33. Trager, W.; Jensen, J. B. Science 1976, 193.
34. Desjardins, R. E.; Canfield, C. J.; Haynes, J. D.; Chulay, J. D. Antimicrob. Agents
Chemother. 1979, 16, 710.
35. Sijwali, P. S.; Kato, K.; Seydel, K. B.; Gut, J.; Lehman, J., et al Proc. Natl. Acad. Sci.
U.S.A. 2004, 8721.
36. Leung, D.; Abbenante, G.; Fairlie, D. P. J. Med. Chem. 2000, 43, 305.
37. Salituro, F. G.; Baker, C. T.; Court, J. J.; Deininger, D. D.; Kim, E. E., et al Bioorg.
Med. Chem. Lett. 1998, 8, 3637.
½
a 2D2
ꢁ
ꢀ55° (c 0.4, CH2Cl2).
1560, 1512, 1454, 1381, 1359, 1260, 1199, 1163, 1071, 1029, 917, 744, 699. 1
NMR (400 MHz, CDCl3) dH 7.98 (d, J = 6.4 Hz, 1H), 7.89 (s, 1H), 7.40–7.10 (m,
m
max (neat)/cmꢀ1 3374, 3030, 2924, 1730, 1646, 1594,
38. Ettari, R.; Nizi, E.; Di Francesco, M. E.; Dude, M. A.; Pradel, G., et al J. Med. Chem.
2008, 51, 996.
H