Synthesis of anti-bacterial peptidomimetics derived from N-acylisatins

Article abstract of DOI:10.1016/j.tetlet.2008.03.007

An efficient synthetic strategy to mono- and bis-glyoxylamide derivatives via the reaction of N-acylisatins with a range of amino acids has been developed. Using this strategy, a series of new peptidomimetics have been synthesized.

Full text of DOI:10.1016/j.tetlet.2008.03.007

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2965–2968
Synthesis of anti-bacterial peptidomimetics derived from N-acylisatins
Wai Ching Cheah, David StC Black, Wai Kean Goh, Naresh Kumar *
School of Chemistry, The University of New South Wales, Sydney, NSW 2052, Australia
Received 4 January 2008; revised 12 February 2008; accepted 3 March 2008
Available online 6 March 2008
Abstract
An efficient synthetic strategy to mono- and bis-glyoxylamide derivatives via the reaction of N-acylisatins with a range of amino acids
has been developed. Using this strategy, a series of new peptidomimetics have been synthesized.
Ó 2008 Elsevier Ltd. All rights reserved.
Peptidomimetics are small peptide-like molecules
designed to vary the properties of an existing peptide mole-
cule by specific structural variation. The ability of mutant
peptides to mimic the properties of natural peptides often
confers on the former greater molecular stability and
improved biological activity.1–3 Such peptidomimetics are
crucial in the pharmaceutical industry in the development
of drug-like compounds from existing peptides.
peptide (RIP) 1.1,6 The efficacy of RIP lies in its ability to
inhibit the synthesis of the agr transcription proteins,
RNAII and RNAIII. This has a downstream effect on
the S. aureus virulence response since many related diseases
such as cellulitis, keratitis, osteomylitis and mastitis were
effectively inhibited.1,6
O
Recent advancements in the development of anti-bacte-
rial agents have shifted to target the various regulatory sys-
tems in bacteria. One such system is the Quorum Sensing
(QS) platform of the bacteria that utilizes diffusible chem-
ical signal molecules to control vital processes such as bio-
luminescence, biofilm development and virulence factor
expression.4
Human pathogenic bacteria such as Gram-positive
Staphylococcus aureus and Staphylococcus epidermis con-
trol their virulence expression through a QS system medi-
ated by oligopeptides.5 These specific peptides are
adapted to induce various virulence phenotypes in response
to the cell population density such as production of host-
cell damaging exotoxins.5
H2N
H2N
Ph
O
HN
O
O
OH
O
OH
O
N
H
O
H
N
O
NH
N
H
N
NH2
OH
N
H
1
Although the RIP has considerable potential to be an
effective inhibitor of S. aureus diseases, these natural pep-
tide-based anti-microbial agents lack the required meta-
bolic stability and absorption rates. However, recent
reports have shown that peptidomimetics have higher
metabolic stability and absorption rates in blood cells
compared to their predecessors.3
It has been shown that S. aureus infections and virulence
can be controlled by a heptapeptide RNAIII inhibiting
*
Corresponding author. Tel.: +612 9385 4698; fax: +612 9385 6141.
E-mail address: n.kumar@unsw.edu.au (N. Kumar).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.007

2966
W. C. Cheah et al. / Tetrahedron Letters 49 (2008) 2965–2968
Table 1
In view of the important biological properties of the
First generation mono-glyoxylamides 8 produced via Scheme 1
peptidomimetics, we report the synthesis of novel anti-bac-
terial mono- and bis-glyoxylamide peptidomimetics. The
synthetic strategy proceeds via a direct and efficient ring-
opening of N-acylisatins with a range of amino acids as
the building blocks.
The precursor N-acetylisatins 5–7 were first prepared
through the acetylation of isatins 2–4 using a modification
of a strategy previously reported by Suida.7 Subsequent
treatment of the N-acetylisatins with various amino-ester
HCl salts and peptides afforded the first generation
mono-glyoxylamides 8a–o (Scheme 1).8
It was found that the ring-opening conditions required
the use of a dual-solvent system CH2Cl2/H2O (2:1) with
yields ranging from 61% to 98% (Table 1). The formation
of the glyoxylamides was further confirmed by an X-ray
crystallographic analysis of 8a (Fig. 1).9
In light of the successful ring-opening with various
amino acid derivatives, the methodology was further
extended to include a range of dipeptides and tripeptides
as the first key step towards generating peptidomimetics
similar to 1.
Entry
R1
Amino acida
Productb
Yieldc (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
a
H
H
H
H
H
Br
Br
Br
Glycine
L-Valine
L-Phenylalanine
D-Phenylalanine
L-Methionine
Glycine
8a
8b
8c
8d
8e
8f
97
97
98
98
85
61
75
69
69
74
75
67
83
83
90
L-Valine
8g
8h
8i
L-Phenylalanine
D-Phenylalanine
L-Methionine
Glycine
Br
Br
8j
CH3
CH3
CH3
CH3
CH3
8k
8l
L-Valine
L-Phenylalanine
D-Phenylalanine
L-Methionine
8m
8n
8o
Amino acid as methyl ester HCl salts.
R2 = Corresponding amino acid substituent.
Isolated yields.
b
c
Various dipeptides and tripeptides were reacted with N-
acetylisatins 5–7 using the reaction conditions exemplified
in Scheme 2. The ring-opening strategy was established to
be relatively general since a range of glyoxylamides 11a–o
was successfully synthesized in reasonably good yields
(Table 2).
Attempts were also made to synthesize bis-glyoxyl-
amides with increased anti-bacterial potency. It was antic-
ipated that these compounds would show multivalent
effects owing to their high affinity towards simultaneous
ligation to binding sites.10
Fig. 1. X-ray crystal structure of 8a.
Using the methodology described earlier and the reac-
tion conditions exemplified in Scheme 3, the core N-gly-
oxyl-bis-isatins11 12a–b were coupled with a range of
amino acids and dipeptides. The initial coupling reaction
with glycine required an excess of the amino acid for
completion of the reaction but only a 3% yield of 14a
was recorded. However, when bulky amino acids and
dipeptides were used, products 14b12–k were isolated in
yields of 20–45% (Table 3).
The peptidomimetics above have been evaluated for
their efficacy against Gram-positive bacteria and it was
found that 11d and 14b exhibited significant anti-bacterial
activity. Further biological effects of these novel com-
pounds are currently being investigated.
In conclusion, a general, versatile synthesis of new
glyoxylamide peptidomimetics has been developed. This
synthesis proceeds via an efficient ring-opening of N-acylis-
R1
O
O
R1
R1
O
R2
i
ii
O
O
OCH3
N
N
N
H
H
O
NH
CH3
O
O
O
H3C
2 (R1 = H)
3 (R1 = Br)
4 (R1 = CH3)
5 (R1 = H)
6 (R1 = Br)
8a-o
7 (R1 = CH3)
Scheme 1. Reagents and conditions: (i) Ac2O, reflux, 4 h; (ii) amino acid derivatives, saturated NaHCO3, CH2Cl2/H2O (2:1, v/v), 0 °C to room
temperature, 24 h.

W. C. Cheah et al. / Tetrahedron Letters 49 (2008) 2965–2968
2967
R1
O
R1
O
H
O
O
D
N
O
H
L
i
H2N
HCl
OCH3
+
N
D
N
L
N
OCH3
O
H
O
O
NH
CH3
O
O
H3C
5 (R1 = H)
9
11b (R1 = H)
+
R1
CH3
O
H
O
CH3
O
i
H
N
L
OCH3
L
D
L
N
OCH3
H2N
N
L
D
N
H
N
H
H
O
O
HCl
O
NH
CH3
O
O
O
10
11j (R1 = H)
Scheme 2. Reagents and conditions: (i) saturated NaHCO3, CH2Cl2/H2O (2:1, v/v), 0 °C to room temperature, 24 h.
Table 2
Second generation mono-glyoxylamides 11 produced via Scheme 2
Entry
R1
Dipeptides and tripeptidesa
Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
a
H
H
H
Br
Br
Br
CH3
CH3
CH3
H
H
Br
Br
CH3
CH3
L-Valine-L-phenylalanine
L-Valine-D-phenylalanine
L-Valine-L-methionine
L-Valine-L-phenylalanine
L-Valine-D-phenylalanine
L-Valine-L-methionine
L-Valine-L-phenylalanine
L-Valine-D-phenylalanine
11a
11b
11c
11d
11e
11f
11g
11h
11i
65
65
55
50
50
48
60
60
55
30
33
30
30
35
30
L-Valine-L-methionine
L-Alanine-L-valine-D-phenylalanine
L-Valine-L-phenylalanine-L-leucine
L-Alanine-L-valine-D-phenylalanine
L-Valine-L-phenylalanine-L-leucine
L-Alanine-L-valine-D-phenylalanine
L-Valine-L-phenylalanine-L-leucine
11j
11k
11l
11m
11n
11o
Peptide derivatives as methyl ester HCl salts.
Isolated yields.
b
R1
O
R1
O
O
H
N
O
N
L
L
O
N
OCH3
OCH3
H
H
O
L
N
i
O
O
NH
NH
O
O
+
L
H2N
OCH3
Ph
Ph
O
O
O
HCl
N
Ph
O
H
O
N
L
L
N
H
R1
O
O
O
R1
12a (R1 = H)
13
14j (R1 = H)
14k (R1 = CH3)
12b (R1 = CH3)
Scheme 3. Reagents and conditions: (i) saturated NaHCO3, CH2Cl2/H2O (4:1, v/v), 0 °C to room temperature, 24 h.

2968
W. C. Cheah et al. / Tetrahedron Letters 49 (2008) 2965–2968
Table 3
Bis-glyoxylamides 14 produced via Scheme 3
Entry
R1
Amino acids and Dipeptidesa
Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
H
H
H
H
Glycine
L-Valine
L-Phenylalanine
D-Phenylalanine
L-Methionine
14a
14b
14c
14d
14e
14f
14g
14h
14i
3
45
35
33
30
40
30
30
28
20
20
H
CH3
CH3
CH3
CH3
H
L-Valine
L-Phenylalanine
D-Phenylalanine
L-Methionine
L-Valine-L-phenylalanine
L-Valine-L-phenylalanine
10
11
a
14j
14k
CH3
Amino acid and peptide derivatives as methyl ester HCl salts.
Isolated yields.
b
solvent evaporated in vacuo. Purification of the residue by silica gel
chromatography with dichloromethane as the eluent and further
recrystallization from dichloromethane/light petroleum afforded 8a as
white crystals, mp 142–145 °C. 1H NMR (300 MHz; CDCl3): d 2.22
(3H, s, PhNHCOCH3), 3.81 (3H, s, COOCH3), 4.19 (2H, d, J =
5.6 Hz, CH2COOCH3), 7.12 (1H, t, J = 7.1 Hz, Haryl), 7.36 (1H, br s,
COCONHCH2), 7.60 (1H, t, J = 7.1 Hz, Haryl), 8.36 (1H, d,
J = 8.3 Hz, Haryl), 8.66 (1H, d, J = 7.5 Hz, Haryl), 10.9 (1H, br s,
PhNHCOCH3). 13C NMR (75 MHz; CDCl3): d 25.3, 41.1, 52.5,
120.6, 122.5, 134.3, 136.6, 142.1, 162.8, 169.1, 169.2, 190.9. IR (Nujol,
m, cmÀ1): 3319, 3261, 3069, 2954, 1743, 1672, 1660, 1574, 1525, 1450,
1294, 1205, 938, 764, 676, 489. HRMS (ESI): m/z 301.0818 (M+Na+;
C13H14N2O5Na requires 301.0818). Anal. Calcd for C13H14N2O5: C,
56.11; H, 5.07; N, 10.07. Found C, 56.27; H, 5.16; N, 10.10.
atins with various amino acid and peptide derivatives. This
reaction scheme generates new classes of peptidomimetics
and offers access to many peptide building blocks for the
development of drug-like compounds from existing
peptides.
Acknowledgement
We thank the University of New South Wales and the
Australian Research Council for their financial support.
References and notes
9. Crystal data for 8a:
C13H14N2O5, colourless, crystal dimension
0.20 Â 0.18 Â 0.15 mm, monoclinic, space group P21/c, a =
1. Gov, Y.; Sudoh, M.; Aube, J.; Borchardt, R. T. J. Pept. Res. 2001, 57,
316–329.
2. Friedler, A.; Zakai, N.; Karni, O.; Broder, Y. C.; Baraz, L.; Kotler,
M.; Loyter, A.; Gilon, C. Biochemistry 1998, 37, 5615–5622.
3. Montero, A.; Albericio, F.; Royo, M.; Herrado´n, B. Eur. J. Org.
Chem. 2007, 1301–1308.
˚
˚
˚
7.720(3) A, b = 22.606(4) A, c = 8.916(3) A, a = 90.00°, b = 119.97(1)°,
3
3
˚
c = 90.00°, V = 1347.9(8) A , Mr = 278.3, Z = 4, Dc = 1.37 Mg/m ,
k = 0.71073 A, l(Mo Ka) = 0.104 mmÀ1, F(000) = 584.0, 2° < h <
˚
25°, R = 0.052, wR = 0.058, S = 1.51, largest difference in peak and
3
˚
hole: 0.37 and À0.31 e/A . Crystallographic data for the structure of
8a reported in this Letter have been deposited with the Cambridge
Crystallograpic Data Centre as Supplementary Publication No.
CCDC-671759.
4. Chen, X.; Schauder, S.; Potier, N.; Dorsselear, A. V.; Pelczer, I.;
Bassler, B. L.; Hughson, F. M. Nature 2002, 415, 545–549.
5. Winans, S. C.; Bassler, B. L. J. Bacteriol. 2002, 184, 873–883.
6. Giacometti, A.; Cirinoni, O.; Gov, Y.; Ghiselli, R.; Prete, M. S. D.;
Mocchegiani, F.; Saba, V.; Orlando, F.; Scalise, G.; Balaban, N.;
Dell’Acqua, G. Antmicrob. Agents Chemother. 2003, 47, 1979–
1983.
7. Suida, W. Ber. Dtsch. Chem. Ges. 1878, 11, 584–586.
8. Representative procedure for 8a: A solution of N-acetylisatin 5
(1.0 mmol) in CH2Cl2 (20 mL) was cooled to 0 °C and glycine methyl
ester hydrochloride (2.5 mmol) was added followed by saturated
aqueous NaHCO3 (2 mL) and H2O (10 mL). The mixture was allowed
to warm to room temperature and stirred for 24 h. The organic layer
was separated and washed successively with HCl (0.5 M, 20 mL) and
water (20 mL). The organic phase was then dried (Na2SO4) and the
10. Ritter, T. K.; Wong, C. H. Angew. Chem., Int. Ed. 2001, 40, 3508–
3533.
11. Black, D. StC.; Moss, G. I. Aust. J. Chem. 1987, 40, 129–142.
12. Compound 14b: mp 270–272 °C. 1H NMR (600 MHz; CDCl3): d 1.01
(12H, m, CH3), 2.30 (2H, m, CH(CH3)2), 3.79 (6H, s, COOCH3), 4.64
(2H, m, NHCHCH(CH3)2), 7.29 (2H, t, J = 7.7 Hz, Haryl), 7.47 (2H,
d, J = 9.0 Hz, COCONHCH), 7.70 (2H, t, J = 7.8 Hz, Haryl), 8.63
(2H, d, J = 8.3 Hz, Haryl), 8.86 (2H, d, J = 8.5 Hz, Haryl), 12.8 (2H, br
s, PhNHCOCO). 13C NMR (150 MHz; CDCl3): d 18.2, 19.5, 31.8,
52.0, 57.9, 112.5, 120.3, 121.2, 124.4, 124.6, 126.8, 135.3, 140.5, 158.8,
190.6. IR (Nujol, m, cmÀ1): 3266, 1746, 1645, 1513. HRMS (ESI): m/z
633.2153 (M+Na+; C30H34N4O10Na requires 633.2173).