Binaphthyl-anchored antibacterial tripeptide derivatives with hydrophobic C-terminal amino acid variations

Article abstract of DOI:10.3762/bjoc.8.142

The facile synthesis of seven new dicationic tripeptide benzyl ester derivatives, with hydrophobic group variations in the C-terminal amino acid component, is described. Moderate to good activity was seen against Gram-positive bacteria in vitro. One cyclohexylsubstituted compound 2c was tested more widely and showed good potency (MIC values ranging from 2-4 μg/mL) against antibiotic-resistant strains of Staphylococcus aureus and Enterococci (VRE, VSE), and against Staphylococcus epidermidis.

Full text of DOI:10.3762/bjoc.8.142

Binaphthyl-anchored antibacterial tripeptide
derivatives with hydrophobic C-terminal
amino acid variations
John B. Bremner*1, Paul A. Keller*1, Stephen G. Pyne*1, Mark J. Robertson1,
K. Sakthivel1, Kittiya Somphol1, Dean Baylis2, Jonathan A. Coates2,
John Deadman3, Dharshini Jeevarajah2 and David I. Rhodes4
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1265–1270.
1School of Chemistry, University of Wollongong, Wollongong, NSW
2522, Australia, 2Avexa Ltd, 576 Swan St, Richmond, Vic 3121,
Australia, 3Chemocopeia Pty Ltd, 114 Kay St, Carlton, Melbourne, Vic
3053, Australia and 4JDJ Bioservices Pty Ltd, 576 Swan St,
Richmond, Vic 3121, Australia
doi:10.3762/bjoc.8.142
Received: 31 March 2012
Accepted: 12 July 2012
Published: 09 August 2012
Email:
This article is part of the Thematic Series "Antibiotic and cytotoxic
peptides".
John B. Bremner* - jbremner@uow.edu.au; Paul A. Keller* -
keller@uow.edu.au; Stephen G. Pyne* - spyne@uow.edu.au
Guest Editor: N. Sewald
* Corresponding author
© 2012 Bremner et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
antibacterials; binaphthyls; cationic peptides; peptides; resistance;
VISA; VRE
Abstract
The facile synthesis of seven new dicationic tripeptide benzyl ester derivatives, with hydrophobic group variations in the C-terminal
amino acid component, is described. Moderate to good activity was seen against Gram-positive bacteria in vitro. One cyclohexyl-
substituted compound 2c was tested more widely and showed good potency (MIC values ranging from 2–4 μg/mL) against anti-
biotic-resistant strains of Staphylococcus aureus and Enterococci (VRE, VSE), and against Staphylococcus epidermidis.
Introduction
Among the most pressing challenges in current healthcare is the protonated, such as telavancin, oritavancin and dalbavancin [5].
resistance of bacterial human pathogenic organisms to anti- An alternative approach to meeting this resistance challenge, at
biotics [1,2], and of particular concern is the resistance to the least in part, is through the design and synthesis of smaller
cationic glycopeptide, vancomycin [3,4]. This challenge is cationic peptidic compounds incorporating features that could
being addressed in a number of ways, which include both circumvent the vancomycin resistance mechanism. In much of
detailed studies aimed at the further understanding of the mech- our work we have been concerned with binaphthyl-based
anism of this resistance, as well as the development of new dicationic peptide derivatives, for example the acyclic tripep-
large glycopeptide analogues containing amine sites that can be tides of type 1 (Figure 1; for example A = CH2CH=CH2,
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Beilstein J. Org. Chem. 2012, 8, 1265–1270.
B = CH2Ph, R = CH2CH2CH(CH3)2, MIC against S. aureus Results and Discussion
4 μg/mL [6]), which show significant promise as antibacterials A concise and flexible approach to all the target compounds
[6-8]. In the development of these antibacterials, it became 2a–g was used, starting from the commercially available amino
apparent that the nature of the C-terminal amino acid derivative acid derivatives 3 and proceeding via the amino benzyl esters 4
was significant, with indications that the hydrophobic groups at (Scheme 1), with the exception of the synthesis of 2c in which
the terminus (Figure 1, group B) [6] and at the α-carbon of the the commercially available 4c was used as the starting material.
amino acid moiety (Figure 1, group A) [6,7] were important. In Addition of the protected central arginine unit by diimide- or
further exploration of the structural space in the latter area, BOP-induced amide bond formation, followed by selective
while maintaining benzyl ester functionality at the terminus Fmoc removal from the respective intermediates 5, then
itself (a free carboxylic acid unit at the C-terminal was delete- provided access to the key intermediate amines 6a–g
rious to activity [8]), we envisaged the introduction of two alkyl (Scheme 1). Diimide-mediated coupling of the previously
substituent units incorporated in a ring system at this carbon, reported lysine containing (S)-binaphthyl acid derivative 7 [8]
resulting in the target compounds 2a–d. Two further com- then afforded the protected tripeptides 8a–g. Removal of the
pounds based on a β–alanine unit with disubstitution at the α- or Pmc (or Pbf) and Boc protecting groups in one pot was then
β-carbons of this unit, 2f and 2e respectively, were accessed achieved by exposure to trifluoroacetic acid, followed by tri-
with a view to assessing the effect of variation in the spatial fluoroacetate/chloride ion exchange on treatment with an excess
disposition of the cycloalkyl or oxacycloalkyl ring on antibacte- of HCl in diethyl ether, and finally evaporation to afford the
rial activity. The conformationally less restricted gem diethyl- salts 2a–g in good overall yields.
substituted compound 2g was also targeted in order to make
antibacterial activity comparisons with the five-membered ring The structures of the final compounds were supported by 1H
analogue 2b. The results of these synthetic and antibacterial and 13C NMR spectroscopy and high-resolution mass spectrom-
testing studies are reported in this paper.
etry. Details of the synthesis and spectral data are given in the
experimental section for the representative compound 2c. The
experimental and spectroscopic data for all the other com-
pounds are included in Supporting Information File 1.
The peptidic dihydrochloride salts 2a–g were tested against the
Gram-positive bacteria Staphylococcus aureus (ATCC 6538)
and four clinical isolates of vancomycin-resistant (and sensi-
tive) enterococci (VRE; Enterococcus faecium), and the results
are shown in Table 1; some compounds were also tested against
Staphylococcus epidermidis (ATCC 12228). Vancomycin was
used as a positive control, and showed a rounded MIC
(minimum inhibitory concentration) value of 2–3 μg/mL against
S. aureus and MIC values of 2, >25, >25 and 3 μg/mL against
the vancomycin sensitive and partially resistant enterococci
Figure 1: Binaphthyl-anchored tripeptide derivatives 1.
Table 1: MIC values (μg/mL) against S. aureus, S. epidermidis and Enterococci of the tripeptide benzyl ester derivatives 2a–g and 9 [6] as their dihy-
drochloride salts.a
Compound
S. aureus
S. epidermidis
VRE243
VRE449
VRE820
VRE987
2a
4
–
–
–
3
3
3
2
–
3
62
62
31
>25
>25
25
16
16
2
31
31
62
62
31
>25
>25
25
31
16
3
2b
3
31
31
2c
2
16
16
2d
3
>25
>25
25
>25
>25
12
2e
3
2f
3–6
2
2g
16
16
9
4
16
8
Vancomycin
2–3
>25
>25
aAll MIC values have been rounded to whole numbers.
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Beilstein J. Org. Chem. 2012, 8, 1265–1270.
Scheme 1: Synthesis of compounds 2a–g. Reagents and conditions: (i) 2a–b,d–g, BnBr, acetone or THF, K2CO3, reflux, 3–12 h; (ii) TFA, DCM, rt,
1–2 h, 2 M HCl/Et2O (HCl salts); (iii) 5a–f: (DIPEA), Fmoc-(R)-Arg(Pmc)-OH (5c) or Fmoc-(R)-Arg(Pbf)-OH (5a–b, d–f), EDCI, HOBt, CH3CN, rt,
3–16 h; 5g: DIPEA, Fmoc-(R)-Arg(Pbf)-OH, BOP, CH3CN, rt, 3–16 h (iv) piperidine, CH3CN, rt, 3–12 h; (v) EDCI, HOBt, CH3CN, rt, 3–72 h; (vi) TFA/
CH2Cl2 (1:1), rt, 2–16 h, then 2 M HCl/Et2O. *Isolated as the HCl salt.
strains, VRE243, VRE449, VRE820 and VRE987, respectively tionality results in good activity against S. aureus and
(Table 1). For comparison purposes, data for the previously S. epidermidis, but a greater variation of activity was seen with
reported [6] isobutyl-substituted analogue 9 (Table 2) are also the enterococcal strains. The systems with four- and five-
included.
membered cycloalkyl rings (2a and 2b) displayed similar activi-
ties, while the cyclohexyl analogue 2c was somewhat better.
While MIC micromolar values should be used for comparative Reducing the hydrophobicity while increasing the hydro-
analysis of activities, the more commonly used concentration of philicity of the six-membered ring in 2c through inclusion of a
micrograms per milliliter is retained in this case. The micro- ring oxygen atom, as in 2d, had a significant detrimental effect
molar values are barely different from the latter, as the molecu- on the activity against the vancomycin-resistant strains VRE449
lar weights for all of the compounds are similar (959–1001; and VRE820. Interestingly, the placement of an extra methylene
vancomycin·HCl, 1486). In most cases, incorporation of a group in the chain, either on the carboxylic ester side (2e) or the
hydrophobic alkyl ring in the chain adjacent to the ester func- amino side (2f), had no or little effect on antibacterial activity,
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Beilstein J. Org. Chem. 2012, 8, 1265–1270.
As a result of its promising initial activity profile, the tripeptide
derivative 2c was subjected to further evaluation (Table 2). It
was tested against methicillin-sensitive (MSSA), methicillin-
resistant (MRSA) and vancomycin-intermediate (VISA)
S. aureus, S. epidermis and vancomycin-resistant (VRE) and
vancomycin-sensitive (VSE) enterococci. The test compound 2c
showed good activity against all these Gram-positive bacteria
with MIC values in the range of 2–4 µg/mL. Again, for com-
parison purposes, results for the published analogue 9 [6],
containing a single isobutyl group in place of the cyclohexyl
group, are also included in Table 2. This tripeptide derivative 9
showed similar, if slightly weaker, antibacterial activity against
these strains, apart from VSE, against which it was signifi-
cantly less potent than 2c.
Table 2: MIC values of compounds 2c and 9 against Gram-positive
isolates.
Straina
MIC50 (range) or MIC [μg/mL]b
Although the mode of action of the tripeptide derivatives has
not been established, our earlier results on compounds of type 1
(Figure 1) and related cyclic systems implicated the possibility
of more than one mode of action [8]. As noted for other cationic
peptide derivatives [9-12], cell membrane damage could well be
one of these actions, together with some more specific interac-
tions. Dual-action type behaviour has been shown for the
vancomycin analogue telavancin, which affects cell wall syn-
thesis and the integrity of the cell membrane [13].
2c
9 [6]
Vancomycin
S. aureus
MSSA (8)
2–4
2–4
4
6
6
6
3
1–2
1–2
6–8
2–3
MRSA (7)
VISA (1)
S. epidermidis (3)
2
E. faecium
VRE (4)
4
2
>32
2–8
Conclusion
VSE (4)
2–4
16
In conclusion, seven novel binaphthyl-anchored tripeptide
derivatives have been prepared and tested for antibacterial
activity against S. aureus and four clinical enterococcal strains.
The dicationic derivatives 2c and 2g showed the best overall
activities. In addition, compound 2c with a hydrophobic cyclo-
hexyl substituent originating from the α-position of the
C-terminal amino acid ester, showed good activity against
S. epidermidis and MSSA, MRSA, VISA and VRE organisms.
Our results confirmed the positive contribution to good Gram-
positive antibacterial activity, engendered by filling of a hydro-
aCompound 2c was tested against a variety of strains (number in
brackets) of S. aureus, S. epidermidis and E. faecium, while com-
pound 9 was tested against only one strain of each organism. Where
the MIC was the same for each strain, no range is given. bWhere only
one strain was tested, the value given is a MIC. S. epidermidis =
Staphylococcus epidermidis; E. faecium = Enterococcus faecium;
MSSA = methicillin-sensitive S. aureus; MRSA = methicillin-resistant
S. aureus; VISA = vancomycin-intermediate S. aureus; VRE =
vancomycin-resistant enterococci; VSE = vancomycin-sensitive entero-
cocci. MIC = minimum inhibitory concentration [μg/mL; rounded to
whole numbers].
regardless of whether a ring oxygen atom was present or not. It phobic area close to the C-terminus of these acyclic tripeptide
appeared that moving the hydrophobic ring substituent position derivatives.
by a small amount in the terminal amino acid unit could be
tolerated in these systems.
Experimental
General notes were those detailed previously in the supporting
The diethyl-substituted peptide derivative 2g was more active information for reference [8].
than the constrained ring comparator compound 2b against the
enterococci, including the vancomycin resistant isolates VRE449 Benzyl 1-((R)-3-amino-1-aza-6-(3,4-dihydro-2,2,5,7,8-
and VRE820, but both had similarly good potencies against pentamethyl-2H-1-benzopyran-6-yl)sulfonyl]guanidino)-2-
S. aureus. In contrast, compound 2c with the cyclohexyl ring oxohexan)cyclohexanecarboxylate (6c). This compound was
was somewhat more active than the isobutyl-substituted ana- prepared in two steps. To a solution of the amine 4c [14]
logue 9. It would thus appear that greater coverage of the hydro- (115 mg, 0.49 mmol) in CH3CN (5 mL) at rt was added HOBt
phobic space available in this region is required for good to (1.2 equiv), EDCI (1.2 equiv) and the acid Fmoc-(R)-Arg(Pmc)-
moderate activity against both the staphylococci and entero- OH [8] (318 mg, 0.48 mmol). The mixture was stirred for ca.
cocci.
3 h, then the solvent was removed under reduced pressure, and
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Beilstein J. Org. Chem. 2012, 8, 1265–1270.
the resulting residue was subjected to silica gel column chroma- CH2Cl2/TFA (6 mL/0.10 mmol) solution was stirred for 12 h at
tography (MeOH/CH2Cl2, 1:99–4:96 as the eluent) to afford the rt. The solvent was removed under reduced pressure, and the
Fmoc-protected precursor 5c as a white foamy solid (402 mg, residue was resuspended in a minimal volume of methanol. The
ESIMS m/z: [M + H]+ 877.9 (100%)). This precursor 5c solution was then treated with an excess of 2 M HCl/diethyl
(200 mg, 0.238 mmol) was then directly deprotected by being ether solution (2 mL, 0.01 mmol) and the solvent evaporated.
stirred in 1 equiv of piperidine/acetonitrile (5 mL per 0.1 mmol The crude product was purified by precipitation from MeOH by
of substrate) for 12 h at rt. The solvent was removed under addition of diethyl ether to yield 2c as an off white solid
reduced pressure, and the crude product was purified by flash (35 mg, 43%). [α]D24 −10.9 (c 3.4, MeOH); 1H NMR (300
column chromatography (silica gel; CH2Cl2/MeOH 15:1) to MHz, CD3OD) δ 0.50 (d, J = 6.4 Hz, 3H), 0.56 (d, J = 6.4 Hz,
afford the desired amine 6c as a white solid (141 mg, 87% two 3H), 0.84–1.02 (m, 2H), 1.03–3.15 (m, 21H), 2.68–2.92 (m,
steps). 1H NMR (500 MHz, CDCl3) δ 1.19–1.44 (m, 16H), 1.30 2H), 2.96–3.20 (m, 2H), 3.91–3.98 (m, 1H), 4.09–4.16 (m, 2H),
(s, 6H, 2CH3 (Pmc)), 2.34 (br s, NH2), 2.10 (s, 3H, CH3 (Pmc)), 4.24–4.36 (m, 1H), 4.42 and 4.54 (ABq, J = 14.6 Hz, 2H), 5.02
2.57 (s, 3H, CH3 (Pmc)), 2.58 (s, 3H, CH3 (Pmc)), 2.61 (t, J = and 5.09 (ABq, J = 12.3 Hz, 2H), 7.06 (t, J = 5.5 Hz, 2H),
6.5 Hz, 2H, CH2 (Pmc)), 3.05–3.29 (m, 2H, CH2N), 3.39–3.50 7.17–7.22 (m, 2H), 7.27–7.36 (m, 7H), 7.44 (d, J = 8.8 Hz, 1H),
(m, 1H, CH (Arg)), 5.06 (ABq, J = 12.6 Hz, 1H), 5.09 (ABq, J 7.53 (d, J = 9.1 Hz, 1H), 7.90 (t, J = 7.0 Hz, 2H), 8.00 (dd, J =
= 12.6 Hz, 1H), 6.41 (s, NH), 7.26–7.41 (m, 5H, ArH), 7.80 (s, 2.3 and 9.1 Hz, 2H), 8.09 (s, NH); 13C NMR (75 MHz,
NH); 13C NMR (125 MHz, CDCl3) δ 12.0, 17.4, 18.4, 21.3, CD3OD) δ 22.5, 22.6, 22.8, 23.0, 25.6, 26.2, 26.3, 27.7, 30.0,
24.5, 25.0, 25.3, 26.7, 26.75, 31.6, 31.9, 32.4, 32.7, 40.5, 54.1, 32.3, 32.9, 33.7, 39.3, 40.3, 42.0, 53.3, 54.3, 60.3, 67.8, 69.0,
57.8, 58.4, 66.7, 73.5, 117.8, 123.9, 127.9, 128.1, 128.4, 133.3, 69.1, 115.9, 116.9, 120.5, 121.7, 124.8, 125.2, 125.9, 126.4,
134.6, 135.3, 135.8, 153.4, 156.3, 174.0, 174.4; ESIMS m/z: 127.5, 127.6, 129.1, 129.2, 129.6, 130.7, 130.9, 131.4, 135.0,
[M + H]+ 656.3 (100%).
135.2, 137.4, 154.0, 155.9, 158.5, 170.7, 173.1, 173.6, 175.4;
ESIMS m/z: [M + H]+ 915.0 (10%), [M + 2H]2+ 457.9 (100);
Benzyl 1-((3R,6R)-3-(3-[(3,4-dihydro-2,2,5,7,8-pentamethyl- HRMS–ESI m/z: [M + H]+ calcd for C53H68N7O7, 914.5175;
2H-1-benzopyran-6-yl)sulfonyl]guanidinopropyl)-9-((S)-2'- found, 914.5130 (100%). HPLC analysis of this compound was
(3-methylbutoxy)-1,1'-binaphth-2-yloxy)-6-(4-(tert-butoxy- also undertaken with a gradient system comprised of H2O
carbonylamino)butyl)-1,4,7-triaza-2,5,8-trioxononan)cyclo- containing 10% CH3CN and 0.1% TFA 90:10:0.5 (A), and
hexanecarboxylate (8c). To a solution of the amine 6c CH3CN containing 0.1% TFA (B). The gradient profile was
(140 mg, 0.213 mmol) in CH3CN (10 mL) at rt was added 0–3 min, linear gradient 0 to 50% B; 4–13 min, linear gradient
HOBt (1.2 equiv), EDCI (1.2 equiv) and the binaphthyl acid 7 50 to 80% of B; 14–15 min, linear gradient 80 to 100% B; tR =
[8] (122 mg, 0.190 mmol). The mixture was stirred for ca. 3 h. 6.1 min, 96% pure.
The solvent was then removed under reduced pressure and the
Determination of minimum inhibitory concen-
resulting residue subjected to silica gel chromatography
(MeOH/CH2Cl2 1:99–4:96 as the eluent) to yield 8c as a white tration (MIC)
solid (163 mg, 67%). [α]D24 −18.6 (c 2.0, MeOH); 1H NMR MIC studies (Table 1) were performed on Staphylococcus
(300 MHz, CDCl3) δ 0.49 (d, J = 6.4 Hz, 3H), 0.54 (d, J = 6.4 aureus wild type (ATCC 6538P), and Staphylococcus epider-
Hz, 3H), 0.66–0.84 (m, 2H), 0.85–1.03 (m, 2H), 1.05–1.62 (m, midis (ATCC 12228) in Mueller–Hinton broth (Oxoid Ltd,
16H), 1.29 (s, 6H), 1.44 (s, 9H), 1.64–1.88 (m, 4H), 1.89–2.14 England) supplemented with 50 mg/L CaCl2. As in [6], MIC
(m, 1H), 2.09 (s, 3H), 2.54–2.64 (m, 2H), 2.55 (s, 3H), 2.57 (s, determinations for clinical isolates of Enterococcus faecium
3H), 2.84–2.96 (m, 2H), 2.97–3.22 (m, 2H), 3.76–3.94 (m, 1H), were conducted by growth in Enterococcosal broth (Becton
4.00–4.07 (m, 2H), 4.36 and 4.54 (ABq, J = 14.6 Hz, 2H), Dickinson Microbiology Systems). Briefly, overnight stationary
4.39–4.48 (m, 1H), 4.78–4.82 (m, NH), 5.06 (s, 2H), 6.14 (br s, phase cultures were diluted 1:1000 into fresh media and then in-
NH) 6.36 (br s, NH), 7.11–7.46 (m, 12H), 7.44 (d, J = 9.1 Hz, cubated with two-fold dilutions of compounds in media, typi-
1H), 7.84 (d, J = 8.9 Hz, 1H), 7.86 (d, J = 7.9 Hz, 1H), 7.92 (d, cally with a highest concentration of 128 µg/mL, in a 96-well
J = 8.8 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H); ESIMS m/z: plate. Plates were incubated overnight at 37 °C and the MIC
[M + H]+ 1280.3 (100%); HRMS–ESI m/z: [M + H]+ calcd for was recorded as the highest concentration at which bacterial
C72H94N7O12S, 1280.6676; found, 1280.6627.
growth was observed.
Benzyl 1-((3R,6R)-6-aminobutyl-3-(3-guanidinopropyl)-9- Compound 2c (Table 2) was tested at JMI Laboratories through
((S)-2'-(3-methylbutoxy)-1,1'-binaphth-2-yloxy)-1,4,7-triaza- Ordway Research Institute (USA) on Staphylococcus aureus
2,5,8-trioxononan)cyclohexanecarboxylate dihydrochloride (MSSA; MRSA; VISA), S. epidermidis and E. faecium (VRE
(2c). The protected amine 8c (106 mg, 0.083 mmol) in 1:1 and VSE). The microdilution reference methods (M7-A6 (2003)
1269

Beilstein J. Org. Chem. 2012, 8, 1265–1270.
8. Bremner, J. B.; Keller, P. A.; Pyne, S. G.; Boyle, T. P.; Brkic, Z.;
David, D. M.; Garas, A.; Morgan, J.; Robertson, M.; Somphol, K.;
Miller, M. H.; Howe, A. S.; Ambrose, P.; Bhavnani, S.; Fritsche, T. R.;
Biedenbach, D. J.; Jones, R. N.; Buckheit, R. W., Jr.; Watson, K. M.;
Baylis, D.; Coates, J. A.; Deadman, J.; Jeevarajah, D.; McCracken, A.;
Rhodes, D. I. Angew. Chem., Int. Ed. 2010, 49, 537–540.
doi:10.1002/anie.200904392
and M11-A6 (2004)) of the CLSI/NCCLS were used. Quality
control ranges for the selected control agent vancomycin from
CLSI/NCCLS M100-S15 (2005) were used. Panels were
produced in volumes of 100 µL/well over a concentration of
0.03–32 µg/mL. A growth control was included for each dilu-
tion series. MIC results were produced by using the M7-A6 and
M11-A6 CLSI/NCCLS procedures in cation-adjusted
Mueller–Hinton broth media with supplements as required for
the test species. The compounds were initially dissolved in
DMSO and then diluted.
9. Haug, B. E.; Stensen, W.; Kalaaji, M.; Rekdal, Ø.; Svendsen, J. S.
J. Med. Chem. 2008, 51, 4306–4314. doi:10.1021/jm701600a
10.Flemming, K.; Klingenberg, C.; Cavanagh, J. P.; Sletteng, M.;
Stensen, W.; Svendsen, J. S.; Flægstad, T. J. Antimicrob. Chemother.
2009, 63, 136–145. doi:10.1093/jac/dkn464
11.Fjell, C. D.; Hiss, J. A.; Hancock, R. E. W.; Schneider, G.
Nat. Rev. Drug Disc. 2012, 11, 37–51. doi:10.1038/nrd3591
12.Sundriyal, S.; Sharma, R. K.; Jain, R.; Bharatam, P. V. J. Mol. Model.
2008, 14, 265–278. doi:10.1007/s00894-008-0268-1
Supporting Information
Supporting Information File 1
13.Higgins, D. L.; Chang, R.; Debabov, D. V.; Leung, J.; Wu, T.;
Krause, K. M.; Sandvik, E.; Hubbard, J. M.; Kaniga, K.;
Schmidt, D. E., Jr.; Gao, Q.; Cass, R. T.; Karr, D. E.; Benton, B. M.;
Humphrey, P. P. Antimicrob. Agents Chemother. 2005, 49, 1127–1134.
doi:10.1128/aac.49.3.1127-1134.2005
Experimental procedures and associated spectroscopic data
(NMR and MS) for the syntheses of compounds 2a–b and
2d–g.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-142-S1.pdf]
14.Tailleur, P.; Berlinguet, L. Can. J. Chem. 1961, 39, 1309–1320.
doi:10.1139/v61-165
Acknowledgements
License and Terms
We thank the former Amrad Operations Pty Ltd and Avexa
Limited, the University of Wollongong and the National Health
and Medical Research Council (Development Grants 303415
and 404528) for their support. We also thank Dr A. McCracken
for assistance, Dr S. Cox for her support in the initial develop-
ment of this project, and T. R. Fritsche, D. J. Biedenbach and R.
N. Jones of JMI Laboratories, North Liberty, Iowa and M. H.
Miller, M. S. Howe, P. Ambrose and S. Bhavnani from Ordway
Research Institute, New York (USA) for the provision of some
assays.
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
References
The definitive version of this article is the electronic one
which can be found at:
1. French, G. L. Int. J. Antimicrob. Agents 2010, 36 (Suppl. 3), S3–S7.
doi:10.1016/S0924-8579(10)70003-0
doi:10.3762/bjoc.8.142
2. Fischbach, M. A.; Walsh, C. T. Science 2009, 325, 1089–1093.
doi:10.1126/science.1176667
3. Rong, S. L.; Leonard, S. N. Ann. Pharmacother. 2010, 44, 844–850.
doi:10.1345/aph.1M526
4. Werner, G.; Strommenger, B.; Witte, W. Future Microbiol. 2008, 3,
547–562. doi:10.2217/17460913.3.5.547
5. Guskey, M. T.; Tsuji, B. T. Pharmacotherapy 2010, 30, 80–94.
doi:10.1592/phco.30.1.80
6. Bremner, J. B.; Keller, P. A.; Pyne, S. G.; Boyle, T. P.; Brkic, Z.;
David, D. M.; Robertson, M.; Somphol, K.; Baylis, D.; Coates, J. A.;
Deadman, J.; Jeevarajah, D.; Rhodes, D. I. Bioorg. Med. Chem. 2010,
18, 2611–2620. doi:10.1016/j.bmc.2010.02.033
7. Bremner, J. B.; Keller, P. A.; Pyne, S. G.; Boyle, T. P.; Brkic, Z.;
Morgan, J.; Somphol, K.; Coates, J. A.; Deadman, J.; Rhodes, D. I.
Bioorg. Med. Chem. 2010, 18, 4793–4800.
doi:10.1016/j.bmc.2010.05.005
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