doi:10.1016/j.bmcl.2007.08.068 
Copyright © 2007 Elsevier Ltd All rights reserved.
Design and synthesis via click chemistry of 8,9-anhydroerythromycin A 6,9-hemiketal analogues with anti-MRSA and -VRE activity
Akihiro Sugawaraa, Toshiaki Sunazukaa, Tomoyasu Hirosea, Kenichiro Nagaia, Yukie Yamaguchia, Hideaki Hanakia, K. Barry Sharplessb and Satoshi Ōmuraa, 
, 
aThe Kitasato Institute, and Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, Japan
bThe Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, BCC-315, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
Received 23 June 2007;
revised 27 August 2007;
accepted 29 August 2007.
Available online 1 September 2007.
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Abstract
An erythromycin analogue, 11,12-di-O-iso-butyryl-8,9-anhydroerythromycin A 6,9-hemiketal (1b), was found to be a potential anti-MRSA and anti-VRE agent. The use of copper catalyzed azide–acetylene cycloaddition, and click chemistry, readily provided 10 types of triazole analogues of 1b in good to nearly quantitative yield. Among the library, 5b exhibited activity against MRSA and VRE bacterial strains, representing more than twice the potency of 1b.
Graphical abstract
One of 10 kinds of triazole compounds, the adamantyl-triazole product 5b, was produced as a potential lead of new antibiotic for use against MRSA and VRE strains, using click methodology.
Keywords: Erythromycin A; Macrolides; Click chemistry; Anti-MRSA and -VRE agent
Figure 1. Structures of erythromycin A, 1a, and 1b.
Scheme 1. Synthesis of 4 as a precursor of click reaction. Reagents and conditions: (a) acetic acid, rt, 0.5 h, 73%; (b) acetic anhydride, acetone, rt, 1 h; (c) aceticformic anhydride, pyridine, 4-dimethylaminopyridine, THF, 0 °C, 1 h, 86% (for 2 steps); (d) iso-butyric anhydride, 4-dimethylaminopyridine (excess), pyridine, rt, 48 h, quant; (e) 10-camphorsulfonic acid, MeOH, rt, 6 h, 97%; (f) propargyl bromide, NaH, THF, rt, 3.5 h, 72%; (g) MeOH, 50 °C, 12 h, quant.
Table 1.
Minimum inhibitory concentrations (MICs) value of EMA and 1b, and 2–4
NT, not tested.
a Staphylococcus aureus FDA209P and Smith: susceptible strains.
b S. aureus MRSA N315 IR94, MRSA N315 IR94 HR-1, MRSA 70, and MRSA 92-1191: MRSA strains isolated from clinical patients.
c S. aureus ISP447: inducibly resistant strain.
d S. aureus ISP217: constitutively resistant strain.
e S. aureus 8325 (pEP2104): encoded by
erm gene.
f S. aureus 8325 (pMS97): encoded by
erm and
mef gene.
g Enterococcus faecalis NCTC12201: encoded by
van A gene.
h E. faecium NCTC12203: encoded by
van A gene.
i E. coli NIHJ JC-2: susceptible Gram-negative strain.
Table 2.
Copper-catalyzed 1,2,3-triazole formation
a Isolated yield.
Table 3.
Minimum inhibitory concentrations (MICs) value of EMA and analogues
a Staphylococcus aureus FDA209P and Smith: susceptible strains.
b S. aureus MRSA N315 IR94, MRSA N315 IR94 HR-1, MRSA 70, and MRSA 92-1191: MRSA strains isolated from clinical patients.
c S. aureus ISP447: inducibly resistant strain.
d S. aureus ISP217: constitutively resistant strain.
e S. aureus 8325 (pEP2104): encoded by
erm gene.
f S. aureus 8325 (pMS97): encoded by
erm and
mef gene.
g Enterococcus faecalis NCTC12201: encoded by
van A gene.
h E. faecium NCTC12203: encoded by
van A gene.
i E. coli NIHJ JC-2: susceptible Gram-negative strain.
Abstract
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