Bioorganic & Medicinal Chemistry Letters 18 (2008) 5078–5082
Bioorganic & Medicinal Chemistry Letters
Design, synthesis, and antibacterial activities of novel 3,6-bicyclolide oximes:
Length optimization and zero carbon linker oximes
*
Datong Tang , Yonghua Gai, Alexander Polemeropoulos, Zhigang Chen, Zhe Wang, Yat Sun Or
Enanta Pharmaceuticals, Inc., 500 Arsenal Street, Watertown, MA 02472, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We designed and synthesized a series of novel 3,6-bicyclolide oximes, possessing linkers of varying
lengths to the secondary binding site. The E isomers exhibited excellent antibacterial profiles against a
broad spectrum of resistant pathogens.
Received 19 June 2008
Revised 30 July 2008
Accepted 31 July 2008
Available online 3 August 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Antibacterial
Bicyclolide
Oxime
MIC
The development of novel, effective, and safe antibacterial
agents is urgently needed to control infectious disease caused
by antibiotic-resistant bacteria. Macrolide antibiotics are an
important class of therapeutic agents against bacterial infec-
tions.1 However, the extensive clinical use of macrolide antibiot-
ics has resulted in an increasing MLSB-resistance in respiratory
pathogens. In our laboratories, we have been pursuing new gen-
erations of macrolides. Recently, EP-1304,2 a 6,11-bicyclolide
core, was discovered. Subsequent chemistry efforts based on this
core structure resulted in EDP-420 (EP-013420),3 our first-in-
class bicyclolide antibiotic clinical candidate, currently in phase
II clinical trial for the treatment of community acquired pneumo-
nia. In continuation of our efforts, we have designed and synthe-
sized 3,6-bicyclolide oxime derivatives possessing linkers of
varying lengths attached to the secondary aromatic binding mo-
tifs4 (see Fig. 1).
6f as mixtures in similar E/Z ratios. The final desired 3,6-bicyclolide
E-oximes 7a–7f were isolated by either crystallization or prepara-
tive reverse-phase HPLC chromatography.5
The structure of ketolide 7b was confirmed by the X-ray crystal-
lography (Fig. 2).
The 3,6-bicyclolides 7a–7f and the reference compound, eryth-
romycin A, were tested against a panel of representative respira-
tory pathogens. Various macrolide- and multidrug-resistant
isolates were included in the panel in order to identify potent ana-
logues that could overcome macrolide resistance. Staphylococcus
aureus 29213, Streptococcus pyogenes 19615, and Streptococcus
pneumoniae 49619 are erythromycin-susceptible strains. Staphylo-
coccus aureus 27660 is an inducibly MLSB-resistant strain encoded
by an ermA gene. Staphylococcus aureus 33591 is an MRSA. Strepto-
coccus pyogenes 2912 is constitutive MLSB-resistant strain encoded
The synthesis of 3,6-bicyclolide oxime is outlined in Scheme 1.
Key intermediate 11,12-carbamate 3,6-bicyclolide 2 was prepared
from 1 in 85% yield in a three-step one-pot fashion. The following
Osmium tetraoxide and sodium periodate mediated olefin cleavage
provided diketone compound 3 in 94% yield. The acid catalyzed
oxime formation was carried out using diketone 3 and hydroxyl-
amine 4a–4f in an aqueous alcoholic media at room temperature.
Oxime formation at C-9 ketone was not observed under these reac-
tion conditions. The resulting oximes 5a–5f were usually about 3
to 1 E/Z mixtures, which underwent 20-deacetylation to give 6a–
N
N
O
O
N
N
N
N
O
N
O
N
O
O
O
O
O
O
O
O
HO
O
HO
O
HO
HO
O
O
O
EP-1304
EDP-420
* Corresponding author. Tel.: +1 617 607 0716; fax: +1 617 6070532.
Figure 1. Structure of 6,11-bicyclolide EP-1304 and EDP-420.
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.07.118