Design, synthesis and structure-activity relationships of 6-O-arylpropargyl diazalides with potent activity against multidrug-resistant Streptococcus pneumoniae

Article abstract of DOI:10.1016/j.bmcl.2005.03.011

A novel series of 6-O-arylpropargyl diazalides was synthesized and evaluated for their antibacterial activity. Members of this series exhibited potent activity against erythromycin-resistant respiratory tract pathogens.

Full text of DOI:10.1016/j.bmcl.2005.03.011

Bioorganic & Medicinal Chemistry Letters 15 (2005) 2653–2658
Design, synthesis and structure–activity relationships of
6-O-arylpropargyl diazalides with potent activity against
multidrug-resistant Streptococcus pneumoniae
Hong Yong,*, Yu Gui Gu, Richard F. Clark, Thomas Marron, Zhenkun Ma, Niru Soni,
Gregory G. Stone, Angela M. Nilius, Kennan Marsh and Stevan W. Djuric
Infectious Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road,
Abbott Park, IL 60044, USA
Received 22 December 2004; revised 2 March 2005; accepted 3 March 2005
Available online 8 April 2005
Abstract—A novel series of 6-O-arylpropargyl diazalides was synthesized and evaluated for their antibacterial activity. Members of
this series exhibited potent activity against erythromycin-resistant respiratory tract pathogens.
Ó 2005 Elsevier Ltd. All rights reserved.
Streptococcus pneumoniae is a critical pathogen causing
community-acquired respiratory tract infections (RTIs).
Currently, a high percentage of clinical isolates of this
important pathogen are resistant to b-lactams, macro-
lides, quinolones and other commonly used antibiotics.1
In order to identify a safe and effective agent to combat
infections caused by multidrug-resistant S. pneumoniae
(MRSP), we have designed and synthesized a series of
novel tricyclic ketolides, named diazalides. Members of
this series exhibit potent activity against MRSP and
improved pharmacological profiles.
between the 6-O position of the macrolide skeleton and
the aryl group play a significant role for the activity
against resistant strains. A propargyl or allyl linker
appears to be optimal.4 In addition, a series of tricyclic
ketolides, exemplified by TE-802, has been reported by
Taisho scientists.5 The analogues are characterized by
a diaza bridge linking the C-9 and the C-11 positions
of the macrolide ring and are therefore called Ôdiaza-
lidesÕ. These diazalides exhibit improved acid stability,
longer in vivo half-life and increased tissue penetration.
To take advantage of the potency profile of the 6-O-
arylpropargyl ketolide series and the pharmacological
profile of the diazalide series, we designed a new series
of analogues (Fig. 1) that combines the structural char-
acteristics of both 6-O-arylpropargyl ketolide and the
Taisho diazalides.
Previous work in this laboratory illustrated that intro-
duction of an arylalkyl group to the 6-O position of
the ketolide skeleton provides a series of compounds
with improved activity against MRSP.2 These com-
pounds are exemplified by cethromycin (ABT-773), a
potent ketolide that is currently in late stage clinical
development. Our structure–activity relationship
(SAR) analysis suggested that the improved activity
against drug resistant organisms was likely due to an an-
chor effect of the aryl group that provides additional
interactions with the molecular target, the bacterial ribo-
some.3 Studies have also indicated that the linker group
Keywords: Macrolide; Ketolide.
*
Corresponding author. Tel.: +1 847 938 6939; fax: +1 847 938
1674; e-mail: hong.yong@abbott.com
The synthesis of these target molecules requires three
major modifications to erythromycin as highlighted in
At present address: Abbott Laboratories, D47H, AP10-3, 100 Abbott
Park Road, Abbott Park, IL 60064-6112, USA.
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.03.011

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H. Yong et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2653–2658
Figure 1. Synthetic modifications required for the construction of 6-O-arylpropargyl diazalides from erythromycin.
Figure 1: (1) installation of a keto group to the C-3 po-
sition; (2) construction of a C-9 to C-11 diaza bridge
group and (3) introduction of a C-6 substitution.
CDI in the presence of DBU and DMAP led to the cor-
responding acylimidazolide. Subsequent reaction of the
acylimidazolide with ethylenediamine provided the cyc-
lic carbamate as a mixture of C-10 diastereomers. The
carbamate intermediate was then treated with acetic acid
which induced the epimerization of the C-10 chiral cen-
tre and facilitated cyclization of the terminal amino
group onto the C-9 keto group to form the tricyclic skel-
eton 2. Hydrolysis of the cladinose sugar at the C-3 po-
sition under acidic conditions followed by Corey–Kim
Our synthesis (Scheme 1) started from 6-O-propargyl-20-
O-benzoyl-400-O-benzoylerythromycin 1, which was pre-
pared according to a published procedure.4 As discussed
earlier, the 6-O-propargyl group was strategically intro-
duced before the C-3 keto and the C-9/C-11 bridge to
prevent undesirable side reactions.3 Reaction of 1 with
Scheme 1. Reagents and conditions: (a) CDI, DBU, DMAP, THF/DMF (3:1); (b) ethylene diamine, CH3CN/H2O (10:1); (c) AcOH, toluene, 59%
for (a)–(c); (d) 2 N HCl, EtOH/H2O (1:1), 55 °C, 2 days, 82%; (e) NCS, DMS, NEt3, CH2Cl2, 75%.

H. Yong et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2653–2658
2655
oxidation of the resulting C-3 hydroxy compound 3 fur-
nished the 6-O-propargyl diazalide 4 which served as a
key intermediate for the following derivatizations.
The methylene homologues of compounds 6 were pre-
pared through an alkynylstannane 8 which was prepared
according to a published procedure.4b Reaction of 4
with tributyltin ethoxide provided a stable intermediate
8 that was purified by chromatography. Coupling of 8
with an arylmethyl halide catalyzed by a palladium cat-
alyst provided 9, which was converted into the desired
diazalide homologues 10 under Stille coupling condi-
tions followed by debenzoylation (Scheme 3).
The 2-fluoro-6-O-propargyl diazalide 5, another key
intermediate, was prepared by reacting compound 4
with NaH and (PhSO2)2NF.6 Treatment of compound
4 or 5 with a variety of aryl halides under the Sonogash-
ira coupling conditions led to coupling products in good
to excellent yields. Finally hydrolysis of the 20-O-pro-
tecting group by heating in methanol provided the de-
sired 6-O-arylpropargyl diazalides 6 and 7 (Scheme 2).
The antibacterial activity of the 6-O-arylpropargyl
diazalides and their homologues was measured as the
Scheme 2. Reagents and conditions: (a) NaH, (PhSO2)2NF, DMF, 0 °C, 40%; (b) Sonogashira coupling (A) ArBr, Pd2dba3, DPPE, CuI, NEt3/
CH3CN or (B) ArBr, Pd(PPh3)2Cl2, CuI, NEt3/CH3CN; (c) MeOH, reflux, 40–80% for two steps.
Scheme 3. Reagents and conditions: (a) Bu3SnOEt, 110 °C, 80%; (b) X-ArCH2X0, Pd(PPh3)4, toluene, 64%; (c) (i) ArSnBu3, Pd(PPh3)4, toluene,
(ii) MeOH, reflux, 30–50%.

Table 1. Antibacterial activity of 6-O-arylpropargyl diazalides and homologues (MIC, lg/mL)
Compds
Ar
MIC (lg/mL)a
S. aureus
6538P
S. aureus
A5177
S. pyogene
EES61
S. pyogene
930
S. pneumoniae
ATCC6303
S. pneumoniae
5979
S. pneumoniae
5649
H. influenzae
GYR1435
Eryb
0.39
0.05
0.1
6.2
0.03
<0.005
0.06
>128
1
>128
0.06
0.03
0.06
>128
16
>128
16
0.25
1
8
2
4
ABT-773
TE-802
0.05
0.1
6a
6b
6c
6d
6e
0.2
0.2
0.1
0.1
0.06
0.2
0.2
0.1
0.1
0.1
0.06
0.03
64
64
64
1
0.03
0.03
>128
>128
>128
2
0.5
8
2
4
2
2
N
1
S
0.03
0.03
0.25
0.25
0.25
N
0.015
60.008
60.004
0.004
F
N
0.5
4
O
N
6f
0.25
0.06
60.008
4
60.008
8
0.06
2
S
N
N
N
N
6g
6h
0.5
0.5
0.125
0.03
60.008
60.008
2
4
60.008
60.008
0.003
0.06
4
2
S
60.008
60.008
N
6i
0.25
0.25
0.03
60.008
60.008
8
60.008
60.008
60.008
60.008
1
4
F
N
7e
0.125
0.25
0.125
0.125

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minimum concentration inhibiting visible bacterial
growth (MIC) by using National Committee for Clinical
Laboratories Standard.7 A panel of erythromycin-sus-
ceptible and resistant strains were selected to assess the
spectrums of antibacterial activity. The strains are
Staphylococcus aureus 6538P (erythromycin-susceptible
strain), S. aureus A5177 (erythromycin-resistant strain
bearing an inducible erm (A) gene), Streptococcus pyog-
enes EES61 (erythromycin-susceptible strain), S. pyoge-
nes 930 (erythromycin-resistant strain bearing
a
constitutive erm (B) gene), S. pneumoniae ATCC 6303
(erythromycin-susceptible strain), S. pneumoniae 5979
(MLSB resistant strain bearing an erm (B) gene), S.
pneumoniae 5649 (efflux-resistant strain bearing a mef
(E) gene) and Haemophilus influenzae GYR1435 (eryth-
romycin-susceptible strain).
The potency of our 6-O-arylpropargyl diazalides is sum-
marized in Table 1. It is apparent that the current series
is highly potent against both erythromycin-susceptible
and resistant Gram-positive organisms. The compounds
of the current series are also active against H. influenzae,
an important Gram-negative respiratory pathogen.
Introduction of the 2-fluoro group has no significant
effects on the antibacterial potency as illustrated by
compounds 7e and g compared to the corresponding
non-fluorinated analogues 6e and g. The structure of
the aryl group plays a significant role for activity against
both susceptible and resistant strains as illustrated by
6a–i. Compounds with a fused bicyclic aryl group
(6d–f) or biaryl group (6g–i) gave the best activity, par-
ticularly against the erythromycin-resistant organisms.
Compounds 10h and i (homologues of 6h and i) demon-
strated further improved activity against S. pyogenes
930.
Another excellent feature of this class of compounds is
their desirable pharmacokinetic (PK) profile. They gen-
erally possess long half-life (t1/2) and high volume of dis-
tribution (Vb)8. For example, compound 6g has t1/2 of
13.9 h and Vb of 30.9 L/kg after iv dosing in dog
(1 mg/kg), while its t1/2 reaches 20.6 h after oral dosing.
The oral bioavailability (F) is 57.4%. In the in vivo effi-
9
cacy study, the ED50 of compound 6g against S. pneu-
moniae 6303 in the mouse protection test model10 is
8 mg/kg.
In conclusion, we have designed and synthesized a series
of 6-O-arylpropargyl diazalides and the methylene
homologues. These compounds demonstrated potent
antibacterial activity against both erythromycin-suscep-
tible and resistant S. pneumoniae and other important
respiratory pathogens. They also showed good PK
profile and potent in vivo efficacy. This series of
compounds represent an important development in the
macrolide/ketolide
investigation.
area
and
warrant
further
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