Synthesis and antibacterial activity of new 9-O-arylpropenyloxime ketolides

Article abstract of DOI:10.1016/j.bmcl.2010.01.153

A novel series of 9-O-arylpropenyloxime ketolide was synthesized and evaluated for their antibacterial activity. This series of ketolide exhibited potent activity against clinically isolated gram-positive strains including Staphylococcus pneumoniae and St

Full text of DOI:10.1016/j.bmcl.2010.01.153

Bioorganic & Medicinal Chemistry Letters 20 (2010) 2671–2674
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antibacterial activity of new 9-O-arylpropenyloxime ketolides
a,*
b
a
Ghilsoo Nam , Yang Soo Kim , Kyung Il Choi
a
Neuro-medicines Research center, Life & Health Division, Korea Institute of Science and Technology (KIST), 5 Wolsong-gil, Seoungbuk-gu, Seoul 136-791, Republic of Korea
Infectious disease Research Center, Asan Medical Center, 388-1 Pungnap-2dong, Songpa-gu, Seoul 138-736, Republic of Korea
b
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of 9-O-arylpropenyloxime ketolide was synthesized and evaluated for their antibacterial
activity. This series of ketolide exhibited potent activity against clinically isolated gram-positive strains
including Staphylococcus pneumoniae and Straptococcus Pyogenes.
Received 28 August 2009
Revised 23 December 2009
Accepted 29 January 2010
Available online 1 March 2010
Ó 2010 Published by Elsevier Ltd.
Keywords:
Ketolides
Macrolide antibiotics
9
-O-Arylpropenyloximes
Antibacterial activity
Multidrug-resistance bacteria have become an increasing prob-
lem for the management of serious infections. On average, world-
wide penicillin resistance in Staphylococcus pneumoniae is about
9-O-Arylpropenyloxime ketolide derivatives (3a–l) were synthe-
sized by Heck coupling reaction of 9-(E)-allyloxime ketolide 8 with
7
several aryl halides. (Scheme 1) Palladium acetate and 2-meth-
oxyphenylbromide were added to the solution of 9-allyloxime keto-
lide 8 in acetonitrile in the presence of tri(o-tolyl)phosphine catalyst
to give 3-methoxyphenyl substituted 9-propenyloxime derivative
2
0%, ranging from under 10% in Africa to almost 40% in Asia; nearly
1,2
one quarter of all US isolated are resistant to penicillin. The resis-
tance of Staphylococcus pyogenes has been increasing in recent
year. High rates of resistance to erythromycin and azithromycin
have also reported as high as 78% in Taiwan 2001 and with high
rates in Spain and Italy.3
8
3a. Compounds 3b–3l were similarly synthesized from 3-meth-
oxyphenylbromide, 3,4-dimethoxyphenylbromide, 3-bromopyri-
dine, 3-bromoquinoline, 3-bromopyrimidine, 4-methoxyphenyl-
bromide, bromothiophene, bromoisoquinoline, 3-bromoindol, 1-
bromoindanone, 2(3-bromophenyl)-1,3-dioxolane and 1,3-benzo-
dioxole-5-bromide in moderate yield. All new compounds were
purified by flash column chromatography and were characterized
Although many of the older antibiotics remain effective, new
drug development crucially need resolve to increase in drug resis-
tance among these important pathogens. Macrolide antibiotics
have been used safely and effectively for treating community-ac-
quired respiratory tract infections since 1950’s. Recently a new
class of erythromycin A derivatives, known as ketolides, has devel-
oped the enhanced antibacterial activity against antimicrobial
1
13
by NMR spectra, such as H, C, homo-COSY, HMQC, HMBC and
HSQC NMR spectrum.
Compound 8 was synthesized by the five steps outlined Scheme 2.
4
9
resistant pathogens. The first ketolide telithromycin is to reach
Hydroxylamine was added to the clarithromycin in ethanol solu-
5
the market and cethromycin has been clinical trials (Fig. 1). These
tion in presence of triethylamine to give 9-hydroxyoxime derivative
1
0
new generation of ketolides have been structural characteristics
which contained a long chained aromatic ring besides having 3-
keto group instead of 3-cladinose sugar ring. This tethered aro-
matic ring has known as important factor to ribosomal binding
sites and relates to inhibition of resistance mechanism.6
4, which was converted into 9-allyloxime 5 by reacting with allyl
bromide and sodium hydride. Then the cladinose was hydrolyzed
0
with 2 N hydrochloric acid followed by acetylation of the 2 -hydroxy
group with acetic anhydride gave 3-hydroxy intermediates 6.11 Oxi-
dation of the 3-hydroxy group was efficiently performed with Cor-
1
2
Herein we describe the synthesis of new 9-O-arylpropenyl-
oxime ketolides which introduced in long chain aromatic ring on
ey–Kim reagent followed by deprotecting of the 2’-acetyl group
with methanol provided the corresponding ketolide 8 in a 70% yield.
The only 3-OH group except for the 11-OH group is oxidized under
Corey–Kim oxidation condition, which is well known method for
9
-oxime position, represented by the structures 3 and the evalua-
tion of their antibacterial activity (Fig. 2).
1
3
the 14-membered macrolide chemistry.
The 9-arylpropenyloxime derivatives 3a–3l were tested for
in vitro antimicrobial activity against gram-positive strains such
as Staphylococcus aureus (MRSA, MSSA), Streptococcus pneumonia
*
Corresponding author.
E-mail address: gsnam@kist.re.kr (G. Nam).
0
960-894X/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2010.01.153

2
672
G. Nam et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2671–2674
N
Long chain heterocyclic ring
N
N
N
O
O
H
N
O
O
N
OCH3
O
O
O
NMe2
O
NMe2
HO
HO
O
O
O
O
O
O
O
O
O
Ketone
Ketolide)
(
1
. Telithromycin
2. Cethromycin
Figure 1. The structural character of recently developed macrolides.
O
tration (MIC) values of produced by the Muller–Hinton agar dilu-
tion method for the compounds 3a–3l are reported Table 1.
Ar
N
15
9
From the analysis of the MIC values of antibacterial inhibitory
activities, most of the ketolide derivatives were active against clin-
ically isolated gram-positive strains. The ketolides were inactive
against MRSA strains and showed moderate activity against MSSA,
as was common with ketolide antibiotics.
OCH3
HO
NMe2
12
OH
6
HO
O
O
O
1
3
O
O
All compounds showed potent activity against the S. pneumo-
niae and S. pyogenes. And also clinical isolated strains S. pneumo-
niae including penicillin intermediate and penicillin susceptible S.
pneumoniae strains, and three strains of clinically gained S. pyoge-
nes explored to highly effect on synthesized ketolides. These clini-
cally isolated penicillin-resistant S. pneumoniae (PRSPs) showed
3
Figure 2. New 9-arylpropenyloxime ketolides.
(
penicillin resistance and intermediate, PRSP), and Streptococcus
almost no inhibition by erythromycin (MIC50 >128 lM) as refer-
ence of macrolides antibiotics. However, most of the synthesized
ketolides displayed good activity against clinically isolated resis-
14
16
pyogenes clinically acquired in Korea. The ATCC29213 for the
methicillin susceptible Streptococcus aureus (MSSA), ATCC49619
for S. pneumoniae and ATCC8668 for S. pyogenes were tested as
a corresponding standard strains. The minimum inhibitory concen-
tant strains which have 0.06
lM of MIC values. Particularly, the
nitrogen contained heteroaromatic derivatives such as pyridine
O
N
O
Ar
N
9
OCH3
9
HO
NMe2
OH
6
5
OCH
O
3
1
2
HO
Heck-reaction
a
HO
NMe
2
O
1
2
OH
6
HO
O
O
O
1
3
O
1
O
O
3
O
O
8
3
OCH3
N
e
OCH3
N
N
c
OCH3
OCH3
N
Ar
=
a
b
f
d
H
N
O
N
O
S
O
O
g
O
h
i
k
l
j
2 3 3
Scheme 1. Reagent and conditions: (a) Pd(OAc) , P(o-Tolyl) , TEA, CH CN/DMF (3/1), ArX (compound, yield); 3-methoxyphenylbromide (3a, 22%), 3,4-dimethoxyphenylbr-
omide (3b, 15%), 3-bromopyridine (3c, 30%), 3-bromoquinoline (3d, 16%), bromopyrimidine (3e, 12%), 4-methoxyphenylbromide (3f, 72%), 2-bromothiophene (3g, 38%),
bromoisoquinoline (3h, 36%), 3-bromoindol (3i, 26%), 1-bromoindanone (3j, 41%), 2(3-bromophenyl)-1,3-dioxolane (3k, 48%), 1,3-dioxole-5-bromide (3l, 56%).

G. Nam et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2671–2674
2673
O
9
OH
N
OCH3
O
9
HO
NMe2
OH
6
OCH3
1
2
HO
HO
1
NMe
2
b
O
a
2 6
OH
HO
O
O
1
3
O
1
OCH3
OH
O
O
O
3
OCH3
OH
O
O
O
O
4
Clarithromycin
O
O
O
N
9
N
9
N
9
OCH3
Ac
O
OCH3 Ac
O
OCH3
HO
NMe2
HO
HO
NMe2
NMe
2
1
2
OH
6
HO
OH
6
12 OH
6
12
O
O
c,d
O
e
O
O
O
O
O
O
1
3
1
3
OCH3
1
3
O
O
O
O
OH
O
O
OH
5
6
7
O
N
9
OCH3
O
HO
NMe2
1
2
OH
6
HO
f
O
O
1
3
O
O
8
Scheme 2. Reagent and conditions: (a) Hydroxylamine, triethylamine, EtOH, 49%; (b) NaH, allylbromide, Ether/DMF (50/50), N
d) Ac O, K CO , acetone, 40 °C, 89%; (e) NCS, dimethylsulfide, triethylamine, CH Cl , ꢀ10 °C, 70%; (f) MeOH, 97%.
2
gas, reflux (8 h), 95%; (c) 12 N HCl, H
2
O, 87%;
(
2
2
3
2
2
Table 1
In vitro antibacterial activity of 9-O-propenylaryloxime ketolides against gram-positive organisms (MIC,
l
g/mL)a
O
Ar
N
9
N
OCH3
OCH
OCH
3
3
OCH3
HO
NMe2
N
N
N
1
2
OH
6
HO
OCH
3
O
3a
3b
3c
3d
3e
3f
O
O
1
3
Ar
=
O
H
O
O
N
N
O
O
S
O
O
3
3g
3h
3i
3j
3k
3l
Organism
MICa
(l
g/mL)
3
a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
S. aureus ATCC29213
MRSA1b
2
1
0.5
0.25
128
128
0.25
0.25
0.25
0.25
0.06
64
0.5
128
128
0.5
0.5
0.5
0.5
0.25
128
0.5
2
0.5
1
1
1
128
128
1
1
1
1
0.25
64
0.25
8
0.06
0.06
0.25
0.06
0.25
0.25
0.5
1
128
128
2
2
2
128
128
1
0.5
1
1
0.25
32
0.5
0.5
0.06
0.06
0.25
0.06
0.25
0.25
128
128
0.5
0.25
0.25
0.25
0.125
64
0.25
0.06
0.06
0.06
0.25
0.06
0.06
0.06
128
126
2
2
1
1
0.5
64
0.5
0.5
0.25
0.25
0.5
0.25
0.5
0.5
128
128
0.25
0.5
0.25
0.25
0.06
32
0.125
0.125
0.06
0.06
0.06
0.06
0.06
0.06
128
128
0.5
1
0.5
0.5
0.25
32
128
128
1
1
1
1
0.25
32
0.25
0.25
0.06
0.06
0.25
0.06
0.25
0.25
128
128
1
1
1
0.5
0.25
64
0.25
0.25
0.06
0.06
0.25
0.06
0.25
0.25
128
128
1
1
0.5
0.5
0.25
64
0.25
0.25
0.06
0.06
0.25
0.06
0.25
0.25
MRSA2b
b
MRSA3
MSSA1
c
MSSA2c
MSSA3c
2
1
S. pneumoiae ATCC49619
d
Penicillin I1
64
1
64
0.25
0.25
1
0.25
1
1
d
Penicillin I2
0.06
4
0.5
1
d
penicillin I3
1
e
Penicillin S1
0.06
0.06
0.06
0.06
0.06
0.06
0.125
0.125
0.25
0.06
0.25
0.25
0.25
0.25
0.25
0.06
0.25
0.25
penicillin S2e
S. pyogenes ATCC8668
f
S. pyogenes 1
S. pyogenes 2f
S. pyogenes 3f
a
b
c
d
e
f
Minimum inhibitory concentration by agar dilution method.
Clinical strains of methicillin resistances. S. aureus.
Clinically islated methicillin susceptible S. aureus.
Clinically isolated penicillin intermediate resistanct S. pneumonie.
Clinically isolated penicillin susceptible S. pneumonias.
Clinically isolated S. pyogenes.

2
674
G. Nam et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2671–2674
7. Representative spectroscopic data of 8: 1H NMR (300 MHz, CDCl
) ppm 1
H
3
(
3c), quinoline (3d) and sulfur contained thienyl (3g) derivatives
NMR (300 MHz, CDCl ppm 0.85 (t, J = 7.32 Hz, 3H, 15-CH ), 0.98 (d,
3
)
2
were highly potent compounds within a series. But isoquinoline
derivative (3h) and pyrimidine substituent (3e) showed less po-
tency than the quinoline compound (3d) which having in different
placed nitrogen of ring. It seems to be important factor of the posi-
tion of nitrogen in the heteroaryl ring.
J = 6.90 Hz, 3H), 1.15 (d, J = 1.97 Hz, 3H), 1.22 (s, 3H, 12-Me), 1.25 (d,
J = 6.06 Hz, 3H), 1.30 (d, J = 2.89 Hz, 3H), 1.32 (d, J = 2.0 Hz, 3H), 1.38 (s, 3H,
6-Me), 1.46–1.57 (m, 2H), 1.65 (m, 1H), 1.69 (m, 1H), 1.97 (m, 1H), 2.26 (s, 6H,
NMe
2
), 2.46 (m, 1H), 2.56 (m, 1H), 2.74 (s, 3H, 6-OMe), 3.04 (m, 1H), 3.15–3.22
(
m, 2H), 3.32 (m, 1H), 3.45 (m, 1H), 3.57 (m, 1H), 3.68 (m, 1H), 3.85 (m, 1H),
3
.89 (m, 1H), 4.31 (dd, J = 6.36 Hz, 7.24 Hz, 2H), 4.46–4.49 (m, 3H), 5.18 (m,
13
The compounds having methoxy group in phenyl ring such as
1H), 5.22 (dd, J = 17.2 Hz, 16.8 Hz, 2H), 5.94 (m, 1H); C NMR (75 MHz, CDCl
3
)
ppm 11.0, 14.7, 14.8, 15.4, 16.6, 18.8, 19.93, 21.6, 21.9, 26.7, 31.0, 33.2, 38.0,
3
a (Ar = 3-OMePh), 3b (Ar = 3,4-(OMe)
and compounds having cyclic-ether type group, 3k (Ar = 3-CH{O(-
CH O}Ph) and 3l (Ar = 3-O(CH )-4-O–Ph) were showed lower
2
Ph) and 3f (Ar = 4-OMePh)
2
40.7 (NMe ), 46.3, 50.2, 51.3, 66.2, 69.8, 70.5, 70.7, 74.0, 75.0, 77.1, 78.1, 78.4,
1
03.6, 118.0, 134.6, 169.7 (C-9), 169.9 (C-1), 205.8 (C-3).
8. Representative spectroscopic data of 3; compound 3a: 1H NMR (300 MHz,
2
)
2
2
CDCl
.19 (s, 3H), 1.72–1.45 (m, 4H), 1.97 (m, 1H), 2.25 (m, 6H), 2.48 (m, 2H), 2.55
m, 1H), 2.76 (m, 3H), 3.26 (m, 5H), 3.54 (m, 2H), 3.78 (m, 1H), 3.81 (s, 3H), 3.82
3
) ppm 0.85 (t, J = 7.31 Hz, 3H), 0.99 (d, J = 6.89 Hz, 3H), 1.15–1.01 (m, 9H),
activities against clinical strains of PRSPs. The potency of 3j con-
taining fused cyclopentanone also was low. Compound 3g
1
(
(
Ar = thienyl) and 3i (Ar = indol) exhibited good potency.
(m, 4H), 4.29 (m, 2H), 4.53 (m, 2H), 5.11 (m, 1H), 6.33 (m, 1H), 6.55 (d,
J = 19.05 Hz, 1H), 6.81 (d, J = 7.57 Hz, 2H), 6.91 (s, 1H), 6.98 (d, J = 7.66 Hz, 1H),
In summary, a new series of 9-O-arylpropenyloxime ketolide
7.23 (t, J = 7.91 Hz, 1H). (75 MHz, CDCl
3
) ppm 11.1, 14.8, 17.1, 18.9, 20.0, 21.6,
was designed, synthesized and evaluated for antibacterial activity
against clinically isolated gram-positive strains in Korea. Com-
pounds 3d (Ar = quinoyl) or 3g (Ar = thienyl) which having nitro-
gen or sulfur atom substituted heteroaryls were most potent
against S. pneumoniae and S. pyogenes in clinical strains. These find-
ings present a good opportunity for the development of new mac-
rolide antibiotics to effectively combat the growing problems of
resistance strains in Korea.
2
1.9, 28.7, 33.3, 38.4, 40.6, 40.8, 47.1, 47.9, 50.3, 51.3, 55.6, 66.3, 69.9, 70.8,
74.1, 74.7, 78.2, 78.5, 79.8, 80.0, 83.8, 88.0, 103.9, 112.2, 113.9, 119.5, 126.1,
1
129.9, 130.7, 133.3, 138.5, 169.7, 170.2, 205.8. compound 3b:
H
NMR
) ppm 0.85 (t, J = 7.25 Hz, 3H), 0.99 (d, J = 6.85 Hz, 3H), 1.05
m, 1H), 1.15 (d, J = 10.68 Hz, 3H), 1.22 (s, 3H), 1.25 (s, 3H), 1.30 (d, J = 7.65 Hz,
H), 1.33 (d, J = 6.7 Hz, 3H), 1.38 (s, 3H), 1.68–1.46 (m, 4H), 1.97 (m, 2H), 2.26
(m, 6H), 2.48 (m, 1H), 2.60 (m, 1H), 2.74 (s, 3H), 3.19 (m, 4H), 3.57 (m, 1H), 3.65
(
(
300 MHz, CDCl
3
3
(
(
m, 1H), 3.88 (s, 3H), 3.90 (s, 3H), 4.31 (m, 2H), 4.33 (s, 1H), 4.61 (m, 2H), 5.11
m, 1H), 6.19 (m, 1H), 6.55 (d, J = 15.81 Hz, 1H), 6.82 (d, J = 8.40 Hz, 1H), 6.92 (d,
13
3
J = 7.53 Hz, 1H), 6.93 (1H, s). C NMR (75 MHz, CDCl );ppm 11.1, 14.7, 15.0,
1
5
1
5.5, 16.6, 18.9, 20.1, 21.6, 21.9, 26.8, 28.7, 33.3, 38.4, 40.6, 47.1, 50.3, 51.3,
6.2, 56.3, 66.3, 69.8, 70.7, 70.7, 74.1, 74.9, 77.6, 78.2, 78.5, 103.9, 109.4, 111.5,
20.1, 123.8, 130.2, 133.4, 149.4, 169.7, 170.0, 205.9.
Acknowledgment
9
.
Clarithromycin was supported by Chong Kun Dang Corporation, CKD research
institute on purpose of research.
This work was financially supported by the MOST of Korea (2N
3250).
10. (a) Morimoto, S.; Adachi, T.; Asaka, T.; Kashimura, M.; Watanabe, Y.; Sota, K.
2
U.S. Patent 4,670,549, 1987.; (b) McGill, J. M.; Johnson, R. Magn. Reson. Chem.
1
993, 31, 273.
11. Nam, G.; Kang, T. W.; Shin, J. H.; Choi, K. L. Bioorg. Med. Chem. Lett. 2006, 16,
69.
References and notes
5
1.
2.
3.
4.
Jacobs, M. R.; Bajaksouzian, S.; Windau, A.; Good, C. E.; Lin, G.; Pankuch, G. A.;
Appelbaum, P. C. Clin. Lab. Med. 2004, 24, 503.
Jacobs, M. R.; Femingham, D.; Appelbaum, P. C.; Gruneberg, R. N. J. Antimicrob.
Chemother. 2003, 52, 229.
Hsueh, P. R.; Teng, L. J.; Lee, C. M.; Huang, W. K.; Wu, T. L.; Wan, J. H.; Yang, D.;
Shyr, J. M.; Chuang, Y. C.; Yan, J. J. Antimicrob. Agents Chemother. 2003, 47, 2152.
For recent reviews, see: (a) Asaka, T.; Manaka, A.; Sugiyama, H. Curr. Top. Med.
Chem. 2003, 3, 961; (b) Zhanel, G. G.; Walters, M.; Noreddin, A.; Vercaigne, L.
M.; Weirzbowski, A.; Embil, J. M.; Gin, A. S.; Dauthwaite, S.; Hoban, D. J. Drugs
12. Corey, E. J.; Kim, C. U. J. Org. Chem. 1973, 38, 1233.
13. (a) Agouridas, C.; Denus, A.; Auger, Y.; Benedetti, Y.; Bonnefoy, A.; Bretin, F.;
Chantot, J.-F.; Dussarat, A.; Fromentin, C.; D’Ambriéres, S. G.; Lachaud, S.;
Laurin, P.; Martret, O. L.; Loyau, V.; Tessot, N. J. Med. Chem. 1998, 41, 4080; (b)
Tanikawa, T.; Asaka, T.; Kashimura, M.; Misawa, Y.; Suzuki, K.; Sato, M.; Kameo,
K.; Morimoto, S.; Nishida, A. J. Med. Chem. 2001, 44, 4027.
14. (a). Diagn. Microbiol. Infect. Dis. 2007, 58, 141; (b) Kim, N. J.; Park, S. J.; Choi, S.-
H.; Lee, M. S.; Choo, E. J.; Kwak, Y. G.; Woo, J. H.; Ryu, J.; Jeong, J. Y.; Kim, Y. S.
Microb. Drug Resist. 2005, 11, 260.
2
002, 62, 1771.
15. All minimum inhibitory concentration (MIC) determination was carried out
using clinically outcomes strains at Asan medical center in Seoul, Korea.
16. Leitner, F.; Misiek, M.; Pursiano, T. A.; Buck, R. E.; Chisholm, D. R.; Deregis, R. G.;
Tsai, Y. H.; Price, K. E. Antimicrob. Agents Chemother. 1976, 10, 426.
5
.
.
(a) Xiong, Y. Q.; Le, T. P. Drugs Today 2001, 37, 617; (b) Nishaminy, N.; Acharya,
P. A. Am. J. Health-Syst. Pharm. 2005, 62, 905.
(a) Hansen, L. H.; Mauvais, P.; Duthwaite, S. Mol. Microb. 1999, 31, 623; (b)
Capobianco, J. O.; Cao, Z.; Shortridge, V. D.; Ma, Z.; Flamm, R. K.; Zhong, P.
Antimicrob. Agents Chemother. 2000, 44, 1562.
6