Synthesis and antibacterial activity of a novel series of acylides active against community acquired respiratory pathogens

Article abstract of DOI:10.1016/j.bmcl.2011.10.101

A novel series of acylides 4 were designed to overcome antibacterial resistance and evaluated for in vitro and in vivo activity. This series of acylides was designed from clarithromycin by changing the substitution on the desosamine nitrogen, followed by

Full text of DOI:10.1016/j.bmcl.2011.10.101

Bioorganic & Medicinal Chemistry Letters 22 (2012) 476–481
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antibacterial activity of a novel series of acylides active
against community acquired respiratory pathogens
Rajesh Kumar a, Sujata Rathy a, Atul K. Hajare a, Yogesh B. Surase a, Jyoti Dullu a, Jitendra S. Jadhav a,
R. Venkataramanan a, Anjan Chakrabarti a, Manisha Pandya b, Pragya Bhateja b, G. Ramkumar b,
Biswajit Das a,
⇑
a Department of Medicinal Chemistry, New Drug Discovery Research, Ranbaxy Research Laboratories, Plot-20, Sector-18, Udyog Vihar, Gurgaon 122001, India
b Department of Infectious Diseases, New Drug Discovery Research, Ranbaxy Research Laboratories, Plot-20, Sector-18, Udyog Vihar, Gurgaon 122001, India
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 acylides 4 were designed to overcome antibacterial resistance and evaluated for in vitro
and in vivo activity. This series of acylides was designed from clarithromycin by changing the substitu-
tion on the desosamine nitrogen, followed by conversion to 3-O-acyl and 11,12-carbamate. These com-
pounds showed significantly potent antibacterial activity against not only Gram-positive pathogens,
including macrolide-lincosamide-streptogramin B (MLSB)-resistant and efflux-resistant strains, but also
Gram-negative pathogens such as Haemophilus influenzae. These acylides also showed better activity
against telithromycin resistant Streptococcus pneumoniae strains.
Received 18 August 2011
Revised 28 September 2011
Accepted 28 October 2011
Available online 9 November 2011
Keywords:
Macrolide
Acylide
Ó 2011 Elsevier Ltd. All rights reserved.
Synthesis
Antibacterial
Macrolide antibiotics enjoy a resurgence of interest within the
pharmaceutical industry.1,2 Second generation macrolide antibiot-
ics such as clarithromycin3 and azithromycin4 have been widely
prescribed for upper and lower respiratory tract infections (RTIs)
because of their superior antibacterial activity and pharmacoki-
netic properties and fewer gastrointestinal (GI) side effects com-
pared to the first generation macrolide erythromycin A. However,
the therapeutic potential of macrolides has been severely compro-
mised due to emergence of bacterial resistance.5 This issue of bac-
terial resistance is driving further research in designing novel
macrolides. Future macrolides should be designed not only to over-
come the resistance but also to address other issues like CYP liabil-
ity and drug-drug interaction, which are observed in erythromycin
and clarithromycin. Our objective was to develop new generation
macrolide which addresses drug resistance problems especially
against clarithromycin and upcoming telithromycin resistant
strains. Additionally, we aspire to have increased activity against
Haemophilus influenzae, and improved drug tolerability and phar-
macokinetic profiles.
group can help macrolides overcome the CYP liability (both as
substrate and inhibitor). Further, Schlunzen et al.9 have concluded
that derivatization at the dimethylamine position could improve
binding and lead to better inhibition. Therefore, the modification
of 30-N,N-dimethyl to 30-N-methyl, N-alkyl intermediate was done
in order to overcome the ‘MLSB phenotype resistance’.
There are reports in literature that modification at C-3 results in
enhanced activity against efflux resistance.10 These structural mod-
ifications have resulted in identification of ketolides11 or acy-
lides.12,13 The introduction of an appropriate acyl group at the 3-
O-position of clarithromycin as in the case of TEA0777 112 and
TEA0929 213 showed enhanced antibacterial activity (Fig. 1). Fur-
ther, 6-O-allylic acylides 314 have also been explored. Substitutions
at the 30-N nitrogen25 of the desosamine sugar have generated
interesting compounds displaying gastrointestinal activities,22
LHRH antagonism23 and inhibition of IL8 release.24 As part of our re-
search efforts directed towards identification of next generation of
macrolides, that exhibit greater efficacy and safety, herein, we re-
port the discovery of a novel series of acylides 4. We focused on
the derivatization on the 30-N of desosamine along with different
3-O-acyl group modifications. A highly efficient synthetic process
was developed to access a large number of acylides. The optimized
substituent’s at these positions were subsequently considered for
further improvement in activity against broader spectrum includ-
ing the resistant pathogens.
Macrolides are known to induce their own hepatic biotransfor-
mation into nitrosoalkanes and these metabolites in-turn inhibit
CYP 3A4.6,21 The 30-N,N-dimethyl on the desosamine sugar is
metabolized to nitroso group that subsequently forms inactive
CYP 3A4-iron-metabolite complex.7 This mechanism accounts for
most of their drug interaction.8 Thus, modification of the methyl
Clarithromycin 5 was used as the starting material for the syn-
thesis of the acylide compounds 11–49, employing the following
general procedure.15 The selective cleavage of cladinose sugar of
⇑
Corresponding author.
E-mail address: biswajit.das.w2@dsin.co.in (B. Das).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.10.101

R. Kumar et al. / Bioorg. Med. Chem. Lett. 22 (2012) 476–481
477
O
O
O
H3C
H3C
CH3
O
H3C
CH3
HO
O
N
CH3
HO
OH
CH3
HO
N
O
NH
H3C
O
O
O
O
O
O
O
O
O
O
CH3
CH
3O
O
N
2
1
NO2
O
O
O
O
O
R1
O
O
HO
N
HO
N
R
O
O
N
O
O
O
O
O
O
O
O
O
O
Ar
Ar
O
O
4
3
Figure 1. Structure of Acylide 1–4.
O
O
O
HO
N
HO
OH
O
a
b
HO
N
HO
OH
O
O
O
O
O
O
O
O
O
OH
O
6
O
OH
5
O
O
O
O
O
BzO
N
H
O
HO
OH
BzO
N
BzO
N
HO
OH
HO
OH
d
c
O
O
O
O
O
O
O
O
O
O
O
O
O
O
OH
O
O
Ar
Ar
7
9
8
O
O
O
O
BzO
N
R
HO
OH
HO
N
R
HO
OH
e
f
O
O
O
O
O
O
O
O
O
O
O
O
Ar
Ar
11-49
10
Scheme 1. Reagents and conditions (a) 1 N HCl, rt, 30 min, 96%; (b) (C6H5CO)2O, Et3N, DCM, rt, 24 h, 68%; (c) ArCH2COOH or ArCH2COOH.HCl, DCC, DMAP, Pyridine, DCM, rt,
8 h, 52–65%; (d) NIS, CH3CN, 0 °C to rt, 25–35%; (e) RX, NaHCO3, rt, 16 h or RCHO, NaCNBH3, AcOH, MeOH, rt, 12 h, 48–62%; (f) MeOH, reflux, 15 h, 81–94%.

478
R. Kumar et al. / Bioorg. Med. Chem. Lett. 22 (2012) 476–481
Table 1
clarithromycin was achieved with 1 N aq HCl at room temperature
to give corresponding 3-hydroxy compound 6. The 20-hydroxy des-
osamine sugar of compound 6 was then protected as benzoate
using benzoic anhydride and triethylamine in dichloromethane
to give compound 7. The 3-O-acyl derivatives 8 were synthesized
by acylation of compound 7 with appropriate acid in presence of
dicyclocarbodimide and subsequent demethylation of 30-N,N-di-
methyl group using N-iodosuccinimide in acetonitrile to give
des-methylated compound 9.21 30-N-alkylation was achieved
through base catalyzed alkylation by using alkyl halide in presence
of inorganic base or by reductive amination with aldehyde to give
the 11,12-diol 10. Finally, the 20-O-benzoyl group was removed by
treatment with methanol to give the target molecule 11–49
(Scheme 1).
Antibacterial activity of Acylides 11–49 against selected respiratory pathogens
O
O
HO
N
R
HO
OH
O
O
O
O
O
O
Ar
Compound
Ar
R
MIC (lg/ml)
Using this general scheme, a number of N-alkylsubstituted 3-O-
acyl derivatives of clarithromycin were synthesized and evaluated
for in vitro antibacterial activity against Streptococcus pneumoniae.
Erythromycin A and Clarithromycin, were used as reference. The
activities reported as minimum inhibitory conc. (MICs) were deter-
S. pneumoniae
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
2-F-Phenyl
2-F-Phenyl
2-F-Phenyl
2-F-Phenyl
2-F-Phenyl
2-F-Phenyl
3-F-Phenyl
3-F-Phenyl
3-F-Phenyl
3-F-Phenyl
3-F-Phenyl
3-F-Phenyl
3-F-Phenyl
4-F-Phenyl
4-F-Phenyl
4-F-Phenyl
4-F-Phenyl
Pyridin-2-yl
Pyridin-2-yl
Pyridin-2-yl
Pyridin-2-yl
Pyridin-2-yl
Pyridin-3-yl
Pyridin-3-yl
Pyridin-3-yl
Pyridin-3-yl
Pyridin-4-yl
Pyridin-4-yl
Pyridin-4-yl
Ethyl
Allyl
Propargyl
Cyclopropyl
Cyclopropylmethyl
Benzyl
0.25
0.25
0.5
16
mined according to NCCLS method.16–18 The removal of the
L
-cladi-
8
0.5
0.125
0.125
2
>16
8
1
2
0.5
0.5
32
nosyl moiety of clarithromycin (compound 6) resulted in
a
Ethyl
Allyl
complete loss of antibacterial activity. The derivatisation of the
30-N-position along with different arylacyl groups variations (com-
pounds 11–49) led to antibacterial activity in varying degree. Dif-
ferent substituents like ethyl, allyl, propargyl, cyclopropyl,
cyclopropylmethyl and benzyl were explored at 30-N-position.
Simultaneously, the role of groups like fluorophenylacetate,
nitrophenylacetate and pyridylacetate were studied at the 3-posi-
tion of macrolide. The results are summarized in Table 1. In the 2-
fluorophenylacetate series, 30-N-substituent with ethyl 11 and allyl
12 were found to be the most active one followed by benzyl 16 and
propargyl 13 compounds. The cyclopropyl 14 and cyclopropylm-
ethyl 15 substitution at 30-N-position showed least activity against
tested pathogens. The 3-fluorobenzylacetate had slightly inferior
activity as compared to the corresponding 2-fluorophenylacetate
derivatives though both followed a similar trend for 30-N diversifi-
cation. The 4-fluorophenyl ester was the least active especially
with 30-N-allyl substituent 25. In the pyridylacetate series, 3-
pyridylacetate series was as active as or slightly better than 2-pyr-
idyl derivatives. The order of activity of the series was ethyl,
allyl>cyclopropylmethyl, propargyl>cyclopropyl. Similar trend
was also observed for the nitrophenyl series. 30-N-ethyl and 30-N-
allyl were the most active of 2-nitrophenyl ester derivatives with
Propargyl
Cyclopropyl
Cyclopropylmethyl
Benzyl
4-F-Benzyl
Ethyl
Allyl
Cyclopropyl
Benzyl
Ethyl
Allyl
Propargyl
Cyclopropyl
Cyclopropylmethyl
Ethyl
1
0.25
0.25
4
>32
>16
0.5
0.25
2
0.25
0.5
>32
32
0.25
2
Allyl
Propargyl
Benzyl
Allyl
Cyclopropyl
Cyclopropylmethyl
Allyl
Propargyl
Cyclopropylmethyl
Cyclopropylmethyl
Ethyl
2-NO2-Phenyl
2-NO2-Phenyl
4-NO2-Phenyl
2-NO2-Phenyl
3-NO2-Phenyl
3-NO2-Phenyl
3-NO2-Phenyl
3-NO2-Phenyl
4-NO2-Phenyl
4-NO2-Phenyl
1
1
0.25
0.06
1
43
44
45
46
47
48
49
MIC values 0.25
l
g/ml. 4-Nitrophenylacetate showed one fold less
Allyl
activity with 30-N-ethyl substituent 48 having MIC of 0.5
l
g/ml.
Propargyl
Cyclopropyl
Ethyl
From Table 1 it is clear that the cyclopropyl and cyclopropylmethyl
derivatives at the 30-N-position were the least active and 30-N-allyl
and 30-N-ethyl derivatives were the most active compounds in all
the series. Based on these preliminary results, further optimization
of the acylide series was done to improve their activity. The pyrid-
2-ylacetate and pyrid-3-yl acetate series with 30-N-allyl and 30-N-
ethyl variations were found to be the most promising and therefore
explored further. It is documented in literature that newer macro-
lide derivatives such as telethromycin, ABT-733 or bridged keto-
lides have additional heterocyclic arm which is responsible for
their enhanced antibacterial activity. Therefore, the 11,12-diols of
the acylide series were further derivatised to make 11,12-cyclic
carbamates analogs employing the following general procedure
(Scheme 2).19 The 11,12-diol 10 was converted to the 11,12-car-
bonate 50 by reaction with triphosgene in presence of pyridine
in DCM at 0 °C and then to 10,11-ene 51 on treatment with
2,2,4,4-tetra methylguanidine in DMF at 80 °C. The 12-OH of 51
was carboxylated with CDI using NaH as base in DMF–THF (3:2)
to give 52, which was subsequently coupled with respective butyl-
amine derivatives 5319 undergoing intramolecular michael addi-
tion to produce the 11,12-cyclic carbamates 54. The 20-O-benzoyl
16
0.5
>32
0.25
0.25
Cyclopropyl
Clarithromycin
Erythromycin
group of these carbamates were finally deprotected to give the re-
quired compounds 55–81. The activity of these was evaluated
against the target pathogens and the results are summarized in
Table 2.
In general, all the acylides 55–81 showed MIC range of 0.008–
0.125 lg/ml against gram positive S. pneumoniae and 0.06–2 lg/
ml against macrolide resistant S. pneumoniae strains. They also
demonstrated excellent activity against Streptococcus pyogenes
strains with upside over telithromycin (MIC range of 0.008–2 lg/
ml) making them suitable candidates for an additional indication
of pharyngitis. Additionally, comparable susceptibility results with
telethromycin against S. pneumoniae and Moraxella catarrhalis iso-
lates was also observed. Compound 63, 66–71, 74, 77, 78 and 80
showed better activities than telithromycin against H. influenzae

R. Kumar et al. / Bioorg. Med. Chem. Lett. 22 (2012) 476–481
479
O
O
O
O
O
i
BzO
N
R
HO
OH
BzO
N
R
ii
O
O
O
O
O
O
O
O
O
O
O
O
O
O
10
Ar
Ar
50
O
O
O
O
N
O
BzO
N
R
HO
N
BzO
N
R
iii
iv
O
O
O
53
O
O
O
O
O
O
O
O
O
O
Ar
52
Ar
51
O
O
O
O
R1
R1
O
O
HO
N
R
BzO
N
R
O
O
N
N
v
O
O
O
O
O
O
O
O
O
O
O
O
Ar
Ar
55-81
54
Scheme 2. Reagents and conditions (i) Triphosgene, Pyr, DCM, 0 °C, 3 h, 90–95%; (ii) TMG, DMF, 80 °C, 6 h, 93–97%; (iii) NaH, CDI, DMF–THF, O °C., 30 min; 95%; (iv)
R1CH2CH2CH2CH2NH2 53, CH3CN, 65 °C, 42–61%; (v) CH3OH, reflux, 15 h, 80–85%.
with MIC less than 0.06
lg/ml. The acylides 55–81 also showed
with MIC range of 0.03–1
lg/ml against low level telithromycin
lower MIC values against atypical pathogens. MIC againstLegionella
pneumophila and Mycoplasma pneumoniae strains was in the range
resistant strains and 0.03–8
lg/ml against high level telithromycin
resistant strains (Table 3 and 4). These acylides were also evalu-
ated for their in vivo potential in murine systemic infection model
using S. pneumoniae 3579 (ermB) and showed promising results.20
These results were comparable with telithromycin and also in
agreement with the previous studies reported where the authors
showed that acylide TEA0777 was significantly more active than
erythromycin A and comparable with clarithromycin in murine
systemic infection model using S. aureus Smith strain.12
In summary, we have identified a novel and potent series of
acylides active against antibiotic resistant respiratory pathogens
and which holds potential as new generation of macrolides. The
introduction of an appropriate acyl group, that is, pyrid-2-ylacetate
to the 3-O-position of clarithromycin along with 30-N-allyl not only
enhanced antibacterial activity but also showed activity against
resistant target pathogens. The series was active against MLSB
resistant RTI pathogens with additional activity against ketolide
resistant strains. The special feature of acylides is that they show
an upside over existing macrolides and ketolides with activity
against S. pyogenes and laboratory generated telithromycin resis-
tant S. pneumoniae erm strains isolates. This novel series of acylides
can be further explored as investigational antibiotics against com-
munity acquired respiratory tract infections.
of 0.004–0.03 and 0.004–0.125 l
g/ml, respectively.20 Activity
against S. pneumoniae mef strains is in agreement with previous
studies as reported for earlier series of acylides.12,13 From a struc-
ture–activity relationship view, it was found that 2-pyridylacetate
series with 30-N-allyl diversity was the most promising. In general,
this series had excellent activity against the target pathogens bet-
ter than 3-pyridylacetate 30-N-allyl series. The 30-N-ethyl 2-pyridy-
lacetate and 30-N-ethyl 3-pyridylacetate series were also found to
have inferior activity. Therefore, the 2-pyridylacetate series with
30-N-allyl was investigated further, varying different heterocycles
tethered to the 11,12-carbamates. The compound 82 which is an
unsubstituted 11,12-cyclic carbamate with no heterocyclic arm at-
tached was also inferior in activity against the target pathogens.
This highlights the role of heterocycle attached to macrolide in
augmenting the activity.
Compounds 62, 63, 65, 67, 73, 74 and 75 were further screened
against telethromycin resistant S. pneumoniae strains. Two types of
telithromycin resistant S. pneumoniae strains generated in the lab
were described as low level and high level telithromycin resistant
strains with MIC range of 4–8 and 32–64
lg/ml against telithromy-
cin, respectively. Interestingly, all the acylides were very active

480
R. Kumar et al. / Bioorg. Med. Chem. Lett. 22 (2012) 476–481
Table 2
Antibacterial activity of Acylides 55–82 against target pathogens
O
O
R1
O
HO
N
R
O
N
O
O
O
O
O
O
Ar
Compound
Ar
R
R1
MIC (ug/ml)
S. pneum. S. pneum. S. pneum. S. pneum. S. pyogene H. influ. Moraxela
6303
49619
(erm)
(mef)
19615
38
8176
3579
994
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
Pyrid-2-yl
Pyrid-2-yl
Pyrid-3-yl
Pyrid-3-yl
Pyrid-2-yl
Pyrid-3-yl
Pyrid-3-yl
Pyrid-2-yl
Pyrid-2-yl
Pyrid-2-yl
Pyrid-3-yl
Pyrid-3-yl
Pyrid-2-yl
Pyrid-3-yl
Pyrid-2-yl
Pyrid-2-yl
Pyrid-2-yl
Pyrid-2-yl
Ethyl 3-(1H-Imidazol-4-yl)-pyridine
Allyl 3-(1H-Imidazol-4-yl)-pyridine
Ethyl 3-(1H-Imidazol-4-yl)-pyridine
Allyl 3-(1H-Imidazol-4-yl)-pyridine
Ethyl 5-(1H-Imidazol-4-yl)-pyridin-2-ylamine 0.06
Allyl 5-(1H-Imidazol-4-yl)-pyridin-2-ylamine 0.06
Ethyl 5-(1H-Imidazol-4-yl)-pyridin-2-ylamine 0.06
Allyl 5-(1H-Imidazol-4-yl)-pyridin-2-ylamine 0.06
Allyl 1H-Imidazo[4,5-b]pyridine
Ethyl 1H-Imidazo[4,5-b]pyridine
Allyl 1H-Imidazo[4,5-b]pyridine
Ethyl 1H-Imidazo[4,5-b]pyridine
Allyl 1H-Pyrrolo[2,3-b]pyridine
Allyl 1H-Pyrrolo[2,3-b]pyridine
Allyl 4-phenyl-1H-imidazole
Allyl 3-(1H-Imidazol-4-yl)-phenylamine
Allyl 3-(1H-Imidazol-4-yl)-pyrimidine
Allyl 5-(1H-Imidazol-4-yl)-pyrimid-2-
ylamine
0.06
0.015
0.06
0.03
0.015
0.008
0.03
0.03
0.06
0.125
0.06
0.06
0.06
0.015
0.03
0.03
0.03
0.06
0.03
0.03
0.03
0.03
1
0.25
2
0.06
0.125
0.125
0.125
0.125
0.06
0.125
0.125
0.5
0.25
0.06
0.25
0.25
0.25
0.25
0.06
0.06
0.06
0.06
0.008
0.03
0.06
0.06
0.06
0.03
2
0.06
0.03
0.06
0.03
0.03
0.03
0.03
0.03
0.03
2
1
0.25
0.125
1
0.125
0.125
0.25
1
0.125
0.125
0.125
0.125
NT
<0.06
0.06
0.125
<0.03
<0.06
<0.03
<0.06
<0.06
<0.06
NT
0.25
0.125
0.25
0.25
0.5
0.25
1
2
1
8
0.25
0.125
0.125
0.125
0.25
0.125
0.06
0.25
0.25
0.06
0.25
0.06
0.06
0.06
0.06
0.03
0.06
0.06
0.03
0.03
0.03
0.5
0.125
0.25
0.125
0.125
0.125
0.125
73
74
75
76
77
78
79
80
81
82
Pyrid-2-yl
Pyrid-2-yl
Pyrid-2-yl
Pyrid-2-yl
Pyrid-2-yl
Pyrid-2-yl
Pyrid-2-yl
Pyrid-2-yl
Allyl 4-(1H-Imidazol-4-yl)-pyridin-2-ylamine 0.03
0.03
0.03
0.015
0.015
0.06
0.03
0.125
0.06
0.06
0.015
0.125
0.125
0.25
0.125
0.5
0.25
0.25
0.25
0.5
0.06
0.125
0.06
0.125
0.5
0.25
0.125
0.125
0.125
0.125
2
NT
<0.06
NT
0.25
<0.06
<0.06
0.06
<0.06
0.125
NT
0.06
0.25
0.125
0.125
0.125
0.06
0.06
0.125
0.125
1
Allyl 4-Furan-2-yl-1H-imidazole
Allyl 5-Furan-2-yl-1H-imidazole
Allyl 4-Furan-3-yl-1H-imidazole
Allyl 3H-Imidazo[4,5-b]pyridine
Allyl 1H-Imidazo[4,5-c]pyridine
Allyl 3H-Imidazo[4,5-c]pyridine
Allyl 9H-Purine
0.06
0.008
0.06
0.125
0.06
0.125
0.06
0.03
0.015
0.06
0.125
0.03
0.125
0.06
0.03
0.015
Pyrid-2-yl
Allyl 9H-Purin-6-ylamine
0.125
0.125
11,12-cyclic carbamate NH
3-O-(2-Pyridylacetyl)-5-O-
(30-N-desmethyl-30-N-
allyl)-clarythromycin
8
Erythromycin
Clarithromycin
Azithromycin
Telithromycin
0.25
0.25
0.25
0.03
0.125
0.125
0.25
8
4
16
0.25
0.5
0.5
1
0.015
0.125
0.25
>16
>16
>16
1
8
4
16
0.25
0.06
0.25
0.03
NT: Not tested
Table 4
Table 3
MIC of acylides against low level telithromycin resistant S. pneumoniae erm (n = 7)
MIC of acylides against high level telithromycin resistant S. pneumoniae erm (n = 12)
Compound
MIC (lg/ml)
Compound
MIC (
lg/ml)
S. pneumoniae
S. pneumoniae
757
162
2840
3489
B739
3271
217
3488
AB14
5099
3390
5051
62
63
65
67
73
74
75
TEL
0.06
0.25
0.5
1
0.125
1
0.5
1
1
4
1
4
2
64
0.25
0.5
0.5
2
0.5
2
0.25
0.5
0.5
2
1
2
0.125
0.5
0.5
2
1
2
0.25
0.5
1
4
2
2
1
64
62
63
65
67
73
74
75
TEL
0.06
0.125
0.5
1
0.125
1
0.03
0.125
0.25
0.5
0.125
0.5
0.03
0.06
0.125
0.25
0.03
0.25
0.125
8
0.03
0.06
0.125
0.25
0.06
0.25
0.125
8
0.06
0.125
0.25
0.25
0.125
0.5
0.03
0.125
0.25
0.5
0.06
0.25
0.25
4
0.5
32
1
64
1
64
1
64
0.5
4
0.25
8
0.25
8

R. Kumar et al. / Bioorg. Med. Chem. Lett. 22 (2012) 476–481
481
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and Rattan A. (Das Biswajit,; Katoch Rita,; Hajare Atul Kashinath,; Kapkoti
Gobind Singh,; Bandyopadhyay Anish,; Venkataramanan Ramadass,; Kumar
Rajesh,; Kurhade Santosh Haribhau,; Rathy Sujata,; Chakrabarti Anjan,; Surase
Yogesh Baban,; Salman Mohammad,; Rattan Ashok) WO Patent 030786,
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16. The MIC assays were performed in accordance with the NCCLS guidelines:
Methods for dilution Antimicrobial Susceptibility Tests for Bacteria that Grow
Aerobically, 5th ed.; NCCLS Document M7-A5; NCCLS, January 2000; 20.
17. Performance Standards for Antimicrobial Susceptibility Testing: Eleventh
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2001; 21, 1.
Acknowledgments
We would like to thank Dr. Mohammed Salman, and Dr. Dha-
ram Vir for their valuable comments and the Analytical Dept. for
the spectral data.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.10.101.
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