Synthesis of macrolones with central piperazine ring in the linker and its influence on antibacterial activity

Article abstract of DOI:10.1016/j.bmc.2011.07.010

Three macrolides, clarithromycin, azithromycin and 11-O-Me-azithromycin have been selected for the construction of a series of new macrolone derivatives. Quinolone-linker intermediates are prepared by Sonogashira-type C(6)-alkynylation of 6-iodoquinolone precursors. The final macrolones, differing by macrolide moiety and substituents at the position N-1 of the quinolone or by the presence of an ethyl ester or free acid on the quinolone unit attached via a linker. The linker comprises of a central piperazine ring bonded to the 4″-O position of cladinose by 3-carbon ester or ether functionality. Modifications of the linker did not improve antibacterial properties compared to the previously reported macrolone compounds. Linker flexibility seems to play an important role for potency against macrolide resistant respiratory pathogens.

Full text of DOI:10.1016/j.bmc.2011.07.010

Bioorganic & Medicinal Chemistry 19 (2011) 7281–7298
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis of macrolones with central piperazine ring in the linker
and its influence on antibacterial activity
a,
⇑
a,
a
a
a
ˇ
´
ˇ ´
´
´
Samra Kapic , Hana Cipcic Paljetak , Ivana Palej Jakopovic , Andrea Fajdetic , Marina Ilijaš ,
a
a
b
c
ˇ ´ a
Vlado Štimac , Karmen Brajša , David J. Holmes , John Berge , Sulejman Alihodzic
a GlaxoSmithKline Research Centre Zagreb, Croatia
b GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA
c GlaxoSmithKline, New Frontiers Science Park, Harlow CM19 5AW, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Three macrolides, clarithromycin, azithromycin and 11-O-Me-azithromycin have been selected for the
construction of a series of new macrolone derivatives. Quinolone-linker intermediates are prepared by
Sonogashira-type C(6)-alkynylation of 6-iodoquinolone precursors. The final macrolones, differing by
macrolide moiety and substituents at the position N-1 of the quinolone or by the presence of an ethyl
ester or free acid on the quinolone unit attached via a linker.
Received 20 April 2011
Revised 6 July 2011
Accepted 8 July 2011
Available online 21 July 2011
The linker comprises of a central piperazine ring bonded to the 400-O position of cladinose by 3-carbon
ester or ether functionality. Modifications of the linker did not improve antibacterial properties compared
to the previously reported macrolone compounds. Linker flexibility seems to play an important role for
potency against macrolide resistant respiratory pathogens.
Keywords:
Antimicrobial activity
Macrolides
Piperazine
Quinolone
Ó 2011 Elsevier Ltd. All rights reserved.
Structure–activity relationship
1. Introduction
In order to obtain derivatives with improved potency against
resistant Gram-positive and relevant Gram-negative strains, we
As the utility of currently used antibiotics becomes compro-
mised by the emergence and subsequent spread of resistant patho-
gens, there is a continuous need for the development of novel
antibacterial agents with broader spectrum of activity, able to com-
bat resistance.
The well-known antibiotic erythromycin A has been used in the
clinic for the treatment of upper respiratory tract infections since
the 1950s.1 Since then, erythromycin and the second generation
macrolides, such as clarithromycin and azithromycin, have been
extensively used for the treatment of upper and lower respiratory
tract infections caused by Gram-positive bacteria.2
In 1995 a novel series of macrolides known as ketolides was
introduced.3,4 These compounds possess a 3-keto and 11,12-carba-
mate functionalities with tethered aromatic groups to the macro-
lide cores. Location of the aryl group on the ketolide scaffold is
considered to be a very important feature for their antibacterial
activity. Ketolides showed excellent potency against the majority
of the key macrolide resistant respiratory pathogens.5,6
have recently reported a novel class of antibacterial compounds,
named macrolones.7–11
This term describes compounds which consist of a macrolide
scaffold with a quinolone unit covalently attached via suitable lin-
ker (Fig. 1). We have studied the SAR trends based on differences in
macrolide moiety, length of the linker with combinations of het-
eroatoms nitrogen and oxygen, positions of binding of the linker
to the quinolone-3-carboxylic unit and substitutions at N-1 posi-
tion of the quinolone unit, as well as the influence of different
quinolone moieties.
It has been shown that elongation of the chain improved po-
tency against key respiratory pathogens resistant to currently used
macrolide antibiotics, especially MLSB resistant strains of S. pyoge-
nes. Some representatives of this class of compounds are presented
at Figure 1.
Here we report the synthesis and the structure–activity rela-
tionships of derivatives having piperazine in the aliphatic linker.
These structures were characterized by the C–C bond at the posi-
tion C-6 of the quinolone-3-carboxylic acid unit and a central
piperazine ring in the linker. Incorporation of a piperazine ring
restricts the conformational flexibility of the linker compared to
the acyclic analogues. However, flexibility of distal parts towards
macrolide and quinolone units remains unchanged. Additional sta-
bilization of molecule was achieved by substituting the 400-ester
bond by an ether bond.12 Ester derivatives have been prepared
⇑
Corresponding author at present address: Galápagos Research Center Ltd,
Departments of Chemistry and Biology, Prilaz baruna Filipovic´a 29, Zagreb, Croatia.
Tel.: +385 1 888 6354; fax: +385 1 888 6443.
E-mail address: samra.kapic@glpg.com (S. Kapic´).
Present address: University of Zagreb, Center for Translational and Clinical
Research, Šalata 2, Zagreb, Croatia.
0968-0896/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2011.07.010

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S. Kapic et al. / Bioorg. Med. Chem. 19 (2011) 7281–7298
N
N
N
N
O
OH
OH
HO
HO
HO
HO
OH
OH
O
O
O
O
O
O
O
O
N
O
O
O
O
O
N
O
O
O
H
N
4''
4''
6'''
O
6'''
OH
O
N
R
OH
O
O
O
O
Cl
1 R = H
3
2 R = Me
N
N
N
O
OH
HO
N
OH
HO
HO
HO
OH
OH
O
O
O
O
O
O
O
O
N
O
O
O
O
O
O
4''
O
4''
6'''
6'''
O
O
OH
O
O
OH
O
O
O
O
N
4
5
Figure 1. Structures of the recently reported macrolone derivatives.
on clarithromycin, azithromycin and 11-O-methyl-azithromycin.
The influence of different substituents at N-1, as well as the impact
of triple, double or single bonds in the linker or the presence of a
C-3 carboxylic group or ester on the quinolone on the antimicrobial
potency are also reported. It was expected that these structures
would provide guidance for future research. Macrolones reported
in this paper are presented by the general formula in Figure 2.
Derivative 7 was isolated by a column chromatography over silica
gel in 22% yield. Deprotection of amine carbamates 7–9 with triflu-
oroacetic acid gave amine derivatives 10–12 in quantitative yields
(Scheme 1).18
(ii) Macrolide chemistry. Clarithromycin and azithromycin, used
for the preparation of starting molecules 13–15 in Scheme 2, are
commercially available, whereas 11-O-methyl-azithromycin19,20
was prepared as reported previously. For the synthesis of com-
pounds 18–20, 14 was used as its 20-O-acetyl derivative. Prepara-
tion of the 400-O-propenoyl esters 13–15 was achieved by
reaction of starting macrolide and 3-chloropropenoyl chloride in
the presence of triethylamine as base.21 Subsequent Michael reac-
tion and removal of the 20-O-acetyl protecting group was used to
prepare compounds 18–20.22 Alternatively the 20-O-acetyl protec-
tion can be removed prior to Michael addition and this route affor-
ded target compounds 16, 17 and 21.21
Michael addition proceeded in a mixture of MeCN/H2O (ratio
10/1) with excess of quinolone-3-carboxylic acid derivatives
10–12 and TEA at 80 °C for 24 h. Products 16–21 were isolated by
column chromatography on silica-gel in moderate yields. It was as-
sumed that low yields for 11-O-methylazithromycin derivatives are
due to sterical hindrance caused by conformational change. Triple
bond in the aliphatic chain was catalytically hydrogenated over
10% Pd/C in MeOH at 5 bar of hydrogen. This procedure avoided
any over-hydrogenation or hydrogenolysis affording analogues
22–27 in low to moderate yields.
2. Results and discussion
2.1. Chemistry
2.1.1. Synthetic route to the target 400-O ester macrolone
derivatives
(i) Quinolone intermediate synthesis. Construction of the linker
started from commercially available 1,1-dimethylethyl 1-pipera-
zinecarboxylate 1 which was quantitatively propargylated to give
intermediate 3, that was subjected to Sonogashira type13,14 of
C–C coupling with 6-iodoquinolone-3-carboxylic acid derivatives
4–6.14–17
This reaction afforded derivatives 8 and 9 in 80–90% yields that
were isolated by a precipitation from n-hexane/EtOAc (ratio 10/1).
X
R2
R1
HO
O
O
O
N
HO
2.1.2. Synthetic route to the target 400-O ether macrolone
derivatives
O
O
O
(i) Quinolone intermediate synthesis. Intermediate 29 was pre-
pared starting from propargyl alcohol 28 and ethyl 1-ethyl-6-
iodo-4-oxo-1,4-dihydro-3-quinolinecarboxylate 4 by Sonogashira
cross-coupling.13,14 This reaction was completed with 92% yield
and the product 29 was isolated by precipitation from n-hexane/
EtOAc (ratio 10/1). Catalytic hydrogenation of alkyne 29 over a
Lindlar catalyst gave the (Z)-alkene 30 in quantitative yield. Alco-
hol 30 was converted into the tert-butyl carbonate 32 which was
used as electrophile23,24 for the Pd-catalyzed N-alkylation of cyclic
amine 33 to afford 34 in quantitative yield. A modified procedure
O
O
O
O
4''
6'''
R4
Y
N
O
N
O
O
N
R3
Y = CO, CH2
X = C=O, X = NMeCH2
R1 = R2 = Me, H
,
R3 = Et, cyPr
R4 = Et, H
Figure 2. General formula of synthesized derivatives.

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S. Kapic et al. / Bioorg. Med. Chem. 19 (2011) 7281–7298
O
O
O
O
I
R2
a)
b)
O
Br
+
+
O
N
NH
O
N
N
N
R1
4 R1 = CH3CH2
R2 = CH3CH2
5 R1 = cyclopropyl R2 = CH3CH2
6 R1 = CH3CH2 R2 = H
2
1
3
O
O
O
O
O
HN
N
O
N
N
R2
R2
c)
O
O
N
N
R1
R1
7 R1 = CH3CH2
8 R1 = cyclopropyl R2 = CH3CH2
9 R1 = CH3CH2 R2 = H
R2 = CH3CH2
10 R1 = CH3CH2
11 R1 = cyclopropyl R2 = CH3CH2
12 R1 = CH3CH2 R2 = H
R2 = CH3CH2
Scheme 1. Synthesis of quinolone intermediates 10–12. Reagents and conditions: (a) MeCN, Na2CO3, 0–50 °C, 24 h; (b) CuI, Pd(II)PPh3Cl2, TEA, MeCN, 50 °C, N2, 2 h; (c)
CF3COOH/CH2Cl2 = 1/1, rt, 1 h.
X
R2
R1
HO
O
O
O
N
HO
O
O
HN
N
O
R4
O
+
O
O
O
O
N
R3
O
O
O
10 R3 = CH3CH2
R4 = CH3CH2
13 X = C=O
R1 = CH3 R2 = H
11 R3 = cyclopropyl R4 = CH3CH2
12 R3 = CH3CH2 R4 = H
14
X = N(CH3)CH2 R1 = H
R2 = CH3
R2 = H
X = N(CH3)CH2 R1 = H
15
X
R2
R1
HO
O
O
N
HO
a)
b)
O
O
O
O
O
O
O
O
O
N
N
O
R4
O
O
N
R3
19 X = N(CH3)CH2 R1 = H
20 X = N(CH3)CH2 R1 = H
21 X = N(CH3)CH2 R1 = H
R2 = CH3 R3 = cyclopropyl R4 = CH3CH2
16 X = C=O
17 X = C=O
R1 = CH3 R2 = H
R1 = CH3 R2 = H
R3 = CH3CH2
R3 = cyclopropyl R4 = CH3CH2
R4 = CH3CH2
R2 = CH3 R3 = CH3CH2
R2 = R3 = CH3CH2
R4 = H
18 X = N(CH3)CH2 R1 = H R2 = CH3 R3 = CH3CH2
R4 = CH3CH2
H
R4 = CH3CH2
X
R2
R1
HO
O
O
O
N
HO
O
O
O
O
O
O
O
O
R4
N
O
N
O
O
N
R3
25 X = N(CH3)CH2 R1 = H
R2 = CH3 R3 = cyclopropyl R4 = CH3CH2
22 X = C=O
23 X = C=O
R1 = CH3 R2 = H
R1 = CH3 R2 = H
R3 = CH3CH2
R3 = cyclopropyl R4 = CH3CH2
R4 = CH3CH2
R4 = CH3CH2
26 X = N(CH3)CH2 R1 = H
27 X = N(CH3)CH2 R1 = H
R2 = CH3 R3 = CH3CH2
R2 = R3 = CH3CH2
R4 = H
24 X = N(CH3)CH2 R1 = H R2 = CH3 R3 = CH3CH2
H
R4 = CH3CH2
Scheme 2. Synthesis of macrolone intermediates 22–27. Reagents and conditions: (a) TEA, H2O/MeCN, 80 °C, 24 h; (b) 10% Pd/C, MeOH, 5 bar, rt, 20 h.

´
S. Kapic et al. / Bioorg. Med. Chem. 19 (2011) 7281–7298
7284
was presented in the synthesis of ketolide antibiotic ABT-77325 for
selective 6-O-alkylation which was originally demonstrated in car-
bohydrate chemistry.26,27 Deprotection of tert-butyl carbamate 34
was completed by brief treatment with trifluoroacetic acid as de-
scribed for compounds 10–1218 to afford compound 35 in quanti-
tative yield (Scheme 3).
present on the cladinose moiety. In 1H NMR spectra of 30 and 32,
the arising of L11-CH and L12-CH proton signals in the downfield
ranges of 5.89–5.91 ppm and 6.54–6.80 ppm, respectively, indi-
cated presence of double C–C bond in the aliphatic linker. The con-
figuration of L11–L12 double bond in the structures of compounds
3
30–32 is Z, indicated by the coupling constants JL11-H,L12-H 12 Hz.
(ii) Macrolide chemistry. Protected 400-O-ether azithromycin der-
ivate 36 was prepared in five steps from commercially available
azithromycin, as previously reported.10 Dess–Martin oxidation28,29
The configuration of the L11–L12 double bond in the structures of
compounds 34–39 is E as indicated by the coupling constants
3JL11-H,L12-H 16 Hz. This stereochemistry is consistent with me-
chanic aspects of allylic amination.31–34
of c-hydroxy group at 36 was performed in DCM at room temper-
ature22,23 for 3 h to afford intermediate 37. The product was not
isolated and reductive alkylation was performed in situ with
2 equiv of amine 35 and NaBH(OAc)3–ZnCl2 as reducing agent.
Derivativee 38 was isolated by column chromatography over sil-
ica-gel in 28% yield. One-pot deprotection and ester hydrolysis
under basic condition was carried out in MeOH/H2O (ratio 3/1)
with 18 equiv of K2CO3 at 50 °C for 5 h to obtain compound 39.
In the final step, the alkene in the linker was catalytically hydroge-
nated with 10% Pd/C in MeOH at a pressure of 5 bar and rt affording
compound 40 (Scheme 4).
In addition, the NMR spectra showed the presence of the ex-
pected signals arising from the quinolone and piperazine atoms.
In the 1H NMR spectra of 7–9, having tert-butylcarboxylate pro-
tecting group, two methylene groups of piperrazine resonate at
3.35 ppm, while the other two at 2.50 ppm, due to their chemical
non equivalence. In the 1H NMR spectra of 10–27, the arising of
piperazine proton signals in the narrow ranges 2.68–2.74 ppm
and 2.45–2.55 ppm respectively, are clear evidence of the equiva-
lence of protons. Similarly, piperazine protons in 34 were observed
at the range of 2.77–3.33 ppm, in constant to that in 35 at 2.37–
2.39 ppm and in macrolone derivatives 38–40 at 2.52–2.60 ppm.
2.1.3. NMR spectroscopy details
The structural assignments for the newly created structures
were confirmed by NMR studies. Atom numbering of quinolone
and macrolone derivatives is shown at Figure 3.
2.2. Antibacterial activity
Antibacterial activity of compounds was determined by a stan-
dard broth microdilution method.35 Azithromycin and clarithro-
mycin were used as controls. The results are shown in Tables 1
and 2 and are expressed as minimum inhibitory concentrations
A downfield shift of 400-H signal from 3.04 ppm in azithromycin
and 3.00 in clarithromycin to 4.70 ppm in 400-ester macrolones
16–27 and an upfield shift to 2.78 ppm for 400-ether macrolones
38–40 was observed.30,31 These observations are consistent with
the 400-O forming part an ester or ether function respectively. It
was noted that the 400-H proton in compounds 16–27 resonates
as a doublet, not as a triplet as in the parent macrolides, in accor-
dance with acylation of a free hydroxyl group at 400 position, that is,
lack of the 400-H and 400-OH coupling. The appearance of 400-H sig-
nals for ether derivatives 38–40 at 2.78 ppm and disappearance
of 13C signal at 176 ppm for C@O were clear evidence of ether bond
(MICs) in units of
lg/mL. The organisms tested represented rele-
vant Gram-positive (Streptococcus pneumoniae, Streptococcus pyog-
enes and Staphylococcus aureus) and Gram-negative (Haemophilus
influenzae and Moraxella catarrhalis) respiratory tract pathogens
that were either sensitive or resistant to macrolide antibiotics.
Macrolide resistance was due to two major mechanisms—produc-
tion of efflux pumps (M), or ribosome modification by methylation.
Methylase expression was inducible (iMLS) or constitutive (cMLS).
O
O
N
O
O
N
O
N
O
HO
O
O
I
a)
O
O
b)
O
HO
+
O
O
O
HO
+
31
30
29
28
4
O
O
O
O
N
O
N
O
O
O
O
c)
d)
O
O
O
N
N
O
+
NH
N
34
33
32
O
O
N
HN
e)
O
N
35
Scheme 3. Synthesis of quinolone intermediate 35. Reagents and conditions: (a) Cu(I)I, Pd(II)PPh3Cl2, TEA, MeCN, 50 °C, N2; (b) 5% Pd/CaCO3-Pb, MeOH, 1 bar, rt, 4 h; (c) n-
Bu4NHSO4, 1 M aq NaOH, DCM, 0–25 °C, 20 h; (d) Pd2 (dba)3, dppb, dry toluene, reflux, 3 h; (e) TFA, DCM, rt, 2.5 h.

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S. Kapic et al. / Bioorg. Med. Chem. 19 (2011) 7281–7298
O
N
O
O
N
O
O
O
O
N
O
O
O
O
OH
O
N
O
O
OH
O
N
O
N
N
O
+
a)
O
O
O
O
O
O
O
O
H
OH
O
O
O
35
O
O
36
37
O
N
O
N
O
O
O
OH
N
HO
O
O
HO
OH
O
b
N
HO
c)
O
O
O
O
O
O
O
O
O
O
O
O
N
O
N
N
O
O
N
N
O
OH
O
O
N
39
38
N
HO
HO
OH
O
N
HO
d)
O
O
O
O
O
O
O
OH
N
N
O
O
N
40
Scheme 4. Synthesis of macrolone intermediates 38–40. Reagents and conditions: (a) Dess–Martin periodinane, DCM, rt, 3 h; (b) NaBH(OAc)3, ZnCl2, rt, 20 h; (c) MeOH/
H2O = 3/1, K2CO3, 50 °C, 5 h, rt, 20 h; (d) 10% Pd/C, MeOH, 5 bar, rt, 20 h.
N
9
8
10
N
OH
O
L7
L5
11
12
13
HO
HO
O
L10
7
L4
L9
O
O
O
3'
6
L1
2'
1'
L12
4'
5'
L2
L3
O
N
N
5'''
8'''
13'''
5
10'''
9'''
3'''
O
14
15
4'''
4
12'''
O
O
6'''
7'''
O
L6 L8
14'''
L11
1
3
1''
2''
L5
2
5''
L7
O
L10
O
1'''
11'''
N
4''
L9
L4
O
O
3''
L2
L12
N
13'''
O
5'''
N
L1
10'''
9'''
3'''
L11
O
L3
4'''
12'''
O
6'''
L8
L6
14'''
O
15'''
16'''
7'''
2'''
N
8'''
11'''
16'''
8
15'''
19
Figure 3. Chemical numbering of quinolone derivative 8 and macrolone derivative 19 as examples.
All quinolone intermediates were antibacterially inactive (Table
Across the scaffolds, quinolone ester macrolones with triple
resistant S. aureus (from >64 lg/mL for 18 and 24, to 0.5, and 0.25
1).
for 20 and 26, respectively) and H. influenzae. However, on the 11-
O-methyl azithromycin scaffold potency of acid 20 against methyl-
ase expressing pneumococcal strains was diminished. Quinolone
esters were mostly inactive against efflux resistant S. aureus, while
displaying good potency against efflux resistant streptococcal spe-
cies. Triple-bonded compounds were slightly more active than
their corresponding reduced counterparts.
Replacement of ethyl by a cyclopropyl at the N-1 position of the
quinolone did not improve antibacterial activity of either triple-
bonded or reduced derivative in the clarithromycin or 11-O-methyl
analogues.
bond in the linker had better antibacterial activity against Gram
positive organisms than their reduced counterparts (16 vs 22, 17
vs 23, 21 vs 27, 18 vs 24, 19 vs 25), Table 2. Regarding Gram neg-
atives, situation is less straightforward and potency of compounds
is comparable (17 vs 23 and 19 vs 25), better for triple bonded (16
vs 22) or better for reduced equivalents (21 vs 27 and 18 vs 24,
against M. catarrhalis). The presence of free carboxylic acid, rather
than ester group on quinolone moiety (20 vs 18 and 26 vs 24)
resulted in improved potency, which is most pronounced on efflux

Table 1
In vitro antibacterial activity of quinolone intermediates (MIC values in
lg/mL)
Phenotype
S. aureus
ATCC
13709
S.
S.
S.
S.
S.
S.
S.
S. pyogenes S.
S.
S.
H.
M.
pneumoniae pyogenes aureus
SP030
pneumoniae
134 GR-
Micro
pyogenes
Finland
11
aureus pneumoniae 166 GR-
PK2
aureus pneumoniae pyogenes influenzae
catarrhalis
ATCC
23246
3565
90256/
97
iMLS
58 Spain
cMLS
Micro
cMLS
PK1
M
Ci137
M
3
ATCC
49247
Finland
M
ery S
ery S
ery S
iMcLS
iMLS
cMLS
AZM
CAM
0.5
0.25
60.125
60.125
60.125
60.125
>64
>64
>64
>64
16
1
>64
>64
>64
>64
>64
>64
>64
32
8
4
8
4
1
8
60.125
60.125
O
O
N
O
O
N
N
O
7
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
O
N
O
HN
N
O
10
O
O
N
O
O
N
N
O
8
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
O
N
O
HN
N
O
O
11
O
N
O
O
N
O
N
34
35
>64
>64
64
64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
O
O
HN
O
N
N
AZM = azithromycin; CAM = clarithromycin; iMLS = inducible resistance to macrolide, licosamide and streptogramin (MLS) antibiotics; iMcL = inducible resistance to macrolide and constitutive resistance to lincosamide anti-
biotics; cMLS = constitutive MLS resistance; M = efflux mediated macrolide resistance.

Table 2
In vitro antibacterial activity of macrolones (MIC values in
lg/ml)
Phenotype
S.
S.
S.
S.
S.
S.
S.
S.
S.
S.
S.
S.
H.
ATCC
M.
aureus pneumoniae pyogenes aureus pneumoniae pyogenes aureus pneumoniae pyogenes aureus pneumoniae pyogenes influenzae catarrhalis
ATCC
13709
ery S
SP030
ery S
3565
ery S
90256/ 134 GR-
97 Micro
iMLS iMcLS
Finland PK2
11
iMLS
58 Spain
166 GR- PK1
Micro
cMLS
Ci137
M
3
ATCC
23246
Finland 49247
M
cMLS cMLS
M
AZM
CAM
0.5
0.25
60.125
60.125
60.125 >64
60.125 >64
>64
>64
16
1
>64
>64
>64
>64
>64
>64
>64
32
8
4
8
4
1
8
60.125
60.125
O
HO
HO
O
N
HO
O
O
O
O
16
O
0.25
60.125
60.125 >64
1
60.125 >64
60.125
8
32
60.125
—
4
1
O
O
N
O
N
O
N
O
O
O
O
HO
HO
O
N
HO
O
O
O
O
O
O
17
4
60.125
60.125 >64
4
0.5
>64
4
16
>64
60.125
60.125 >64
4
O
N
O
N
O
N
O
O
O
O
HO
HO
O
O
N
HO
O
O
22
4
60.125
60.125 >64
16
0.25
>64
8
16
>64
60.125
60.125 >64
4
O
O
O
O
N
O
O
N
O
N
O
O
O
HO
HO
O
N
HO
O
O
O
23
4
60.125
60.125 >64
16
0.5
>64
4
16
>64
60.125
60.125 >64
4
O
O
O
O
N
O
O
N
O
N
O
O
N
N
OH
O
HO
HO
O
OH
O
O
O
O
21
1
60.125
60.125 >64
60.125
60.125 >64
60.125
32
16
60.125
60.125
4
1
O
O
O
N
O
N
O
O
N
(continued on next page)

Table 2 (continued)
Phenotype
S.
S.
S.
S.
S.
S.
S.
S.
S.
S.
S.
S.
H.
ATCC
M.
aureus pneumoniae pyogenes aureus pneumoniae pyogenes aureus pneumoniae pyogenes aureus pneumoniae pyogenes influenzae catarrhalis
ATCC
13709
ery S
SP030
ery S
3565
ery S
90256/ 134 GR-
97 Micro
iMLS iMcLS
Finland PK2
11
iMLS
58 Spain
166 GR- PK1
Micro
cMLS
Ci137
M
3
ATCC
23246
Finland 49247
M
cMLS cMLS
M
N
N
OH
HO
HO
O
OH
O
O
O
O
27
1
60.125
60.125
60.125 >64
60.125
60.125 >64
60.125
32
64
60.125
60.125
0.5
2
0.25
O
N
O
O
O
O
N
O
N
O
N
N
OH
HO
HO
O
O
O
O
O
O
18
4
60.125 >64
0.5
0.25
>64
1
32
>64
1
32
8
O
O
O
N
O
N
O
N
O
O
N
N
OH
O
HO
HO
O
O
O
O
O
O
19
4
60.125
60.125 >64
0.25
60.125 >64
0.5
32
64
60.125
0.5
16
4
O
O
N
O
N
O
N
O
O
N
N
OH
HO
HO
O
O
O
O
O
O
20
0.25
60.125
60.125
60.125
8
8
60.125 >64
4
16
0.5
60.125
60.125
1
0.5
O
O
O
O
N
O
N
OH
O
N
N
N
OH
HO
HO
O
O
O
O
O
O
24
4
60.125 >64
32
2
>64
8
>64
>64
2
2
32
0.25
O
N
O
O
O
O
N
O
N
O
N
N
OH
O
HO
HO
O
O
O
O
O
O
25
4
60.125
60.125 >64
>64
0.25
>64
32
32
>64
60.125
1
16
O
O
O
N
O
O
N
N
O

Table 2 (continued)
Phenotype
S.
S.
S.
S.
S.
S.
S.
S.
S.
S.
S.
S.
H.
ATCC
M.
aureus pneumoniae pyogenes aureus pneumoniae pyogenes aureus pneumoniae pyogenes aureus pneumoniae pyogenes influenzae catarrhalis
ATCC
13709
ery S
SP030
ery S
3565
ery S
90256/ 134 GR-
97 Micro
iMLS iMcLS
Finland PK2
11
iMLS
58 Spain
166 GR- PK1
Micro
cMLS
Ci137
M
3
ATCC
23246
Finland 49247
M
cMLS cMLS
M
N
N
OH
HO
HO
O
O
O
O
O
O
26
60.125 60.125
60.125
4
16
60.125 >64
60.125
32
0.25 60.125
60.125
1
0.5
O
N
O
O
O
OH
N
O
N
O
N
HO
HO
HO
OH
N
O
O
O
39
2
60.125
60.125 >64
>64
1
>64
32
64
8
8
4
16
0.5
O
O
O
O
N
O
OH
N
N
O
O
N
U
U
O
O
N
U
O
U
*
U
U
O
U
U
U
U
U
O
O
O
U
40
8
60.125
0.5
>64
32
4
>64
8
>64
32
0.25
8
32
U
O
O
O
U
U
O
N
O
U
U
O
N
O
N
O
AZM = azithromycin; CAM = clarithromycin; iMLS = inducible resistance to macrolide, licosamide and streptogramin (MLS) antibiotics; iMcL = inducible resistance to macrolide and constitutive resistance to lincosamide anti-
biotics; cMLS = constitutive MLS resistance; M = efflux mediated macrolide resistance.

´
S. Kapic et al. / Bioorg. Med. Chem. 19 (2011) 7281–7298
7290
Two compounds with the quinolone carboxylic acid attached to
1,1-dimethylethyl 4-(2-propyn-1-yl)-1-piperazinecarboxylate 3
azithromycin scaffold via an ether bond (39 and 40) had very mea-
gre potency against resistant strains, regardless of the underlying
resistance mechanism, showing, in this case, the attachment to
the macrolide via ester bond to be more favourable.
In comparison to the clinically important macrolide antibiotics
azithromycin and clarithromycin, the macrolones reported showed
improved activity against macrolide resistant strains. However,
compared to previously reported macrolones,7–11 introduction of
a cyclic structure within the aliphatic linker did not confer any
great advantage to antibacterial potency, especially against cMLS
S. pyogenes, where none of the compounds showed MIC below
(0.363 g, 1.617 mmol) were added. Reaction mixture stirred at
room temperature for 20 min and heated to 50 °C and bis(triphen-
ylphosphine)palladium (II) chloride (0.03 g, 0.04 mmol) was
added. Reaction mixture stirred at 50 °C for 2 h. Solvent was evap-
orated and residue was diluted with EtOAc (10 mL) and water
(10 mL). The aq layer was back extracted with EtOAc (2 ꢀ 10 mL).
The organic was dried over K2CO3, and evaporated in vacuum
yielding oil product (0.8 g).
The oil product (0.8 g) was added to a silica gel column and was
eluted with DCM/MeOH/NH4OH = 90/5/0.5. Collected fractions
(0.50 g) were diluted with mixture of n-hexane/EtOAc 10/1 and
product was filtered, washed with n-hexane/EtOAc 10/1 and dried
to give crude product 7 (0.37 g, Y = 59%).
8 lg/mL. Furthermore none of the compounds displayed activity
against cMLS S. aureus strain which constitutively express the
methyltransferase gene. It should be noted that the ketolides teli-
thromycin and cethromycin are also inactive36 against these
strains.
MS(m/z): calcd for MH+: 467.57, found: 468.21 (98.81%).
HRMS calcd for C26H34N3O5 (M+H)+ 468.2498; found 468.2492.
1H NMR (500 MHz, DMSO) d: 8.69 (1H, 2000-H, s), 8.22 (1H, 5000-H,
d), 7.81 (1H, 8000-H, d), 7.78 (1H, 7000-H, dd), 4.,40 (2H, 11000-CH2, q),
4.23 (2H, 13000-CH2, q), 3.60 (2H, L10-CH2), 3.35 (4H, L5, L6-CH2,
ov), 2.50 (4H, L7, L8-CH2, m), 1,40 (9H, L1-CH3, s), 1.36 (3H,
15000-CH3, t), 1.29 (3H, 14000-CH3, t).
3. Conclusion
In conclusion, structures characterized by the C–C bond at the
position C-6 of the quinolone-3-carboxylic acid and central piper-
azine ring in the linker attached via ester/ether bond at C400–OH to
the macrolide scaffolds were prepared.
Compounds with a free 4-quinolone 3-carboxylic acid were
antibacterially more potent than their ester counterparts. Attach-
ment of linker to the 400 position by an ester, rather than an ether
bond, proved to be more favorable for antibacterial activity.
The most active compounds 20 and 26 exhibited improved po-
tency against iMLSb and efflux resistant Gram-positive bacteria
and H. influenzae.
13C NMR (125 MHz, DMSO) d: 172.38 (4000-CO), 164.79 (12000-CO),
154.24 (L3-CO), 149.59 (2000-CH), 138.58 (9000-C), 135.40 (7000-CH),
129.72 (5000-CH), 128.60 (10000-C), 119.08 (6000-C), 118.35 (8000-CH),
110.94 (3000-C), 86.50 (L11-C), 84.40 (L12-C), 79. 22 (L2-C), 60.20
(13000-CH2), 51.49 (L5, L6, L7, L8-CH2), 48.39 (11000-CH2), 47.13
(L10-CH2), 28.42 (L1-CH3), 14.70 (15000-CH3), 14.67 (14000-CH3).
IR (KBr, cmꢁ1) 1980, 2931, 2798, 2762, 1722, 1695, 1631, 1606,
1589, 1544, 1489, 1457, 1417, 1365, 1342, 1314, 1297, 1247, 1233,
1165, 1123, 1086, 1053, 1005.
4.4. Ethyl 1-cyclopropyl-6-[3-(4-{[(1,1-
dimethylethyl)oxy]carbonyl}-1-piperazinyl)-1-propyn-1-yl]-4-
oxo-1,4-dihydro-3-quinolinecarboxylate (8)
4. Synthetic procedures
4.1. 1,1-Dimethylethyl 4-(2-propyn-1-yl)-1-piperazinecarboxyla
te (3)
According to the procedure for synthesis of compound 7 was syn-
thesized compound 8 starting from ethyl 1-cyclopropyl-6-iodo-4-
oxo-1,4-dihydro-3-quinolinecarboxylate 5 (2.0 g, 5.22 mmol) and
4-(2-propyn-1-yl)-1-piperazinecarboxylate 3 (1.4 g, 6.26 mmol).
The oil product (1.8 g) was added to a silica gel column and was
eluted with DCM/MeOH/NH4OH = 90/5/0.5. Collected fractions
(2.95 g) were diluted with mixture of n-hexane/EtOAc 10/1 and
product was filtered, washed with n-hexane/EtOAc 10/1 and dried
to give crude product 8 (2.83 g, Y = 98%).
To the degassed solution of piperazine-1-carboxylic acid tert-
butyl ester 1 (1.0 g, 5.37 mmol) in acetonitrile (10 mL) were added
Na2CO3 (1.71 g, 16.11 mmol) and mixture was stirred for 20 min.
The suspension was heated to 50 °C and 3-bromo-propyne 2
(897.3 lL, 8.06 mmol) was added. The solvent was evaporated
and the residue was extracted with EtOAc and water (2 ꢀ 50 mL).
Organic layer was washed with NaCl and NaHCO3 (2 ꢀ 50 mL).
The organic layer was dried over K2CO3 and evaporated in vacuum
yielding (0.97 g Y = 73%) oil product 3.
MS(m/z): calcd for MH+: 479.58, found: 480.19 (96.64%).
HRMS calcd for C27H33N3O5 (M+H)+ 480.2484; found 480.2498.
1H NMR (500 MHz, DMSO) d: 8.48 (1H, 2000-H, s), 8.17 (1H, 5000-H,
d), 8.06 (1H, 8000-H, d), 7.83 (1H, 7000-H, dd), 4.23 (2H, 13000-CH2, q),
3.66 (1H, 11000-H, q), 3.60 (2H, L10-CH2, s), 3.37 (4H, L5, L6-CH2,
ov), 2.50 (4H, L7, L8-CH2, m), 1.40 (9H, L1-CH3, s), 1.28 (3H, 14000-
CH3, t), 1.23 (2H, 15000-CH2, dd), 1.10 (2H, 16000-CH2, dd).
MS(m/z): calcd for MH+: 225.31, found: 225.12 (90.06%).
HRMS calcd for C12H21N2O2 (M+H)+ 225.1603; found. 225.1594.
1H NMR (500 MHz, DMSO) d: 3.32 (4H, L5, L6-CH2, ov), 3.29 (2H,
L
10-CH2, s), 3.17 (1H, L12-CH, t), 2.38 (4H, L7, L8-CH2), 1.39 (9H,
L1-CH3).
13C NMR (125 MHz, DMSO) d: 154.17 (L3-CO), 79.36 (L2-C),
13C NMR (125 MHz, DMSO) d: 172.46 (4000-CO), 164.61 (12000-CO),
154.25 (L3-CO), 149.04 (2000-CH), 140.45 (9000-C), 135.29 (7000-CH),
129.34 (5000-CH), 127.95 (10000-C), 119.30 (6000-C), 118.67 (8000-CH),
110.67 (3000-C), 86.62 (L11-C), 84.39 (L12-C), 79. 20 (L2-C), 60.26
(13000-CH2), 51.51 (L5, L6, L7, L8-CH2), 47.15 (L10-CH2), 35.13 (11000-
CH), 28.42 (L2-CH3), 14.66 (14000-CH3), 7.96 (15000, 16000-CH2).
IR (KBr, cmꢁ1) 2977, 2933, 2813, 1728, 1691, 1637, 1597, 1545,
1486, 1455, 1421, 1365, 1346, 1318, 1245, 1173, 1128, 1088, 1034.
79.17 (L12-CH), 76.29 (L11-C), 51.25 (L5, L6, L7, L8-CH2), 46.40 (L10
CH2), 28.41 (L1-CH3).
-
IR (KBr, cmꢁ1) 3300, 3243, 2976, 2932, 2859, 2814, 2761, 1689,
1456, 1419, 1365, 1298, 1244, 1168, 1121, 1085, 1006, 901.
4.3. Ethyl 6-[3-(4-{[(1,1-dimethylethyl)oxy]carbonyl}-1-pipera
zinyl)-1-propyn-1-yl]-1-ethyl-4-oxo-1,4-dihydro-3-quinolineca
rboxylate (7)
4.5. 6-[3-(4-{[(1,1-Dimethylethyl)oxy]carbonyl}-1-piperazinyl)-
1-propyn-1-yl]-1-ethyl-4-oxo-1,4-dihydro-3-quinolinecarboxy
lic acid (9)
To the solution of ethyl 1-ethyl-6-iodo-4-oxo-1,4-dihydro-3-
quinolinecarboxylate 4 (0.5 g, 1.35 mmol) was dissolved in dry
acetonitrile (13.5 mL) under N2 at room temperature and copper(I)
iodide (0.03 g, 0.14 mmol), triethylamine (6.6 mL, 47.10 mmol) and
According to the procedure for synthesis of compound 7 com-
pound 9)was synthesized starting from 1-ethyl-6-iodo-4-oxo-1,

´
7291
S. Kapic et al. / Bioorg. Med. Chem. 19 (2011) 7281–7298
4-dihydro-3-quinolinecarboxylic acid 6 (0.49 g, 1.43 mmol) and 4-
(2-propyn-1-yl)-1-piperazinecarboxylate (0.45 g, 2.00 mmol)
47.81 (L10-CH2), 45.82(L5, L6-CH2), 35.13 (11000-CH), 14.66
(14000-CH3), 7.95 (15000, 16000-CH2).
3
and isolated directly without column chromatography by dilution
with mixture of n-hexane/EtOAc 10/1 and product was filtered,
washed with n-hexane/EtOAc 10/1 and dried to give crude product
9 (0.75 g, Y = 88%).
IR (KBr, cmꢁ1) 2926, 2805, 1724, 1631, 1594, 1543, 1487, 1452,
1383, 1348, 1319, 1245, 1181, 1164, 1090, 1045, 1010, 929.
4.8. 1-Ethyl-4-oxo-6-[3-(1-piperazinyl)-1-propyn-1-yl]-1,4-
dihydro-3-quinolinecarboxylic acid (12)
MS(m/z): calcd for MH+: 439.51, found: 440.20 (69.92%).
1H NMR (500 MHz, DMSO) d: 8.62 (1H, 2000-H, s), 8.20 (1H, 5000-H,
d), 7.91 (1H, 8000-H, d), 7.82 (1H, 7000-H, dd), 4.40 (2H, 11000-CH2, q),
3.60 (2H, L10-CH2), 3.35 (4H, L5, L6-CH2, ov), 2.50 (4H, L7, L8-CH2,
m), 1.40 (9H, L1-CH3, s), 1.36 (3H, 15000-CH3, t).
Applying the same protocol as for the synthesis of compound
10, compound 12 was obtained from the compound 9 (0.75 g,
1.71 mmol). Pure product 12 (0.45 g, Y = 77%) was obtained as
white crystalline product.
13C NMR (125 MHz, DMSO) d: 172.40 (4000-CO), 166.81 (12000-CO),
154.25 (L3-CO), 149.38 (2000-CH), 139.63 (9000-C), 135.40 (7000-CH),
129.35 (5000-CH), 128.10 (10000-C), 119.12 (6000-C), 118.46 (8000-CH),
110.80 (3000-C), 86.55 (L11-C), 84.41 (L12-C), 79. 20 (L2-C), 51.50
(L5, L6, L7, L8-CH2), 48.40 (11000-CH2), 47.16 (L10-CH2), 28.42
(L1-CH3), 14.70 (15000-CH3).
MS(m/z): calcd for MH+: 39.39, found: 340.2 (67.92%).
1H NMR (500 MHz, DMSO) d: 8.60 (1H, 2000-H, s), 8.18 (1H, 5000-H,
d), 7.86 (1H, 8000-H, d), 7.82 (1H, 7000-H, dd), 4.40 (2H, 11000-CH2, q),
3.52 (2H, L10-CH2), 2.74 (4H, L5, L6-CH2, ov), 2.48 (4H, L7, L8-CH2,
m), 1.36 (3H, 15000-CH3, t).
13C NMR (125 MHz, DMSO) d: 172.40 (4000-CO), 166.79 (12000-CO),
149.54 (2000-CH), 139.34 (9000-C), 135.40 (7000-CH), 129.59 (5000-CH),
128.13 (10000-C), 119.46 (6000-C), 118.26 (8000-CH), 110.70 (3000-C),
87.21 (L11-C), 84.18 (L12-C), 53.09 (L7, L8-CH2), 48.40 (11000-CH2),
45.76 (L5, L6-CH2), 47.75 (L10-CH2), 14.70 (15000-CH3).
4.6. Ethyl 1-ethyl-4-oxo-6-[3-(1-piperazinyl)-1-propyn-1-yl]-
1,4-dihydro-3-quinolinecarboxylate (10)
To the solution of 7 (0.26 g, 0.56 mmol) in DCM (2.5 mL) was
added CF3COOH (2.5 mL, 0.024 mol). .Reaction mixture was stirred
at rt for 2.5 h. To the reaction mixture were added DCM (10 mL)
and water (10 mL). Layers were separated, water layer was ex-
tracted with DCM (2 ꢀ 10 mL) and to the water layer DCM
(10 mL) was added and pH adjusted from 1.8 to 9.5 by addition
of aq soln NH4OH. Layers were separated; water layer was ex-
tracted with DCM (2 ꢀ 15 mL). The organic extract was dried
(K2CO3) and concentrated under vacuum to afford title product
10 (0.17 g, Y = 82%) as yellow crystalline product.
4.9. 4‘‘-O-(3-{4-[3-(1-Ethyl-3-ethoxycarbonyl-1,4-dihydro-4-
oxo-quinolyn-6-yl)prop-2-ynyl]piperazine-1-yl}propyonyl)-6-
O-methyl-erythromycin A (16)
To the stirred solution of 13 (0.08 g, 0.10 mmol) in acetonitrile
(4 mL) was added ethyl 1-ethyl-4-oxo-6-[3-(1-piperazinyl)-
1-propyn-1-yl]-1,4-dihydro-3-quinolinecarboxylate 10 (0.15 g,
0.41 mmol), H2O (0.1144 mL) and Et3N (0.045 mL). Reaction
mixture was stirred at 80 °C for 24 h and diluted with EtAc
(10 mL) and poured into satd NaHCO3 (10 mL). The organic phase
was separated from aqueous phase and the aqueous phase ex-
tracted with EtAc (2 ꢀ 10 mL). The combined organic extracts were
washed (brine), dried (K2CO3), filtered and the solvent removed
under reduced pressure. The residue purified by low-pressure col-
umn chromatography in system of solvents and DCM/MeOH/
NH3 = 90/5/0.5; afterwards 16 (0.115 g, Y = 92%) as beige crystal-
line product.
MS(m/z): calcd for MH+: 367.45, found: 368.15 (96.01%).
HRMS calcd for C21H25N3O3 (M+H)+ 368.1974; found 368.1982.
1H NMR (500 MHz, DMSO) d: 8.69 (1H, 2000-H, s), 8.22 (1H, 5000-H,
d), 7.82 (1H, 8000-H, d), 7.78 (1H, 7000-H, dd), 4.41 (2H, 11000-CH2, q),
4.23 (2H, 13000-CH2, q), 3.52 (2H, L10-CH2, s), 2.74 (4H, L5, L6-CH2,
ov), 2.48 (4H, L7, L8-CH2, ov), 1.36 (3H, 15000-CH3, t), 1.29 (3H,
14000-CH3, t).
13C NMR (125 MHz, DMSO) d: 172.40 (4000-CO), 164.81 (12000-CO),
149.58 (2000-CH), 138.51 (9000-C), 135.36 (7000-CH), 129.68 (5000-CH),
128.61 (10000-C), 119.28 (6000-C), 118.33 (8000-CH), 110.91 (3000-C),
87.12 (L11-C), 84.18 (L12-C), 60.19 (13000-CH2), 52.81 (L7, L8-CH2),
48.39 (11000-CH2), 47.76 (L10-CH2), 45.68 (L5, L6-CH2), 14.71
(15000-CH3), 14.69 (14000-CH3).
MS(m/z): calcd for MH+: 1169.45, found: 1169.63 (91.34%).
HRMS calcd for
1169.6902.
C
62H97N4O17 (M+H)+ 1169.6849; found.
1H NMR (500 MHz, CDCl3) d: 8.60 (1H, 5000-H, d), 8.49 (1H, 2000-H,
s), 7.70 (1H, 7000-H, dd), 7.37 (1H, 8000-H, dd), 5.07 (1H, 13-H, dd),
4.99 (1H, 100-H, dd), 4.69 (1H, 400-H, d), 4.59 (1H, 10-H., d), 4.41
(2H, 13000-CH2, q), 4.35 (1H, 500-H, dq), 4.25 (1H, 11000-CH, q), 3.78
(1H, 3-H, ov), 3.77 (1H, 11-H, ov), 3.74 (1H, 50-H, m), 3.65 (1H, 5-
H, d), 3.53 (2H, L10-CH2, s), 3.31 (3H, 300O-CH3, s), 3.19 (1H, 20-H,
dd), 3.04 (3H, 6O-CH3, s), 3.00 (1H, 10-H, dq), 2.90 (1H, 2-H, dq),
2.75 (2H, L3-CH2, ov), 2.68 (4H, L7, L8-CH2, ov), 2.58 (1H, 8-H, m),
2.56 (1H, 30-H, m), 2.55 (2H, L2-CH2, ov), 2.53 (4H, L5, L6-CH2, ov),
2.41 (1H, 200a-H, d), 2.32 (6H, 30N-(CH3)2, s), 1.94 (1H, 4-H, m),
1.91 (1H, 14a-H, m), 1.84 (1H, 7a-H, dd), 1.70 (1H, 7b-H, dd),
1.66 (1H, 4’a-H, m), 1.63 (1H, 200b-H, dd), 1.54 (3H, 15000-CH3, t),
1.48 (1H, 14b-H, m), 1.42 (3H, 14000-CH3, t), 1.38 (3H, 6-CH3, s),
1.25 (1H, 40b-H, ov), 1.22 (3H, 2-CH3, d), 1.20 (3H, 50-CH3, d),
1.18 (3H, 500-CH3, d), 1.15 (3H, 300-CH3, s), 1.14 (3H, 8-CH3, d),
1.13 (3H, 10-CH3, d), 1.12 (3H, 12-CH3, s), 1.11 (3H, 4-CH3, d),
0.85 (3H, 15-CH3, t).
IR (KBr, cmꢁ1) 2932, 2818, 1719, 1688, 1630, 1592, 1544, 1487,
1449, 1383, 1365, 1313, 1227, 1189, 1165, 1129, 1084, 1026, 953.
4.7. Ethyl 1-cyclopropyl-4-oxo-6-[3-(1-piperazinyl)-1-propyn-1-
yl]-1,4-dihydro-3-quinolinecarboxylate (11)
Applying the same protocol as for the synthesis of compound
10, compound 11 was obtained from the compound 8 (2.83 g,
5.90 mmol). Pure product 11 (0.66 g, Y = 28%) was obtained as
white crystalline product.
MS(m/z): calcd for MH+: 379.46, found: 380.14 (94.58%).
HRMS calcd for C22H25N3O3 (M+H)+ 380.1974; found 380.1981.
1H NMR (500 MHz, DMSO) d: 8.48 (1H, 2000-H, s), 8.17 (1H, 5000-H,
d), 8.06 (1H, 8000-H, d), 7.83 (1H, 7000-H, dd), 4.23 (2H, 13000-CH2, q),
3.66 (1H, 11000-CH, q), 3.52 (2H, L10-CH2, s), 2.73 (4H, L5, L6-CH2,
ov), 2.47 (4H, L7, L8-CH2, ov), 1.28 (3H, 14000-CH3, t), 1.24 (2H,
15000-CH2, dd), 1.10 (2H, 16000-CH2, dd).
13C NMR (125 MHz, CDCl3) d: 220.96 (9-CO), 175.63 (1-CO),
173.45 (4000-CO), 171.80 (L1-CO), 165.52 (12000-CO), 148.47 (2000-CH),
137.95 (9000-C), 135.23 (7000-CH), 131.50 (5000-CH), 129.05 (10000-C),
119.96 (6000-C), 115.55 (8000-CH), 111.48 (3000-C), 101.97 (10-CH),
95.91 (100-CH), 85.78 (L11-C), 84.04 (L12-C), 80.35 (5-CH), 78.59
(400-CH), 78.18 (3-CH), 77.90 (6-C), 76.49 (13-CH), 74.20 (12-C),
13C NMR (125 MHz, DMSO) d: 172.48 (4000-CO), 164.62 (12000-CO),
149.02 (2000-CH), 140.37 (9000-C), 135.25 (7000-CH), 129.30 (5000-CH),
127.94 (10000-C), 119.51 (6000-C), 118.65 (8000-CH), 110.64 (3000-C),
87.21 (L11-C), 84.17 (L12-C), 60.26 (13000-CH2), 53.06 (L7, L8-CH2),

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7292
72.68 (300-C), 70.95 (20-CH), 69.00 (11-CH), 67.67 (50-CH), 65.22 (30-
CH), 62.90 (500-CH), 60.90 (13000-CH2), 53.31 (L3-CH2), 52.69
(L2-CH2), 51.96 (L7, L8-CH2), 50.58 (6O-CH3), 49.37 (300O-CH3),
48.82 (11000-CH), 47.62 (L10-CH2), 45.24 (8-CH), 44.76 (2-CH),
40.13 (3’N-(CH3)2), 39.11 (7-CH2), 38.69 (4-CH), 37.09 (10-
CH), 35.10 (200-CH2), 32.40 (L5, L6-CH2), 28.79 (40-CH2), 21.78 (50-
CH3), 21.03 (300-CH3), 20.94 (14-CH2), 19.60 (6-CH3), 18.28
(500-CH3), 17.94 (8-CH3), 15.89 (12-CH3), 15.86 (2-CH3), 14.42
(15000,-CH3), 14.34 (14000-CH3), 12.26 (10-CH3), 10.50 (15-CH3), 9.03
(4-CH3).
4.11. 9-Deoxo-4‘‘-O-(3-{4-[3-(1-ethyl-3-ethoxycyrbonyl-1,4-
dihydro-4-oxo-quinolin-6-yl)prop-2-ynyl]piperazine-1-
il}propyonyl)-9a,11-O-dimethyl-9a-aza-9a-homoerythromycin
A (18)
Applying the same protocol as for the synthesis of compound
16, compound 18 was obtained from the compound 14 (0.16 g,
0.16 mmol) and ethyl 1-ethyl-4-oxo-6-[3-(1-piperazinyl)-1-
propyn-1-yl]-1,4-dihydro-3-quinolinecarboxylate
10
(0.17 g,
0.46 mmol). Crude product was purified by low-pressure column
chromatography in system of solvents and DCM/MeOH/NH3 = 90/
5/0.5; after warded 18 (0.02 g, Y = 5%) was obtained as white crys-
talline product.
IR (KBr, cmꢁ1) 2976, 2935, 2821, 1733, 1691, 1640, 1599, 1489,
1456, 1379, 1315, 1228, 1170, 1084, 1012, 807.
MS(m/z): calcd for MH+: 1184.51, found: 1184.62 (70.60%)
HRMS calcd for
1184.7361.
C
63H102N5O16 (M+H)+ 1184.7322; found
4.10. 4‘‘-O-(3-{4-[3-(1-Cyclopropyl-3-etoxycarbonyl-1,4-dihy
dro-4-oxo-quinolin-6-yl)prop-2-ynyl]piperazine-1-il}propyo
nyl)-6-O-metil-erythromycin A (17)
1H NMR (500 MHz, CDCl3) d: 8.56 (1H, 5000-H, d), 8.48 (1H, 2000-H,
s), 7.69 (1H, 7000-H, dd), 7.40 (1H, 8000-H, d), 5.16 (1H, 100-H, d), 4.69
(1H, 13-H, dd), 4.70 (1H, 400-H, d), 4.58 (1H, 10-H., d), 4.41 (2H,
13000-CH2, ov), 4.42 (1H, 500-H, ov), 4.39 (1H, 3-H, ov), 4.25 (2H,
11000-CH, q), 3.80 (1H, 50-H, m), 3.62 (1H, 5-H, d), 3.59 (3H, 11O-
CH3, s), 3.53 (2H, L10-CH2, s), 3.40 (1H, 11-H, s), 3.32 (3H, 300O-
CH3, s), 3.26 (1H, 20-H, dd), 2.76 (2H, L3-CH2, ov), 2.76 (1H, 2-H,
ov), 2.70 (1H, 10-H, ov), 2.68 (4H, L7, L8-CH2, ov), 2.60 (1H, 30-H,
ov), 2.59 (2H, L2-CH2, ov), 2.54 (4H, L5, L6-CH2, ov), 2.52 (1H, 9a-
H, ov), 2.40 (1H, 200a-H, d), 2.34 (6H, 30N-(CH3)2, s), 2.25 (3H, 9 N-
CH3, s), 2.07 (1H, 9b-H, t), 2.01 (1H, 8-H, ov), 2.01 (1H, 4-H, ov),
1.92 (1H, 14a-H, m), 1.73 (1H, 7a-H, d), 1.68 (1H, 40a-H, m), 1.61
(1H, 200b-H, dd), 1.55 (3H, 15000-CH2, t), 1.47 (1H, 14b-H, m), 1.42
(3H, 14000-CH3, t), 1.32 (1H, 7b-H, ov), 1.27 (3H, 6-CH3, s), 1.26
(1H, 40b-H, ov), 1.22 (3H, 300-CH3, s), 1.19 (3H, 2-CH3, d), 1.18
(3H, 500-CH3, d), 1.17 (3H, 5’-CH3, d), 1.12 (3H, 12-CH3, s), 1.03
(3H, 10-CH3, d), 1.06 (3H, 4-CH3, d), 0.91 (8-CH3, d), 0.89 (15-
CH3, t).
Applying the same protocol as for the synthesis of compound
16, compound 17 was obtained from the compound 13 (0.20 g,
0.25 mmol) and ethyl 1-cyclopropyl-4-oxo-6-[3-(1-piperazinyl)-
1-propyn-1-yl]-1,4-dihydro-3-quinolinecarboxylate 11 (0.19 g,
0.50 mmol). Crude product was purified by low-pressure column
chromatography in system of solvents and DCM/MeOH/NH3 = 90/
5/0.5; after warded 17 (0.12 g, Y = 37%) was obtained as white
crystalline product.
MS(m/z): calcd for MH+: 1181.48, found: 1181.63 (94.34%)
HRMS calcd for
1181.6871
C
63H97N4O17 (M+H)+ 1181.6849; found
1H NMR (500 MHz, CDCl3) d: 8.59 (1H, 2000-H, s), 8.54 (1H, 5000-H,
d), 7.86 (1H, 8000-H, dd), 7.71 (1H, 7000-H, dd), 5.08 (1H, 13-H, dd),
5.00 (1H, 100-H, dd), 4.69 (1H, 400-H, d), 4.59 (1H, 10-H., d), 4.40
(2H, 13000-CH2, q), 4.34 (1H, 500-H, dq), 3.78 (1H, 3-H, ov), 3.77
(1H, 11-H, ov), 3.74 (1H, 50-H, m), 3.66 (1H, 5-H, d), 3.54 (2H,
13C NMR (125 MHz, CDCl3) d: 177.91 (1-CO), 173.45 (4000-CO),
171.91 (L1-CO), 165.56 (12000-CO), 148.45 (2000-CH), 137.92 (9000-C),
135.29 (7000-CH), 131.45 (5000-CH), 129.04 (10000-C), 119.99 (6000-C),
115.56 (8000-CH), 111.45 (3000-C), 102.23 (10-CH), 94.71 (100-CH),
85.84(L11-C), 84.01 (L12-C), 83.41 (5-CH), 78.87 (400-CH), 77.99 (3-
CH), 77.71 (13-CH), 84.94 (11-CH), 73.06 (6-C), 74.30 (12-C),
73.10 (300-C), 70.91 (20-CH), 70.91 (9-CH2), 67.64 (50-CH), 65.40
(30-CH), 62.71 (500-CH), 62.56 (10-CH), 62.06 (11O-CH3), 60.89
(13000-CH2), 53.33 (L3-CH2), 52.64 (L2-CH2), 51.97 (L7, L8-CH2),
49.36 (300OCH3), 48.82 (11000-CH), 47.58 (L10-CH2), 45.36 (2-CH),
42.57 (7-CH2), 42.62 (4-CH), 40.22 (30N-(CH3)2), 35.82 (9N–CH3),
34.99 (200-CH2), 32.36 (L5, L6-CH2), 29.17 (40-CH2), 27.56 (6-CH3),
L
10-CH2, s), 3.48 (1H, 11000-CH, m), 3.31 (3H, 300O-CH3, s), 3.18 (1H,
20-H, dd), 3.04 (3H, 6O-CH3, s), 3.00 (1H, 10-H, dq), 2.90 (1H, 2-H,
dq), 2.75 (2H, L3-CH2, ov), 2.68 (4H, L7, L8-CH2, ov), 2.59 (1H, 8-H,
m), 2.56 (2H, L2-CH2, ov), 2.53 (4H, L5, L6-CH2, ov), 2.52 (1H, 3’-H,
m), 2.42 (1H, 200a-H, d), 2.30 (6H, 30N–(CH3)2, s), 1.95 (1H, 4-H,
m), 1.91 (1H, 14a-H, m), 1.84 (1H, 7a-H, dd), 1.70 (1H, 7b-H, dd),
1.64 (1H, 40a-H, m), 1.62 (1H, 200b-H, dd), 1.49 (1H, 14b-H, m),
1.40 (3H, 14000-CH3, t), 1.38 (3H, 6-CH3, s), 1.34 (2H, 15000-CH2, dq),
1.22 (1H, 40b-H, ov), 1.21 (3H, 2-CH3, d), 1.19 (3H, 50-CH3, d),
1.16 (3H, 500-CH3, d), 1.15 (3H, 300-CH3, s), 1.15 (2H, 16000-CH2, ov),
1.14 (3H, 8-CH3, d), 1.13 (3H, 10-CH3, d), 1.12 (3H, 12-CH3, s),
1.11 (3H, 4-CH3, d), 0.85 (3H, 15-CH3, t).
26.62
(8-CH),
22.11
(8-CH3),
21.73
(300-CH3),
21.65
13C NMR (125 MHz, CDCl3) d: 220.97 (9-CO), 175.63 (1-CO),
173.52 (4000-CO), 171.81 (L1-CO), 165.45 (12000-CO), 148.51
(2000-CH), 139.86 (9000-C), 135.09 (7000-CH), 131.03 (5000-CH), 128.32
(10000-C), 120.14 (6000-C), 116.44 (8000-CH), 111.37 (3000-C), 102.01
(10-CH), 95.91 (100-CH), 85.76 (L11-C), 84.09 (L12-C), 80.35 (5-CH),
78.59 (400-CH), 78.18 (3-CH), 77.90 (6-C), 76.68 (13-CH), 74.19
(12-C), 72.69 (300-C), 70.96 (20-CH), 69.00 (11-CH), 67.73 (50-CH),
65.24 (3’-CH), 62.90 (500-CH), 60.90 (13000-CH2), 53.34 (L3-CH2),
52.72 (L2-CH2), 52.02 (L7, L8-CH2), 50.58 (6OCH3), 49.36 (300OCH3),
47.62 (L10-CH2), 45.25 (8-CH), 44.77 (2-CH), 40.18 (30N-(CH3)2),
39.12 (7-CH2), 38.69 (4-CH), 37.09 (10-CH), 35.11 (200-CH2),
34.42 (11000-CH), 32.45 (L5, L6-CH2), 28.67 (40-CH2), 21.80
(50-CH3), 21.04
(14-CH2), 21.24 (50-CH3), 17.64 (500-CH3), 16.98 (12-CH3), 14.58
(2-CH3), 14.42 (15000-CH2), 14.34 (14000-CH3), 11.18 (15-CH3), 9.16
(4-CH3), 7.09 (10-CH3).
IR (KBr, cmꢁ1) 2974, 2935, 2825, 1732, 1693, 1639, 1599, 1489,
1455, 1380, 1315, 1228, 1167, 1128, 1092, 1079, 1051, 1014, 985,
959, 807.
4.12. 9-Deoxo-4‘‘-O-(3-{4-[3-(1-cycloprpyl-3-ethoxycarbonyl-
1,4-dihydro-4-oxo-quinolin-6-yl)prop-2-ynyl]piperazine-1-
il}propyonyl)-9a,11-O-dimethyl-9a-aza-9a-homoerythromycin
A (19)
(300-CH3), 20.94 (14-CH2), 19.61 (6-CH3), 18.28 (500-CH3), 17.94
(8-CH3), 15.89 (12-CH3), 15.86 (2-CH3), 14.34 (14000-CH3), 12.27
(10-CH3), 10.50 (15-CH3), 9.02 (4-CH3), 8.14 (15000, 16000-CH2).
IR (KBr, cmꢁ1) 3454, 2975, 2937, 2829, 1736, 1693, 1642, 1601,
1546, 1486, 1459, 1379, 1345, 1248, 1171, 1126, 1109, 1051, 1034,
1013.
Applying the same protocol as for the synthesis of compound
16, compound 19 was obtained from the compound 14 (0.20 g,
0.20 mmol) and ethyl 1-cyclopropyl-4-oxo-6-[3-(1-piperazinyl)-
1-propyn-1-yl]-1,4-dihydro-3-quinolinecarboxylate 11 (0.15 g,
0.40 mmol) and formed product was 20Oac derivate that was dis-
solved in methanol (50 mL) and reaction mixture was stirred

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S. Kapic et al. / Bioorg. Med. Chem. 19 (2011) 7281–7298
at50 °C over night. Crude product was purified by low-pressure
column chromatography in system of solvents and DCM/MeOH/
NH3 = 90:5:0.5; after warded 19 (0.03 g, Y = 6%) was obtained as
white crystalline product.
(1H, 500-H, ov), 4.39 (2H, 11000-CH2, ov), 4.37 (1H, 3-H, ov), 3.88
(1H, 50-H, m), 3.63 (1H, 5-H, d), 3.58 (3H, 11O-CH3, s), 3.55 (2H,
L
10-CH2, s), 3.40 (1H, 11-H, s), 3.32 (3H, 300O-CH3, s), 3.29 (1H,
200a-H, d), 2.24 (3H, 9N-CH3, s), 2.05 (1H, 9b-H, ov), 2.02 (1H, 8-
H, ov), 2.01 (1H, 4-H, ov), 1.92 (1H, 14a-H, m), 1.73 (1H, 7a-H, d),
1.60 (1H, 200b-H, ov), 1.60 (3H, 15000-CH2, t), 1.46 (1H, 14b-H, m),
1.33 (1H, 7b-H, ov), 1.27 (1H, 40b-H, ov), 1.25 (3H, 6-CH3, s), 1.21
(3H, 50-CH3, d), 1.18 (3H, 2-CH3, d), 1.15 (3H, 500-CH3, d), 1.14
(3H, 300-CH3, s), 1.11 (3H, 12-CH3, s), 1.05 (3H, 10-CH3, ov), 1.02
(3H, 4-CH3, ov), 0.92 (8-CH3, ov), 0.88 (15-CH3, ov).
MS(m/z): calcd for MH+: 1196.54, found: 1196.62 (84.35%).
HRMS calcd for
C
64H102N5O16 (M+H)+ 1196.7322; found
1196.7361.
1H NMR (500 MHz, CDCl3) d: 8.58 (1H, 2000-H, s), 8.54 (1H, 5000-H,
d), 7.86 (1H, 8000-H, d), 7.70 (1H, 7000-H, dd), 5.17 (1H, 100-H, d), 4.69
(1H, 13-H, dd), 4.70 (1H, 400-H, d), 4.58 (1H, 10-H., d), 4.40 (2H,
13000-CH2, ov), 4.44 (1H, 500-H, ov), 4.38 (1H, 3-H, ov), 3.80 (1H, 50-
H, m), 3.63 (1H, 5-H, d), 3.59 (3H, 11O-CH3, s), 3.53 (2H, L10-CH2,
s), 3.47 (2H, 11000-CH, m), 3.41 (1H, 11-H, s), 3.33(3H, 300O-CH3, s),
3.26 (1H, 2’-H, dd), 2.75 (1H, 2-H, ov), 2.72 (2H, L3-CH2, ov), 2.69
(1H, 10-H, ov), 2.68 (4H, L7, L8-CH2, ov), 2.59 (1H, 30-H, ov), 2.55
(2H, L2-CH2, ov), 2.54 (4H, L5, L6-CH2, ov), 2.53(1H, 9a-H, ov),
2.40 (1H, 200a-H, d), 2.32 (6H, 30N-(CH3)2, s), 2.25 (3H, 9N–CH3, s),
2.09 (1H, 9b-H, t), 2.02 (1H, 4-H, ov), 1.96 (1H, 8-H, ov), 1.93
(1H, 14a-H, m), 1.74 (1H, 7a-H, d), 1.68 (1H, 40a-H, m), 1.61 (1H,
200b-H, dd), 1.35 (3H, 15000-CH2, dq), 1.48 (1H, 14b-H, m), 1.42 (3H,
14000-CH3, t), 1.31 (1H, 7b-H, ov), 1.27 (3H, 6-CH3, s), 1.26 (1H,
40b-H, ov), 1.21 (3H, 300-CH3, s), 1.20 (3H, 2-CH3, d), 1.17 (3H,
500-CH3, d), 1.15 (3H, 50-CH3, d), 1.13 (3H, 12-CH3, s), 1.13 (2H,
16000-CH2, dq), 1.07 (3H, 4-CH3, d), 1.04 (3H, 10-CH3, d), 0.91 (8-
CH3, d), 0.89 (15-CH3, t).
13C NMR (125 MHz, DMSO) d: 177.91 (4000-CO), 177.88 (1-CO),
172.06 (L1-CO), 166.81 (12000-CO), 147.98 (2000-CH), 138.35 (9000-C),
136.78 (7000-CH), 130.64 (5000-CH), 126.59 (10000-C), 121.57 (6000-C),
116.45 (8000-CH), 109.39 (3000-C), 102.00 (10-CH), 94.79 (100-CH),
87.41(L11-C), 85.01 (11-CH), 83.77 (5-CH), 83.47 (L12-C), 78.96
(400-CH), 78.01 (3-CH), 77.88 (13-CH), 74.42 (12-C), 73.25 (6-C),
73.09 (300-C), 71.09 (20-CH), 70.96 (9-CH2), 67.57 (50-CH), 65.52
(30-CH), 62.81 (500-CH), 62.70 (10-CH), 62.13 (11O-CH3), 53.42
(L3-CH2), 52.82 (L2-CH2), 52.05 (L7, L8-CH2), 49.80 (11000-CH),
49.46 (300OCH3), 47.64 (L10-CH2), 45.44 (2-CH), 42.78 (7-CH2),
42.56 (4-CH), 35.82 (9N-CH3), 34.99 (200-CH2), 32.74 (L5, L6-CH2),
29.70 (40-CH2), 27.67 (6-CH3), 26.75 (8-CH), 22.23 (8-CH3), 21.77
(14-CH2), 21.70 (50-CH3), 21.35 (300-CH3), 17.75 (500-CH3), 17.09
(12-CH3), 14.70 (2-CH3), 14.65 (15000-CH2), 11.30 (15-CH3), 9.45
(4-CH3), 7.25 (10-CH3).
13C NMR (125 MHz, CDCl3) d: 177.92 (1-CO), 173.52 (4000-CO),
171.92 (L1-CO), 165.49 (12000-CO), 148.49 (2000-CH), 139.85 (9000-C),
135.15 (7000-CH), 130.99 (5000-CH), 128.32 (10000-C), 120.18 (6000-C),
116.44 (8000-CH), 111.36 (3000-C), 102.29 (10-CH), 94.72 (100-CH),
85.82(L11-C), 84.95 (11-CH), 84.08 (L12-C), 83.43 (5-CH), 78.88
(400-CH), 78.00 (3-CH), 77.72 (13-CH), 73.07 (6-C), 74.31(12-C),
73.11 (300-C), 70.92 (20-CH), 70.92 (9-CH2), 67.71 (50-CH), 65.43
(30-CH), 62.72 (500-CH), 62.57 (10-CH), 62.07 (11O-CH3), 60.90
(13000-CH2), 53.36 (L3-CH2), 52.68 (L2-CH2), 52.03 (L7, L8-CH2),
49.36 (300OCH3), 47.62 (L10-CH2), 45.37 (2-CH), 42.59 (7-CH2),
42.64 (4-CH), 40.26 (30N–(CH3)2), 35.83 (9N–CH3), 35.01 (200-CH2),
34.41 (11000-CH), 32.41 (L5, L6-CH2), 29.01 (4’-CH2), 27.57 (6-CH3),
26.63 (8-CH), 22.12 (8-CH3), 21.75(300-CH3), 21.66 (14-CH2), 21.26
(50-CH3), 17.64 (500-CH3), 16.98 (12-CH3), 14.58 (2-CH3), 14.33
(14000-CH3), 11.19 (15-CH3), 9.15 (4-CH3), 8.13 (15000-CH2), 8.13
(16000-CH2), 7.09 (10-CH3).
4.14. 9-Deoxo-4‘‘-O-(3-{4-[3-(1-ethyl-3-ethxycarbonyl-1,4-
ihydro-4-oxo-quinolin-6-yl)prop-2-ynyl]piperazine-1-
yl}propyonyl)-9a-methyl-9a-aza-9a-homoerythromycin A (21)
Applying the same protocol as for the synthesis of compound
16, compound 21 was obtained from the compound 15 (0.49 g,
0.61 mmol) and Ethyl 1-ethyl-4-oxo-6-[3-(1-piperazinyl)-1-pro-
pyn-1-yl]-1,4-dihydro-3-quinolinecarboxylate
10
(0.90 g,
2.45 mmol). Crude product was purified by low-pressure column
chromatography in system of solvents and DCM/MeOH/
NH3 = 90:5:0.5; after warded 21 (0.29 g, Y = 40%) was obtained as
white crystalline product.
MS(m/z): calcd for MH+: 1170.50, found: 1170.63 (72.54%).
HRMS calcd for
1170.7236.
C
62H100N5O16 (M+H)+ 1170.7165; found
1H NMR (500 MHz, CDCl3) d: 8.59 (1H, 5000-H, d), 8.49 (1H, 2000-H,
s), 7.69 (1H, 7000-H, dd), 7.41 (1H, 8000-H, d), 5.20 (1H, 100-H, dd), 4.71
(1H, 13-H, ov), 4.71 (1H, 400-H, ov), 4.57 (1H, 10-H., d), 4.42 (2H,
13000-CH2, q), 4.25 (1H, 3-H, ov), 4.25 (2H, 11000-CH, q), 3.81 (1H,
500-H, m), 3.70 (1H, 11-H, s), 3.66 (1H, 50-H, ov), 3.63 (1H, 5-H, d),
3.54 (2H, L10-CH2, s), 3.32 (3H, 300O-CH3, s), 3.23 (1H, 20-H, dd),
2.76 (1H, 2-H, ov), 2.71 (1H, 10-H, ov), 2.75 (2H, L3-CH2, ov), 2.68
(4H, L7, L8-CH2, ov), 2.56 (2H, L2-CH2, ov), 2.55 (4H, L5, L6-CH2,
ov), 2.55 (1H, 30-H, ov), 2.55 (1H, 9a-H, ov), 2.39 (1H, 200a-H, d),
2.32 (3H, 9N-CH3, s), 2.31 (6H, 30N-(CH3)2, s), 2.07 (1H, 9b-H, ov),
2.04 (1H, 8-H, ov), 2.01 (1H, 4-H, ov), 1.91 (1H, 14a-H, m), 1.78
(1H, 7a-H, d), 1.68 (1H, 40a-H, m), 1.61 (1H, 200b-H, dd), 1.47 (1H,
14b-H, m), 1.55 (3H, 14000-CH3, t), 1.31 (3H, 6-CH3, s), 1.42 (3H,
15000-CH2, dq), 1.29 (1H, 7b-H, ov), 1.26 (1H, 40b-H, ov), 1.21 (3H,
2-CH3, ov), 1.19 (3H, 500-CH3, ov), 1.14 (3H, 50-CH3, ov), 1.15 (3H,
300-CH3, ov), 1.11 (3H, 12-CH3, ov), 1.09 (3H, 10-CH3, d), 1.06 (3H,
4-CH3, d), 0.91 (8-CH3, ov), 0.89 (15-CH3, ov).
IR (KBr, cmꢁ1) 2984, 2936, 2824, 1733, 1693, 1642, 1600, 1546,
1600, 1485, 1456, 1379, 1345, 1327, 1318, 1247, 1166, 1128, 1077,
1014, 960, 918.
4.13. 9-Deoxo-4‘‘-O-(3-{4-[3-(1-ethyl-3-carboxy-1,4-ihydro-4-
oxo-quinolin-6-yl)prop-2-ynyl]piperazine-1-yl}propyonyl)-
9a,11-O-dimethyl-9a-aza-9a-homoerythromycin A (20)
Applying the same protocol as for the synthesis of compound
16, compound 20 was obtained from the compound 14 (0.20 g,
0.20 mmol) and 1-Etil-1,4-dihidro-4-okso-6-[3-(1-piperazinil)-1-
propin-1-il]-3-kinolinkarboksilna kiselina 12 (0.45 g, 1.33 mmol)
and formed product was 20Oac derivate that was dissolved in
methanol (50 mL) and reaction mixture was stirred at 50 °C over
night. Crude product was purified by low-pressure column chro-
matography in system of solvents and DCM/MeOH/NH3 = 90/5/
0.5; after warded 19 (0.09 g, Y = 6%) was obtained as white crystal-
line product.
13C NMR (125 MHz, CDCl3) d: 178.84 (1-CO), 173.45 (4000-CO),
171.91 (L1-CO), 165.58 (12000-CO), 148.45 (2000-CH), 137.94 (9000-C),
135.28 (7000-CH), 131.47 (5000-CH), 129.60 (10000-C), 120.00 (6000-C),
115.57 (8000-CH), 111.47 (3000-C), 102.25 (10-CH), 94.56 (100-CH),
85.84(L11-C), 84.02 (L12-C), 83.09 (5-CH), 78.72 (400-CH), 77.59
(3-CH), 77.33 (13-CH), 74.15 (11-CH), 73.53 (6-C), 73.50 (12-C),
72.94 (300-C), 70.81 (20-CH), 70.00 (9-CH2), 68.24 (50-CH), 67.73
(500-CH), 65.56 (30-CH), 62.42 (10-CH), 60.90 (13000-CH2), 53.34 (L3-
MS(m/z): calcd for MH+: 1156.46, found: 1156.54 (92.46%).
HRMS calcd for
1156.4662.
C
61H98N5O16 (M+H)+ 1156.4638; found.
1H NMR (500 MHz, DMSO) d: 8.77 (1H, 2000-H, s), .59 (1H 5000-H,
d), 7.85 (1H, 7000-H, dd), 7.60 (1H, 8000-H, d), 5.16 (1H, 100-H, d),
4.75 (1H, 400-H, d), 4.68 (1H, 13-H, dd), 4.60 (1H, 10-H., d), 4.42

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7294
CH2), 52.68 (L2-CH2), 51.99 (L7, L8-CH2), 49.32 (300OCH3), 48.82
(11000-CH), 47.60 (L10-CH2), 45.09 (2-CH), 42.10 (7-CH2), 42.10
(4-CH), 40.24 (30N-(CH3)2), 36.15 (9N-CH3), 34.86 (200-CH2),
32.38 (L5, L6-CH2), 28.79 (40-CH2), 27.46 (6-CH3), 26.69 (8-CH),
22.77 (50-CH3), 21.86 (8-CH3), 21.21 (300-CH3), 21.36 (14-
CH2), 17.73 (500-CH3), 16.09 (12-CH3), 14.43 (2-CH3), 14.43
(14000-CH3), 14.34 (15000-CH2), 11.18 (15-CH3), 8.93 (4-CH3), 7.26
(10-CH3).
filtration of the catalyst and evaporation of organic solvent product
23 (0.05 g, Y = 50%) as white crystalline product.
MS(m/z): calcd for MH+: 1185.49, found: 1185.77 (90.75%).
HRMS calcd for
1185.7205.
C
63H101N4O17 (M+H)+ 1185.7162; found
1H NMR (500 MHz, CDCl3) d: 8.60 (1H, 2000-H, s), 8.29 (1H, 5000-H,
d), 7.86 (1H, 8000-H, dd), 7.54 (1H, 7000-H, dd), 5.06 (1H, 13-H, dd),
4.98 (1H, 100-H, dd), 4.68 (1H, 400-H, d), 4.60 (1H, 10-H., d), 4.39
(2H, 13000-CH2, q), 4.31 (1H, 500-H, dq), 3.77 (1H, 3-H, ov), 3.77
(1H, 11-H, ov), 3.75 (1H, 50-H, m), 3.64 (1H, 5-H, ov), 3.47 (1H,
11000-CH, m), 3.32 (3H, 300O-CH3, s), 3.30 (1H, 20-H, ov), 3.03 (3H,
6O-CH3, s), 3.00 (1H, 10-H, ov), 2.94 (1H, 2-H, ov), 2.91 (1H, 30-H,
m), 2.77 (2H, L12-CH2, ov), 2.77 (2H, L3-CH2, ov), 2.64 (4H, L7,
L8-CH2, ov), 2.60 (2H, L2-CH2, ov), 2.59 (1H, 8-H, ov), 2.55 (4H, L5,
L6-CH2, ov), 2.54 (6H, 30N-(CH3)2, s), 2.50 (2H, L10-CH2, ov), 2.42
(1H, 200a-H, d), 1.94 (1H, 4-H, ov), 1.92 (1H, 14a-H, ov), 1.88 (2H,
L11-CH2, ov), 1.83 (1H, 40a-H, ov), 1.80 (1H, 7a-H, ov), 1.67
(1H, 7b-H, ov), 1.63 (1H, 200b-H, ov), 1.49 (1H, 14b-H, m), 1.41
(3H, 14000-CH3, t), 1.37 (3H, 6-CH3, s), 1.33 (3H, 15000-CH3, dq), 1.30
(1H, 40b-H, ov), 1.22 (3H, 50-CH3, ov), 1.20 (3H, 2-CH3, ov), 1.13
(3H, 500-CH3, ov), 1.13 (3H, 300-CH3, ov), 1.13 (3H, 8-CH3, ov), 1.13
(3H, 10-CH3, ov), 1.13 (2H, 16000-CH2, ov), 1.12 (3H, 12-CH3, ov),
1.10 (3H, 4-CH3, ov), 0.84 (3H, 15-CH3, t).
IR (KBr, cmꢁ1) 2972, 2933, 2822, 1732, 1692, 1639, 1599, 1489,
1456, 1379, 1315, 1230, 1168, 1094, 1048, 1014, 959, 903, 807.
4.15. 4‘‘-O-(3-{4-[3-(1-Ethyl-3-ethoxycarbonyl-1,4-dihydro-4-
oxo-quinolin-6-yl)propyl]piperazine-1-yl}propyonyl)-6-O-
methyl-erythromycin A (22)
Hydrogenation of compound 16 (0.10 g, 0.09 mmol) in methnol
(30.0 mL) over 10% Pd–C (0.03 g) at hydrogen pressure 5.0 bars for
20 h afforded after filtration of the catalyst and evaporation of or-
ganic solvent product 22 (0.05 g, Y = 36%) as white crystalline
product.
MS(m/z): calcd for MH+: 1173.48, found: 1173.82 (73.95%).
HRMS calcd for
1173.7130.
C
62H101N4O17 (M+H)+ 1173.7162; found
1H NMR (500 MHz, CDCl3) d: 8.51 (1H, 2000-H, s), 8.35 (1H, 5000-H,
d), 7.54 (1H, 7000-H, dd), 7.41 (1H, 8000-H, dd), 5.07 (1H, 13-H, dd),
4.99 (1H, 100-H, dd), 4.69 (1H, 400-H, d), 4.61 (1H, 10-H., d), 4.41
(2H, 13000-CH2, q), 4.33 (1H, 500-H, dq), 4.27 (1H, 11000-CH, q), 3.76
(1H, 3-H, ov), 3.76 (1H, 11-H, ov), 3.78 (1H, 50-H, m), 3.65 (1H, 5-
H, ov), 3.31 (3H, 300O-CH3, s), 3.28 (1H, 20-H, ov), 3.03 (3H, 6O-
CH3, s), 3.00 (1H, 10-H, ov), 2.92 (1H, 2-H, dq), 2.78 (2H, L12-CH2,
ov), 2.75 (2H, L3-CH2, ov), 2.60 (4H, L7, L8-CH2, ov), 2.59 (1H, 8-H,
ov), 2.56 (4H, L5, L6-CH2, ov), 2.55 (2H, L2-CH2, ov), 2.48 (1H,
30-H, m), 2.48 (6H, 30N-(CH3)2, s), 2.45 (2H, L10-CH2, ov), 2.41 (1H,
200a-H, d), 1.95 (1H, 4-H, ov), 1.93 (2H, L11-CH2, ov)1.90 (1H, 14a-
H, ov), 1.84 (1H, 7a-H, ov), 1.81 (1H, 40a-H, ov), 1.67 (1H, 7b-
H, ov), 1.63 (1H, 200b-H, ov), 1.49 (1H, 14b-H, m), 1.41 (3H,
14000-CH3, t), 1.38 (3H, 6-CH3, s), 1.55 (3H, 15000-CH3, t), 1.28 (1H,
40b-H, ov), 1.22 (3H, 2-CH3, d), 1.20 (3H, 50-CH3, d), 1.14 (3H, 500-
CH3, ov), 1.15 (3H, 300-CH3, ov), 1.14 (3H, 8-CH3, ov), 1.13 (3H, 10-
CH3, ov), 1.12 (3H, 12-CH3, ov), 1.11 (3H, 4-CH3, ov), 0.85 (3H, 15-
CH3, t).
13C NMR (125 MHz, DMSO) d: 220.95 (9-CO), 175.66 (1-CO),
174.45 (4000-CO), 171.55 (L1-CO), 165.70 (12000-CO), 148.17 (2000-CH),
138.85 (9000-C), 138.75 (6000-C), 133.00 (7000-CH), 128.38 (10000-C),
126.54 (5000-CH), 116.56 (8000-CH), 110.66 (3000-C), 101.62 (10-CH),
95.89 (100-CH), 80.44 (5-CH), 78.64 (400-CH), 78.15 (6-C), 77.98
(3-CH), 76.69 (13-CH), 74.20 (12-C), 72.72 (300-C), 70.74 (20-CH),
69.01 (11-CH), 67.05 (50-CH), 65.17 (30-CH), 62.85 (500-CH), 60.79
(13000-CH2), 56.91 (L10-CH2), 52.88 (L3-CH2), 52.00 (L2-CH2), 51.65
(L7, L8-CH2), 50.58 (6O-CH3), 49.44 (300O-CH3), 45.18 (8-CH),
44.74 (2-CH), 39.77 (30N-(CH3)2), 39.08 (7-CH2), 38.73 (4-CH),
37.13 (10-CH), 35.06 (200-CH2), 34.43 (11000-CH), 32.75
(L12-C), 31.72 (L5, L6-CH2), 30.04 (40-CH2), 27.12 (L11-C), 21.58 (50-
CH3), 21.03 (300-CH3), 20.92 (14-CH2), 19.64 (6-CH3), 18.27 (500-
CH3), 17.94 (8-CH3), 15.88 (12-CH3), 15.88 (2-CH3), 14.34 (14000-
CH3), 12.25 (10-CH3), 10.49 (15-CH3), 9.19 (4-CH3), 8.04 (15000-
CH3), 8.04 (16000-CH3).
IR (KBr, cmꢁ1) 2972, 2940, 2830, 1732, 1691, 1610, 1489, 1457,
1457, 1376, 1349, 1246, 1171, 1084, 1012, 985, 959, 891.
13C NMR (125 MHz, CDCl3) d: 220.95 (9-CO), 175.64 (1-CO),
174.33 (4000-CO), 171.64 (L1-CO), 165.52 (12000-CO), 148.14 (2000-CH),
138.76 (6000-C), 136.90 (9000-C), 133.15 (7000-CH), 127.06 (5000-CH),
129.15 (10000-C), 115.62 (8000-CH), 110.75 (3000-C), 101.71 (10-CH),
95.90 (100-CH), 80.46 (5-CH), 78.63 (400-CH), 78.16 (6-C), 77.95
(3-CH), 76.55 (13-CH), 74.20 (12-C), 72.71 (300-C), 70.85 (20-
CH), 69.01 (11-CH), 67.24 (50-CH), 65.16 (30-CH), 62.87 (500-CH),
60.79 (13000-CH2), 57.07 (L10-CH2), 53.01 (L3-CH2), 52.25 (L2-CH2),
51.95 (L7, L8-CH2), 50.59 (6O-CH3), 49.41 (300O-CH3), 48.79
(11000-CH), 45.19 (8-CH), 44.75 (2-CH), 39.94 (30N-(CH3)2), 39.10
4.17. 9-Deoxo-400-O-(3-{4-[3-(1-tyl-3-ethoxycarbonyl-1,4-
ihydro-4-oxo-quinolin-6-yl)proypl]piperazine-1-yl}propyonyl)-
9a,11-O-dimethyl-9a-aza-9a-homoerythromycin A (24)
Applying the same protocol as for the synthesis of compound
22, compound 24 was obtained from 18 (0.05 g, 0.04 mmol) after
filtration of the catalyst and evaporation of organic solvent product
24 (0.01 g, Y = 12%) as white crystalline product.
MS(m/z): calcd for MH+: 1188.54, found: 1188.77 (70.42%).
(7-CH2), 38.71 (4-CH), 37.13 (10-CH), 35.08 (200-CH2), 32.77 (L12
-
HRMS calcd for
1188.7672.
C
63H106N5O16 (M+H)+ 1188.7635; found
C), 31.90 (L5, L6-CH2), 28.79 (40-CH2), 27.37 (L11-C), 21.62 (50-
CH3), 21.04 (300-CH3), 20.93 (14-CH2), 19.63 (6-CH3), 18.27 (500-
CH3), 17.94
1H NMR (600 MHz, CDCl3) d: 8.49 (1H, 2000-H, s), 8.35 (1H, 5000-H,
d), 7.52 (1H, 7000-H, dd), 7.38 (1H, 8000-H, d), 5.16 (1H, 100-H, d), 4.70
(1H, 400-H, d), 4.69 (1H, 13-H, dd), 4.58 (1H, 10-H., d), 4.42 (1H, 500-H,
ov), 4.40 (2H, 13000-CH2, ov), 4.39 (1H, 3-H, ov), 4.25 (2H, 11000-CH, q),
3.78 (1H, 50-H, m), 3.62 (1H, 5-H, d), 3.59 (3H, 11O-CH3, s), 3.41
(1H, 11-H, s), 3.32 (3H, 300O-CH3, s), 3.25 (1H, 20-H, dd), 2.77 (2H,
L12-CH2, ov), 2.75 (1H, 2-H, ov), 2.70 (2H, L2-CH2, ov), 2.67 (1H,
10-H, ov), 2.57 (1H, 30-H, ov), 2.53 (4H, L5, L6-CH2, ov), 2.51 (2H,
L3-CH2, ov), 2.51 (4H, L7, L8-CH2, ov), 2.50 (1H, 9a-H, ov), 2.40
(1H, 200a-H, d), 2.35 (2H, L10-CH2, t), 2.30 (6H, 30N-(CH3)2, s), 2.24
(3H, 9N-CH3, s), 2.07 (1H, 9b-H, t), 2.01 (1H, 8-H, ov), 2.01 (1H,
4-H, ov), 1.92 (1H, 14a-H, m), 1.85 (2H, L11-CH2, ov), 1.75 (1H,
7a-H, d), 1.66 (1H, 40a-H, m), 1.61 (1H, 200b-H, dd), 1.55 (3H,
(8-CH3), 15.88 (12-CH3), 15.88 (2-CH3), 14.50 (15000-CH3), 14.35
(14000-CH3), 12.25 (10-CH3), 10.49 (15-CH3), 9.17 (4-CH3).
IR (KBr, cmꢁ1) 2969, 2936, 2883, 2826, 1731, 1687, 1609, 1494,
1455, 1377, 1315, 1227, 1166, 1083, 1012, 808.
4.16. 4‘‘-O-(3-{4-[3-(1-Cyclopropyl-3-ethoxycarbonyl-1,4-
dihyydro-4-oxo-quinolin-6-l)propyl]piperazine-1-
yl}propyonyl)-6-O-methyl-erythromycin A (23)
Applying the same protocol as for the synthesis of compound
22, compound 23 was obtained from 17 (0.09 g, 0.08 mmol) after

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S. Kapic et al. / Bioorg. Med. Chem. 19 (2011) 7281–7298
15000-CH2, t), 1.47 (1H, 14b-H, m), 1.42 (3H, 14000-CH3, t), 1.32 (1H,
4.19. 9-Deoxo-400-O-(3-{4-[3-(1-ethyl-3-carboxy-1,4-dihydro-4-
oxo-quinolin-6-yl)propyl]piperazine-1-yl}propyonyl)-9a,11-O-
dimethyl-9a-aza-9a-homoerythromycin A (26)
7b-H, ov), 1.27 (1H, 40b-H, ov), 1.26 (3H, 6-CH3, s), 1.20 (3H, 300-
CH3, s), 1.19 (3H, 2-CH3, d), 1.16 (3H, 500-CH3, d), 1.12 (3H, 50-
CH3, d), 1.10 (3H, 12-CH3, s), 1.05 (3H, 4-CH3, ov), 1.03 (3H, 10-
CH3, ov), 0.91 (8-CH3, d), 0.89 (15-CH3, t).
Applying the same protocol as for the synthesis of compound
22, compound 26 was obtained from 20 (0.05 g, 0.04 mmol) after
filtration of the catalyst and evaporation of organic solvent product
26 (0.05 g, Y = 90%) as yellow crystalline product.
13C NMR (75 MHz, CDCl3) d: 177.35 (1-CO), 173.69 (4000-CO),
171.42 (L1-CO), 165.52 (12000-CO), 147.51 (2000-CH), 138.72 (6000-C),
136.27 (9000-C), 132.53 (7000-CH), 128.70 (10000-C), 126.60 (5000-CH),
114.86 (8000-CH), 110.28 (3000-C), 101.78 (10-CH), 94.15 (100-CH),
84.39 (11-CH), 82.93 (5-CH), 78.35 (400-CH), 77.41 (3-CH), 77.15
(13-CH), 73.79 (12-C), 72.54 (6-C), 72.54 (300-C), 70.41 (20-CH),
70.41 (9-CH2), 67.20 (50-CH), 64.90 (30-CH), 62.14 (10-CH), 62.02
(500-CH), 61.50 (11O-CH3), 60.22 (13000-CH2), 57.02 (L10-CH2), 52.92
(L3-CH2), 52,45 (L2-CH2), 52.31 (L7, L8-CH2), 48.79 (300OCH3), 48.17
(11000-CH), 44.83 (2-CH), 42.14 (7-CH2), 42.06 (4-CH), 39.74
(30N-(CH3)2), 35.30 (9N-CH3), 34.50 (200-CH2), 32.44 (L12-C), 31.96
(L5, L6-CH2), 29.06 (40-CH2), 27.78(L11-C), 27.05 (6-CH3), 26.13
(8-CH), 22.20 (8-CH3), 21.58 (50-CH3), 21.15 (14-CH2), 20.73
(300-CH3), 17.11 (12-CH3), 16.44 (500-CH3), 14.01 (15000-CH2), 13.94
(14000-CH3),13.81(2-CH3),10.66(15-CH3),8.62(4-CH3),6.59(10-CH3).
MS(m/z): calcd for MH+: 1160.49, found. 1161.53 (78.85%).
1H NMR (500 MHz, CDCl3) d 8.77 (1H, 2000-H, s), 8.37 (1H, 5000-H,
d), 7.68 (1H, 7000-H, dd), 7.56 (1H, 8000-H, d), 5.16 (1H, 100-H, dd), 4.69
(1H, 13-H, ov), 4.69 (1H, 400-H, ov), 4.58 (1H, 10-H, d), 4.39 (1H, 3-H,
ov), 4.39 (1H, 500-H, ov), 4.39 (2H, 11000-CH2, ov), 3.79 (1H, 50-H, m),
3.61 (1H, 5-H, ov), 3.58 (3H, 11O-CH3, s), 3.40 (1H, 11-H, s), 3.32
(1H, 20-H, ov), 3.32 (3H, 300O-CH3, s), 2.83 (2H, L12-CH2, m), 2.74
(1H, 2-H, ov), 2.72 (2H, L2-CH2, ov), 2.68 (1H, 10-H, ov), 2.68 (1H,
30-H, ov), 2.68 (8H, L5, L6, L7, L8-CH2, ov), 2.52 (2H, L3-CH2, ov),
2.52 (1H, H-9a, ov), 2.41 (1H, 200a-H), 2.36 (2H, L10-CH2, ov), 2.36
(6H, 30N(CH3)2, s), 2.24 (3H, 9 N-CH3, s), 2.07 (1H, 8-H, ov), 2.07
(1H, 9b-H, ov), 2.00 (1H, 4-H, ov), 1.89 (1H, 14a-H, ov), 1.89 (2H,
L
11-CH2, ov), 1.73 (1H, 7a-H, ov), 1.73 (1H, 40a-H, ov), 1.60 (1H,
4.18. 9-Deoxo-4‘‘-O-(3-{4-[3-(1-cycloproyp-3-ethoxycyrbonyl-
1,4-dihydro-4-oxo-quinolin-6-yl)propyl]piperazine-1-
il}propyonyl)-9a,11-O-dimethyl-9a-aza-9a-homoerythromycin
A (25)
200b-H, ov), 1.60 (3H, 15000-CH3, ov), 1.47 (1H, 14b-H, m), 1.28 (1H,
7b-H, ov), 1.28 (1H, 40b-H, ov), 1.26 (3H, 6-CH3, s), 1.20 (3H, 2-
CH3, ov), 1.20 (3H, 50-CH3, ov), 1.14 (3H, 500-CH3, ov), 1.13 (3H,
300-CH3, ov), 1.11 (3H, 12-CH3, ov), 1.04 (3H, 4-CH3, ov), 1.04 (3H,
10-CH3, ov), 0.91 (3H, 8-CH3, ov), 0.90 (3H, 15-CH3, ov).
Applying the same protocol as for the synthesis of compound
22, compound 25 was obtained from 19 (0.11 g, 0.01 mmol) after
filtration of the catalyst and evaporation of organic solvent product
25 (0.01 g, Y = 5%) as white crystalline product.
13C NMR (300 MHz, CDCl3) d 178.39 (1-CO), 177.95(4000-CO),
172.04 (L1-CO), 167.29 (12000-CO), 147.44 (2000-CH), 140.81 (6000-C),
137.49 (9000-C), 134.85 (7000-CH), 126.66 (10000-C), 126.35 (5000-CH),
116.31 (8000-CH), 108.83 (3000-C), 102.23(10-CH), 94.82 (100-CH),
85.06 (11-H), 83.67 (5-CH), 78.97 (400-CH), 78.10 (3-H), 77.88
(13-CH), 74.43 (12-CH), 73.22 (300-C), 73.17 (6-C), 71.08 (20-CH),
70.11 (9-CH2), 67.51 (50-CH), 65.51 (30-CH), 62.83 (500-CH), 62.70
(10-H), 62.15 (11O-CH3), 57.45 (L10-CH2), 53.48 (L2-CH2), 53.02
MS(m/z): calcd for MH+: 1200.55, found. 1199.54 (48.20%).
1H NMR (500 MHz, CDCl3) d: 8.54 (1H, 2000-H, s), 8.53 (1H, 5000-H,
d), 7.73 (1H, 8000-H, d), 7.71 (1H, 7000-H, dd), 5.17 (1H, 100-H, d), 4.69
(1H, 13-H, dd), 4.73 (1H, 400-H, d), 4.59 (1H, 10-H., d), 4.48 (1H, 500-H,
ov), 4.40 (2H, 13000-CH2, ov), 4.35 (1H, 3-H, ov), 3.80 (1H, 50-H, m),
3.64 (1H, 5-H, d), 3.59 (3H, 11O-CH3, s), 3.47 (2H, 11000-CH, m),
3.40 (1H, 11-H, s), 3.33(3H, 300O-CH3, s), 3.28 (1H, 20-H, dd), 2.77
(2H, L12-CH2, ov), 2.75 (1H, 2-H, ov), 2.70 (2H, L3-CH2, ov), 2.69
(1H, 10-H, ov), 2.69 (4H, L7, L8-CH2, ov), 2.59 (1H, 30-H, ov), 2.55
(2H, L2-CH2, ov), 2.54 (4H, L5, L6-CH2, ov), 2.52(1H, 9a-H, ov),
2.40 (1H, 200a-H, d), 2.32 (6H, 30N-(CH3)2, s), 2.30 (2H, L10-CH2, s),
2.27 (3H, 9N-CH3, s), 2.09 (1H, 9b-H, t), 2.00 (1H, 4-H, ov), 1.96
(1H, 8-H, ov), 1.92 (1H, 14a-H, m), 1.85 (2H, L11-CH2, ov),
1.72 (1H, 7a-H, d), 1.67 (1H, 40a-H, m), 1.60 (1H, 200b-H, dd), 1.35
(3H, 15000-CH2, dq), 1.48 (1H, 14b-H, m), 1.41 (3H, 14000-CH3, t),
1.31 (1H, 7b-H, ov), 1.26 (3H, 6-CH3, s), 1.26 (1H, 40b-H, ov), 1.22
(3H, 300-CH3, s), 1.20 (3H, 2-CH3, d), 1.17 (3H, 500-CH3, d), 1.15
(3H, 50-CH3, d), 1.13 (3H, 12-CH3, s), 1.13 (2H, 16000-CH2, dq), 1.06
(3H, 4-CH3, d), 1.03 (3H, 10-CH3, d), 0.91 (8-CH3, d), 0.89 (15-
CH3, t).
(L7, L8-CH2), 52.81 (L5, L6-CH2), 49.70 (11000-CH2), 49.45 (300O-CH3)
,
45.47 (2-CH), 42.77 (7-CH2), 42,62 (4-CH), 40.45 (30N-CH3), 35.93
(9 N-CH3), 35.14 (200-CH2), 33.01 (L12-CH2), 32.54 (L3-CH2), 29.70
(40-CH2), 28.18 (L11-CH2), 27.67 (6-CH3), 26.75 (8-CH), 22.23
(8-CH3), 21.78 (14-CH2), 21.75 (50-CH3), 21.36 (300-CH3), 17.75
(500-CH3), 17.12 (12-CH3), 14.74 (15000-CH3), 14.67 (2-CH3), 11.29
(15-CH3), 9.37 (4-CH3), 7.22 (10-CH3).
4.20. 9-Deoxo-400-O-(3-{4-[3-(1-ethyl-3-etoksikathoxycarbonylr
bonil-1,4-dihydro-4-oxo-quinolin-6-ill)propropylpil]piperazin
e-1-yl}propyonyl)-9a-methyl-9a-aza-9a-homoerythromycin A
(27)
Applying the same protocol as for the synthesis of compound
22, compound 27 was obtained from 21 (0.25 g, 0.21 mmol) after
filtration of the catalyst and evaporation of organic solvent product
was purified by low-pressure column chromatography in system of
solvents and DCM/MeOH/NH3 = 90:5:0.5; after warded 27 (0.03 g,
Y = 13%) as white crystalline product.
13C NMR (125 MHz, CDCl3) d: 177.60 (1-CO), 172.52 (4000-CO),
171.90 (L1-CO), 165.49 (12000-CO), 147.49 (2000-CH), 139.85 (9000-C),
139.40 (6000-C), 135.55 (7000-CH), 130.99 (5000-CH), 128.30 (10000-C),
116.45 (8000-CH), 111.30 (3000-C), 102.00 (10-CH), 94.70 (100-CH),
83.20 (5-CH), 78.88 (400-CH), 78.36 (3-CH), 77.70 (13-CH), 84.95
(11-CH), 73.00 (6-C), 74.74(12-C), 73.10 (300-C), 70.92 (20-CH),
70.90 (9-CH2), 67.50 (50-CH), 65.43 (30-CH), 62.70 (500-CH), 62.44
(10-CH), 62.07 (11O-CH3), 60.90 (13000-CH2), 57.62 (L10-CH2),
53.30 (L3-CH2), 52.68 (L2-CH2), 52.00 (L7, L8-CH2), 49.36 (300O-
CH3), 45.30 (2-CH), 42.64 (4-CH), 42.00 (7-CH2), 40.26 (30N-
(CH3)2), 35.80 (9N-CH3), 35.01 (200-CH2), 32.42 (L12-CH2), 34.41
(11000-CH), 32.40 (L5, L6-CH2), 29.41 (40-CH2), 27.78(L11-CH2),
27.21 (6-CH3), 26.64 (8-CH), 22.02 (8-CH3), 21.85 (300-CH3), 21.66
(14-CH2), 21.13 (50-CH3), 17,64 (500-CH3), 16.88 (12-CH3), 14.38
(2-CH3), 14.33 (14000-CH3), 11.20 (15-CH3), 9.18 (4-CH3), 8.13
(15000-CH2), 8.13 (16000-CH2), 7.09 (10-CH3).
MS(m/z): calcd for MH+: 1174.51, found: 1175.04 (70.26%).
HRMS calcd for
1174.7542.
C
62H104N5O16 (M+H)+ 1174.7478; found
1H NMR (500 MHz, DMSO) d: 8.68 (1H, 2000-H, s), 8.05 (1H, 5000-H,
d), 7.74 (1H, 8000-H, d), 7.64 (1H, 7000-H, dd), 4.92 (1H, 100-H, dd), 4.75
(1H, 13-H, ov), 4.55 (1H, 400-H, ov), 4.47 (1H, 10-H, d), 4.41 (2H, 11000-
CH, q), 4.34 (1H, 500-H, ov), 4.23 (2H, 13000-CH2, ov), 4.17 (1H, 3-H,
ov), 3.73 (1H, 50-H, m), 3.48 (1H, 5-H, d), 3.45 (1H, 11-H, s), 3.22
(3H, 300O-CH3, s), 3.05 (1H, 20-H, dd), 2.73 (2H, L12-CH2, ov), 2.71
(1H, 10-H, ov), 2.67 (1H, 2-H, ov), 2.57 (2H, L3-CH2, ov), 2.45 (4H,
L5, L6-CH2, ov), 2.43 (2H, L2-CH2, ov), 2.40 (1H, 30-H, ov), 2.39
(1H, 9a-H, ov), 2.37 (1H, 20-CH), 2.35 (L10-CH2, ov), 2.34 (1H, 200a-
H, d), 2.21 (6H, 30N-(CH3)2, ov), 2.21 (3H, 9N-CH3, ov), 2.12 (1H,

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7296
9b-H, t), 1.91 (1H, 4-H, ov), 1.88 (L11-CH2, ov), 1.77 (1H, 14a-H, m),
1.68 (1H, 200b-H, dd), 1.58 (1H, 40a-H, m), 1.50 (1H, 7a-H, d), 1.36
(3H, 15000-CH2, t), 1.29 (3H, 14000-CH3, t), 1.27 (1H, 7b-H, ov), 1.16
(1H, 14b-H, ov), 1.16 (3H, 6-CH3, ov), 1.15 (1H, 40b-H, ov), 1.10
(3H, 50-CH3, ov), 1.09 (3H, 300-CH3, ov), 1.08 (3H, 2-CH3, ov), 1.04
(3H, 500-CH3, ov), 1.02 (3H, 12-CH3, ov), 0.96 (3H, 4-CH3, ov), 0.95
(3H, 10-CH3, ov), 0.86 (8-CH3, d), 0.80 (15-CH3, t).
4.23. Ethyl 6-[(1E)-3-({[(1,1-dimethylethyl)oxy]carbonyl}oxy)-
1-propen-1-yl]-1-ethyl-4-oxo-1,4-dihydro-3-quinolinecar
boxylate (32)
To the solution of 30 (0.29 g, 0.96 mmol) in DCM (5 mL) at 0 °C
bis(1,1-dimethylethyl) dicarbonate 31 (0.377 g, 1.73 mmol), and
tetrabutylamoniumhydrogen sulfate (0.0195 g, 0.06 mmol) were
added. Than to the reaction mixture was dropped solution of NaoH
(0.115 g, 2.88 mmol) in water (0.35 mL). Reaction mixture was stir-
red gradually to 25 °C and stirred over night. To the reaction mix-
ture were added DCM (20 mL) and water (20 mL). Layers were
separated, water layer was extracted with DCM (2 ꢀ 10 mL) and
collected organic extracts were dried (K2CO3) and concentrated un-
der vacuum and residue was dissolved in EtOAc. n-hexane 1/10
and precipitate was filtered off to afford pure product 33
(0.354 g, Y = 92%).
13C NMR (125 MHz, DMSO) d: 177.61 (1-CO), 173.24 (4000-CO),
172.11 (L1-CO), 165.24 (12000-CO), 148.98 (2000-CH), 139.37 (6000-C),
137.31 (9000-C), 133.76 (7000-CH), 129.03 (10000-C), 125.90 (5000-CH),
117.62 (8000-CH), 110.30 (3000-C), 102.61 (10-CH), 94.91 (100-CH),
83.91 (5-CH), 78.45 (400-CH), 77.97 (3-CH), 76.89 (13-CH), 75.46
(11-CH), 74.11 (300-C), 73.18 (12-CH), 72.99 (6-C), 71.03 (20-CH),
69.18 (9-CH2), 67.28 (50-CH), 65.40 (30-CH), 62.73 (500-CH), 62.00
(10-CH), 57.04 (L10-CH2), 53.13 (L2, L3-CH2), 49.33 (300O-CH3),
48.72 (11000-CH2), 45.13 (2-CH), 42.28 (7-CH2), 42.20 (4-CH), 40.86
(30N-(CH3)2, 36.29 (9N-CH3), 34.84 (200-CH2), 32.99 (L5, L6-CH2),
32.73 (L12-CH2), 30.69 (40-CH2), 28.47 (14-CH2) ,27.98 (6-CH3),
27.76 (L11-CH2), 25.93 (8-CH3), 22.61 (8-CH3), 22.32 (50-CH3),
21.48 (14-CH2), 21.24 (300-CH3), 18.29 (12-CH3), 18.22 (500-CH3),
15.16 (2-CH3), 14,95 (15000-CH3), 14.85 (14000-CH3), 11.48 (15-CH3),
9.51 (2-CH3), 7.30 (10-CH3).
MS(m/z): calcd for MH+: 402.46, found: 402.2 (90.58%).
HRMS calcd for C22H27NO6 (M+H)+ 300.1230; found 300.1206.
1H NMR (500 MHz, DMSO) d: 8.70 (1H, 2000-H, s), 8.09 (1H, 5000-H,
d), 7.85 (1H, 8000-H, d), 7.69 (1H, 7000-H, dd), 6.80 (1H, L12-CH, d), 5.89
(1H, L11-CH, dt), 4.85 (2H, L10-CH2, dd), 4.42 (2H, 11000-CH2, q), 4.24
(2H, 13000-CH2, q), 1.42 (9H, L1-CH3, s), 1.37 (3H, 15000-CH3, t), 1.30
(3H, 14000-CH3, t).
IR (KBr, cmꢁ1) 2953, 2922, 2852, 1690, 1613, 1453, 1378, 1318,
1238, 1169, 1079, 1013, 893, 863, 811.
13C NMR (125 MHz, DMSO) d:172.51 (4000-CO), 164.53 (12000-CO),
152.69 (L3-CO), 148.84 (2000-CH), 137.72 (9000-C), 132.90 (7000-CH),
132.04 (6000-C), 130.94 (L12-CH), 128.10 (10000-C), 126.91 (L11-CH),
126.07 (5000-CH), 117.46 (8000-CH), 110.22 (3000-C), 81.65 (L2-C),
63.11 (L10-CH2), 59.65 (13000-CH2), 47.86 (11000-CH2), 27.24
(L1-CH3), 14.32 (14000-CH3), 14.23 (15000-CH3).
4.21. Ethyl 1-ethyl-6-(3-hydroxy-1-propyn-1-yl)-4-oxo-1,4-
dihydro-3-quinolinecarboxylate (29)
Applying the same protocol as for the synthesis of compound 7,
compound 29 was obtained from ethyl 1-ethyl-6-iodo-4-oxo-1,4-
dihydro-3-quinolinecarboxylate 4 (2.60 g, 7.00 mmol) and propar-
gyl alcohol 28 (0.50 mL, 8.4 mmol) as crude crystalline product 29
(2.03 g, Y = 97%) as white crystalline product.
4.24. Ethyl 6-[(1E)-3-(4-{[(1,1-dimethylethyl)oxy]carbonyl}-1-
piperazinyl)-1-propen-1-yl]-1-ethyl-4-oxo-1,4-dihydro-3-
quinolinecarboxylate (34)
MS(m/z): calcd for MH+: 299.58, found: 300.2 (83.9%).
To the dry solution of 33 (0.085 g, 0.45 mmol) in toluene (5 mL)
were added 32 (0.2 g, 0.5 mmol), Pd2(dba)3 (0.123 g, 0.135 mmol)
and dppb (0.115 g, 0.27 mmol). Reaction mixture was refluxed
for 3 h. Solvent was evaporated and to the residue EtOAc was
added, catalyst precipitated, and filtered off. Solvent was evapo-
rated and residue was dissolved in DCM, n-hexane was added
and precipitate was filtered off. Precipitate was dissolved in MeCN
but crystal was not obtained and solvent was evaporated yielding
brown oily product (0.2279 g, Y = 99%).
HRMS calcd for C17H18NO4 (M+H)+ 300.1230; found 300.1106.
1H NMR (500 MHz, DMSO) d: 8.70 (1H, 2000-H, s), 8.22 (1H, 5000-H,
d), 7.82 (1H, 8000-H, d), 7.77 (1H, 7000-H, dd), 4.42 (2H, 11000-CH2, q),
4.35 (2H, L10-CH2, s), 4.23 (2H, 13000-CH2, q), 1.37 (3H, 15000-CH3, t),
1.30 (3H, 14000-CH3, t).
13C NMR (125 MHz, DMSO) d:172.03 (4000-CO), 164.46 (12000-CO),
149.20 (2000-CH), 138.22 (9000-C), 134.83 (7000-CH), 129.07 (10000-C),
128.77 (5000-CH), 118.75 (6000-C), 117.97 (8000-CH), 110.56 (3000-C),
90.86 (L11-CH), 82.59 (L12-CH), 59.81 (13000-CH2), 49.45 (L10-CH2),
48.00 (11000-CH2), 14.30 (15000-CH3), 14.30 (14000-CH3).
MS(m/z): calcd for MH+: 470.58, found: 470.4 (68.45%), LC-UV
(91.7%).
HRMS calcd for C26H36N3O5 (M+H)+ 470.2649; found 470.2646.
1H NMR (500 MHz, DMSO) d: 8.66 (1H, 2000-H, s), 8.17 (1H, 5000-H,
d), 7.95 (1H, 7000-H, dd), 7.77 (1H, 8000-H, d), 6.71 (1H, L12-CH, d), 6.42
(1H, L11-CH, dt), 4.41 (2H, 11000-CH2, q), 4.24 (2H, 13000-CH2, q), 3.33
(4H, L5, L6-CH2, ov), 3.15 (2H, L10-CH2, d), 2.37 (4H, L7, L8-CH2, m),
1.39 (9H, L1-CH3, s), 1.37 (3H, 15000-CH3, t), 1.30 (3H, 14000-CH3, t).
13C NMR (125 MHz, DMSO) d:173.22 (4000-CO), 165.16 (12000-CO),
154.41 (L3-CO), 149.08 (2000-CH), 138.29 (9000-C), 133.82 (6000-C),
131.04 (L12-CH), 130.58 (7000-CH), 129.51 (L11-CH), 129.07 (10000-C),
124.56 (5000-CH), 118.16 (8000-CH), 110.75 (3000-C), 79.26 (L2-C),
60.49 (L10-CH2), 60.22 (13000-CH2), 52.95 (L7, L8-CH2), 48.48
(11000-CH2), 40.94 (L5, L6-CH2), 28.61 (L1-CH3), 14.96 (15000-CH3),
14.87 (14000-CH3).
4.22. Ethyl 1-ethyl-6-[(1Z)-3-hydroxy-1-propen-1-yl]-4-oxo-1,4-
dihydro-3-quinolinecarboxylate (30)
To the solution of 29 (0.5 g, 1.67 mmol) in DMC (4 mL) and eth-
anol (4 mL) Lindlar catalyst (0.18 g. Pd/CaCO3-Pb 5%) was added.
Reaction mixture was hydrogenated (p = atm t = 25 °C) for 4 h. Cat-
alyst was filtered off and solvent evaporated yielding title product
30 (0.47 g, Y = 93%).
MS(m/z): calcd for MH+: 302.34, found: 302.1 (95.5%).
HRMS calcd for C17H20NO4 (M+H)+ 300.1230; found 300.1206.
1H NMR (500 MHz, DMSO) d: 8.69 (1H, 2000-H, s), 8.06 (1H, 5000-H,
d), 7.67 (1H, 7000-H, dd), 7.82 (1H, 8000-H, d), 6.54 (1H, L12-CH, d),
5.91 (1H, L11-CH, dt), 4.42 (2H, 11000-CH2, q), 4.24 (2H, 13000-CH2,
q), 4.30 (2H, L10-CH2, ddd), 1.38 (3H, 15000-CH3, t), 1.31 (3H,
14000-CH3, t).
IR (KBr, cmꢁ1) 3433, 2973, 2939, 1737, 1459, 1376, 1346, 1315,
1273, 1169, 1113, 1080, 1056, 1015, 1000, 959, 905.
13C NMR (125 MHz, DMSO) d:173.08 (4000-CO), 165.04 (12000-CO),
149.11 (2000-CH), 137.78 (9000-C), 133.49 (6000-C), 127.65 (L12-CH),
133.53 (7000-CH), 135.29 (L11-CH), 128.56 (10000-C), 126.38 (5000-CH),
117.63 (8000-CH), 110.59 (3000-C), 60.09 (L10-CH2), 60.32 (13000-CH2),
48.32 (11000-CH2), 14.78 (15000-CH3), 14.71 (14000-CH3).
4.25. Ethyl 1-ethyl-4-oxo-6-[(1E)-3-(1-piperazinyl)-1-propen-1-
yl]-1,4-dihydro-3-quinolinecarboxylate (35)
To the solution of 34 (0.185 g, 0.394 mmol) in DCM (1.85 mL)
was added CF3COOH (1.85 mL, 0.024 mol). Reaction mixture was

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S. Kapic et al. / Bioorg. Med. Chem. 19 (2011) 7281–7298
stirred at rt for 2.5 h. To the reaction mixture were added DCM
(20 mL) and water (20 mL). Layers were separated, water layer
was extracted with DCM (2 ꢀ 10 mL) and to the water layer DCM
(20 mL) was added and pH adjusted from 1.8 to 9.5 by addition
of aq soln NH4OH. Layers were separated; water layer was ex-
tracted with DCM (2 ꢀ 15 mL). The organic extract was dried
(K2CO3) and concentrated under vacuum to afford title product
35 (0.689 g, Y = 47.6%).
CH), 129.78 (10000-C), 128.25 (L11-CH2), 126.26 (5000-CH), 116.18
(8000-CH), 111.55 (3000-C), 100.29 (10-CH), 95.48 (100-CH), 88.19 (400-
CH), 86.56 (11-CH), 85.19 (12-CH), 83.79 (5-CH), 77.62 (3-CH),
76.45 (13-CH), 74.25 (300-C), 73.82 (6-C), 72.19 (L1-CH2), 70.89
(20-CH), 68.19 (50-CH), 68.09 (9-CH2), 64.89 (500-CH), 63.54 (30-
CH), 61.61 (10-CH), 61.20 (13000-CH2), 60.96 (L10-CH2), 55.44 (L3-
CH2), 53.03 (L5-L8-CH2), 49.89 (300O-CH3), 49.18 (11000-CH2), 45.21
(2-CH), 43.93 (7-CH2), 41.69 (4-CH), 41.00 (30N-(CH3)2), 36.09
(200-CH2), 34.76 (9N-CH3), 31.09 (40-CH2), 27.87 (L2-CH2), 27.17
(6-CH3), 26.57 (8-CH3), 22.42 (14-CH2), 22.36 (300-CH3), 21.99
(8-CH3), 21.87 (20-CH3), 21.76 (50-CH3), 18.80 (500-CH3), 15.17 (2-
CH3), 14.87 (15000-CH3), 14.75 (14000-CH3), 14.18 (12-CH3), 11.66
(4-CH3), 10.70 (15-CH3), 5.55 (10-CH3).
MS(m/z): calcd for MH+: 370.46, found: 369.6 (68.45%), LC-UV
(91.7%).
HRMS calcd for C21H28N3O3 (M+H)+ 370.2125; found 370.2114.
1H NMR (500 MHz, DMSO) d: 8.66 (1H, 2000-H. s), 8.17 (1H, 5000-H,
d), 7.76 (1H, 8000-H, d), 7.95 (1H, 7000-H, dd), 6.70 (1H, L12-CH, d), 6.40
(1H, L11-CH, dt), 4.41 (1H, 11000-CH, q), 4.24 (2H, 13000-CH2, q), 3.11
(2H, L10-CH2, d), 2.77 (4H, L5, L6-CH2, ov), 2.39 (4H, L7, L8-CH2,
ov), 1.37 (2H, 15000-CH2, dd), 1.29 (3H, 14000-CH3, t).
IR (KBr, cmꢁ1) 3437, 1969, 2825, 1728, 1634, 1609, 1552, 1478,
1456, 1380, 1276, 1257, 1170, 1110, 1092, 1046, 1013, 982, 959,
899.
13C NMR (125 MHz, DMSO) d: 172.61 (4000-CO), 164.53 (12000-CO),
148.49 (2000-CH), 137.68 (9000-C), 133.25 (6000-C), 130.73 (L12-CH),
129.94 (7000-CH), 128.41 (10000-C), 128.41 (L11-CH), 123.86 (5000-CH),
117.56 (8000-CH), 110.05 (3000-C), 60.53 (L10-CH2), 59.61 (13000-CH2),
53.24 (L7, L8-CH2), 47.86 (11000-CH), 45.08(L5, L6-CH2), 14.35 (15000-
CH3), 14.25 (14000-CH3).
4.27. 4’’-O-[(3-{4-[(2E)-3-(3-carboxy-1-ethyl-4-oxo-1,4-dihydro-
6-quinolinyl)-2-propen-1-yl]-1-piperazinyl}propyl)-9-deoxo-
9a-methyl-9a-aza-9a-homoerythromycin A (39)
To the solution of 13 (0.1145 g. 0.093 mmol) in MeOH (7.5 mL)
was added solution of K2CO3 (0.232 g. 1.68 mmol) in water
(2.5 mL) and heated to 50 °C for 5 h. Reaction mixture was stirred
at rt over night. MeOH was evaporated and to the residue DCM
(20 mL) and water (15 mL) were added. Layers were separated
and water layer extracted with DCM (2 ꢀ 20 mL). The organic ex-
tract was dried (K2CO3) and concentrated under vacuum to afford
title product 13 (0.0982 g. yield 93.3%). Product was dissolved in
EtOAc. N-Hexane was added and precipitate was filtered off to af-
ford pure product (0.0693 g. yield 65.7%).
IR (KBr, cmꢁ1) 3417, 3292, 2942, 2850, 1725, 1625, 1609, 1588,
1496, 1496, 1453, 1385, 1453, 1385, 1335, 1307, 1224, 1184, 1161,
1125, 1087, 1031, 995, 937.
4.26. 20-O-Acetyl-11-O,12-O-carbonyl-4’’-O-{3-[4-((2E)-3-{1-
ethyl-3-[(ethyloxy)carbonyl]-4-oxo-1,4-dihydro-6-quinolinyl}-
2-propen-1-yl)-1-piperazinyl]propyl}-9-deoxo-9a-methyl-9a-
aza-9a-homoerythromycin A (38)
To the solution of 36 (0.355 g. 0.41 mmol) in DCM (5 mL) was
added Dess–Martin periodinane (0.209 g. 0.49 mmol). Reaction
mixture was stirred at rt for 3 h. According to TLC performed in
DCM/MeOH/NH4OH = 90/9/0.5 conversion was complete. Precipi-
tate was filtered off and to the residue 35 (0.3 g. 0.81 mmol). NaB-
H(AOc)3 (0.172 g. 0.81 mmol) and ZnCl2 (0.056 g. 0.41 mmol) were
added. Reaction mixture was stirred at rt over night. Solvent was
evaporated and residue (1.0863 g) was purified by flash chroma-
tography on a 20 g silica gel column. Product was eluted with a
system of solvents EtOAc/n-hexane/TEA 100/100/20, after warded
38 (0.14 g, Y = 28%) as white crystalline product.
MS(m/z): calcd for MH+: 1130.46, found: 1130.8 (94.63%). LC-
UV (97.15%).
HRMS calcd for
1130.7212.
C
60H100N5O15 (M+H)+ 1130.7210; found
1H NMR (500 MHz, DMSO) d: 8.74 (1H, 2000-H, s), 8.47 (1H, 5000-H,
d), 7.87 (1H, 7000-H, dd), 7.58 (1H, 8000-H, d), 6.67 (2H, L12-CH, d), 6.47
(1H, L11-CH, dt), 5.12 (1H, 100-H, dd), 4.72 (1H, 13-H, ov), 4.52 (1H,
10-H, d), 4.37 (2H, 11000-CH, q), 4.29 (1H, 500-H, ov), 4.24 (1H, 3-H,
ov), 3.65 (1H, 11-H, s), 3.64 (2H, L1-CH2, ov), 3.75 (1H, 50-H, m),
3.61 (1H, 5-H, d), 3.32 (3H, 300O-CH3, s), 3.22 (L10-CH2, ov), 3.19
(1H, 20-H, ov), 2.77 (1H, 400-H, ov), 2.74 (1H, 2-H, ov), 2.67 (1H,
10-H, ov), 2.52 (1H, 9a-H, ov), 2.52 (1H, 30-H, ov), 2.52 (8H, L5, L6,
L7, L8-CH2, ov), 2.44 (2H, L3-CH2, ov), 2.37 (1H, 200a-H, d), 2.27
(6H, 30N-(CH3)2, ov), 2.31 (3H, 9N-CH3, ov), 2.03 (1H, 9b-H, t),
2.00 (1H, 8-CH, ov), 1.95 (1H, 4-H, ov), 1.89 (1H, 14a-H, m), 1.80
(1H, 7a-H, d), 1.77 (2H, L2-CH2, ov), 1.64 (1H, 40a-H, m), 1.59 (3H,
15000-CH2, t), 1.50 (1H, 200b-H, dd), 1.43 (1H, 14b-H, ov), 1.32 (3H,
6-CH3, ov), 1.31 (3H, 500-CH3, ov), 1.27 (1H, 7b-H, ov), 1.24
(3H, 50-CH3, ov), 1.19 (1H, 40b-H, ov), 1.19 (3H, 300-CH3, ov), 1.17
(3H, 2-CH3, ov), 1.09 (3H, 10-CH3, ov), 1.09 (3H, 12-CH3, ov), 1.04
(3H, 4-CH3, ov), 0.90 (8-CH3, d), 0.88 (15-CH3, t).
MS(m/z): calcd for MH+: 1227.55, found: 1226.7 (73.44%).
HRMS calcd for
1226.7442.
C
65H104N5O17 (M+H)+ 1226.7422; found
1H NMR (500 MHz, DMSO) d: 8.47 (1H, 2000-H, ov), 8.47 (1H, 5000-
H, ov), 7.75 (1H, 7000-H, dd), 7.45 (1H, 8000-H, d), 6.65 (2H, L12-CH, d),
6.40 (1H, L11-CH, dt), 5.06 (1H, 100-H, dd), 4.89 (1H, 13-H, ov), 4.75
(1H, 20-H, dd), 4.55 (1H, 10-H, d), 4.25 (2H, 11000-CH, q), 4.25 (1H, 500-
H, ov), 4.43 (1H, 11-H, s), 4.42 (1H, 3-H, ov), 4.40 (2H, 13000-CH2, ov),
3.67 (2H, L1-CH2, ov), 3.65 (1H, 50-H, m), 3.54 (1H, 5-H, d), 3.33 (3H,
300O-CH3, s), 3.22 (L10-CH2, d), 2.85 (1H, 2-H, ov), 2.84 (1H, 10-H,
ov), 2.78 (1H, 400-H, ov), 2.75 (1H, 30-H, ov), 2.58 (8H, L5, L6, L7,
L8-CH2, ov), 2.44 (2H, L3-CH2, ov), 2.39 (1H, 9a-H, ov), 2.30 (1H,
200a-H, d), 2.26 (6H, 30N-(CH3)2, ov), 2.21 (3H, 9N-CH3, ov), 2.07
(1H, 9b-H, t), 2.07 (3H, 20-CH3, s), 1.94 (1H, 8-CH, ov), 1.84 (1H,
4-H, ov), 1.81 (2H, L2-CH2, ov), 1.79 (1H, 14a-H, m), 1.70 (1H, 40a-
H, m), 1.58 (1H, 7a-H, d), 1.55 (3H, 15000-CH2, t), 1.51 (1H, 200b-H,
dd), 1.51 (1H, 14b-H, ov), 1.42 (3H, 14000-CH3, t), 1.41 (3H, 12-CH3,
ov), 1.33 (1H, 7b-H, ov), 1.30 (3H, 500-CH3, ov), 1.27 (3H, 6-CH3,
ov), 1.27 (1H, 40b-H, ov), 1.26 (3H, 300-CH3, ov), 1.21 (3H, 50-CH3,
ov), 1.19 (3H, 2-CH3, ov), 1.05 (3H, 10-CH3, ov), 0.94 (3H, 4-CH3,
ov), 0.92 (8-CH3, d), 0.88 (15-CH3, t).
13C NMR (125 MHz, DMSO) d: 178.28 (1-CO), 178.00 (4000-CO),
167.20 (12000-CO), 147.50 (2000-CH), 138.18 (9000-C), 131.04 (L12
-
CH2), 131.50 (7000-CH), 129.30 (L11-CH2), 125.00 (5000-CH), 116.53
(8000-CH), 102.45 (10-CH), 94.88 (100-CH), 87.81 (400-CH), 73.92
(11-CH), 74.31 (12-CH), 83.14 (5-CH), 77.86 (3-CH), 77.53 (13-
CH), 73.83 (300-C), 73.71 (6-C), 72.72 (L1-CH2), 71.05 (20-CH),
67.98 (50-CH), 70.12 (9-CH2), 64.81 (500-CH), 65.36 (30-CH), 62.40
(10-CH), 61.00 (L10-CH2), 52.00 (L3-CH2), 53.15 (L5-L8-CH2), 49.62
(300O-CH3), 49.62 (11000-CH2), 45.26 (2-CH), 42.32 (7-CH2), 42.07
(4-CH), 40.34 (30N-(CH3)2), 35.49 (200-CH2), 36.31 (9N-CH3), 28.77
(40-CH2), 27.57 (L2-CH2), 27.57 (6-CH3), 26.80 (8-CH3), 21.26
(14-CH2), 21.88 (300-CH3), 21.98 (8-CH3), 21.67 (50-CH3), 18.47
(500-CH3), 14.71 (2-CH3), 14.72 (15000-CH3), 16.27 (12-CH3), 9.11
(4-CH3), 11.24 (15-CH3), 7.42 (10-CH3).
13C NMR (125 MHz, DMSO) d:177.57 (1-CO), 174.52 (4000-CO),
170.28 (20-CO), 166.24 (12000-CO), 153.73 (11,12-CO), 148.49 (2000-
CH), 138.15 (9000-C), 134.23 (6000-C), 132.13 (L12-CH2), 130.33 (7000-

´
S. Kapic et al. / Bioorg. Med. Chem. 19 (2011) 7281–7298
7298
IR (KBr, cmꢁ1) 2978, 2933, 2799, 1718, 1695, 1625, 1608, 1585,
Acknowledgments
1550, 1495, 1455, 1419, 1392, 1365, 1342 1310, 1288, 1248, 1226,
1172, 1135, 1085, 1029, 995 937.
ˇ
The Authors thank Ana Cikoš, Biserka Metelko and Dubravka
Gembarovski from the Structure and Analysis Group for recorded
data. We wish to thank Goran Kragol and Gorjana Lazarevski for
their scientific insights during this investigation and constructive
advisees. We would also like to thank Višnja Majzel for excellent
technical assistance.
4.28. 4’’-O-[(3-{4-[3-(3-carboxy-1-ethyl-4-oxo-1,4-dihydro-6-
quinolinyl)propyl]-1-piperazinyl}propyl)-9-deoxo-9a-methyl-
9a-aza-9a-homoerythromycin A (40)
Compound 14 (0.05 g. 0.04 mmol) was dissolved in MeOH
(20 mL) and catalyst (0.01 g. Pd/C 10%) was added. Reaction mix-
ture was hydrogenated (p = 2.2 bar. t = 25 °C) over night. Catalyst
was filtered off and solvent evaporated yielding title product 15
(0.045 g. yield 90.0%). Product was dissolved in EtOAc. n-Hexane
was added and precipitate was filtered off to afford pure product
(0.0386 g. yield 78.0%).
References and notes
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MS(m/z): calcd for MH+: 1132.48, found: 1132.7 (97.12%).
HRMS calcd for
1132.7377.
C
60H102N5O15 (M+H)+ 1132.7367; found
1H NMR (500 MHz, DMSO) d: 8.78 (1H, 2000-H, s), 8.36 (1H, 5000-H,
d), 7.69 (1H, 7000-H, dd), 7.56 (1H, 8000-H, d), 5.09 (1H, 100-H, dd), 4.72
(1H, 13-H, ov), 4.55 (1H, 10-H, d), 4.40 (2H, 11000-CH, q), 4.25 (1H, 500-
H, ov), 4.19 (1H, 3-H, ov), 3.73 (1H, 50-H, m), 3.71 (1H, 11-H, s), 3.63
(2H, L1-CH2, ov), 3.61 (1H, 5-H, d), 3.32 (3H, 300O-CH3, s), 3.30 (1H,
20-H, ov), 2.83 (2H, L12-CH, ov), 2.83 (1H, 30-H, ov), 2.77 (1H, 400-H,
ov), 2.74 (1H, 2-H, ov), 2.72 (1H, 10-H, ov), 2.60 (8H, L5, L6, L7,
L8-CH2, ov), 2.56 (1H, 9a-H, ov), 2.50 (2H, L3-CH2, ov), 2.46 (6H,
30N-(CH3)2, ov), 2.46 (L10-CH2, ov), 2.35 (3H, 9N-CH3, ov), 2.33
(1H, 200a-H, d), 2.11 (1H, 9b-H, t), 2.00 (1H, 8-CH, ov), 1.96 (1H,
4-H, ov), 1.92 (1H, L11-CH, ov), 1.87 (1H, 14a-H, m), 1.81 (2H, L2-
CH2, ov), 1.76 (1H, 40a-H, m), 1.73 (1H, 7a-H, d), 1.60 (3H, 15000-
CH2, t), 1.52 (1H, 200b-H, dd), 1.45 (1H, 14b-H, ov), 1.32 (3H,
6-CH3, ov), 1.31 (1H, 7b-H, ov), 1.30 (3H, 500-CH3, ov), 1.25 (1H,
40b-H, ov), 1.23 (3H, 300-CH3, ov), 1.20 (3H, 50-CH3, ov), 1.17 (3H,
2-CH3, ov), 1.12 (3H, 10-CH3, ov), 1.10 (3H, 12-CH3, ov), 1.03 (3H,
4-CH3, ov), 0.92 (8-CH3, d), 0.89 (15-CH3, t).
Overcome Resistance to Erythromycin
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13C NMR (125 MHz, DMSO) d:178.68 (1-CO), 178.39 (4000-CO),
167.28 (12000-CO), 147.54 (2000-CH), 140.54 (6000-C), 137.57 (9000-C),
134.79 (7000-CH), 126.73 (10000-C), 126.38 (5000-CH), 116.37 (8000-CH),
108.90 (3000-C), 102.06 (10-CH), 94.89 (100-CH), 87.99 (400-CH),
83.20 (5-CH), 77.92 (3-CH), 77.34 (13-CH), 74.37 (12-CH), 73.91
(300-C), 73.90 (6-C), 73.64 (11-CH), 72.62 (L1-CH2), 70.94 (20-CH),
70.00 (9-CH2), 67.40 (50-CH), 65.38 (30-CH), 64.75 (500-CH), 62.82
(10-CH), 57.14 (L10-CH2), 54.92 (L3-CH2), 52.27 (L5-L8-CH2),
49.68 (11000-CH2), 49.61 (300O-CH3), 45.29 (2-CH), 42.20 (7-CH2),
42.20 (4-CH), 40.00 (30N-(CH3)2), 36.37 (9N-CH3), 35.45 (200-CH2),
32.99 (L12-CH2), 29.96 (40-CH2), 27.63 (L11-CH2), 27.24
(6-CH3), 27.16 (L2-CH2), 26.72 (8-CH3), 21.99 (8-CH3), 21.73 (50-
CH3), 21.73 (300-CH3), 21.35 (14-CH2), 18.44 (500-CH3), 16.35 (12-
CH3), 14.73 (15000-CH3), 14.72 (2-CH3), 11.22 (15-CH3), 8.38 (4-
CH3), 7.52 (10-CH3).
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1383, 1274, 1170, 1109, 1084, 1060, 1014, 959.
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serum. Double dilutions of tested compounds were prepared
using TECAN Genesis 150.37 Bacteria were grown on appropriate
agar plates (by Becton Dickinson, USA)—Columbia agar with 5%
sheep blood for Streptococci and M. catarrhalis, Mueller-Hinton
chocolate agar for H. influenzae and Mueller–Hinton agar for
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