Novel ureas and thioureas of 15-membered azalides with antibacterial activity against key respiratory pathogens

Article abstract of DOI:10.1016/j.ejmech.2009.02.001

The new ureas and thioureas of 15-membered azalides, N″-substituted 9a-(N′-carbamoyl-γ-aminopropyl) (4), 9a-(N′-thiocarbamoyl-γ-aminopropyl) (6), 9a-[N′-(β-cyanoethyl)-N′-(carbamoyl-γ-aminopropyl)] (8) and 9a-[N′-(β-cyanoethyl)-N′-(thiocarbamoyl-γ-aminopr

Full text of DOI:10.1016/j.ejmech.2009.02.001

European Journal of Medicinal Chemistry 44 (2009) 3459–3470
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Novel ureas and thioureas of 15-membered azalides with antibacterial activity
against key respiratory pathogens
,
b
c
c
a
ˇ ´ a
´
´
ˇ ´
ꢀ
*
´
Mirjana Bukvic Krajacic , Predrag Novak , Miljenko Dumic , Mario Cindric , Hana Cipcic Paljetak ,
a
ꢀ
´
Nedjeljko Kujundzic
a GlaxoSmithKline Research Centre Zagreb, Prilaz baruna Filipovi´ca 29, HR-10000 Zagreb, Croatia
b Department of Analytical Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102a, HR-10000 Zagreb, Croatia
c PLIVA – CROATIA Ltd., Research and Development, Prilaz baruna Filipovi´ca 29, HR-10000 Zagreb, Croatia
a r t i c l e i n f o
a b s t r a c t
The new ureas and thioureas of 15-membered azalides, N00-substituted 9a-(N0-carbamoyl-
g
g
-aminop
-aminop
Article history:
ropyl) (4), 9a-(N0-thiocarbamoyl-
g
-aminopropyl) (6), 9a-[N0-(
b
-cyanoethyl)-N0-(carbamoyl-
Received 18 September 2008
Received in revised form
27 January 2009
ropyl)] (8) and 9a-[N0-(
b
-cyanoethyl)-N0-(thiocarbamoyl-
g
-aminopropyl)] (10) of 9-deoxo-9-dihydro-9a-
aza-9a-homoerythromycin A (2), were synthesized and structurally characterized by NMR and IR
spectroscopic methods and mass spectrometry. The new compounds were evaluated in vitro against
a panel of erythromycin susceptible and erythromycin-resistant Gram-positive and Gram-negative
bacterial strains. These compounds displayed an excellent overall antibacterial in vitro activity against
erythromycin sensitive Gram-positive strains, Streptococcus pneumoniae, Streptococcus pyogenes, Staph-
ylococcus aureus, and good against negative strains, Moraxella catarrhalis and Haemophilus influenzae.
In addition, several ureas with naphthyl substituents (4f, 4g, 4h) showed better activity in comparison to
azithromycin against inducible resistant S. pyogenes. Ureas with naphthyl substituents 4g, 4h and
thiourea 8h displayed moderate activity against constitutively resistant S. pneumoniae.
Accepted 7 February 2009
Available online 20 February 2009
Keywords:
Azalides
Ureas
Thioureas
Structure elucidation
Antibacterial activity
Ó 2009 Elsevier Masson SAS. All rights reserved.
1. Introduction
macrolides (M), lincosamides (L), and streptogramine B (SB), the so-
called MLSB phenotype [4]. The continuing emergence of multi-
Macrolides have a long history as effective therapeutic agents
for treating infectious diseases [1,2]. They are still in the centre of
interest of many research groups and pharmaceutical companies
and much effort is directed toward the discovery of new macrolide
antibiotics by chemical modification of the existing classes of
natural derivatives. The goal is to obtain novel therapeutic agents
having an improved overall biological profile with a special
emphasis on resistant bacterial strains. Of particular interest are
azalides, semisynthetic derivatives of erythromycin A [1,3], which
were found to display a wide antimicrobial spectrum and the ability
to concentrate within host cells with high accumulation ratios. The
predominant mechanisms of resistance to macrolides in Gram-
positive microorganisms are target site modifications by methyla-
tion that prevents the binding of the antibiotic to the ribosome
(encoded by the erm gene), and efflux mechanisms, mediated by
the mef (streptococci) and msr (staphylococci) genes. The methyl-
ation of the ribosomal RNA bases leads to cross-resistance to
drug-resistant Gram-positive and Gram-negative pathogens
imposes a serious threat to the health-care community and inten-
sifies the search for new and more effective agents in order to
overcome this problem. Recently, crystal structures of some ribo-
some–macrolide complexes [5,6] and NMR studies [7] have thrown
new light on understanding the principles of how these antibiotics
interact with their targets and thus can be useful in the process of
designing compounds with bioactivity. Recently published novel
14- to 16-membered 11-azalides and 16-membered 11,12-diazalide,
starting from 16-membered macrolides, exhibited strong antibac-
terial activity against inducible resistant bacteria Streptococcus
pneumoniae [8,9].
In our previous papers we have reported the synthesis and
antibacterial activity of novel sulfonylureas of 15-membered aza-
lides [10] and conjugates of azithromycin and sulfonamides [11]
which showed significant improvements in activity against induc-
ible resistant Streptococcus pyogenes in comparison with macrolide
antibiotic azithromycin. These results encouraged us to continue
and extend our investigation on a series of related compounds. The
main goal of this research was to expand the range of antimicrobial
activity, especially against MLSB and efflux resistant S. pyogenes and
* Corresponding author. Tel.: þ385 1 6051165; fax: þ385 1 6051001.
ˇ ´
E-mail address: mirjana.2.bukvic-krajacic@gsk.com (M. Bukvic´ Krajacic).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.02.001

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M. Bukvi´c Krajaci´c et al. / European Journal of Medicinal Chemistry 44 (2009) 3459–3470
3460
S. pneumoniae strains by replacing sulfonylcarbamoyl group at the
propyl chain with carbamoyl and thiocarbamoyl groups. We believe
that this could be a step forward in the discovery of novel bioactive
macrolide compound. Hence, the present paper describes the
synthesis, structure elucidation, acid stability and antibacterial in
vitro evaluation of new ureas and thioureas of 15-membered aza-
intermediates, 9a-(
oethyl)- -aminopropyl] derivative 7 were prepared by Michael
addition of acrylonitrile and catalytic hydrogenation with PtO2
according to procedure described in the previous paper [10].
g b-cyan
-aminopropyl) derivative 3 and 9a-[N0-(
g
N00-Aryl substituted 9a-(N0-carbamoyl-
g
-aminopropyl) (4), 9a-(N0-
-cyanoethyl)-N0-(car-
-cyanoethyl)-N0-(thioc
g-aminopropyl)] (10) derivatives were obtained by the
thiocarbamoyl-
bamoyl-
-aminopropyl)] (8) and 9a-[N0-(
arbamoyl-
g b
-aminopropyl) (6), 9a-[N0-(
lides derived from 2, e.g. N00-substituted N0-(carbamoyl-
ropyl) (4), N0-(thiocarbamoyl- -aminopropyl) (6), N0-(
oethyl)-N0-(carbamoyl- -aminopropyl) (8) and N0-(
-cyanoethyl)-
N0-(thiocarbamoyl-
-aminopropyl) (10) moieties (Scheme 1).
g-aminop
g
b
g
b
-cyan
g
b
reaction of corresponding isocyanates and thioisocyanates with
amines 3 and 7 in high yield. Reaction proceeded smoothly in an
aprotic solvent and at room temperature to form less polar prod-
ucts (Scheme 1).
g
2. Results and discussion
2.1. Chemistry
2.2. Structural characterization
The addition of isocyanates or thiocyanates to primary and
secondary amines is an efficient method for the preparation of
substituted ureas and thioureas, respectively.[12] The key
The structures of all synthesized compounds were determined
by IR and NMR spectroscopies and mass spectrometry. In the IR
spectra of the novel ureas 4 and 6 and thioureas 8 and 10 new
Scheme 1. Synthesis of novel ureas and thioureas of 15-membered azalides. Reagents and conditions: i, acrylonitrile, 60 ꢀC, 10 h; ii, H2/5% Pt/C, 5% hydrochloric acid, 4 bar, r.t., 40 h;
iii, alkyl or aryl isocyanate/isothiocyanate, CH2Cl2, room temperature, 1 h; iv, 1 M hydrochloric acid, r.t.; v, 1 eq acrylonitrile, methanol, reflux, 10 h.

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3461
bands were observed at approximately 1681–1645 cmꢁ1 and
845.5851
1549–1557 cmꢁ1 which corresponded to ureido group C]O
stretching vibrations. The bands at approximately 1537–1552 cmꢁ1
were diagnostic for the presence of a thioureido group C]S. In the
IR spectrum absorption bands of compounds 8 and 10 observed at
approximately 2249 cmꢁ1 were assigned to C^N stretching
vibrations.
CN
H
N
N
The assignments of proton and carbon chemical shifts were
made by a combined use of one- (1H and APT) and two-dimensional
(gCOSY, gHSQC and gHMBC) NMR spectra. Carbon and proton
chemical shifts of all compounds are given in the Experimental
part. The appearance of new signals with respect to 2 was observed
in 13C NMR spectrum indicating the presence of carbamoyl (dC
154.1–159.4 ppm) and thiocarbamoyl (dC 180.8–183.3 ppm) groups.
274.1456
S
735.5007
N
N
OH
OH
HO
With respect to 2, additional signals at w48 ppm (CH2-
w27 ppm (CH2- ) and w47 ppm (CH2- ) as well as those at
w44 ppm (CH2-
0), w17 ppm (CH2- 0) and w120 ppm (C^N)
confirmed the presence of the -aminopropyl chain and -cyan
oethyl chain, respectively. The substitutions at 9a-N and C- -NH2
were confirmed by changes in the chemical shifts of carbons at
positions 9 and 10 of the azalide aglycon ring and C- of the propyl
chain in comparison with the parent compounds 2, 3 and 7.
Changes in chemical shifts of CH2- carbons in ureas 4 and 6 and
a),
OH
b
a
g
b
O
O
O
O
g
b
g
O
O
g
+
OH
g
577.4064
M + H
thioureas 8 and 10 indicated structural differences imposed by the
inserted ureido and thioureido groups (at 38–39 ppm and
43–44 ppm, respectively). The presence of alkyl and aryl substitu-
ents was confirmed by characteristic singlets observed in the
regions 118–142 ppm in the carbon spectrum and 7.0–8.3 ppm in
the proton spectrum. In the HMBC spectra of the ureas/thiourea the
observed cross-peaks between carbamoyl/thiocarbamoyl groups
and three pairs of methylene protons in the propyl and cyanoethyl
(559.3958)
O
420.2961
m/z 1008.6307
(402.2856,
384.2750,
366.2644)
Fig. 1. Proposed fragmentation pattern of the thiourea 10d based on the accurate mass
MS/MS experiments with theoretically calculated masses. Values in parentheses
represent the obtained loss of water after dissociation.
chains (CH2-
where substitution occurred.
g a
, CH2-a00 and CH2- 0) were indicators of the sites
derivatives which was found to be a common characteristic of
macrolide [16,17] and azalide compounds [18].
Mass measurement accuracy, as experimentally determined,
was within the specified limit for the instrument used (better than
5 ppm), in experiments performed with intact compounds, while
the results obtained by MS/MS experiments were in the range of
5 ꢂ 3.5 ppm. Deduced elemental compositions of fragment ions
with theoretically calculated masses (Fig. 1) indicated that 10d
protonated precursor ion fragmentation with m/z 1008.6318 most
likely began with a single- or a two-step fragmentation of the
complete side chain. In the first step, a cleavage of a thiocarbamoyl
group initiated dissociation (m/z 1008.6318 / 845.5901) followed
by a complete side chain elimination (m/z 845.5901 / 735.5062).
Additional support for the predicted fragmentation that occurred
through a single-step fragmentation pathway was the side chain
product ion detected at m/z 274.1441. The result of both fragmen-
tation pathways with the same outcome pointed toward the
cleavage at position 9a-N as the most preferable position for frag-
mentation, and further product ion formation after glycosidic bond
cleavages (m/z 735.5062 / 420.2937 desosamine and cladinose
and m/z 735.5062 / 577.4101 cladinose cleavage). Neutral losses of
water molecules indicated the number of labile hydroxyl groups
with maximum losses of three water molecules, m/z 420.2937 /
m/z 402.2830 / m/z 384.2742 / m/z 366.2622. Similar fragmen-
tation pattern was observed for other compounds too.
The acidic stability studies of the active N0-[(1-naph-
thyl)carbamoyl-
naphthyl)carbamoyl-
g b
-aminopropyl] 4f and N0-[( -cyanoethyl)-N0-(1-
g
-aminopropyl] 8f derivatives were carried
out in 0.01 M HCl aqueous hydrochloric acid at 37 ꢀC as a model of
artificial gastric juice. We used here LC/UV and LC/MS methods to
study kinetics of hydrolysis for ureas 4f and 8f and their degrada-
tion products. The mass spectra of the reaction mixtures after 10 h
showed only precursor ions at m/z 803.1 and 856.1, which were
indicative for the cleavage of the cladinose sugars giving decla-
dinosyl compounds 5f and 9f, respectively. No further degradation
products were observed under the studied conditions as previously
observed for azithromycin and its sulfonamido conjugates [11,15].
The regioselective hydrolysis of 4f and 8f in 1.0 M hydrochloric acid
at room temperature, furnished the decladinosyl derivatives 5f and
9f, alternatively prepared as the analytical standards.
The hydrolytic degradation of 5f and 9f followed pseudo first-
order kinetics as observed for the related compounds [9]. Reaction
rate constants (k) were determined from the exponential fit analysis
of the plot of the reactant concentration (4f and 8f) versus time. The
calculated rate constants for 50% decay (t1/2) are listed in Table 1.
The activation energies of hydrolysis of glycosidic bonds for 5f
and 9f were also determined and amounted to 91.1 kJ/mol and
Table 1
2.3. Acid stability
Pseudo first-order reaction rate constants and t1/2 values for 4f and 8f.
t/ꢀC
4f
8f
It was reported that in aqueous acidic media erythromycin
derivatives underwent intramolecular cyclization reactions [13,14]
to form inactive products. The decomposition of azithromycin [15]
and its sulfonamido conjugates [11] included only hydrolysis of the
cladinose sugar glycosidic bond leading to the inactive decladinosyl
k/minꢁ1
5.83 ꢃ 10ꢁ3
t1/2a/min
k/minꢁ1
6.41 ꢃ 10ꢁ3
t1/2a/min
37
119
108
a
Calculated according to t1/2 ¼ ln 2/k.

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M. Bukvi´c Krajaci´c et al. / European Journal of Medicinal Chemistry 44 (2009) 3459–3470
3462
88.5 kJ/mol, respectively (Fig. 2). These values were similar to those
obtained for azithromycin 105.9 kJ/mol [13] and its sulphonamide
conjugates (90.5 kJ/mol and 89.9 kJ/mol) [11].
Decladinosyl derivatives 5f and 9f, obtained by the hydrolysis in
acidic media, were tested only against panel of S. pneumoniae
strains. As we expected decladinosyl urea derivative 9f did not
show activity against tested strains. However, decladinosyl urea
derivative 5f showed significant activity against erythromycin
2.4. In vitro antibacterial activity
susceptible S. pneumoniae strain (1
mg/ml), as well as efflux resis-
tant S. pneumoniae strain (8 g/ml) comparable to azithromycin.
m
The in vitro minimum inhibitory concentrations (MICs) for ureas
4 and 8, thioureas 6, 10 and azithromycin as a selected standard,
against common pathogens are listed in Tables 2 and 3. Ureas 4 and
8 and thioureas 6 and 10 showed a significant improvement in
antibacterial activity against all tested macrolide-susceptible and
resistant bacteria (Tables 2 and 3) in comparison with carbamoyl/
thiocarbamoyl derivatives [12], sulfonylcarbamoyl derivatives [10]
and azithromycin–sulfonamide conjugates [11]. Several ureas with
naphthyl substituents (4f, 4g, 4h) were superior in vitro to the
azithromycin against inducible resistant S. pyogenes with MICs
In conclusion, the introduction of carbamoyl and thiocarbamoyl
group to the 9a position of azithromycin like azalide skeleton via
propyl linker proved to be promising method to tackle the resis-
tance problems. As a result of a preliminary optimization of an
alkyl/aryl moiety at the carbamoyl and thiocarbamoyl group,
several new ureas with naphthyl substituents (4f, 4g, 4h) have been
prepared, which showed better activity against inducible resistant
S. pyogenes in comparison to azithromycin. In acidic conditions
compounds exhibited azithromycin like stability. Novel ureas and
thioureas of 15-membered azalides showed their potential to serve
as a good platform for further investigation in order to discover
new derivatives having an improved overall biological profile with
a special emphasis on resistant bacterial strains.
2 mg/ml (Tables 2 and 3). In Tables 2 and 3 it is clearly seen that
ureas 4f, 4g and thioureas 6c, 6d, 6e and 6f possess good activity
against efflux resistant S. pyogenes, comparable to azithromycin. In
general, all tested compounds had high in vitro activity against
erythromycin susceptible Gram-positive aerobes, S. pneumoniae
and S. pyogenes (MIC ꢄ 0.125
mg/ml). Ureas 4 and 8 and thioureas 6
3. Experimental
and 10 exhibited excellent activity against susceptible Staphylo-
coccus aureus, but lacked activity against resistant S. aureus strains.
Ureas 4f, 4g and thiourea 6f also showed in vitro activity against
3.1. General methods
efflux resistant S. pneumoniae with MICs 4 mg/ml and their activities
TLC was performed on Merck 60 F254 plates using
CH2Cl2:CH3OH:NH3 (25%) ¼ 90:9:1.5 as eluents. Column chroma-
tography was performed on Merck silica gel 60 (0.043–0.060 mm).
The purity of the isolated compounds was better than 90%
according to LC/MS measurements. ESI-MS/MS spectra were
obtained on Q-TOF Micromass spectrometer equipped with the
lock-spray (Waters Corporation, Manchester, UK) connected to an
CapLC liquid chromatography system (Waters Corporation) under
the following conditions: positive ion mode, source temp 450 ꢀC,
capillary 3.4 kV, sample cone 30 V and collision energy 40 eV.
were comparable with those observed for azithromycin. Ureas 4g,
4h and 8h showed moderate activity against cMLS S. pneumoniae.
In vitro activities of ureas 4 and 8, thioureas 6 and 10 against key
community-acquired Gram-negative respiratory pathogens were
improved in comparison with sulfonylureas [10] and azithromycin–
sulfonamide conjugates [11]. Ureas 4f, 4g and 4h demonstrated
high activity against Moraxella catarrhalis. Naphthyl substituted
ureas 4f, 4g and 4h showed better activity against Gram-negative
pathogens involved in respiratory tract infections (RTIs), M. catar-
rhalis and Haemophilus influenzae than derivatives with phenyl ring
on the alkyl side chain 4b–4d. In the case of phenyl–ethyl substit-
uents in 4d and 6d the presence of thiocarbamoyl moiety seemed
to improve activity against H. influenzae, MIC 16 mg/ml and 2 mg/ml,
respectively. The urea 8 with cyanoethyl chain showed similar
antibacterial activity in comparison to the urea 4.
Surprisingly, the observed increase of antibacterial activity in
the series of ureas and thioureas 4, 6, 8 and 10 in comparison with
those of their analogs 11 and 12 [12] was opposite to the results
obtained for the sulfonylcarbamoyl derivatives 13, 14 and 15 [10,11]
where a decrease of activity was found when sulfonylcarbamoyl
moiety was further away from the azalide ring (Fig. 3).
Leucine enkephalin (C28H37N2O7) at concentration 100 pg/ml dis-
solved in the solution of acetonitrile and water (1:1, v/v) with
addition of 0.1% formic acid (v/v) was infused into the reference
sprayer as internal lock-mass standard (m/z 556.2771). Mass
concentration of 1
ml solution of analyte injected onto the column
was 0.1 g/ml (Waters Symmetry C18, 5
m
m
m 0.32 ꢃ150 mm). The
analyte was isocratically eluted over 10 min with mixture of
acetonitrile and water (8:2, v/v) with addition of 0.1% formic acid
(v/v). Flow rate was 10
mobile phase.
m
l minꢁ1 and the analyte was diluted in the
3.2. Spectroscopic measurements
-4,25
NMR experiments were carried out on a Bruker Avance DRX500
spectrometer operating at 500.13 MHz for 1H, and 125.77 MHz, for
13C, respectively, with a 5 mm diameter inverse detection probe
and a z-axis gradient coil. Standard spectral conditions were used.
The solvents were pyridine-d5 and CDCl3 and all experiments were
performed at ambient temperature. TMS was used as the internal
standard. IR spectra were recorded in KBr pellets on a Nicolet
Magna 760 FT-IR spectrometer. The number of scans was 16 and the
4f
-4,45
8f
-4,65
-4,85
-5,05
-5,25
-5,45
-5,65
-5,85
-6,05
-6,25
resolution was 4 cmꢁ1
.
3.3. General procedure for the preparation of ureas 4, 8 and
thioureas 6, 10
3,18
3,23
3,28
3,33
1/T(K)x10-3
To the solution of 3 or 7 (1.84 mmol) in dichloromethane (30 ml)
isocyanate or isothiocyanate (1.97 mmol) was added and the
reaction mixture was stirred about 1 h at the temperature 0–5 ꢀC.
Fig. 2. Arrhenius plot of temperature versus pseudo first-order reaction rates of 4fa
and 8f.

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M. Bukvi´c Krajaci´c et al. / European Journal of Medicinal Chemistry 44 (2009) 3459–3470
3463
Table 2
Antibacterial activity (MIC/m
g mlꢁ1) of carbamoyl and thiocarbamoyl analogs 4 and 6.
Compounds
X
4a
4b
4c
4d
4f
4g
4h
6b
6c
6d
6e
6f
1
O
O
O
O
O
O
O
S
S
S
S
S
R0
S. aureus ATCC 29213
S. pneumoniae
S. pneumoniae-M
2
0.25
0.5
1
0.5
1
1
0.5
0.5
1
0.5
1
0.5
ꢄ0.125
ꢄ0.125
ꢄ0.125
ꢄ0.125
ꢄ0.125
ꢄ0.125
ꢄ0.125
ꢄ0.125
ꢄ0.125
ꢄ0.125
ꢄ0.125
ꢄ0.125
ꢄ0.125
32
16
16
32
4
4
16
16
8
8
8
4
8
S. pneumoniae-cMLS
S. pyogenes
S. pyogenes-iMLS
>64
ꢄ0.125
8
32
1
16
32
16
>64
>64
>64
ꢄ0.125
8
32
2
16
16
16
>64
16
16
>64
64
>64
>64
>64
ꢄ0.125
64
ꢄ0.125
ꢄ0.125
ꢄ0.125
ꢄ0.125
ꢄ0.125
ꢄ0.125
ꢄ0.125
ꢄ0.125
ꢄ0.125
ꢄ0.125
4
4
8
1
2
2
4
2
4
2
8
8
4
4
1
2
4
4
1
2
4
4
1
2
4
4
1
2
8
8
8
4
S. pyogenes-M
16
2
8
16
8
16
2
4
8
8
M. catarrhalis ATCC 23246
H. influenzae ATCC 49247
E. faecalis ATCC 29212
E. coli ATCC 25922
0.5
1
4
0.25
2
8
0.25
2
8
ꢄ0.125
1
8
2
16
8
8
16
16
32
16
16
8
16
32
iMLS: inducible resistance to macrolide, lincosamide and streptogramin (MLS) antibiotics, cMLS: constitutive MLS resistance, M: efflux mediated macrolide resistance.
The crude product was evaporated, wherefrom by column chro-
matography on silica gel using solvent system CH2Cl2:CH3OH:NH3
(25%) ¼ 90:9:1.5 pure compound was obtained.
(C-40), 68.3 (C-50), 96.1 (C-100), 35.6 (C-200), 73.7 (C-300), 49.7 (300
OMe), 78.9 (C-400), 66.2 (C-500), 15.6 (2 Me), 10.4 (5 Me), 29.0 (6 Me),
22.7 (8 Me), 9.8 (10 Me), 18.4 (12 Me), 23.6 (50 Me), 21.6 (300 Me),
19.5 (500 Me), 49 (
(NHCONH), 42.0 (CH, a), 23.6 (CH3, b).
a-CH2); 28.2 (b-CH2), 39.1 (g-CH2), 158.8
3.3.1. 9-Deoxo-9-dihydro-9a-(N0-isopropylcarbamoyl-
aminopropyl)-9a-aza-9a-homoerythromycin A (4a)
g
-
Yield 76.2%. MS m/z: (ES): MHþ ¼ 877.2. IR (KBr) [
n
/cmꢁ1]: 3410,
3.3.2. 9-Deoxo-9-dihydro-9a-(N0-phenylcarbamoyl-
g-
2972, 2937, 1730, 1672, 1598, 1553, 1500, 1458, 1379, 1167, 1054. 1H
aminopropyl)-9a-aza-9a-homoerythromycin A (4b)
NMR (pyridine-d5)
d
3.12 (1H, H-2), 4.76 (1H, H-3), 2.52 (1H, H-4),
Yield 51.2%. MS m/z: (ES): MHþ ¼ 911.2. IR (KBr) [
n
/cmꢁ1]: 3410,
4.16 (1H, H-5), 1.95, 1.6 (2H, H-7), 2.23 (1H, H-8), 2.73; 2.24 (2H, H-
9), 3.09 (1H, H-10), 4.22 (1H, H-11), 5.44 (1H, H-13), 1.74; 2.15 (2H,
H-14), 0.97 (3H, H-15), 5.00 (1H, H-10), 3.63 (1H, H-20), 2.71 (1H, H-
30), 2.19 (6H, 30 NMe2),1.37; 1.17 (2H, H-40), 4.01 (1H, H-50), 5.29 (1H,
H-100), 2.45; 1.53 (2H, H-200), 3.52 (3H, 300 OMe), 3.31 (1H, H-400), 4.65
(1H, H-500), 1.37 (3H, 2 Me), 1.58 (3H, 4 Me), 1.76 (3H, 6 Me), 0.95
(1H, H-8 Me), 1.39 (3H, 10 Me), 1.40 (3H, 12 Me), 1.16 (3H, 50 Me),
2972, 2937, 1730, 1672, 1598, 1553, 1500, 1458, 1379, 1167, 1054,
897.753. 1H NMR (pyridine-d5)
d 3.13 (1H, H-2), 4.76 (1H, H-3), 2.51
(1H, H-4), 4.16 (1H, H-5), 1.92; 1.60 (2H, H-7), 2.24 (1H, H-8), 2.73;
2.23 (2H, H-9), 3.09 (1H, H-10), 4.20 (1H, H-11), 5.43 (1H, H-13),
2.17, 1.84 (2H, H-14), 0.95 (3H, H-15), 4.98 (1H, H-10), 3.62 (1H, H-
20), 2.70 (1H, H-30), 2.17 (6H, 30 NMe2),1.41; 1.15 (2H, H-40), 3.99 (1H,
H-50), 5.26 (1H, H-100), 2.43; 1.52 (2H, H-200), 3.50 (3H, 300 OMe), 3.31
(1H, H-400), 4.64 (1H, H-500), 1.36 (3H, 2 Me), 1.59 (3H, 4 Me), 1.75
(3H, 6 Me), 0.95 (1H, H-8 Me), 1.37 (3H, 10 Me), 1.40 (3H, 12 Me),
1.33 (3H, 300 Me), 1.68 (3H, 500 Me), 3.23; 2.78 (2H,
-CH2), 3.43; 3.37 (2H, -CH2), 4.24 (1H, isopropyl, CH, a), 1.15 (3H,
isopropyl, CH3, b); 13C NMR (pyridine-d5)
177.7 (C-1), 45.5 (C-2),
a-CH2), 1.95 (2H,
b
g
d
1.35 (3H, 50 Me),1.32 (3H, 300 Me),1.69 (3H, 500 Me), 3.26; 2.75 (2H,
CH2), 1.96; (2H, -CH2), 3.45; 3.39 (2H, -CH2), 7.88 (2H, phenyl, b),
7.30 (2H, phenyl, c), 6.98 (1H, phenyl, d), 6.52 (NH), 9.16 (NH); 13C
NMR (pyridine-d5) 177.7 (C-1), 45.5 (C-2), 79.5 (C-3), 41.9 (C-4),
a-
79.3 (C-3), 42.0 (C-4), 84.1 (C-5), 74.7 (C-6), 42 (C-7), 28 (C-8), 64 (C-
9), 61 (C-10), 75.7 (C-11), 75.4 (C-12), 77.9 (C-13), 22.4 (C-14), 11.6
(C-15), 103.6 (C-10), 71.8 (C-20), 65.8 (C-30), 40.6 (30 NMe2), 30.6
b
g
d
Table 3
Antibacterial activity (MIC/m
g mlꢁ1) of carbamoyl and thiocarbamoyl analogs 8 and 10.
Compounds
X
8a
8b
8c
8d
8f
8g
8h
10b
10c
10d
10e
10f
1
O
O
O
O
O
O
O
S
S
S
S
S
R0
S. aureus ATCC 29213
S. pneumoniae
S. pneumoniae-M
S. pneumoniae-cMLS
S. pyogenes
S. pyogenes-iMLS
4
1
2
4
1
1
2
2
1
1
1
4
0.5
ꢄ0.125
ꢄ0.125
ꢄ0.125
ꢄ0.125
ꢄ0.125
ꢄ0.125
ꢄ0.125
ꢄ0.125
ꢄ0.125
ꢄ0.125
ꢄ0.125
ꢄ0.125
ꢄ0.125
32
32
16
64
ꢄ0.125
16
8
64
16
16
32
ꢄ0.125
16
8
32
16
ꢄ0.125
8
32
16
32
64
ꢄ0.125
8
32
32
ꢄ0.125
8
16
64
ꢄ0.125
32
32
4
8
>64
ꢄ0.125
32
32
0.5
4
>64
ꢄ0.125
16
32
4
8
32
32
>64
ꢄ0.125
32
64
16
32
64
>64
64
>64
ꢄ0.125
32
32
4
16
>64
>64
64
64
ꢄ0.125
ꢄ0.125
ꢄ0.125
8
8
16
8
8
4
S. pyogenes-M
8
0.5
2
16
32
16
2
4
32
16
16
4
4
16
16
M. catarrhalis ATCC 23246
H. influenzae ATCC 49247
E. faecalis ATCC 29212
E. coli ATCC 25922
0.5
4
32
8
0.5
4
16
8
1
2
16
32
1
4
32
16
ꢄ0.125
8
32
8
1
8
2
64
16
iMLS: inducible resistance to macrolide, lincosamide and streptogramin (MLS) antibiotics, cMLS: constitutive MLS resistance, M: efflux mediated macrolide resistance.

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M. Bukvi´c Krajaci´c et al. / European Journal of Medicinal Chemistry 44 (2009) 3459–3470
3464
H
H
N R1
N R1
X
X
NH
N
CN
H
N R1
X
N
N
N
N
O
N
O
N
O
OH
HO
OH
HO
OH
HO
HO
HO
HO
OH
OH
OH
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
OH
OH
OH
8
X=O
O
4 X=O
6 X=S
O
O
11 X=O
12 X=S
10 X=S
Antibacterial activity increased
R
R
H
H
N SO2
N SO2
O
O
NH
N
R
CN
H
N SO2
O
N
N
N
OH
HO
N
O
N
O
N
O
OH
HO
OH
HO
HO
HO
HO
OH
O
OH
OH
O
O
O
O
O
O
O
O
O
O
O
O
O
O
OH
OH
OH
13
14
15
O
O
O
Antibacterial activity increased
Fig. 3. Antibacterial activities of urea and thiourea derivatives of 15-membered azalides in comparison to sulfonylurea analogs.
84.1 (C-5), 74.7 (C-6), 41.7 (C-7), 29.1 (C-8), 64 (C-9), 64 (C-10), 75.9
(C-11), 73.7 (C-12), 77.9 (C-13), 22.4 (C-14), 11.5 (C-15), 103.6 (C-10),
71.8 (C-20), 65.8 (C-30), 40.5 (30 NMe2), 30.4 (C-40), 68.3 (C-50), 96.2
(C-100), 35.7 (C-200), 75.4 (C-300), 49.7 (300 OMe), 78.8 (C-400), 66.2 (C-
500), 15.7 (2 Me), 10.4 (4 Me), 28.3 (6 Me), 22.6 (8 Me), 9.6 (10 Me),
103.6 (C-10), 71.8 (C-20), 65.8 (C-30), 40.6 (30 NMe2), 30.7 (C-40), 68.3
(C-50), 96.2 (C-100), 35.6 (C-200), 73.7 (C-300), 49.7 (300 OMe), 78.8 (C-
400), 66.6 (C-500), 15.6 (2 Me), 10.4 (4 Me), 29.0 (6 Me), 22.7 (8 Me),
9.7 (10 Me), 18.4 (12 Me), 22.0 (50 Me), 21.6 (300 Me), 19.5 (500 Me), 49
(a
-CH2); 29.2 (
a), 128.7 (phenyl, c), 127.8 (phenyl, b), 127.0 (phenyl, d), 44.3
(a
00-CH2).
b-CH2), 39.4 (g-CH2), 159.4 (NHCONH),141.9 (phenyl,
18.4 (12 Me), 22.0 (50 Me), 19.5 (300 Me), 21.6 (500 Me), 49.8 (
29.2 ( -CH2), 39.0 ( -CH2), 156.5 (NHCONH), 141.9 (phenyl, a), 129.2
a-CH2);
b
g
(phenyl, c), 121.7 (phenyl, d), 118.9 (phenyl, b).
3.3.4. 9-Deoxo-9-dihydro-9a-(N0-phenylethylcarbamoyl-
aminopropyl)-9a-aza-9a-homoerythromycin A (4d)
g-
3.3.3. 9-Deoxo-9-dihydro-9a-(N0-benzylcarbamoyl-
aminopropyl)-9a-aza-9a-homoerythromycin A (4c)
g-
Yield 53.2%. MS m/z: (ES): MHþ ¼ 939.3. IR (KBr) [
n
/cmꢁ1]: 3444,
Yield 47.2%. MS m/z: (ES): MHþ ¼ 925.2. IR (KBr) [
n
/cmꢁ1]: 3410,
2972, 2937, 1729, 1672, 1598, 1553, 1500, 1458, 1379, 1168. 1H NMR
(pyridine-d5) d 2.86 (1H, H-2), 4.19 (1H, H-3), 2.1 (1H, H-4), 3.64
2972, 2937, 1730, 1672, 1598, 1553, 1500, 1458, 1379, 1167; 1H NMR
(pyridine-d5)
d
3.12 (1H, H-2), 4.77 (1H, H-3), 2.53 (1H, H-4), 4.17
(1H, H-5), 2.02; 1.74 (2H, H-7), 2.04 (1H, H-8), 2.7; 2.19 (2H, H-9),
2.85 (1H, H-10), 3.74 (1H, H-11), 4.69 (1H, H-13), 1.89, 1.49 (2H,
H-14), 0.89 (3H, H-15), 4.43 (1H, H-10), 3.24 (1H, H-20), 2.46 (1H, H-
30), 2.30 (6H, 30 NMe2), 1.68; 1.25 (2H, H-40), 3.50 (1H, H-50), 4.97
(1H, H-100), 2.35; 1.53 (2H, H-200), 3.32 (3H, 300 OMe), 2.99 (1H, H-400),
4.07 (1H, H-500),1.21 (3H, 2 Me),1.10 (3H, 4 Me),1.35 (3H, 6 Me), 0.98
(1H, H-8 Me), 1.13 (3H, 10 Me), 1.08 (3H, 12 Me), 1.22 (3H, 50 Me),
(1H, H-5), 1.95; 2.53 (2H, H-7), 2.2 (1H, H-8), 2.79; 2.26 (2H, H-9),
3.2 (1H, H-10), 4.22 (1H, H-11), 5.44 (1H, H-13), 1.73; 2.15 (2H, H-
14), 0.96 (3H, H-15), 5.00 (1H, H-10), 3.63 (1H, H-20), 2.73 (1H, H-30),
2.19 (6H, 30 NMe2), 1.39; 1.16 (2H, H-40), 4.01 (1H, H-50), 5.28 (1H, H-
100), 2.43; 1.50 (2H, H-200), 3.52 (3H, 300 OMe), 3.31 (1H, H-400), 4.68
(1H, H-500), 1.35 (3H, 2 Me), 1.58 (3H, 4 Me), 1.27 (3H, 6 Me), 0.93
(1H, H-8 Me), 1.37 (3H, 10 Me), 1.41 (3H, 12 Me), 1.26 (3H, 50 Me),
1.24 (3H, 300 Me), 1.30 (3H, 500 Me), 3.4; 2.8 (2H,
-CH2), 3.22; 3.16 (2H, -CH2), 3.41 (2H,
00-CH2), 2.82 (2H,
7.28 (1H, phenyl, d), 7.22 (2H, phenyl, c), 7.19 (1H, phenyl, b); 13C
NMR (pyridine-d5) 178.1 (C-1), 44.9 (C-2), 79.4 (C-3), 40.7 (C-4),
a
-CH2), 1.75 (2H,
00-CH2),
1.33 (3H, 300 Me), 1.69 (3H, 500 Me), 3.3, 2.79 (2H,
(2H, -CH2), 3.5; 3.4 (2H, -CH2), 6.96 (1H, NH), 6.53 (1H, NH), 7.54
(2H, phenyl, b), 7.32 (2H, phenyl, c), 7.22 (1H, phenyl, d), 4.64 (2H,
00-CH2); 13C NMR (pyridine-d5)
177.7 (C-1), 44.7 (C-2), 79.4 (C-3),
a
-CH2), 2.25; 1.90
b
g
a
b
b
g
d
a
d
83.3 (C-5), 74.7 (C-6), 40.5 (C-7), 28.7 (C-8), 64.5 (C-9), 62 (C-10),
73.0 (C-11), 74.7 (C-12), 78.0 (C-13), 21.2 (C-14), 11.1 (C-15), 103.1
(C-10), 70.8 (C-20), 65.7 (C-30), 40.4 (30 NMe2), 28.0 (C-40), 68.9 (C-50),
42.0 (C-4), 84.1 (C-5), 74.7 (C-6), 41.8 (C-7), 28.3 (C-8), NA (C-9), 61.5
(C-10), 75.7 (C-11), 75.4 (C-12), 77.9 (C-13), 22.4 (C-14), 11.1 (C-15),

ˇ
M. Bukvi´c Krajaci´c et al. / European Journal of Medicinal Chemistry 44 (2009) 3459–3470
3465
95.8 (C-100), 35.0 (C-200), 72.8 (C-300), 49.5 (300 OMe), 77.9 (C-400), 65.9
(C-500), 15.2 (2 Me), 9.4 (4 Me), 27.0 (6 Me), 23.0 (8 Me), 7.9 (10 Me),
16.5 (12 Me), 21.4 (50 Me), 21.5 (300 Me), 18.4 (500 Me), 49.1 (
-CH2);
28.5 ( -CH2), 38.7 ( -CH2), 158.8 (NHCONH), 41.8 (
00-CH2); 36.7
00-CH2), 139.7 (phenyl, a), 128.9 (phenyl, c), 128.4 (phenyl, d), 126.1
3.3.7. 9-Deoxo-9-dihydro-9a-{N0-[1-(1-naphthyl)ethyl]carbamoyl-
g
-aminopropyl}-9a-aza-9a-homoerythromycin A (4h)
a
Yield 49.0%. MS m/z: (ES): MHþ ¼ 989.3. IR (KBr) [
n
/cmꢁ1]: 3414,
b
g
a
2967, 2934, 1728, 1645, 1556, 1459, 1378, 1286, 1167, 1122, 1054, 901,
(b
801, 779. 1H NMR (pyridine-d5)
d 3.13 (1H, H-2), 4.74 (1H, H-3), 2.51
(phenyl, b).
(1H, H-4), 4.17 (1H, H-5), 1.93; 1.60 (2H, H-7), 1.92 (1H, H-8), 2.76;
2.27 (2H, H-9), 3.09 (1H, H-10), 4.23 (1H, H-11), 5.44 (1H, H-13),
1.71; 2.16 (2H, H-14), 0.93 (3H, H-15), 5.01 (1H, H-10), 3.63 (1H, H-
20), 2.73 (1H, H-30), 2.19 (6H, 30 NMe2), 1.40; 1.16 (2H, H-40), 4.00
(1H, H-50), 5.22 (1H, H-100), 2.44; 1.51 (2H, H-200), 3.51 (3H, 300 OMe),
3.30 (1H, H-400), 4.64 (1H, H-500), 1.35 (3H, 2 Me), 1.60 (3H, 4 Me),
1.74 (3H, 6 Me), 0.94 (1H, H-8 Me), 1.36 (3H, 10 Me), 1.40 (3H, 12
Me), 1.36 (3H, 50 Me), 1.33 (3H, 300 Me), 1.68 (3H, 500 Me), 3.27; 2.69
3.3.5. 9-Deoxo-9-dihydro-9a-[N0-(1-naphthyl)carbamoyl-
aminopropyl]-9a-aza-9a-homoerythromycin A (4f)
g-
Yield 55.2%. MS m/z: (ES): MHþ ¼ 961.3. IR (KBr) [
n
/cmꢁ1]:
3390, 2972, 2937, 1727, 1660, 1549, 1456, 1378, 1260, 1167, 1053,
900, 792, 773. 1H NMR (pyridine-d5)
d 3.12 (1H, H-2), 4.76 (1H,
H-3), 2.52 (1H, H-4), 4.16 (1H, H-5), 1.95, 1.59 (2H, H-7), 2.26
(1H, H-8), 2.73; 2.24 (2H, H-9), 3.09 (1H, H-10), 4.22 (1H, H-11),
5.44 (1H, H-13), 1.74; 2.15 (2H, H-14), 0.97 (3H, H-15), 5.00 (1H,
H-10), 3.63 (1H, H-20), 2.71 (1H, H-30), 2.19 (6H, 30 NMe2), 1.37;
1.17 (2H, H-40), 4.01 (1H, H-50), 5.29 (1H, H-100), 2.45; 1.53 (2H,
H-200), 3.52 (3H, 300 OMe), 3.31 (1H, H-400), 4.65 (1H, H-500), 1.37
(3H, 2 Me), 1.58 (3H, 4 Me), 1.76 (3H, 6 Me), 0.95 (1H, H-8 Me),
1.39 (3H, 10 Me), 1.40 (3H, 12 Me), 1.16 (3H, 50 Me), 1.33 (3H, 300
(2H,
CH), 1.70 (3H,
a
-CH2), 1.89 (2H,
b-CH2), 3.47, 3.39 (2H, g -
-CH2), 6.19 (1H, a00
b
00-CH3), 8.19 (1H, h, naphthyl), 7.82 (1H, e, naphthyl),
7.72 (1H, d, naphthyl), 7.58 (1H, b, naphthyl), 7.53 (1H, g, naphthyl),
7.47 (1H, f, naphthyl), 7.43 (1H, c, naphthyl) 9.18 (1H, NH); 13C NMR
(pyridine-d5) d 177.7 (C-1), 45.5 (C-2), 79.4 (C-3), 42.0 (C-4), 84.0 (C-
5), 74.7 (C-6), 41.9 (C-7), 28.2 (C-8), 63.9 (C-9), 61.6 (C-10), 75.7 (C-
11), 75.4 (C-12), 77.9 (C-13), 22.4 (C-14), 11.1 (C-15), 103.6 (C-10),
71.7 (C-20), 65.8 (C-30), 40.5 (30 NMe2), 30.5 (C-40), 68.2 (C-50), 96.1
(C-100), 35.5 (C-200), 73.7 (C-300), 49.7 (300 OMe), 78.8 (C-400), 66.2 (C-
500), 15.6 (2 Me), 10.3 (4 Me), 29.0 (6 Me), 22.7 (8 Me), 9.7 (10 Me),
Me), 1.68 (3H, 500 Me), 3.23; 2.78 (2H,
3.43; 3.37 (2H, -CH2), 7.61 (1H, b, naphthyl), 7.49 (1H, c,
a-CH2), 1.87 (2H, b-CH2),
g
naphthyl), 8.45 (1H, d, naphthyl), 8.31 (1H, e, naphthyl), 7.44
(1H, f, naphthyl), 7.89 (1H, g, naphthyl), 7.86 (1H, h, naphthyl);
18.4 (12 Me), 22.0 (50 Me), 21.6 (300 Me), 19.8 (500 Me), 49.6 (
29.2 ( -CH2), 39.2 ( -CH2), 158.5 (NHCONH), 45.8 ( -
00-CH), 22.6 (b00
a-CH2);
13C NMR (pyridine-d5)
d
177.7 (C-1), 45.5 (C-2), 79.4 (C-3), 41.9
b
g
a
(C-4), 84.1 (C-5), 74.7 (C-6), 42 (C-7), 28.2 (C-8), 64.6 (C-9), 61.8
(C-10), 75.8 (C-11), 75.4 (C-12), 77.9 (C-13), 22.4 (C-14), 11.5 (C-
15), 103.6 (C-10), 71.7 (C-20), 65.8 (C-30), 40.5 (30 NMe2), 30.4 (C-
40), 68.3 (C-50), 96.1 (C-100), 35.6 (C-200), 73.7 (C-300), 49.7 (300
OMe), 78.8 (C-400), 66.2 (C-500), 15.6 (2 Me), 10.4 (4 Me), 29.0 (6
Me), 22.7 (8 Me), 9.8 (10 Me), 18.4 (12 Me), 23.6 (50 Me), 21.6 (300
CH3), 131.5 (C, a, naphthyl), 129.3 (CH, b, naphthyl), 127.7 (CH, c,
naphthyl), 125.9 (CH, d, naphthyl), 126.5 (CH, e, naphthyl), 122.8
(CH, f, naphthyl), 133.2 (CH, g, naphthyl), 131.6 (CH, h, naphthyl).
3.3.8. 9-Deoxo-9-dihydro-9a-(N0-phenylthiocarbamoyl-
aminopropyl)-9a-aza-9a-homoerythromycin A (6b)
g-
Me), 19.5 (500 Me), 49 (
a
-CH2); 29.2 (
b
-CH2), 39.1 (
g
-CH2), 157.2
Yield 43.1%. MS m/z: (ES): MHþ ¼ 927.3. IR (KBr) [
n
/cmꢁ1]: 3440,
(NHCONH), 128.8 (CH, h, naphthyl), 127.9 (C, i, naphthyl), 126.5
(CH, c, naphthyl), 126.1 (CH, g, naphthyl), 125.8 (CH, f, naphthyl),
123.0 (C, j, naphthyl), 122.5 (CH, e, naphthyl), 119.5 (CH, d,
naphthyl), 123.5 (CH, b, naphthyl).
2969, 2935,1728,1667,1552,1456,1380,1284,1167,1054,1013, 900,
699. 1H NMR (CDCl3)
d 2.84 (1H, H-2), 3.13 (1H, H-3), 2.00 (1H, H-4),
3.61 (1H, H-5), 2.26; 1.72 (2H, H-7), 2.04 (1H, H-8), 3.73 (1H, H-11),
4.68 (1H, H-13), 1.88; 1.50 (2H, H-14), 0.90 (3H, H-15), 4.44 (1H, H-
10), 3.23 (1H, H-20), 2.50 (1H, H-30), 2.32 (6H, 30 NMe2), 1.70; 1.24
(2H, H-40), 3.52 (1H, H-50), 5.00 (1H, H-100), 2.33; 1.55 (2H, H-200),
3.32 (3H, 300 OMe), 3.02 (1H, H-400), 4.07 (1H, H-500), 1.20 (3H, 2 Me),
1.08 (3H, 4 Me), 1.33 (3H, 6 Me), 0.98 (3H, 8 Me), 1.15 (3H, 10
Me), 1.07 (3H, 12 Me), 1.36 (3H, 50 Me), 1.33 (3H, 300 Me), 1.68 (3H, 500
3.3.6. 9-Deoxo-9-dihydro-9a-[N0-(2-naphthyl)carbamoyl-
aminopropyl]-9a-aza-9a-homoerythromycin A (4g)
g-
Yield 55.2%. MS m/z: (ES): MHþ ¼ 961.3. IR (KBr) [
n
/cmꢁ1]:
3408, 2969, 2934, 1728, 1681, 1557, 1456, 1379, 1279, 1167, 1053,
1013, 897, 746. 1H NMR (pyridine-d5)
d
2.90 (1H, H-2), 4.18 (1H, H-
Me), 3.3; 2.7 (2H,
(2H, phenyl, c), 7.33 (2H, phenyl, b), 7.23 (1H, phenyl, d); 13C NMR
(CDCl3) 177.8 (C-1), 45.3 (C-2), 79.5 (C-3), 40.4 (C-4), 84.0 (C-5),
a-CH2), 1.87 (2H, b-CH2), 3.67 (2H, g-CH2), 7.38
3), 2.45 (1H, H-4), 3.65 (1H, H-5), 1.78, 1.42 (2H, H-7), 2.07 (1H, H-
8), 2.76; 2.24 (2H, H-9), 3.72 (1H, H-11), 4.72 (1H, H-13), 1.89; 1.49
(2H, H-14), 0.89 (3H, H-15), 4.42 (1H, H-10), 3.23 (1H, H-20), 2.53
(1H, H-30), 2.28 (6H, 30 NMe2), 1.61; 1.22 (2H, H-40), 3.50 (1H, H-50),
4.95 (1H, H-100), 2.33; 1.51 (2H, H-200), 3.31 (3H, 300 OMe), 3.03 (1H,
H-400), 4.09 (1H, H-500), 1.21 (3H, 2 Me), 1.09 (3H, 4 Me), 1.37 (3H, 6
Me), 0.95 (1H, H-8 Me), 1.18 (3H, 10 Me), 1.07 (3H, 12 Me), 1.20 (3H,
d
74.8 (C-6), 40.7 (C-7), 28.8 (C-8), 64.4 (C-9), 62 (C-10), 74.3 (C-11),
74.6 (C-12), 78.0 (C-13), 21.3 (C-14), 11.2 (C-15),103.2 (C-10), 70.9 (C-
20), 65.6 (C-30), 40.4 (30 NMe2), 29.0 (C-40), 68.9 (C-50), 96.0 (C-100),
35.0 (C-200), 72.8 (C-300), 49.5 (300 OMe), 78.0 (C-400), 65.9 (C-500), 15.4
(2 Me), 9.7 (4 Me), 26.7 (6 Me), 22.8 (8 Me), 8.4 (10 Me), 16.5 (12
50 Me), 1.23 (3H, 300 Me), 1.34 (3H, 500 Me), 2.54 (2H,
(2H, -CH2), 3.33; 3.18 (2H, -CH2), 8.04 (1H, naphthyl, h), 7.72
a
-CH2), 1.78
Me), 21.4 (50 Me), 21.5 (300 Me), 18.4 (500 Me), 49.0 (
CH2), 43.4 ( -CH2),181.2 (NHCSNH),137.3 (phenyl, a),129.6 (phenyl,
c), 126.6 (phenyl, b), 125.3 (phenyl, d).
a-CH2); 27.1 (b-
b
g
g
(1H, naphthyl, d), 7.69 (1H, naphthyl, g), 7.53 (1H, naphthyl, c),
7.50 (1H, naphthyl, b), 7.38 (1H, naphthyl, f), 7.28 (1H, naphthyl, e);
13C NMR (pyridine-d5)
d
178.0 (C-1), 44.9 (C-2), 79.6 (C-3), 40.4 (C-
3.3.9. 9-Deoxo-9-dihydro-9a-(N0-benzylthiocarbamoyl-
aminopropyl)-9a-aza-9a-homoerythromycin A (6c)
g-
4), 84 (C-5), 72.7 (C-6), 41 (C-7), 28.7 (C-8), 65 (C-9), 62 (C-10), 75
(C-11), 74.8 (C-12), 77.9 (C-13), 21.2 (C-14), 11.1 (C-15), 103.2 (C-10),
70.7 (C-20), 65.6 (C-30), 40.3 (30 NMe2), 30.5 (C-40), 69.0 (C-50), 96.2
(C-100), 34.9 (C-200), 72.7 (C-300), 49.5 (300 OMe), 77.9 (C-400), 66.0 (C-
500), 15.3 (2 Me), 9.5 (4 Me), 29 (6 Me), 22.9 (8 Me), 9 (10 Me), 16.7
Yield 51.1%. MS m/z: (ES): MHþ ¼ 941.3. IR (KBr) [
n
/cmꢁ1]: 3443,
2969, 2935, 1727, 1667, 1552, 1456, 1380, 1284, 1167, 1054, 1013, 901,
748, 701. 1H NMR (pyridine-d5 e)
d 3.12 (1H, H-2), 4.74 (1H, H-3),
2.51 (1H, H-4), 4.15 (1H, H-5), 1.93 (2H, H-7), NA (1H, H-8), 2.77;
2.50 (2H, H-9), 3.10 (1H, H-10), 4.20 (1H, H-11), 5.46 (1H, H-13),
1.72; 2.16 (2H, H-14), 0.97 (3H, H-15), 5.05 (1H, H-10), 3.62 (1H,
H-20), 2.70 (1H, H-30), 2.19 (6H, 30 NMe2), 1.38; 1.17 (2H, H-40), 4.00
(1H, H-50), 5.26 (1H, H-100), 2.43; 1.53 (2H, H-200), 3.50 (3H, 300 OMe),
3.31 (1H, H-400), 4.64 (1H, H-500), 1.37 (3H, 2 Me), 1.58 (3H, 4 Me),
1.76 (3H, 6 Me), 0.95 (1H, H-8 Me), 1.39 (3H, 10 Me), 1.40 (3H, 12
(12 Me), 21.5 (50 Me), 21.4 (300 Me), 18.3 (500 Me), 49 (
-CH2), 38.0 ( -CH2), 156.5 (NHCONH), 137.6 (C, b, naphthyl),
a-CH2); 27.6
(b
g
120.3 (CH, c, naphthyl), 128.6 (CH, h, naphthyl), 127.4 (CH, e,
naphthyl), 123.8 (CH, f, naphthyl), 126.0 (CH, g, naphthyl), 129.0
(CH, a, naphthyl), 114.5 (CH, d, naphthyl), 129.6 (C, j, naphthyl),
134.2 (C, i, naphthyl).

ˇ
M. Bukvi´c Krajaci´c et al. / European Journal of Medicinal Chemistry 44 (2009) 3459–3470
3466
Me),1.36 (3H, 50 Me),1.32 (3H, 300 Me),1.67 (3H, 500 Me), 3.3; 2.8 (2H,
-CH2), 2.06 (2H, -CH2), 3.78 (2H, -CH2), 3.8 (2H,
00-CH2), 7.51
(2H, phenyl, c), 7.30 (2H, phenyl, b), 7.22 (1H, phenyl, d); 13C NMR
(pyridine-d5) 177.7 (C-1), 45.5 (C-2), 79.5 (C-3), 41.9 (C-4), 84.0 (C-
3.3.12. 9-Deoxo-9-dihydro-9a-[N0-(1-naphthyl)thiocarbamoyl-
aminopropyl]-9a-aza-9a-homoerythromycin A (6f)
g-
a
b
g
a
Yield 35.1%. MS m/z: (ES): MHþ ¼ 977.3. IR (KBr) [
n
/cmꢁ1]: 3424,
d
2964, 2933, 1728, 1537, 1460, 1378, 1280, 1166, 1052, 1014, 902, 794,
5), 74.8 (C-6), 41.7 (C-7), 28 (C-8), 64.1 (C-9), 61.4 (C-10), 75.8 (C-11),
75.5 (C-12), 77.9 (C-13), 22.3 (C-14), 11.1 (C-15), 103.5 (C-10), 71.7 (C-
20), 65.8 (C-30), 40.5 (30 NMe2), 30.7 (C-40), 68.2 (C-50), 96.2 (C-100),
35.6 (C-200), 73.7 (C-300), 49.7 (300 OMe), 79.2 (C-400), 66.2 (C-500), 15.7
(2 Me), 10.4 (4 Me), 29.0 (6 Me), 22.7 (8 Me), 9.6 (10 Me), 18.4 (12
794. 1H NMR (pyridine-d5)
d 3.11 (1H, H-2), 4.74 (1H, H-3), 2.49 (1H,
H-4), 4.14 (1H, H-5), 1.96; 1.88 (2H, H-7), 1.71 (1H, H-8), 2.76; 2.30
(2H, H-9), 3.08 (1H, H-10), 4.18 (1H, H-11), 5.39 (1H, H-13), 1.72;
2.10 (2H, H-14), 0.91 (3H, H-15), 4.98 (1H, H-10), 3.63 (1H, H-20),
2.71 (1H, H-30), 2.19 (6H, 30 NMe2), 1.38; 1.18 (2H, H-40), 4.01 (1H, H-
50), 5.29 (1H, H-100), 2.43; 1.50 (2H, H-200), 3.52 (3H, 300 OMe), 3.30
(1H, H-400), 4.64 (1H, H-500), 1.35 (3H, 2 Me), 1.58 (3H, 4 Me), 1.27
(3H, 6 Me), 0.95 (1H, H-8 Me), 1.38 (3H, 10 Me), 1.38 (3H, 12 Me),
1.26 (3H, 50 Me), 1.32 (3H, 300 Me), 1.68 (3H, 500 Me), 3.26; 2.83 (2H,
Me), 23.6 (50 Me), 21.6 (300 Me), 19.5 (500 Me), 49.5 (
CH2), 43.4 ( -CH2), 183 (NHCSNH), 48.3 (
00-CH2), 133.2 (phenyl, a),
128.6 (phenyl, b), 127.8 (phenyl, c), 127.3 (phenyl, d).
a-CH2); 29 (b-
g
a
3.3.10. 9-Deoxo-9-dihydro-9a-[N0-(
b
-phenylethyl)thiocarbamoyl-
a-CH2), 2.19 (2H, b-CH2), 3.87 (2H, g-CH2), 7.53 (1H, c, naphthyl),
g
-aminopropyl]-9a-aza-9a-homoerythromycin A (6d)
7.91 (1H, d, naphthyl), 7.80 (1H, e, naphthyl), 7.64 (1H, h, naphthyl),
7.49 (1H, f, naphthyl), 7.38 (1H, g, naphthyl),8.40 (1H, b, naphthyl);
Yield 50.1%. MS m/z: (ES): MHþ ¼ 955.3. IR (KBr) [
n
/cmꢁ1]: 3438,
2969, 2935, 1727, 1667, 1552, 1456, 1380, 1284, 1167, 1054, 1013, 901,
13C NMR (pyridine-d5)
d 177.7 (C-1), 45.5 (C-2), 79.1 (C-3), 42.2 (C-
748, 701. 1H NMR (pyridine-d5)
d
3.14 (1H, H-2), 4.75 (1H, H-3), 2.51
4), 84.0 (C-5), 74.6 (C-6), 42.1 (C-7), 28.1 (C-8), 64.4 (C-9), 61.5 (C-
10), 75.4 (C-11), 75.3 (C-12), 77.8 (C-13), 22.4 (C-14), 11.1 (C-15),
103.5 (C-10), 71.7 (C-20), 65.8 (C-30), 40.5 (30 NMe2), 30.7 (C-40), 68.2
(C-50), 96.0 (C-100), 35.6 (C-200), 73.7 (C-300), 49.7 (300 OMe), 79.0 (C-
400), 66.2 (C-500), 15.5 (2 Me), 10.3 (4 Me), 28.9 (6 Me), 22.8 (8 Me),
10.0 (10 Me), 18.4 (12 Me), 22.0 (500 Me), 21.6 (300 Me), 19.3 (500 Me),
(1H, H-4), 4.17 (1H, H-5), 1.93; 1.58 (2H, H-7), 2.24 (1H, H-8), 2.77;
2.28 (2H, H-9), 3.09 (1H, H-10), 4.20 (1H, H-11), 5.42 (1H, H-13),
2.15, 1.69 (2H, H-14), 0.94 (3H, H-15), 4.99 (1H, H-10), 3.63 (1H, H-
20), 2.73 (1H, H-30), 2.19 (6H, 30 NMe2), 1.38; 1.17 (2H, H-40), 4.01
(1H, H-50), 5.29 (1H, H-100), 2.43; 1.54 (2H, H-200), 3.52 (3H, 300 OMe),
3.30 (1H, H-400), 4.65 (1H, H-500), 1.35 (3H, 2 Me), 1.58 (3H, 4 Me),
1.71 (3H, 6 Me), 0.95 (1H, H-8 Me), 1.37 (3H, 10 Me), 1.40 (3H, 12
Me), 1.38 (3H, 50 Me), 1.33 (3H, 300 Me), 1.67 (3H, 500 Me), 3.34; 2.76
(2H,
3.17 (2H,
phenyl, d); 13C NMR (pyridine-d5)
3), 42.0 (C-4), 84.1 (C-5), 74.7 (C-6), 42.0 (C-7), 64.3 (C-9), 61.5 (C-
10), 75.7 (C-11), 75.3 (C-12), 77.9 (C-13), 22.4 (C-14), 11.3 (C-15),
103.5 (C-10), 71.7 (C-20), 65.8 (C-30), 40.5 (30 NMe2), 30.7 (C-40), 68.2
(C-50), 96.2 (C-100), 35.6 (C-200), 73.7 (C-300), 49.7 (300 OMe), 78.8 (C-
400), 66.2 (C-500), 15.6 (2 Me), 10.4 (4 Me), 28.0 (6 Me), 22.7 (8 Me),
9.7 (10 Me), 18.5 (12 Me), 22.0 (50 Me), 21.6 (300 Me), 19.5 (500 Me),
48.8 (a-CH2); 29.2 (b-CH2), 44.1 (g-CH2), 183.3 (NHCSNH), 133.1 (C,
c, naphthyl), 129.3 (CH, d, naphthyl), 128.6 (CH, e, naphthyl), 126.8
(CH, f, naphthyl), 126.3 (CH, g, naphthyl), 125.6 (CH, h, naphthyl),
123.2 (CH, b, naphthyl),131.5 (CH, c, naphthyl), 131.1 (C, j, naphthyl),
135.1 (C, i, naphthyl).
a
-CH2), 1.93 (2H,
00-CH2), 7.26 (2H, phenyl, c), 7.28 (2H, phenyl, b), 7.20 (1H,
177.7 (C-1), 45.5 (C-2), 79.4 (C-
b-CH2), 4.06 (2H, g-CH2), 3.42 (2H, a
00-CH2),
b
d
3.3.13. 9-Deoxo-9-dihydro-9a-[N0-(
b
-cyanoethyl)-N0-
isopropylcarbamoyl-
g-aminopropyl]-9a-aza-9a-homoerythromycin
A (8a)
Yield 30.5%. MS m/z: (ES): MHþ ¼ 930.2. IR (KBr) [
n
/cmꢁ1]: 3435,
2972, 2936, 2877, 2249, 1726, 1637, 1529, 1459, 1377, 1168, 1053,
1013. 1H NMR (pyridine-d5)
d 3.16 (1H, H-2), 4.69 (1H, H-3), 2.51
49.7 (
CH2); 35.6 (
(phenyl, b), 126.5 (phenyl, d).
a
-CH2); 28.0 (
b
-CH2), 46.2 (
g
-CH2), 183 (NHCSNH), 49.7 (a00
-
(1H, H-4), 4.15 (1H, H-5), 2.05; 1.87 (2H, H-7), 2.21 (1H, H-8), 2.74;
2.28 (2H, H-9), 3.10 (1H, H-10), 4.20 (1H, H-11), 5.37 (1H, H-13),
2.17; 1.70 (2H, H-14), 0.94 (3H, H-15), 5.00 (1H, H-10), 3.62 (1H, H-
20), 2.69 (1H, H-30), 2.17 (6H, 30 NMe2), 1.40; 1.16 (2H, H-40), 4.03
(1H, H-50), 5.26 (1H, H-100), 2.45; 1.53 (2H, H-200), 3.52 (3H, 300 OMe),
3.32 (1H, H-400), 4.65 (1H, H-500), 1.35 (3H, 2 Me), 1.62 (3H, 4 Me),
1.78 (3H, 6 Me), 0.99 (1H, H-8 Me), 1.35 (3H, 10 Me), 1.40 (3H, 12
Me), 1.36 (3H, 50 Me), 1.33 (3H, 300 Me), 1.69 (3H, 500 Me), 3.26; 2.51
b
00-CH2), 140.2 (phenyl, a), 129.3 (phenyl, c), 128.8
3.3.11. 9-Deoxo-9-dihydro-9a-[N0-(3-phenylpropyl)thiocarbamoyl-
g
-aminopropyl]-9a-aza-9a-homoerythromycin A (6e)
Yield 21.1%. MS m/z: (ES): MHþ ¼ 969.3. IR (KBr) [
n
/cmꢁ1]:
3438, 2969, 2935, 1727, 1667, 1553, 1455, 1380, 1284, 1167, 1054,
1013, 902, 745, 700. 1H NMR (pyridine-d5)
d
3.14 (1H, H-2), 4.74
(2H,
0-CH2), 2.93 (2H,
NMR (pyridine-d5)
a
-CH2), 1.97 (2H,
0-CH2), 4.33 (1H, CH, a), 1.19 (3H, CH3, b); 13C
177.7 (C-1), 45.5 (C-2), 79.3 (C-3), 41.5 (C-4),
b-CH2), 3.56; 3.41 (2H, g-CH2), 3.83; 2.71 (2H,
(1H, H-3), 2.51 (1H, H-4), 4.16 (1H, H-5), 1.93; 1.58 (2H, H-7), 2.20
(1H, H-8), 2.75; 2.24 (2H, H-9), 3.10 (1H, H-10), 4.20 (1H, H-11),
5.43 (1H, H-13), 2.16, 1.69 (2H, H-14), 0.95 (3H, H-15), 4.99 (1H, H-
10), 3.62 (1H, H-20), 2.65 (1H, H-30), 2.19 (6H, 30 NMe2), 1.38; 1.18
(2H, H-40), 3.99 (1H, H-50), 5.28 (1H, H-100), 2.44; 1.53 (2H, H-200),
3.52 (3H, 300 OMe), 3.31 (1H, H-400), 4.64 (1H, H-500), 1.35 (3H, 2
Me), 1.60 (3H, 4 Me), 1.74 (3H, 6 Me), 0.95 (1H, H-8 Me), 1.38 (3H,
10 Me), 1.40 (3H, 12 Me), 1.36 (3H, 50 Me), 1.33 (3H, 300 Me), 1.68
(3H, 500 Me), 3.30; 2.78 (2H,
CH2), 3.81 (2H,
00-CH2), 2.04 (2H,
(2H, phenyl, c), 7.18 (1H, phenyl, d), 7.23 (2H, phenyl, b); 13C NMR
(pyridine-d5) 177.7 (C-1), 45.5 (C-2), 79.4 (C-3), 41.9 (C-4), 84.1
a
b
d
83.8 (C-5), 74.7 (C-6), 41.2 (C-7), 29.1 (C-8), 63.7 (C-9), 60.5 (C-10),
75.9 (C-11), 75.3 (C-12), 78.1 (C-13), 22.0 (C-14), 11.5 (C-15), 103.5
(C-10), 71.7 (C-20), 65.8 (C-30), 40.5 (30 NMe2), 30.4 (C-40), 68.2 (C-50),
96.2 (C-100), 35.6 (C-200), 73.7 (C-300), 49.7 (300 OMe), 78.8 (C-400), 66.2
(C-500),15.8 (2 Me),10.3 (4 Me), 28.1 (6 Me), 23.3 (8 Me), 8.8 (10 Me),
18.3 (12 Me), 22.0 (50 Me), 21.4 (300 Me), 19.5 (500 Me), 48.9 (
27.4 ( -CH2), 46.5 ( -CH2), 43.7 (
0-CH2), 17.5 ( 0-CH2), 119.7 (CN),
157.5 (NCONH), 42.9 (CH, isopropyl, a), 23.7 (CH3, isopropyl, b).
a-CH2),
a
-CH2), 2.04 (2H,
b
-CH2), 3.81 (2H,
g-
b
g
a
b
a
b
00-CH2), 2.67 (2H,
g
00-CH2), 7.27
d
3.3.14. 9-Deoxo-9-dihydro-9a-[N0-(
b
-cyanoethyl)-N0-
(C-5), 74.7 (C-6), 41.8 (C-7), 28 (C-8), 64 (C-9), 61.5 (C-10), 75.8 (C-
11), 75.3 (C-12), 77.9 (C-13), 22.4 (C-14), 11.1 (C-15), 103.5 (C-10),
71.7 (C-20), 65.8 (C-30), 40.5 (30 NMe2), 30.7 (C-40), 68.3 (C-50), 96.2
(C-100), 35.6 (C-200), 73.7 (C-300), 49.7 (300 OMe), 78.8 (C-400), 66.2 (C-
500), 15.6 (2 Me), 10.4 (4 Me), 29.0 (6 Me), 22.7 (8 Me), 9.7 (10 Me),
phenylcarbamoyl-g-aminopropyl]-9a-aza-9a-homoerythromycin
A (8b)
Yield 35.5%. MS m/z: (ES): MHþ ¼ 964.3. IR (KBr) [
n
/cmꢁ1]: 3450,
2972, 2938, 2877, 2249,1728,1650,1534,1447,1378,1315,1167,1053,
1013, 897, 755, 1H NMR (CDCl3)
d 2.89 (1H, H-2), 4.11 (1H, H-3), 2.03
18.4 (12 Me), 22.0 (50 Me), 21.6 (300 Me), 19.5 (500 Me), 48 (
29.2 ( -CH2), 43.4 ( -CH2), 183 (NHCSNH), 44.3 (
00-CH2), 31.5 (b00
CH2), 33.5 (
00-CH2), 133.2 (phenyl, a), 128.8 (phenyl, b), 128.7
(phenyl, c), 126.2 (phenyl, d).
a
-CH2);
(1H, H-4), 3.62 (1H, H-5),1.79; 1.33 (2H, H-7), 2.1 (1H, H-8), 3.00; 2.18
(2H, H-9), 2.86 (1H, H-10), 3.76 (1H, H-11), 4.65 (1H, H-13),1.89; 1.51
(2H, H-14), 0.89 (3H, H-15), 4.44 (1H, H-10), 3.24 (1H, H-20), 2.49 (1H,
H-30), 2.32 (6H, 30 NMe2), 1.69; 1.22 (2H, H-40), 3.48 (1H, H-50), 4.97
b
g
a
-
g

ˇ
M. Bukvi´c Krajaci´c et al. / European Journal of Medicinal Chemistry 44 (2009) 3459–3470
3467
(1H, H-100), 2.35; 1.57 (2H, H-200), 3.32 (3H, 300 OMe), 3.01 (1H, H-400),
4.04 (1H, H-500),1.20 (3H, 2 Me),1.09 (3H.4 Me),1.33 (3H, 6 Me),1.00
(1H, 8 Me), 1.11 (3H, 10 Me), 1.07 (3H, 12 Me), 1.21 (3H, 50 Me), 1.24
(2 Me), 9.5 (4 Me), 27.1 (6 Me), 23.4 (8 Me), 7.2 (10 Me),16.2 (12 Me),
21.4 (50 Me), 21.5 (300 Me), 18.5 (500 Me), 49.0 (
-CH2); 27.0 ( -CH2),
47.4 ( -CH2), 44.4 (
0-CH2); 17.4 ( 0-CH2), 157.4 (NHCONH), 119.1
(CN), 42.1 (
00-CH2), 36.5 ( 00-CH2), 139.6 (phenyl, a), 129.0 (phenyl,
c), 128.4 (phenyl, b), 126.2 (phenyl, d).
a
b
g
a
b
(3H, 300 Me),1.31(3H, 500 Me), 3.32 (2H,
2.89 (2H, -CH2), 3.68; 2.87 (2H,
0-CH2), 2.80 (2H,
phenyl, b), 7.27 (2H, phenyl, c), 7.03 (1H, phenyl, d); 13C NMR (CDCl3)
178.1 (C-1), 44.9 (C-2), 79.8 (C-3), 40.1 (C-4), 83.4 (C-5), 74.7 (C-6),
a
-CH2), 2.54 (2H,
b
-CH2), 3.25;
a
b
g
a
b
0-CH2), 7.40 (2H,
d
b
3.3.17. 9-Deoxo-9-dihydro-9a-[N0-( -cyanoethyl)-N0-(1-
39.7 (C-7), 29.0 (C-8), 63 (C-9), 74.7 (C-12), 77.9 (C-13), 21.1 (C-14),
11.1 (C-15), 102.9 (C-10), 70.9 (C-20), 65.7 (C-30), 40.4 (30 NMe2), 29.0
(C-40), 68.8 (C-50), 96.0 (C-100), 35.0 (C-200), 72.8 (C-300), 49.4 (300 OMe),
77.9 (C-400), 65.9 (C-500), 15.5 (2 Me), 9.5 (4 Me), 27.0 (6 Me), 23.3 (8
Me), 7.4 (10 Me),16.3 (12 Me), 21.4 (50 Me), 21.5 (300 Me),18.4 (500 Me),
naphthyl)carbamoyl- -aminopropyl]-9a-aza-9a-
g
homoerythromycin A (8f)
Yield 36.1%. MS m/z: (ES): MHþ ¼ 1014.3. IR (KBr) [
n
/cmꢁ1]:
3439, 2972, 2937, 2249, 1727, 1642, 1528, 1501, 1460, 1377, 1168,
1053, 1013, 794, 773. 1H NMR (CDCl3)
d 2.86 (1H, H-2), 3.94 (1H, H-
47.6 (
a
-CH2), 27.3 (
b
-CH2), 48.9 (
g
-CH2), 44.4 (
a
0-CH2),17.3 (
b
00-CH2),
3), 2.02 (1H, H-4), 3.54 (1H, H-5), 1.78, 1.37 (2H, H-7), 2.10 (1H, H-8),
2.82; 2.31 (2H, H-9), 2.86 (1H, H-10), 3.75 (1H, H-11), 4.63 (1H, H-
13), 1.88; 1.49 (2H, H-14), 0.89 (3H, H-15), 4.40 (1H, H-10), 3.23 (1H,
H-20), 2.44 (1H, H-30), 2.31 (6H, 30 NMe2), 1.69; 1.25 (2H, H-40), 3.44
(1H, H-50), 4.74 (1H, H-100), 2.31; 1.50 (2H, H-200), 3.28 (3H, 300 OMe),
3.06 (1H, H-400), 3.95 (1H, H-500),1.19 (3H, 2 Me),1.07 (3H, 4 Me),1.31
(3H, 6 Me), 0.99 (1H, H-8 Me),1.14 (3H,10 Me),1.08 (3H,12 Me),1.20
119.2 (CN),155.3 (NCONH),138.9 (phenyl, a),128.7 (phenyl, c),123.3
(phenyl, d), 121.0 (phenyl, b).
3.3.15. 9-Deoxo-9-dihydro-9a-[N0-(
b
-cyanoethyl)-N0-
benzylcarbamoyl-
g-aminopropyl]-9a-aza-9a-homoerythromycin
A (8c)
Yield 34.1%. MS m/z: (ES): MHþ ¼ 978.3. IR (KBr) [
n
/cmꢁ1]: 3417,
(3H, 50 Me), 1.20 (3H, 300 Me), 1.28 (3H, 500 Me), 2.41; 2.86 (2H,
CH2), 1.94 (2H, -CH2), 3.58; 3.41 (2H, -CH2), 3.73 (2H,
0-CH2),
2.79 (2H,
0-CH2), 7.91 (1H, e, naphthyl), 7.83 (1H, h, naphthyl), 7.68
(1H, b, naphthyl), 7.60 (1H, d, naphthyl), 7.50 (1H, f, naphthyl), 7.47
(1H, g, naphthyl), 7.43 (1H, c, naphthyl); 13C NMR (CDCl3)
178.0 (C-
a-
2971, 2936, 2876, 2248, 1694, 1644, 1538, 1455, 1377, 1267, 1167,
b
g
a
1053, 1012, 900, 732, 700. 1H NMR (CDCl3)
d
2.89 (1H, H-2), 4.10
b
(1H, H-3), 2.05 (1H, H-4), 3.62 (1H, H-5), 1.79, 1.41 (2H, H-7), 2.05
(1H, H-8), NA (2H, H-9), NA (1H, H-10), 3.73 (1H, H-11), 4.57 (1H, H-
13), 1.88; 1.46 (2H, H-14), 0.89 (3H, H-15), 4.45 (1H, H-10), 3.22 (1H,
H-20), 2.66 (1H, H-30), 2.33 (6H, 30 NMe2), NA (2H, H-40), 3.53 (1H,
H-50), 4.76 (1H, H-100), 2.28; 1.52 (2H, H-200), 3.30 (3H, 300 OMe), 3.01
(1H, H-400), 4.05 (1H, H-500), 1.21 (3H, 2 Me), 1.08 (3H, 4 Me), 1.31
(3H, 6 Me), 1.01 (1H, 8 Me), 1.05 (3H, 10 Me), 1.11 (3H, 12 Me), 1.22
d
1), 44.8 (C-2), 79.9 (C-3), 40.0 (C-4), 83.6 (C-5), 74.6 (C-6), 39.7
(C-7), 29.3 (C-8), 63 (C-9), 60 (C-10), 74.7 (C-11), 74.6 (C-12), 78.2
(C-13), 21.0 (C-14), 11.1 (C-15), 102.9 (C-10), 70.9 (C-20), 65.6 (C-30),
40.3 (30 NMe2), 29.0 (C-40), 68.7 (C-50), 95.8 (C-100), 34.8 (C-200), 72.7
(C-300), 49.4 (300 OMe), 77.8 (C-400), 65.6 (C-500), 15.5 (2 Me), 9.4 (4
Me), 27.1 (6 Me), 23.3 (8 Me), 7.3 (10 Me), 16.2 (12 Me), 21.5 (50 Me),
(3H, 50 Me), 1.24 (3H, 300 Me), 1.22 (3H, 500 Me), 3.32; 2.85 (2H,
CH2), 1.70 (2H, -CH2), 3.25 (2H, -CH2), 3.55 (2H,
0-CH2), 2.69 (2H,
0-CH2), 4.40 (2H, 00-CH2), 7.33 (2H, phenyl, b), 7.29 (2H, phenyl, c),
7.14 (1H, phenyl, d); 13C NMR (CDCl3)
177 (C-1), 44.8 (C-2), 79 (C-
a-
b
g
a
21.4 (300 Me), 18.3 (500 Me), 49.3 (
44.4 (
0-CH2); 17.2 ( 00-CH2), 156.3 (NHCONH), 119.1 (CN), 134.3 (C,
a-CH2); 27.7 (b-CH2), 47.8 (g-CH2),
b
a
a
b
d
a, naphthyl), 134.0 (C, i, naphthyl), 129.4 (CH, c, naphthyl), 128.4
(CH, h, naphthyl), 125.7 (CH, b, naphthyl), 125.8 (CH, f, naphthyl),
125.8 (CH, c, naphthyl), 126.2 (CH, g, naphthyl), 122.8 (CH, d,
naphthyl), 122.1 (CH, e, naphthyl).
3), 39.3 (C-4), 83 (C-5), 74.8 (C-6), 39.2 (C-7), 28.9 (C-8), 63 (C-9), 60
(C-10), 74.6 (C-11), 74.6 (C-12), 78 (C-13), 21.3 (C-14), 11.2 (C-15),
102.9 (C-10), 71.0 (C-20), 65.6 (C-30), 39.3 (30 NMe2), 28.9 (C-40), 68.7
(C-50), 96.4 (C-100), 35.2 (C-200), 72.7 (C-300), 50.3 (300 OMe), 77.8 (C-
400), 66.0 (C-500), 15.7 (2 Me), 9.6 (4 Me), 26.9 (6 Me), 23.8 (8 Me), 6.8
(10 Me), 16.1 (12 Me), 21.4 (50 Me), 21.5 (300 Me), 18.6 (500 Me), 50.3
3.3.18. 9-Deoxo-9-dihydro-9a-[N0-(
b
-cyanoethyl)-N0-(2-
naphthyl)carbamoyl- -aminopropyl]-9a-aza-9a-
g
(
a
-CH2); 27.3 (
157.5 (NHCONH), 119 (CN), 44.7 (
(phenyl, b), 128.7 (phenyl, c), 127.5 (phenyl, d).
b
-CH2), 48.3 (
g
-CH2), 44.3 (
a
0-CH2); 17.2 (
b
00-CH2),
homoerythromycin A (8g)
a
00-CH2), 140.3(phenyl, a), 129.3
Yield 33.1%. MS m/z: (ES): MHþ ¼ 1014.3. IR (KBr) [
n
/cmꢁ1]:
3444, 2972, 2937, 2249, 1712, 1650, 1543, 1503, 1456, 1377, 1167,
1053, 1013, 749. 1H NMR (CDCl3)
d 2.91 (1H, H-2), 4.09 (1H, H-3),
3.3.16. 9-Deoxo-9-dihydro-9a-[N0-(
b
-cyanoethyl)-N0-
2.04 (1H, H-4), 3.61 (1H, H-5), 1.78, 1.37 (2H, H-7), 2.05 (1H, H-8),
NA (2H, H-9), NA (1H, H-10), 3.77 (1H, H-11), 4.64 (1H, H-13), 1.88;
1.49 (2H, H-14), 0.89 (3H, H-15), 4.89 (1H, H-10), 3.23 (1H, H-20),
2.46 (1H, H-30), 2.30 (6H, 30 NMe2), 1.67; 1.21 (2H, H-40), 3.47 (1H,
H-50), 4.43 (1H, H-100), 2.30; 1.48 (2H, H-200), 3.31 (3H, 300 OMe),
2.91 (1H, H-400), 4.01 (1H, H-500), 1.19 (3H, 2 Me), 1.08 (3H, 4 Me),
1.34 (3H, 6 Me), 1.01 (1H, H-8 Me), 1.12 (3H, 10 Me), 1.20 (3H, 12
phenylethylcarbamoyl- -aminopropyl]-9a-aza-9a-
g
homoerythromycin A (8d)
Yield 30.1%. MS m/z: (ES): MHþ ¼ 992.3. IR (KBr) [
n
/cmꢁ1]: 3444,
2971, 2936, 2876, 2249, 1694, 1644, 1538, 1455, 1377, 1267, 1167,
1053, 1012, 700. 1H NMR (CDCl3)
d 2.89 (1H, H-2), 4.05 (1H, H-3),
2.02 (1H, H-4), 3.61 (1H, H-5), 1.81, 1.37 (2H, H-7), 2.03 (1H, H-8),
2.83, 2.33 (2H, H-9), 2.71 (1H, H-10), 3.70 (1H, H-11), 4.60 (1H, H-
13), 1.88; 1.51 (2H, H-14), 0.89 (3H, H-15), 4.44 (1H, H-10), 3.23 (1H,
H-20), 2.48 (1H, H-30), 2.31 (6H, 30 NMe2), 1.69, 1.23 (2H, H-40), 3.46
(1H, H-50), 4.94 (1H, H-100), 2.32; 1.56 (2H, H-200), 3.31 (3H, 300 OMe),
2.99 (1H, H-400), 4.03 (1H, H-500), 1.22 (3H, 2 Me), 1.09 (3H, 4 Me),
1.31 (3H, 6 Me), 0.99 (1H, H-8 Me), 1.08 (3H, 10 Me), 1.06 (3H, 12
Me), 1.21 (3H, 50 Me), 1.23 (3H, 300 Me),1.24 (3H, 500 Me), 3.2; 2.8 (2H,
Me), 1.20 (3H, 50 Me), 1.19 (3H, 300 Me), 1.31 (3H, 500 Me), NA (2H,
CH2), 1.89 (2H, -CH2), 3.5 (2H, -CH2), 3.74 (2H,
0-CH2), 2.82 (2H,
0-CH2), 7.96 (1H, h, naphthyl), 7.75 (1H, c, naphthyl), 7.74 (1H, d,
naphthyl), 7.74 (1H, g, naphthyl), 7.49 (1H, a, naphthyl), 7.41 (1H, f,
naphthyl), 7.35 (1H, e, naphthyl); 13C NMR (CDCl3)
177 (C-1), 44.3
a-
b
g
a
b
d
(C-2), 79.4 (C-3), 39.7 (C-4), 83.0 (C-5), 73.9 (C-6), 39.3 (C-7), 28.5
(C-8), 62.7 (C-9), 60 (C-10), 74.1 (C-11), 74.0 (C-12), 77.8 (C-13),
20.5 (C-14), 10.4 (C-15), 102.4 (C-10), 70.1 (C-20), 64.8 (C-30), 39.7
(30 NMe2), 28.3 (C-40), 68.3 (C-50), 95.4 (C-100), 34.4 (C-200), 72.1 (C-
300), 48.8 (300 OMe), 77.1 (C-400), 65.0 (C-500), 15.0 (2 Me), 8.93 (4
Me), 26.4 (6 Me), 23.2 (8 Me), 6.66 (10 Me), 15.8 (12 Me), 20.9 (500
a
-CH2), 1.86 (2H,
2.67 (2H,
0-CH2), 3.48 (2H,
phenyl, b), 7.21 (2H, phenyl, c), 7.20 (1H, phenyl, d); 13C NMR
(CDCl3) 178.1 (C-1), 44.9 (C-2), 80.2 (C-3), 40.0 (C-4), 83.5 (C-5),
b
-CH2), 3.05 (2H,
g
-CH2), 3.60, 3.50 (2H,
a
0-CH2),
b
a
00-CH2), 2.84 (2H,
b
00-CH2), 7.28 (2H,
d
74.7 (C-6), 39.5 (C-7), 28.9 (C-8), 63.4 (C-9), 60 (C-10), 74.4 (C-11),
74.6 (C-12), 78.3 (C-13), 21.1 (C-14), 11.1 (C-15), 102.9 (C-10), 70.9 (C-
20), 65.7 (C-30), 40.4 (30 NMe2), 28.9 (C-40), 68.8 (C-50), 96.1 (C-100),
35.1 (C-200), 72.8 (C-300), 49.4 (300 OMe), 77.9 (C-400), 65.9 (C-500), 15.5
Me), 20.6 (300 Me), 17.8 (500 Me), 48.4 (
CH2), 43.7 (
0-CH2); 16.7 ( 00-CH2), 154.9 (NHCONH), 118.6 (CN),
a-CH2); 26.8 (b-CH2), 47.0 (g-
a
b
135.9 (CH, a, naphthyl), 120.9 (CH, b, naphthyl), 127.8 (CH, c,
naphthyl), 126.7 (CH, d, naphthyl), 123.9 (CH, e, naphthyl), 125.5

ˇ
M. Bukvi´c Krajaci´c et al. / European Journal of Medicinal Chemistry 44 (2009) 3459–3470
3468
(CH, f, naphthyl), 116.6 (CH, h, naphthyl), 133.4 (C, i, naphthyl),
129.7 (C, j, naphthyl).
699. 1H NMR (CDCl3)
d 2.89 (1H, H-2), 4.16 (1H, H-3), 2.18 (1H, H-4),
3.63 (1H, H-5), 1.80; 1.33 (2H, H-7), 2.05 (1H, H-8), 2.78; 2.20 (2H,
H-9), 2.85 (1H, H-10), 3.73 (1H, H-11), 4.62 (1H, H-13), 1.89; 1.50
(2H, H-14), 0.90 (3H, H-15), 4.45 (1H, H-10), 3.24 (1H, H-20), 2.48
(1H, H-30), 2.32 (6H, 30 NMe2), 1.69; 1.24 (2H, H-40), 3.50 (1H, H-50),
4.98 (1H, H-100), 2.37; 1.59 (2H, H-200), 3.33 (3H, 300 OMe), 3.02 (1H,
H-400), 4.10 (1H, H-500), 1.19 (3H, 2 Me), 1.09 (3H, 4 Me), 1.33 (3H, 6
Me), 0.99 (1H, H-8 Me), 1.11 (3H, 10 Me), 1.08 (3H, 12 Me), 1.23 (3H,
3.3.19. 9-Deoxo-9-dihydro-9a-[N0-(
b
-cyanoethyl)-N0-[1-(1-
naphthyl)ethyl]carbamoyl-g-aminopropyl]-9a-aza-9a-
homoerythromycin A (8h)
Yield 30.0%. MS m/z: (ES): MHþ ¼ 1042.4. IR (KBr) [
n
/cmꢁ1]:
3444, 2972, 2936,1728,1634,1520,1456,1377,1168,1053,1013, 801,
779. 1H NMR (CDCl3)
d
2.86 (1H, H-2), 4.11 (1H, H-3), 2.01 (1H, H-4),
50 Me), 1.25 (3H, 300 Me), 1.31 (3H, 500 Me), 3.12, 2.46 (2H,
2.78 (2H, -CH2), 4.08; 3.82 (2H, -CH2), 4.23 (2H,
0-CH2), 2.87 (2H,
0-CH2), 7.30 (2H, phenyl, b), 7.27 (2H, phenyl, c), 7.19 (1H, phenyl,
d), 5.78 (2H, 178.3 (C-1), 44.9 (C-2),
%-CH2). 13C NMR (CDCl3)
a-CH2),
3.60 (1H, H-5), 1.76, 1.38 (2H, H-7), 1.99 (1H, H-8), 2.66; 2.12 (2H, H-
9), 2.74 (1H, H-10), 3.67 (1H, H-11), 4.59 (1H, H-13), 1.88; 1.49 (2H,
H-14), 0.92 (3H, H-15), 4.44 (1H, H-10), 3.23 (1H, H-20), 2.47 (1H, H-
30), 2.30 (6H, 30 NMe2), 1.69; 1.31 (2H, H-40), 3.51 (1H, H-50), 5.00
(1H, H-100), 2.36; 1.59 (2H, H-200), 3.31 (3H, 300 OMe), 3.03 (1H, H-400),
4.06 (1H, H-500), 1.23 (3H, 2 Me), 1.08 (3H, 4 Me), 1.68 (3H, 6 Me),
0.98 (1H, 8 Me), 1.04 (3H, 10 Me), 1.32 (3H, 12 Me), 1.24 (3H, 50 Me),
b
g
a
b
a
d
79.5 (C-3), 40.4 (C-4), 83.3 (C-5), 74.3 (C-6), 40.1 (C-7), 28.8 (C-8),
63.2 (C-9), 59.6 (c-10), 74.2 (C-11), 74.6 (C-12), 78.2 (C-13), 21.2 (C-
14), 11.2 (C-15), 102.9 (C-10), 70.9 (C-20), 65.7 (C-30), 40.4 (30 NMe2),
28.9 (C-40), 68.7 (C-50), 95.8 (C-100), 35.0 (C-200), 72.8 (C-300), 49.4 (300
OMe), 78.0 (C-400), 65.7 (C-500), 15.4 (2 Me), 9.4 (4 Me), 27.2 (6 Me),
23.4 (8 Me), 7.7 (10 Me),16.3 (12 Me), 21.4 (50 Me), 21.5 (300 Me),18.5
1.25 (3H, 300 Me), 1.30 (3H, 500 Me), 3.02; 2.30 (2H,
a
-CH2), 1.88 (2H,
0-CH2), 2.72 (2H, 0-CH2), 5.80;
00-CH2), 8.15 (1H, b, naphthyl), 7.85 (1H,
b
-CH2), 3.20 (2H,
g
-CH2), 3.59 (2H,
a
b
5.03 (2H,
a
00-CH2),1.68 (3H,
b
(500 Me), 48.1 (
a
-CH2), 26.4 (
b
-CH2), 55.0 (
g
-CH2), 49.2 (
a
0-CH2), 16.5
d, naphthyl), 7.76 (1H, e, naphthyl), 7.54 (1H, h, naphthyl), 7.52 (1H,
(b
0-CH2), 119.0 (CN), 180.8 (NCSNH), 138.1 (phenyl, a), 128.3 (phenyl,
c, naphthyl), 7.48 (1H, g, naphthyl), 7.45 (1H, f, naphthyl); 13C NMR
c), 126.9 (phenyl, b), 126.7 (phenyl, d).
(CDCl3)
d 177.4 (C-1), 44.2 (C-2), 79.9 (C-3), 39.6 (C-4), 82.9 (C-5),
73.8 (C-6), 39.4 (C-7), 28.2 (C-8), 63.2 (C-9), 60 (C-10), 77.4 (C-11),
74.0 (C-12), 78.9 (C-13), 20.6 (C-14), 10.8 (C-15), 102.3 (C-10), 70.3
(C-20), 65.1 (C-30), 40.4 (30 NMe2), 29.8 (C-40), 68.1 (C-50), 95.1 (C-100),
34.4 (C-200), 72.2 (C-300), 48.7 (300 OMe), 78.9 (C-400), 65.2 (C-500), 13.5
(2 Me), 9.0 (4 Me), 26.5 (6 Me), 22.4 (8 Me), 6.9 (10 Me), 14.9 (12
Me), 21.8 (500 Me), 21.2 (300 Me), 16.5 (500 Me), 49.4 (
CH2), 48 ( -CH2), 43 (
00-CH2); 17.0 ( 00-CH2), 158 (NHCONH), 118.7
(CN), 46.0 (
00-CH2), 21.8 ( 00-CH2), 139.1 (C, a, naphthyl), 133.4 (C, i,
3.3.22. 9-Deoxo-9-dihydro-9a-[N0-(
b
-cyanoethyl)-N0-(
b
-
phenylethyl)thiocarbamoyl-g-aminopropyl]-9a-aza-9a-
homoerythromycin A (10d)
Yield 36.0%. MS m/z: (ES): MHþ ¼ 1008.4. IR (KBr) [
n
/cmꢁ1]:
3444, 2972, 2936, 2250, 1727, 1530, 1455, 1380, 1169, 1053, 1012,
a
-CH2); 26.8 (
b
-
896, 701. 1H NMR (CDCl3)
d 2.91 (1H, H-2), 4.01 (1H, H-3), 2.02 (1H,
g
a
b
H-4), 3.62 (1H, H-5), 1.82,1.33 (2H, H-7), 2.27 (1H, H-8), 3.69 (1H, H-
11), 4.58 (1H, H-13), 1.89; 1.48 (2H, H-14), 0.89 (3H, H-15), 4.45 (1H,
H-10), 3.23 (1H, H-20), 2.47 (1H, H-30), 2.31 (6H, 30 NMe2), 1.69; 1.25
(2H, H-40), 3.49 (1H, H-50), 4.90 (1H, H-100), 2.32; 1.56 (2H, H-200),
3.30 (3H, 300 OMe), 2.97 (1H, H-400), 3.99 (1H, H-500), 1.19 (3H, 2 Me),
1.10 (3H, 4 Me), 1.33 (3H, 6 Me), 1.01 (1H, H-8 Me), 1.08 (3H, 10
Me), 1.06 (3H, 12 Me), 1.16 (3H, 50 Me), 1.23 (3H, 300 Me), 1.21 (3H, 500
a
b
naphthyl), 130, 5 (C, j, naphthyl), 128.1 (CH, d, naphthyl), 127.3 (CH,
e, naphthyl), 125.7 (CH, c, naphthyl), 125.1 (CH, g, naphthyl), 124.3
(CH, f, naphthyl), 122.9 (CH, b, naphthyl), 121.6 (CH, h, naphthyl).
3.3.20. 9-Deoxo-9-dihydro-9a-[N0-(
phenylthiocarbamoyl- -aminopropyl]-9a-aza-9a-
b
-cyanoethyl)-N0-
g
Me), 3.44, 3.27 (2H,
CH2), 2.98, 2.88 (2H,
a
b
-CH2), 2.19 (2H,
b
-CH2), 3.96; 3.94 (2H, a0
00-CH2); 2.90 (2H, b00
-
-
homoerythromycin A (10b)
0-CH2), 3.98, 3.86 (2H,
a
Yield 30.0%. MS m/z: (ES): MHþ ¼ 980.3. IR (KBr) [
n
/cmꢁ1]: 450,
CH2), 7.30 (phenyl, b), 7.26 (phenyl, c), 7.19 (phenyl, d); 13C NMR
2972, 2937, 2877, 2249,1726,1522,1456,1375,1167,1053,1013, 900,
(CDCl3) d 178.0 (C-1), 44.8 (C-2), 80.8 (C-3), 39.5 (C-4), 83.5 (C-5),
701. 1H NMR (CDCl3)
d
2.90 (1H, H-2), 4.05 (1H, H-3), 2.01 (1H, H-4),
74.6 (C-6), 38.8 (C-7), 28.8 (C-8), 74.9 (C-11), 74.9 (C-12), 78.4 (C-
13), 21.0 (C-14), 11.1 (C-15), 102.9 (C-10), 71.0 (C-20), 65.6 (C-30), 40.3
(30 NMe2), 28.9 (C-40), 68.7 (C-50), 96.4 (C-100), 35.1 (C-200), 72.7 (C-
300), 49.4 (300 OMe), 77.7 (C-400), 66.0 (C-500), 15.7 (2 Me), 9.6 (4 Me),
27.1 (6 Me), 23.7 (8 Me), 6.8 (10 Me), 16.2 (12 Me), 18.4 (50 Me), 21.4
3.59(1H, H-5),1.79; 1.32 (2H, H-7), 2.07 (1H, H-8), 2.78; 2.1 (2H, H-9),
2.88 (1H, H-10), 3.73 (1H, H-11), 4.64 (1H, H-13), 1.89; 1.49 (2H, H-
14), 0.88 (3H, H-15), 4.45 (1H, H-10), 3.25 (1H, H-20), 2.51 (1H, H-30),
2.33 (6H, 30 NMe2), 1.72; 1.22 (2H, H-40), 3.50 (1H, H-50), 4.95 (1H,
H-100), 2.32; 1.58 (2H, H-200), 3.31 (3H, 300 OMe), 3.02 (1H, H-400), 4.05
(1H, H-500),1.21 (3H, 2 Me),1.07 (3H, 4 Me),1.28 (3H, 6 Me), 0.99 (1H,
H-8 Me),1.14 (3H,10 Me),1.08 (3H,12 Me),1.21 (3H, 50 Me),1.24 (3H,
(300 Me), 21.5 (500 Me), 50 (
0-CH2); 16.6 0-CH2), 47.0
a
-CH2); 27.1 (
b
-CH2), 49.4 (
g-CH2), 49.2
(a
(
b
(a
00-CH2); 35.2
(b
00-CH2), 181.1
(NHCSNH), 119.0 (CN), 139.2 (phenyl, a), 129.0 (phenyl, b), 128.5
(phenyl, c), 126.3 (phenyl, d).
300 Me),1.25 (3H, 500 Me), 3.02 (2H,
(2H, -CH2), 4.27; 4.15 (2H,
0-CH2), 3.02 (2H,
phenyl, b), 7.34 (2H, phenyl, c), 7.22 (1H, phenyl, d). 13C NMR (CDCl3)
178.1 (C-1), 44.9 (C-2), 80.2 (C-3), 40.0 (C-4), 83.6 (C-5), 74.8 (C-6),
a
-CH2), 2.23 (2H,
b-CH2), 3.51; 2.8
0-CH2), 7.33 (2H,
g
a
b
3.3.23. 9-Deoxo-9-dihydro-9a-[N0-(
b
-cyanoethyl)-N0-(3-
d
phenylpropyl)thiocarbamoyl-g-aminopropyl]-9a-aza-9a-
39.7 (C-7), 29.3 (C-8), 65 (C-9), 74.7 (C-11), 74.6 (C-12), 78.2 (C-13),
21.0 (C-14), 11.1 (C-15), 103.0 (C-10), 70.9 (C-20), 65.7 (C-30), 40.4 (30
NMe2), 28.9 (C-40), 68.8 (C-50), 96.0 (C-100), 35.1 (C-200), 72.8 (C-300),
49.4 (300 OMe), 77.8 (C-400), 66.0 (C-500),15.6 (2 Me), 9.5 (4 Me), 27.0 (6
Me), 23.2 (8 Me), 7.3 (10 Me),16.2 (12 Me), 21.4 (50 Me), 21.5 (300 Me),
homoerythromycin A (10e)
Yield 39.0%. MS m/z: (ES): MHþ ¼ 1022.4. IR (KBr) [
n
/cmꢁ1]: 3438,
2970, 2935, 2870, 2248,1726,1530,1455,1377,1167,1053,1012, 749,
700. 1H NMR (pyridine-d5)
d 3.18 (1H, H-2), 4.64 (1H, H-3), 2.49 (1H,
H-4), 4.15 (1H, H-5), 2.00, 1.86 (2H, H-7), 2.17 (1H, H-8), 2.28; 2.71
(2H, H-9), 3.12 (1H, H-10), 4.18 (1H, H-11), 5.37 (1H, H-13), 2.17; 1.73
(2H, H-14), 0.93 (3H, H-15), 5.01 (1H, H-10), 3.63 (1H, H-20), 2.70 (1H,
H-30), 2.17 (6H, 30 NMe2), 1.69; 1.31 (2H, H-40), 3.51 (1H, H-50), 5.00
(1H, H-100), 2.36; 1.59 (2H, H-200), 3.52 (3H, 300 OMe), 3.31 (1H, H-400),
4.62 (1H, H-500),1.36 (3H, 2 Me),1.63 (3H, 4 Me),1.77 (3H, 6 Me), 0.98
(1H, H-8 Me),1.33 (3H,10 Me),1.39 (3H,12 Me),1.35 (3H, 50 Me),1.36
18.6 (500 Me), 49.2 (
16.4 (
0-CH2), 119.0 (CN), 182.4 (NCONH), 139.9 (phenyl, a), 128.7
(phenyl, b), 127.1 (phenyl, c), 126.3 (phenyl, d).
a-CH2), 26.2 (b-CH2), 50.2 (g-CH2), 49.3 (a
0-CH2),
b
3.3.21. 9-Deoxo-9-dihydro-9a-[N0-(
b
-cyanoethyl)-N0-
benzylthiocarbamoyl- -aminopropyl]-9a-aza-9a-
g
homoerythromycin A (10c)
(3H, 300 Me),1.69 (3H, 500 Me), 3.33(2H,
3.75 (2H, -CH2), 4.40; 4.29 (2H,
0-CH2), 3.21 (2H,
%-CH2); 2.17 (2H, %-CH2), 2.70 (2H, %-CH2), 7.28 (phenyl, b), 7.23
a
-CH2), 2.10 (2H,
b-CH2), 3.95;
Yield 44.0%. MS m/z: (ES): MHþ ¼ 994.4. IR (KBr) [
n
/cmꢁ1]: 3444,
g
a
b
00-CH2), 3.98 (2H,
2972, 2937, 2877, 2249, 1721, 1531, 1455, 1379, 1167, 1053, 1012, 896,
a
b
g

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M. Bukvi´c Krajaci´c et al. / European Journal of Medicinal Chemistry 44 (2009) 3459–3470
3469
(phenyl, c), 7.21 (phenyl, d).13C NMR (pyridine-d5)
d
177.6 (C-1), 45.5
(1H, f), 7.37 (1H, g), 7.80 (1H, h), 9.02 (1H, NH), 6.36 (1H, NH). 13
C
(C-2), 79.9 (C-3), 41.1 (C-4), 83.8 (C-5), 74.8 (C-6), 41 (C-7), 29.1 (C-8),
63.5 (C-9), 60.1 (C-10), 76.1 (C-11), 75.2 (C-12), 78.2 (C-13), 22.1 (C-
14), 11.4 (C-15), 103.4 (C-10), 71.8 (C-20), 65.8 (C-30), 40.5 (30 NMe2),
30.3 (C-40), 68.2 (C-50), 96.4 (C-100), 35.7 (C-200), 73.7 (C-300), 49.7 (300
OMe), 78.7 (C-400), 66.3 (C-500), 15.9 (2 Me), 10.4 (4 Me), 27.9 (6 Me),
23.2 (8 Me), 8.5 (10 Me),18.4 (12 Me), 22.0 (50 Me), 21.6 (300 Me),19.6
NMR (pyridine-d5)
d
177.6 (C-1), 45.7 (C-2), 78.0 (C-3), 38.6 (C-4),
93 (C-5), 74.9 (C-6), 42 (C-7), 31 (C-8), 77.7 (C-11), 75.9 (C-12), 78.2
(C-13), 22.7 (C-14), 11.6 (C-15), 105.9 (C-10), 71.6 (C-20), 66.2 (C-30),
41.0 (30 NMe2), 30.5 (C-40), 70.0 (C-50), 17.2 (2 Me), 9.6 (4 Me), 28.1
(6 Me), 22.0 (8 Me), 8 (10 Me), 18.7 (12 Me), 21.8 (50 Me), 51 (
30.6 (b-CH2), 39.4 (g-CH2), 157.6 (NHCONH), 136.8 (C, j), 135.3 (C, i),
129.3 (CH, h), 128.2 (CH, a), 127.0 (CH, c), 126.5 (C, g), 126.2 (CH, f),
123.9 (CH, b), 122.8 (CH, e), 119.6 (CH, d).
a
-CH2),
(500 Me), 49.3 (
0-CH2), 46.1
a
-CH2); 26.4 (
b
-CH2), 49.3 (
g
-CH2), 48.4 (
a
0-CH2); 16.7
(b
(a
00-CH2); 31.5
(
b
00-CH2), 33.6
(g
00-CH2), 182.5
(NHCSNH), 119.5 (CN), 142.5 (phenyl, a), 128.8 (phenyl, b), 128.7
(phenyl, c), 126.1 (phenyl, d).
3.4.2. 5-O-Desosaminyl-9-deoxo-9-dihydro-9a-[N0-(
b-
cyanoethyl)-N0-(1-naphthyl)carbamoyl-
9a-homoerythronolide A (9f)
g-aminopropyl]-9a-aza-
3.3.24. 9-Deoxo-9-dihydro-9a-[N0-(
b
-cyanoethyl)-N0-(1-
naphthyl)thiocarbamoyl- -aminopropyl]-9a-aza-9a-
g
Yield 80.2%. MS m/z: (ES): MHþ ¼ 856.1. 1H NMR (CDCl3)
d 2.62
homoerythromycin A (10f)
(1H, H-2), 3.31 (1H, H-3), 2.01 (1H, H-4), 3.15 (1H, H-5),1.51,1.33 (2H,
H-7), 2.13 (1H, H-8), 2.90, 2.36 (2H, H-9), 2.97 (1H, H-10), 3.83 (1H,
H-11), 4.65 (1H, H-13), 1.93; 1.57 (2H, H-14), 0.90 (3H, H-15), 3.55
(1H, H-10), 3.09 (1H, H-20), 2.46 (1H, H-30), 2.36 (6H, 30 NMe2), 1.73;
1.13 (2H, H-40), 3.15 (1H, H-50), 1.16 (3H, 2 Me), 0.95 (3H, 4 Me), 1.28
(3H, 6 Me), 0.94 (1H, 8 Me), 1.14 (3H, 10 Me), 1.08 (3H, 12 Me), 1.11
Yield 36.0%. MS m/z: (ES): MHþ ¼ 1030.4. IR (KBr) [
n
/cmꢁ1]:
3444, 2970, 2935, 2870, 2249, 1727, 1530, 1455, 1377, 1167, 1053,
1012. 1H NMR (pyridine-d5)
d 3.18 (1H, H-2), 4.69 (1H, H-3), 2.51
(1H, H-4), 4.17(1H, H-5), 2.03 1.86 (2H, H-7), 2.24(1H, H-8), 2.77;
2.31 (2H, H-9), 3.15(1H, H-10), 4.23 (1H, H-11), 5.37 (1H, H-13), 2.16;
1.68 (2H, H-14), 0.91 (3H, H-15), 5.00 (1H, H-10), 3.61 (1H, H-20), 2.70
(1H, H-30), 2.15 (6H, 30 NMe2), 1.39; 1.14 (2H, H-40), 4.04 (1H, H-50),
5.26 (1H, H-100), 2.46; 1.56 (2H, H-200), 3.51 (3H, 300 OMe), 3.31 (1H,
H-400), 4.64 (1H, H-500), 1.37 (3H, 2 Me), 1.63 (3H, 4 Me), 1.79 (3H, 6
Me), 0.98 (1H, H-8 Me), 1.34 (3H, 10 Me), 1.41 (3H, 12 Me), 1.35 (3H,
(3H, 50 Me), 3.37, 2.33 (2H,
(2H, -CH2), 3.72, 3.56 (2H,
a
a
-CH2), 2.13, 1.73 (2H,
b-CH2), 3.87, 3.25
g
0-CH2), 2.79 (2H, 0-CH2), 8.02 (1H, d,
b
naphthyl), 7.85 (1H, e, naphthyl), 7.77 (1H, h, naphthyl), 7.58 (1H, c,
naphthyl), 7.54 (1H, b, naphthyl), 7.51 (1H, f, naphthyl), 7.50 (1H, g,
naphthyl). 13C NMR (CDCl3)
d 177.8 (C-1), 44.5 (C-2), 78.6 (C-3), 36.7
500 Me), 1.32 (3H, 300 Me), 1.68 (3H, 500 Me), 3.42, 2.55 (2H,
2.39 (2H, -CH2), 4.33, 4.08 (2H, -CH2), 4.64, 4.42 (2H,
0-CH2), 3.38
(2H,
0-CH2), 7.72 (naphthyl, b), 7.47 (naphthyl, c), 7.79 (naphthyl,
d), 7.86 (naphthyl, e), 7.43 (naphthyl, g), 7.59 (naphthyl, g), 8.49
(naphthyl, h); 13C NMR (pyridine-d5)
178.7 (C-1), 46.3 (C-2), 80.6
a
-CH2),
(C-4), 91.6 (C-5), 74.2 (C-6), 38.1 (C-7), 28.5 (C-8), 59 (C-9), 57 (C-10),
75.2 (C-11), 74.6 (C-12), 78.2 (C-13), 21.0 (C-14),10.9 (C-15),106.2 (C-
10), 70.2 (C-20), 65.8 (C-30), 40.3 (30 NMe2), 28.8 (C-40), 69.5 (C-50),15.1
(2 Me), 7.8 (4 Me), 24.2 (6 Me), 22 (8 Me), 6.1 (10 Me), 16.1 (12 Me),
b
g
a
b
d
21.0 (50 Me), 49.4 (
a-CH2), 27.0 (b-CH2), 48.6 (g-CH2), 44.8 (a
0-CH2),
(C-3), 42.0 (C-4), 84.6 (C-5), 75.6 (C-6), 41.6 (C-7), 30.1 (C-8), 64.5 (C-
9), 61.2 (C-10), 77.0 (C-11), 76.0 (C-12), 79.0 (C-13), 22.8 (C-14), 12.1
(C-15), 104.2 (C-10), 72.6 (C-20), 66.5 (C-30), 41.3 (30 NMe2), 31.1 (C-
40), 69.0 (C-50), 97.2 (C-100), 36.4 (C-200), 74.5 (C-300), 50.5 (300 OMe),
79.5 (C-400), 67.1 (C-500), 16.6 (2 Me), 11.0 (4 Me), 28.7 (6 Me), 24.0 (8
Me), 9.1 (10 Me), 19.1 (12 Me), 22.8 (50 Me), 22.4 (300 Me), 20.3 (500
17.4 (
b
0-CH2),157.0 (NCON),119.2 (CN),134.9 (C, i, naphthyl),134.4 (C,
j, naphthyl), 131.4 (C, a, naphthyl), 128.1 (CH, e, naphthyl), 126.7 (CH,
h, naphthyl), 126.6 (CH, c, naphthyl), 126.1 (CH, f, naphthyl), 125.9
(CH, b, naphthyl), 125.6 (CH, g, naphthyl), 123.7 (CH, d, naphthyl).
3.5. Acid stability of 4f and 8f
Me), 50.0 (a-CH2), 27.6 (b-CH2), 51.0 (g-CH2), 49.3 (a -
0-CH2); 17.4 (b0
CH2), 185.0 (NHCSNH), 120.4 (CN), 139. C(C, a, naphthyl), 128.0 (CH,
b, naphthyl), 126.8 (CH, c, naphthyl), 128.3 (CH, d, naphthyl), 135.7
(C, j, naphthyl), 129.4 (CH, e, naphthyl) 127.1 (CH, f, naphthyl), 127.4
(CH, g, naphthyl), 125.4 (CH, h, naphthyl), 133.2 (C, i, naphthyl).
3.5.1. Preparation of 5f hydrolysate in 0.01 M HCl
Solution of 4f in 0.01 M HCl of concentration 1 mg/ml (100 ml)
was stirred for 10 h at room temperature. After isolation and
purification procedures, described in Section 3.3.1, the pure 5f was
1
obtained. Its H and 13C NMR spectra were identical to the spectra
3.4. General procedure for the hydrolysis of 4f and 8f
of the 5f authentic sample.
The suspension of 4f or 8f (0.55 mmol) in 1 M hydrochloric acid
(5 ml) was stirred for 12 h at room temperature, the pH was
adjusted to 9.5–10 by adding 1 M NaOH and was extracted with
CH2Cl2 (3 ꢃ 4 ml). The combined organic layers were washed with
water, dried over anhydrous Na2SO4, evaporated to dryness under
reduced pressure to give crude product wherefrom by chroma-
tography on silica gel column using CH2Cl2:CH3OH:NH3
(25%) ¼ 90:9:1.5 as eluents pure 5f or 9f were obtained.
3.5.2. HPLC assay and decay data
The solution of 4f or 8f in 0.01 M HCl aqueous hydrochloric acid
(concentration of 1 mg/ml) was held at 25 ꢀC, 30 ꢀC, 37 ꢀC and 40 ꢀC
for 10 h. The sample of the solution (20 ml) was taken each 20 min,
and the course of reaction was monitored by the reverse phase
HPLC. Each experiment was repeated three times, and displayed
data represent average values.
An Agilent 1100 Series LC/MSD trap, SL model with an electro-
spray interface (ESI), a binary pump, degasser, autosampler, ther-
mostatted column compartment and diode array detector was
used. The analysis was carried out with UV detection at 240 nm on
3.4.1. 5-O-Desosaminyl-9-deoxo-9-dihydro-9a-[N0-(1-
naphthyl)carbamoyl-g-aminopropyl]-9a-aza-9a-
homoerythronolide A (5f)
a YMC Pack Pro C18 column, 150 ꢃ 4.6 mm i.d., 3
with a mobile phase consisted of channel A 40 mM ammonium
acetonitrile.
mm particle size
Yield 88.0%. MS m/z: (ES): MHþ ¼ 803.1. 1H NMR (pyridine-d5)
d
2.99 (1H, H-2), 4.23 (1H, H-3), 2.48 (1H, H-4), 4.15 (1H, H-5), 1.87,
acetate buffer solution (pH ¼ 5) and channel
B
1.70 (2H, H-7), 2.15 (1H, H-8), 2.88; 2.24 (2H, H-9), 3.13 (1H, H-10),
4.15 (1H, H-11), 5.43 (1H, H-13), 2.24; 1.70 (2H, H-14), 0.87 (3H, H-
15), 4.91 (1H, H-10), 3.61 (1H, H-20), 2.61 (1H, H-30), 2.19 (6H, 30
NMe2), 1.37; 1.18 (2H, H-40), 3.46 (1H, H-50), 1.53 (3H, 2 Me), 1.49
(3H, 4 Me), 1.64 (3H, 6 Me), 1.05 (3H, 8 Me), 1.34 (3H, 10 Me), 1.38
Gradient elution at flow rate 1.0 ml minꢁ1 started with 10% of
channel B and ended after 15 min with 90% of channel B. The ESI
source was operated in the positive ion mode. Nitrogen was used as
nebulizing and drying gas at 350 ꢀC. The m/z range scanned in the
MS measurement was 200–1200. Complete system control, data
acquisition and processing were done using the ChemStation for
LC/MSD version 4.2 from Agilent.
(3H, 12 Me), 1.13 (3H, 50 Me), 2.77 (2H,
(2H, -CH2), 7.57 (1H, b), 7.43 (1H, c), 8.42 (1H, d), 8.25 (1H, e), 7.34
a-CH2), 1.96 (2H, b-CH2), 3.53
g

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M. Bukvi´c Krajaci´c et al. / European Journal of Medicinal Chemistry 44 (2009) 3459–3470
3470
Reaction rate constants were determined by using exponential
Acknowledgements
We areindebted toAna Cikos and BiserkaMetelko for performing
fit method available within Excel program. The activation energies
for hydrolysis of the glycosidic bond in 6a and 6b were calculated
according to the Arrhenius equation (1).
ꢀ
ˇ
ˇ
NMR experiments and Karmen Brajsa for antibacterial experiments.
This study was supported by the Ministry of Science, Education and
Sports of the Republic of Croatia (Projects No.119-1191342-1083 and
No. 006-0000000-3216).
ln k ¼ ln A ꢁ Ea=RT
(1)
where A is the temperature factor, Ea is the activation energy, R is
the ideal gas constant (8.3184 J Kꢁ1 molꢁ1) and T is the thermody-
namic temperature.
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