Design, synthesis, and structure-activity relationship studies of conformationally restricted mutilin 14-carbamates

Article abstract of DOI:10.1016/j.bmcl.2011.12.063

We report herein the design, synthesis, and structure-activity relationship studies of conformationally restricted mutilin 14-carbamates based on the structure of SB-222734. The antibacterial activities of these newly synthesized compounds were also evaluated and compared with linezolid and retapamulin. Results showed that most of the target compounds exhibit good potency in inhibiting the growth of Gram-positive bacteria including Methicillin- susceptible Staphylococcus aureus MSSA (MIC: 0.0625-2 μg/mL), Methicillin-resistant S. aureus MRSA (MIC: 0.0625-2 μg/mL), Methicillin-susceptible Staphylococcus epidermidis MSSE (MIC: 0.0625-2 μg/mL), Methicillin-resistant S. epidermidis MRSE (MIC: 0.0625-2 μg/mL), and Streptococcus pneumonia (MIC: 0.0625-4 μg/mL). In particular, three remarkable compounds of this series (12l, 12m, and 21l) exhibited comparable in vitro antibacterial profiles to that of retapamulin.

Full text of DOI:10.1016/j.bmcl.2011.12.063

Bioorganic & Medicinal Chemistry Letters 22 (2012) 814–819
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis, and structure–activity relationship studies
of conformationally restricted mutilin 14-carbamates
⇑
Liqiang Fu , Xin Liu , Chenyu Ling, Jianjun Cheng, Xingsheng Guo, Huili He, Shi Ding, Yushe Yang
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China
a r t i c l e i n f o
a b s t r a c t
Article history:
We report herein the design, synthesis, and structure–activity relationship studies of conformationally
restricted mutilin 14-carbamates based on the structure of SB-222734. The antibacterial activities of these
newly synthesized compounds were also evaluated and compared with linezolid and retapamulin. Results
showed that most of the target compounds exhibit good potency in inhibiting the growth of Gram-positive
Received 18 October 2011
Revised 9 December 2011
Accepted 12 December 2011
Available online 20 December 2011
bacteria including Methicillin-susceptible Staphylococcus aureus MSSA (MIC: 0.0625–2
lin-resistant S. aureus MRSA (MIC: 0.0625–2 g/mL), Methicillin-susceptible Staphylococcus epidermidis
MSSE (MIC: 0.0625–2 g/mL), Methicillin-resistant S. epidermidis MRSE (MIC: 0.0625–2 g/mL), andStrep-
tococcus pneumonia (MIC: 0.0625–4 g/mL). In particular, three remarkable compounds of this series (12l,
12m, and 21l) exhibited comparable in vitro antibacterial profiles to that of retapamulin.
Ó 2011 Elsevier Ltd. All rights reserved.
lg/mL), Methicil-
l
Keywords:
Pleuromutilin
Gram-positive bacteria
Conformationally restriction
l
l
l
Due to rapid emergence of multi-drug-resistant Gram-positive
bacteria including Methicillin-resistant Staphylococcus aureus
(MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), and
vancomycin-resistant enterococci (VRE),1,2 there is an urgent need
to identify and develop new antibacterial agents with novel mech-
anisms of action against drug-resistant bacterial strains.3 One
strategy is to re-evaluate old generation of antibiotics that have
not been widely used in clinical trials. One example of this class
of under-exploited antibiotics is the natural product pleuromutilin
(1).4
Pleuromutilin (Fig. 1) was first isolated in 1951 from basidiomy-
cetes Pleurotus and Pleurotus passeckerianus and displays modest
in vitro activity against Gram-positive organisms.5 Further studies
have shown that this class of antibiotics interfered with bacterial
protein synthesis via a specific interaction with the 23S rRNA of
the 50S bacterial ribosome subunit.6,7 These compounds offer a
distinct profile and show no cross-resistance with any other class
of antibiotics. GSK’s novel pleuromutilin analogue retapamulin
(Fig. 1) was first approved for human use as a topical antimicrobial
agent to treat skin infections in 2007.8 Other pleuromutilin deriv-
atives from Nabriva Therapeutics AG such as BC-3205, BC-3781
and BC-7013 (Fig. 1) have entered clinical trials in 2009.9 Another
series of pleuromutilin analogues that attracted great attention is
the C-14 acyl-carbamate derivatives which are under investigation
primarily by GSK.10,11 They reported one potent pleuromutilin ana-
logue with C-14 aroyl-carbamate side chain, SB-222734 (1), which
had excellent antibacterial potency but further development was
hindered by the compound’s atrocious water solubility (Fig. 1). Re-
cently, our group identified the novel water-soluble pleuromutilin
analogue Fu-23 (2), which showed excellent in vitro and in vivo
antibacterial activity and was selected as an intravenous adminis-
tration antimicrobial agent candidate for the treatment of serious
bacterial infections.12,13
Previous structure–activity relationship (SAR) studies demon-
strated the importance of the substituent at C-14 in pleuromutilin
derivatives.14–16 Although pleuromutilin exhibits activity against
Gram-positive bacteria, modifications at the C-14 side chain have
a significant impact on antibacterial activity, while having only a
limited effect on antimicrobial profiles. Basic- or neutral-substi-
tuted aromatic side-chain structures result in remarkable increase
in activity against S. aureus compared with pleuromutilin.4,9 In
continuation of our efforts to find novel potent pleuromutilin ana-
logue through structural modification of SB-222734, we explored
the structure–activity relationship (SAR) by employing conforma-
tional restriction strategy. In this letter, we reported the design,
synthesis, and SAR of a series of novel conformationally restricted
mutilin 14-carbamates. Their in vitro antibacterial activities were
evaluated against a panel of Gram-positive pathogens, including
pathogens resistant to current therapies.
The key intermediate 4-epi-mutilin 14-chloroformate 5 was
synthesized from commercially available pleuromutilin in three
steps as shown in Scheme 1. The skeletal rearranged intermediate
4, colloquially known as 4-epi-mutilin, was synthesized in two
steps from pleuromutilin via an acid-catalyzed 1,5-hydride shift
and hydrolysis.12,17 Then 14-chloroformate 5 was formed by treat-
ment of 4-epi-mutilin with triphosgene.18
⇑
Corresponding author. Tel./fax: +86 21 50806786.
E-mail address: ysyang@mail.shcnc.ac.cn (Y. Yang).
Both authors contributed equally to this work.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.12.063

L. Fu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 814–819
815
Figure 1. Pleuromutilin and its derivatives.
Scheme 1. Reagents and conditions: (a) (CH3O)3CH, MeOH, H2SO4, 18 h, 95%; (b) NaOH, MeOH, H2O, 65 °C, 1.5 h, 97%; (c) Py, triphosgene, THF, 0 °C, 3 h, 89%.
Scheme 2. Reagents and conditions: (a) NBS, BPO, CCl4, 80 °C, 12 h, 85–93%; (b) NH3–MeOH, reflux, 2 h, 91–97%; (c) NaH, THF, PMBCl, rt, 6 h, 88%; (d) (i) primary or secondary
amine, NaOt-Bu, Pd2(dba)3, BINAP, toluene, 80 °C, 12 h, 75–83%; (ii) TFA, anisole, reflux, 24 h, 90–95%; (e) K2CO3, MeOH, 99%; (f) NaH, THF, 5, rt, 6 h, 65–85%; (g) dioxane,
ZnCl2–concd HCl, 25 °C, 5 h, 80–91%; (h) SnCl2Á2H2O, EtOH, reflux, 3 h, 92%.
The scaffold isoindolin-1(1H)-ones (8a–8e and 9) was prepared
from methyl 2-methylbenzoate (6) according to reported method
as shown in Scheme 2.19 Thus, 6 was treated with N-bromosuccin-
imide (NBS) under radical conditions producing the corresponding
brominated derivative 7, which was then cyclized in the presence
of methanolic ammonia to obtain the isoindolinone derivatives in
near quantitative yield. 5-Amino-substituted isoindolin-ones
(8f–8k) were synthesized via an alternate route. Alkylation of 9
gave compound 10 with the protecting para-methoxyl benzyl
(PMB) group.20 The next step involved the Buchwald–Hartwig ami-
nation to install of amine moiety, followed by treatment of these
lactam with trifluoroacetic acid (TFA) in the presence of anisole re-
sulted in the removal of the benzyl protecting group of the lactam
nitrogen to produce the isoindolin-1(1H)-ones (8f–8j).21 Removal

816
L. Fu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 814–819
Scheme 3. Reagents and conditions: (a) Py, THF, 2-chloroacetyl chloride or 3-chloropropionyl chloride, 0 °C, 2 h, 91–93%; (b) secondary amine, NaI, THF, reflux, 2 h, 93–95%.
Scheme 4. Reagents and conditions: (a) PyBOP, EDC, DIEA, DMF, Boc-L-AA-OH, 50 °C; (b) 4.0 M HCl–dioxane, 0 °C to rt, 1 h, 55–68% two steps.
Scheme 5. Reagents and conditions: (a) EtOCOCl, TEA, DCM, 0 °C, 3 h, 76%; (b) PPA, 140 °C, 3 h, 63%; (c) BBr3 (1 M in DCM), À78 °C to rt, 5 h, 91%; (d) acetone, K2CO3,
Br(CH2)nBr, reflux, 8 h, 51–57%; (e) secondary amine, NaI, THF, reflux, 2 h, 86–91%; (f) KNO3, H2SO4, 0 °C, 56–63%; (g) NaH, THF, 5, rt, 6 h, 75–88%; (g) dioxane, ZnCl2–concd
HCl, 25 °C, 4 h, 50–62%; (h) SnCl2Á2H2O, EtOH, reflux, 3 h, 87%.

L. Fu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 814–819
817
Table 1
In vitro minimum inhibitory concentration (MIC,
l
g/mL) values against various clinical isolates
Compds
R1
R2
R3
MICa
(lg/mL)
MSSAb
MRSAc
MSSEd
MRSEe
S.p.f
n = 5
n = 6
n = 5
n = 5
n = 3
12a
12b
12c
12d
12e
H
H
H
H
F
H
H
H
H
H
0.125
2
0.5
0.125
0.5
0.125
2
0.5
0.125
0.5
0.125
2
0.5
0.125
0.5
0.125
2
0.5
0.125
0.5
0.125
4
0.5
0.125
0.5
OMe
NO2
H
H
NO2
N
12f
12g
12h
H
H
H
H
H
H
0.5
2
0.5
2
0.5
2
0.5
2
0.5
4
O
N
N
0.125
0.125
0.125
0.125
0.25
MeN
12i
12j
H
H
H
H
BnNH
CF3CONH
2
2
2
2
2
2
2
2
2
4
12k
12l
12m
H
NH2
H
H
H
NH2
NH2
H
H
0.125–0.25
0.0625–0.125
0.0625–0.125
0.125–0.25
0.0625–0.125
0.0625–0.125
0.125–0.25
0.0625–0.125
0.0625–0.125
0.125–0.25
0.0625–0.125
0.0625–0.125
0.125–0.25
0.0625–0.125
0.0625–0.125
N
NH
O
14a
14b
14c
H
H
H
H
H
H
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1
1
O
N
N
NH
MeN
HO
0.5
0.5
0.25
0.5
0.5
O
N
NH
0.25
2
O
2
N
NH
14d
14e
14f
H
H
H
H
H
H
0.5
0.5
2
0.5
0.5
2
0.25
0.5
2
0.25
0.5
2
0.5
0.5
4
O
O
2
N
NH
MeN
HO
O
N
2
NH
N
2
O
14g
14h
14i
14j
Linezolid
Retapamulin
SB-222734g
Val
H
H
H
H
H
H
H
0.5
0.5
1
0.25
0.5–1
0.0625–0.125
0.0625
0.5
0.5
1
0.25
1
0.5
0.5
1
0.25
0.5–1
0.0625–0.125
0.0625
0.5
0.5
1
0.25
1
0.5
0.5
2
0.5
Ala
Vla
Pro
H
2
0.125
0.0625
0.125
0.0625
0.0625–0.125
0.0625
a
b
c
d
e
f
MIC were determined by the agar microdilution method according to NCCLS standards (M7-A6, 2003).
MSSA = Methicillin-susceptible Staphylococcus aureus.
MRSA = Methicillin-resistant Staphylococcus aureus.
MSSE = Methicillin-susceptible Staphylococcus epidermidis.
MRSE = Methicillin-resistant Staphylococcus epidermidis.
S.p. = Streptococcus pneumoniae.
g
See Refs. 10 and 13.
of the trifluoroacetic group of 8j with potassium carbonate affor-
ded the corresponding 5-aminoisoindolin-1-one (8k).
Completion of the synthesis required the coupling of 5 and 8a–
8k to produce 11a–11k, which was treated with saturated solution
of zinc chloride in concentrated hydrochloride acid resulting in a
reverse 1,5-hydride shift to afford compounds 12a–12k in satisfac-
tory yields.22 The amino substituted 12l and 12m were obtained in
a high yields by reduction of the corresponding nitro compounds
12c and 12e by refluxing in SnCl2Á2H2O ethanol solution,
respectively.23

818
L. Fu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 814–819
Table 2
In vitro minimum inhibitory concentration (MIC,
l
g/mL) values against various clinical isolates
Compds
R2
R3
MICa
(lg/mL)
MSSAb
MRSAc
MSSEd
MRSEe
S.p.f
n = 5
n = 6
n = 5
n = 5
n = 3
21a
21b
21c
21d
H
H
NO2
NO2
OMe
H
OMe
H
1
2
1
0.5
0.25
0.25
1
2
0.25
0.125
1
0.25
0.25
1
0.25
0.25
1
0.25
0.25
2
2
N
21e
21f
H
H
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1
0.5
1
O
O
2
N
O
2
N
21g
21h
21i
21j
H
H
H
H
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
O
MeN
O
3
N
O
3
N
O
3
N
O
MeN
4
N
21k
H
0.5
0.5
0.5
0.5
0.5
O
O
21l
NH2
H
0.0625–0.125
0.5–1
0.0625–0.125
0.0625
0.0625–0.125
1
0.125
0.0625
0.0625–0.125
0.5–1
0.0625–0.125
0.0625
0.0625–0.125
1
0.125
0.0625
0.0625–0.125
2
0.0625–0.125
0.0625
Linezolid
Retapamulin
SB-222734g
a
b
c
d
e
f
MIC were determined by the agar microdilution method according to NCCLS standards (M7-A6, 2003).
MSSA = Methicillin-susceptible Staphylococcus aureus.
MRSA = Methicillin-resistant Staphylococcus aureus.
MSSE = Methicillin-susceptible Staphylococcus epidermidis.
MRSE = Methicillin-resistant Staphylococcus epidermidis.
S.p. = Streptococcus pneumoniae.
g
See Refs. 10 and 13.
The intermediate 13a and 13b were obtained in good yields by
In parallel, we were exploring the impact of constriction of the
five-membered lactam ring to the corresponding six-membered
homologs. The synthesis of substituted 3,4-dihydroisoquinolin-
1(2H)-one building block as conformationally restricted side
chains is summarized in Scheme 5. 2-(3-Methoxyphenyl)-1-ethan-
amine (15) was treated with ethyl chloroformate to furnish carba-
mate 16 in 76% yield. The subsequent cyclization of compound 16
with PPA (polyphosphoric acid) provided bicyclic lactam com-
pound 19a in 63% yield.25 Compound 19b was prepared with sim-
ilar procedure as 19a using 2-phenylethanamine as starting
material.26 Compound 19a was demethylated by treatment with
BBr3 (boron tribromide) to obtain the desired intermediate 17 in
high yield. The general synthetic approach to intermediates
19e–19k is also shown in Scheme 5. The synthesis begins with
alkylation of compound 17 to install the 2- to 4-carbon linker
followed by coupling to secondary amine to afford 19e–19k. In
acylation of 12m with 2-chloroacetyl chloride and 3-chloropropio-
nyl chloride, respectively at room temperature, which reacted with
the appropriate secondary amine in the presence of potassium io-
dide to afford the desired analogues 14a–14f in high yields
(Scheme 3).
The preparation of derivatives 14g–14j was carried out via the
routes illustrated in Scheme 4 in a short synthetic procedure start-
ing from 12m and 12l. Initial acylation of 12m and 12l with the
appropriate Boc-amino acid in dry DMF in the presence of
PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexa-
fluorophosphate) and EDC (1-ethyl-3-(3-dimethylaminopropyl)
carbodiimide) provided the acylation intermediate. The removal
of the BOC (tert-butoxycarbonyl) group was readily accomplished
by exposing to 4.0 M HCl solution in dioxane, producing 14g–14j
hydrochlorides in moderate yields.24

L. Fu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 814–819
819
addition, 19a and 19b were nitrated with potassium nitrate in sul-
Acknowledgments
furic acid at 0 °C to give 19c and 19d with 56% and 63% yield,
respectively. Finally, the analogs 21a–21k were prepared in two
steps using the same reaction condition as isoindolin-1(1H)-one
derivatives. The amino substituted 21l was obtained by reduction
of compound 21d with SnCl2Á2H2O ethanol solution.
We are grateful to National Science and Technology Major Pro-
ject for the support of this research. The project described was sup-
ported by Key New Drug Creation and Manufacturing Program,
China (Number: 2009ZX09301-001). Dr. Safiyyah Forbes and Dr.
Tuanli Yao are acknowledged for critical reading of this
manuscript.
The in vitro antibacterial activity of these compounds against a
spectrum of resistant and susceptible Gram-positive bacteria was
summarized in Tables 1 and 2 with linezolid and retapamulin as
positive controls. The result clearly showed that most of the com-
pounds displayed potent antibacterial activities and compounds
12a, 12d, 12h, 12k, 14j, and 21c showed at least a 4-fold more
potent activities against most pathogens compared with linezolid.
In particular, the amino substituent compounds 12l, 12m, and 21l
were found to be comparable to retapamulin for all tested suscep-
tible organisms and more potent than retapamulin for tested resis-
References and notes
1. Tacconelli, E.; Angelis, G.; Cataldo, M.; Pozzi, E.; Cauda, R. J. Antimicrob.
Chemother. 2008, 61, 26.
2. Davies, J.; Davies, D. Microbiol. Mol. Biol. Rev. 2010, 74, 417.
3. Silver, L. L. Clin. Microbiol. Rev. 2011, 24, 71.
4. Hunt, E. Drugs Future 2000, 25, 1163.
5. Kavanagh, K.; Hervey, A.; Robbins, W. Proc. Natl. Acad. Sci. U.S.A. 1951, 37,
570.
6. Long, S. K.; Hansen, H.; Jakobsen, L.; Vester, B. Antimicrob. Agents Chemother.
2006, 50, 1458.
7. Davidovich, C.; Bashan, A.; Yaggie, R. D.; Gontarek, R. R. Proc. Natl. Acad. Sci.
U.S.A. 2007, 104, 4291.
tant organisms, with MIC values of 0.0625–0.125
both MRSA and MRSE.
lg/mL against
The non-substituted isoindolin-1(1H)-one analog 12a was
slightly more potent than the corresponding dihydroisoquinolin-
1(2H)-one analog 21b, while both the methoxy compounds 12b
and 21a showed greatly reduced potency against most strains in
the panel. It is interesting to note that 21c was the most potent
overall among the nitro analogs (12c, 12e, 21c, and 21d) and more
potent than both 21a and 21d, while analog with fluorine substitu-
ent (12d) also exhibit good activity. A dramatic increase in activity
against all test organisms was observed with the amino analog 12l
as compared to the corresponding nitro analog 12c. Interestingly,
the same trend was observed when comparing 12m and 21l, indi-
cating that an amino moiety may contribute to the enhancement of
activity. However, amino compound 12k was relatively less active
compared to 12l, 12m, and 21l. To assess the further optimization
potential of amino analogs, 12m and 12l were acylated with differ-
ent basic side chains and appropriate amino acid to produce
14a–14j smoothly, however, all had decreased activity relative to
the parent compounds (12m and 12l). Interestingly, in these cases
proline derivative 14j showed slightly better activity in compari-
son to valine and alanine analogues (14g, 14h and 14i). Due to
these observations, we hypothesized that there was potentially a
small binding pocket in the active site that accommodated these
small amino substituent and increased the induced-fit binding.27
The effect of substitution at the R3 position was explored in
order to produce compounds with the most optimal antibacterial
activity. The isoindolin-1(1H)-one analogues containing a mor-
pholinyl (12f), piperidinyl (12g), benzylamine (12i), trifluoroaceta-
mide (12j) groups were less active than compound 12a, while the
4-methyl-piperazinyl (12h) and amino (12k) analogues showed
slight increase in activity. In addition, the antibacterial activity of
compounds 21e to 21k which possessed 2 to 4 carbon linkers
and different amine-substitution at the R3 position did not show
great change in their antibacterial activity. It may be explained that
compounds with these types of linkers could not improve the bind-
ing affinity.
8. Daum, S. R.; Kar, S.; Kirkpatrick, P. Nat. Rev. Drug Discov. 2007, 6,
865–866.
9. Novak, R.; Shlaes, D. M. Cur. Opin. Investig. Drugs. 2010, 11, 182.
10. Brooks, G.; Burgess, W.; Colthurst, D.; Hinks, J. D. Bioorg. Med. Chem. 2001, 9,
1221.
11. Phillips, A. O.; Sharaf, H. L. Expert Opin. Ther. Pat. 2007, 17, 429.
12. Fu, L.; Liu, X.; Cheng, J.; He, H.; Cai, Z.; Guo, X.; Ding, S.; Yang, Y. Org. Process Res.
Dev. 2010, 14, 815.
13. Fu, L.; Jiang, Z.; Liu, X.; He, H.; Cai, Z.; Yang, Y. Bioorg. Med. Chem. Lett. 2009, 19,
5407.
14. (a) Egger, H.; Reinshagen, H. J. Antibiot. 1976, 29, 915; (b) Egger, H.; Reinshagen,
H. J. Antibiot. 1976, 29, 923.
15. Hirokawa, Y.; Kinoshita, H.; Tanaka, T.; Nakata, K.; Kitadai, N.; Fujimoto, K.;
Kashimoto, S.; Kojima, T.; Kato, S. J. Med. Chem. 2008, 51, 1991.
16. Hirokawa, Y.; Kinoshita, H.; Tanaka, T.; Nakatamura, K.; Kitadai, N.; Fujima, K.;
Kashimoto, S.; Kojima, T. Bioorg. Med. Chem. Lett. 2008, 18, 3556.
17. Bich, A. J.; Holzapfel, C. W.; Rickards, R. W. Tetrahedron 1966, 8, 359.
18. Andemichael, Y.; Chen, J.; Clawson, J.; Dai, W.; Diederich, A.; Downing, S.;
Freyer, A. Org. Process Res. Dev. 2009, 13, 729.
19. (a) Pellicciari, R.; Camaioni, E.; Costantino, G.; Formentini, L.; Sabbatini, P.;
Venturoni, F.; Eren, G.; Bellocchi, D.; Chiarugi, A.; Moroni, F. ChemMedChem
2008, 3, 914; (b) Jagtap, P.; Southan, G.; Baloglu, E.; Ram, S.; Marton, A.;
Salzman, A.; Szabó, C. Bioorg. Med. Chem. Lett. 2004, 14, 81; (c) Williams, R.;
Manka, J.; Rodriguez, A.; Vinson, P.; Niswender, C.; Weaver, C. D.; Jones, C. K.;
Conn, P.; Lindsley, C. W. Bioorg. Med. Chem. Lett. 2011, 21, 1350.
20. Véronique, R.; Axel, C.; Eric, D.; Stéphane, L.; Grandclaudona, P. Tetrahedron
2005, 61, 665.
21. Wolfe, J.; Buchwald, S. Tetrahedron Lett. 1997, 38, 6359.
22. Representative spectroscopic data. Compound 12h. 1H NMR (300 MHz, CDCl3) d
7.74 (d, J = 8.8 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 6.83 (s, 1H), 6.64 (dd, J = 16.5,
10.6 Hz, 1H), 5.89 (d, J = 8.9 Hz, 1H), 5.40 (d, J = 11.0 Hz, 1H), 5.23 (d,
J = 16.9 Hz, 1H), 4.69 (s, 2H), 3.44–3.32 (m, 5H), 2.61 (bs s, 4H), 2.45–2.30
(m, 3H), 2.33–2.10 (m, 4H), 2.02 (m, 1H), 1.87–1.06 (m, 8H), 1.64 (s, 3H), 1.19
(s, 3H), 0.89 (d, J = 6.4 Hz, 3H), 0.77 (d, J = 6.2 Hz, 3H). 13C NMR (126 MHz,
CDCl3)
d 217.15, 166.21, 155.23, 150.94, 143.21, 139.06, 126.27, 120.97,
117.38, 115.63, 107.27, 74.59, 70.97, 58.24, 54.60, 48.80, 47.62, 45.95, 45.49,
44.75, 43.99, 42.19, 36.88, 36.06, 34.51, 30.50, 26.89, 26.21, 24.87, 16.94, 15.34,
11.51. HRMS-ESI (m/z) calcd for
C
34H48N3O5 [M+H]+: 578.3594; found:
578.3588.
23. Representative spectroscopic data. Compound 12m. 1H NMR (300 MHz, CDCl3) d
7.24 (d, J = 8.7 Hz, 1H), 7.13 (d, J = 1.5 Hz, 1H), 6.95 (dd, J = 8.7, 1.5 Hz, 1H), 6.63
(dd, J = 17.3, 11.1 Hz, 1H), 5.90 (d, J = 8.2 Hz, 1H), 5.39 (d, J = 11.2 Hz, 1H), 5.23
(d, J = 17.2 Hz, 1H), 4.67 (s, 2H), 3.40 (s, 1H), 2.37 (t, 1H), 2.30–2.14 (m, 4H),
1.64 (s, 3H), 1.85–1.23 (m, 8H), 1.19 (s, 3H), 0.88 (d, 3H), 0.77 (d, 3H). 13C NMR
(126 MHz, CDCl3) d 217.04, 166.54, 150.77, 147.07, 138.99, 132.20, 130.62,
123.75, 121.35, 117.39, 109.38, 74.55, 71.14, 58.18, 48.54, 45.45, 44.72, 43.94,
42.14, 36.83, 36.03, 34.47, 30.46, 26.85, 26.19, 24.85, 16.91, 15.30, 11.50.
HRMS-ESI (m/z) calcd for C29H38N2NaO5 [M+Na]+: 517.2678; found: 517.2683.
24. Wangsell, F.; Russo, F.; Sävmarker, J.; Rosenquist, A.; Samuelsson, B.; Larhed, M.
Bioorg. Med. Chem. Lett. 2009, 19, 4711.
In conclusion, a series of pleuromutilin derivatives with novel
conformationally restricted side chains were synthesized and eval-
uated. The results of antibacterial activities indicated that most of
the pleuromutilin derivatives gave moderate to excellent antibac-
terial activity. The three remarkable compounds of this series
(12l, 12m, and 21l) exhibited comparable in vitro antibacterial pro-
files to that of retapamulin. Clearly the amino substituent is crucial
to the activity of such derivatives. A more comprehensive study of
these derivatives will be reported in due course.
25. Gao, M.; Wang, M.; Miller, K.; Sledge, G.; Zheng, Q. Eur. J. Med. Chem. 2008, 43,
2211.
26. Decker, M.; Krauth, F.; Lehmann, J. Bioorg. Med. Chem. 2006, 14, 1966.
27. Davidovich, C.; Bashan, A.; Auerbach-Nevo, T.; Yaggie, R.; Gontarek, R.; Yonath,
A. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 4291.