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A. Thorarensen et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2823–2827
diazotization and cyanation. Bromination and reaction
with triphenyl phosphine provided phosphine 28.
Deprotonation with NaH and condensation with the
fully functionalized aldehyde 29 afforded the desired
alkene 30 as a 1:1 mixture of E/Z isomers. The alkene
30 was hydrolyzed and separated to provide the pure
E (31) and Z (32) isomers.
prepared in a similar but lower yielding sequence (not
shown but in vitro activity was similar to that of the
truncated analog 39, validating our approach that only
linkers that illustrated the potential to replace the amide
justified the preparation of the more complex analog for
direct comparison across multiple linkers). Unfortu-
nately, the fully functionalized oxadiazole analog
resisted any oxidation.
Since a trans substituted cyclopropane yields a very sim-
ilar spatial arrangement to the amide and the alkene, al-
kene 30 was converted to a cyclopropane. It was
discovered after extensive attempts that alkene 30 was
very unreactive. Screening of over 30 methylene transfer
conditions found that only Pddba with excess diazo-
methane was able to achieve cyclopropanation with
complete conversion of the desired E-alkene.15 The
Z-alkene was found to be inert to cyclopropanation
under any conditions. Attempts to separate the remaining
Z-alkene failed, thus ozonization was utilized to convert
the remaining alkene to readily separated materials. The
desired trans cyclopropane 33 was obtained in poor
yields due to decomposition during the ozonolysis but
with high purity.
The ability of the new linker as amide replacement was
monitored by its activity against Staphylococcus aureus.
Not surprisingly we found that the thioamide 9 is equi-
potent with the corresponding amide, Table 2. It is
intriguing that the spectrum of activity for the thioamide
is improved though the reason for that activity improve-
ment is not clear. The conversion of an amide to a thio-
amide represents the smallest possible change in linker
construction. The removal of the linker as in 14 and
21 results in analogs devoid of activity. Likewise, when
the linker is replaced with five-membered ring heterocy-
cles such as 37 and 39 all activity is lost. A flexible linker
such as alkane 25 exhibits faint antibacterial activity.
The alkenes provide a rigid scaffold and the activity of
the E-alkene 31 is equal to the potency of the corre-
sponding amide. This indicates that the amide is not
essential for activity and serves to hold the pharmaco-
phores at the appropriate distances. Therefore, it is
not surprising that the corresponding cyclopropyl linker
found in 33 is nearly as active as the corresponding
E-alkene 31. The Z-alkene 32 possessed poor activity
indicating that the A- and the B-rings were inappropri-
ately positioned.
Another linker that has been reported in the literature as
a viable bioisostere for amides is a triazole.16 Modeling
indicates that the triazole can occupy similar conforma-
tions as the amide, although the B-ring would be slightly
shifted. In addition the triazole retains the hydrogen
bonding pattern of the amide. In order to prepare this
linker, we initiated a model study for its assembly,
Scheme 6. Fortunately, classical literature observations
were reproduced and depending on whether the hydro-
chloride salt of benzimidate was used or not we obtained
either the triazole or oxadiazole as single isomers out of
each reaction in modest yields.17 Conversion of the
methyl groups to the acids was troublesome and was
achieved with chromium oxidation for the oxadiazole
36, and under basic conditions with KMnO4 for triazole
38.18 The fully functionalized triazole analog was
The work described herein clearly demonstrates that the
purpose of the amide linker is to appropriately position
the aryl rings and it does not have a role as a recognition
element. The amide can be replaced with several
functionalities such as the E-alkene and the trans cyclo-
propyl without significant deterioration in the MIC
activity. These findings have enabled us to propose a
NH
Table 2. Antibacterial activity of new linkers in this report
HCl
Br
R
Compound
MICa (lg/mL)
Ph
OMe
35
SAURb
0.5
EFAEc SEPIdd
SPNEe HINFf
O
Xylene
reflux
60%
2
9
32
32
4
0.125
4
16
128
64
N
Br
N
0.125
36
R = Me
1) (COCl)2
14
21
25
31
32g
33
37
39
128
>128
32
>128
>128
>128
128
128
>128
>128
32
>128
>128
>128
>128
>128
16
NaCr2O7
10%
64
32
2) NH2NH2
20%
R = CO H
0.25
0.5
>128
64
O
OH
37
2
NH
HCl
34
16
4
>128
>128
>128
>128
32
8
>128
>128
>128
Ph
OMe
Br
R
35
>128
>128
>128
>128
>128
>128
H
N
Dowex-OH
Xylene
reflux
a Minimal inhibitory concentration.
b Staphylococcus aureus UC 9218.
c Enterococcus faecalis UC 9217.
d Staphylococcus epidermidis UC 12084.
e Streptococcus pneumoniae UC 9912.
f Haemophilus influenzae 30063.
N
N
38 R = Me
74%
KMnO4 / NaOH
38%
39 R = CO2H
g This is a 97.9/2.1 cis/trans mixture and the activity can be mainly
attributed to the trans impurity.
Scheme 6.