766
T. E. Renau et al. / Bioorg. Med. Chem. Lett. 12 (2002) 763–766
Table 1. Intrinsic antibacterial activity andpotentiation activity of
the peptidomimetic EPIs against PAM 1032a
isolated as the di-protected hemiaminal. The epoxide,
when treatedwith various amines (whose syntheses are
described in Schemes 3 and 4) afforded the analogues
6a–6c. These derivatives, which incorporate the struc-
b
CompdMIC
(mg/mL)
MPC8c (mg/mL)
1
>512
128
64
>512
256
512
>512
>512
128
256
512
>512
16
128
128
64
128
10
5
1.25
10
5
10
10
10
2.5
5
20
20
2.5
5
tural features foundin 1 andcompounsd
MPC8s as low as 1.25 mg/mL (Table 1).
4–5, had
2a
2b
3a
3b
3c
3d
4a
4b
4c
4d
4e
5a
5b
6a
6b
6c
The results for compounds 2–6, when viewedcollec-
tively, demonstrate that a peptide backbone is not
essential for the potentiation activity of this class of
compounds. They suggest that a di-cationic compound,
with an appropriate lipophilicity range, coupledwith an
overall topology comparable to that of MC-02,595
appear to be features that leadto the inhibition of
MDR pumps in P. aeruginosa. Efforts are underway to
substantiate these predictions.
1.25
5
2.5
aCompounds were evaluated in PAM 1032, a strain of Pseudomonas
aeruginosa derived from PA01 that over-expresses the MexAB-OprM
efflux pump.6,8
Acknowledgements
bMIC: minimum concentration (mg/mL) of efflux pump inhibitor
requiredto inhibit the growth of PAM 1032.
This work was principally funded by Daiichi Pharma-
ceuticals, Ltd. The authors thank Scott Hecker, William
Watkins, Dean Boojamra andBret Benton for their
review of the manuscript.
cMPC8: minimum concentration (mg/mL) of efflux pump inhibitor
required to reduce (potentiate) the MIC of levofloxacin 8-fold.
The tertiary amides 3a–3d (Scheme 2), which lack one of
the two stereocenters, were readily accessible from
methyl acrylate andprovidedan opportunity to incor-
porate various structurally diverse building blocks that
couldnot otherwise be preparedfrom commercially
available amino acids. The aliphatic analogue 3d was
roughly as potent as the aromatic derivatives 3a–3c
(Table 1). In general, compounds from this class dis-
playeda goodseparation between potentiation activity
andantibacterial activity.
References and Notes
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