´
T. Tomašic et al. / Bioorg. Med. Chem. Lett. 19 (2009) 153–157
156
Table 3
taining compounds as inhibitors of MurD ligase from E. coli.
Although our highest ranked virtual screening compound (R)-6
was practically inactive, starting from it, we managed to obtain
inhibitors of MurD. Compounds (R)-27 and (S)-27, bearing the
5-benzylidenerhodanine moiety, inhibited MurD with IC50 values
Inhibitory activity of MurD inhibitors (R)-27 and (S)-27 against other Mur ligases.
Compound
RAa,%
MurE
MurC
MurF
(R)-27
(S)-27
78
76
96
91
79
77
of 174 and 206 lM, respectively, and were also found to be more
specific for MurD than other Mur ligases. They thus constitute a
promising starting point for the development of novel, more potent
inhibitors of this enzyme by using structure-based drug design.
a
Residual activity of the enzyme in the presence of the tested compound at 250
l
M.
Acknowledgments
This work was supported by the European Union FP6 Integrated
Project EUR-INTAFAR (Project No. LSHM-CT-2004-512138) under
the thematic priority of Life Sciences, Genomics, and Biotechnology
for Health, and the Slovenian Research Agency (P1-0208, P1-0230,
J1-6693). The authors thank Professor Dr. Roger Pain for critical
reading of the manuscript.
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with RA values between 68% and 74% at 250 lM, their 3-substi-
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chemistry of Glu, since compound (S)-27, containing
most as potent as (R)-27, containing -Glu. The difference in
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the previously reported N-sulfonyl- - and
-Glu-based inhibitors.26
L-Glu, was al-
D
L
D
To test the specificity of compounds (R)-27 and (S)-27 for MurD
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lM concen-
ˇ
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D-Glu
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in inhibitors of the enzymes that act on UDP-containing
substrates.47,49,54
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