238
G. D. Francisco et al. / Bioorg. Med. Chem. Lett. 14 (2004) 235–238
Table 2. Activity of other phenyl heteroaryl urea derivatives
were prepared. There was no significant difference in
activity between the carbamate derviatives (5a and 5b)
and the urea derivatives (3q and 3n).
Acknowledgements
We would like to thank Dr. Jerauld Skotnicki for help-
ful discussion. We would like to thank Dr. David Shlaes
for his support of the program.
As is evident from Table 2, other phenyl heteroaryl
urea derivatives investigated (20–24) were not as active
as many of the phenyl thiazoyl derivatives listed in
Table 1.
References and notes
In summary, many substituted phenyl thiazolyl urea
and carbamate derivatives were identified as a new
class of bacterial cell-wall biosynthesis inhibitors.
They demonstrated good activity against MurA and
MurB and gram-positive bacteria including MRSA,
VRE and PRSP. However, when tested in the pre-
sence of 4% bovine serum albumin, their MIC values
increased to greater than 128 mg/mL against PRSP.
The derivative 3p with clog P of 2.64 demonstrated
antibacterial activity against both gram-positive and
gram-negative bacteria with MIC values in the range
of 0.5–8.0 mg/mL. It also demonstrated improved
MIC value (64 mg/mL) against PRSP when tested in
the presence of 4% serum albumin. Since many com-
pounds 3c–e, 3j, 3k, 3n, and 3o are more active than
vancomycin against gram-positive bacteria, they are
good leads for further investigation. The compounds 3c
and 3d demonstrated IC50 of 32.1 and 4.2 mg/mL in the
soluble peptidoglycan screen using a strain of S. epi-
dermides.15 Thus, the cell wall biosynthesis inhibition
(MurA and MurB) of 3c and 3d is responsible for at
least part of their antimicrobial activity. Recently, anti-
microbial activity of some related diaryl ureas16,17 have
been shown to act by inhibition of bacterial respira-
tion.16 It is likely that the antimicrobial activity of the
phenyl thiazolyl urea and carbamate derivatives are due
to inhibition of both bacterial cell-wall biosynthesis and
bacterial respiration.
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