W.-L. Wang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7151–7154
7153
Table 1
Inhibition of E. coli MetAP enzyme activity and E. coli AS19 cell growth by salicylate-based derivatives
R3
Cl
R1
HOOC
R2
S
R2
S
R1
Cl
R1
S
R3
HOOC
HOOC
4 12
-
13 14
15 21
-
,
Compd
R1
R2
R3
Inhibition of enzymatic activity, IC50
,
l
M
Inhibition of bacterial growth, IC50, l
Ma
Co(II)
Mn(II)
Fe(II)
E. coli AS19
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
OH
OH
OH
OCH3
OCH3
H
H
H
H
OH
OCH3
OH
OH
OH
OCH3
OCH3
H
H
H
H
H
H
H
F
H
CH3
Cl
H
CH3
H
H
CH3
Cl
65.2
81.0
87.7
254
256
249
251
329
166
118
290
88.1
77.4
74.1
203
70.9
>500
464
80.2
90.7
62.7
89.8
160
39.1
109.1
73.0
500
270
>500
267
253
203
29.9
>500
3.1
6.8
4.9
208
106
192
167
112 (100)
73.1 (47)
34.1 (28)
>1000 (>234)
550 (272)
>1000 (>204)
>1000 (>222)
871 (306)
641 (297)
51.4 (33)
829 (521)
74.6 (38)
161 (87)
48.5 (30)
>1000 (>268)
>1000 (>282)
>1000 (>234)
>1000 (>248)
159
143
336
118
97.5
97.3
33.7
37.8
36.6
19.1
11.4
17.4
33.8
F
F
Cl
Cl
Cl
Cl
Cl
OCH3
OCH3
H
CH3
Cl
H
CH3
H
H
CH3
a
MIC values in mg/L are in parentheses.
selective MetAP inhibitors are desired lead compounds to optimize
their antibacterial activity, while minimizing their human toxicity.
It is interesting to note that all of the compounds with good en-
zyme inhibition and antibacterial activity (4–6, 13, and 15–17)
have a hydroxyl group, along with a carboxyl group at the adjacent
position, indicating the importance of the salicylate moiety in
interaction with MetAP, probably through metal chelation. Com-
pounds missing this hydroxyl group (9–12, 20, and 21) or com-
pounds with this hydroxyl group replaced by a methoxyl group
(7, 8, 14, 18, and 19) all showed significantly lower enzyme inhibi-
tion and low or no antibacterial activity. While this hydroxyl group
is indispensable, the hydroxyl group alone is not sufficient for inhi-
bition, because we showed previously that mono-hydroxyl analogs
of the catechol series displayed no enzyme inhibition.18 Therefore,
both the hydroxyl group and the carboxyl group in the salicylate
derivatives are required for effective inhibition of MetAP. Com-
pounds 18–21 showed noticeable potency and selectivity on the
Mn(II)-form of MetAP. Lacking the hydroxyl group, they all have
a carboxyl group, and their selectivity towards the Mn(II) form is
consistent with the results from furan carboxylates we reported
earlier.11 In that case, the carboxyl group directly coordinates with
the catalytic metal ions, and the coordination contributes to their
Mn(II)-form selectivity. However, their lack of antibacterial activity
is possibly due to their poor potency on the Fe(II)-form of MetAP.
In summary, structure–function analysis of the newly synthe-
sized salicylate derivatives as inhibitors of E. coli MetAP clearly
indicates that replacement of one of the two hydroxyl groups to
a carboxyl group on the catechol scaffold (change from 1 to 2 or
3, Fig. 1) can be accommodated by MetAP, and the potency and
selectivity on the Fe(II)-form can be maintained. Both the hydroxyl
group and the carboxyl group in the salicylate derivatives are in-
volved in enzyme inhibition and required for antibacterial activity.
The demonstrated activity of these salicylate derivatives on MetAP
enzyme and on E. coli cells, coupled with their likely better chem-
ical stability and favorable pharmacokinetic properties, provides a
new starting point for the design and discovery of MetAP inhibitors
as new antibacterial agents with a novel mechanism of action.
Acknowledgments
This work was supported by National Institutes of Health
Grants R01 AI065898 and R56 AI065898 and by Indiana University
School of Medicine (BRG) and Indiana University and Purdue Uni-
versity at Indianapolis (RSFG).
References and notes
1. Giglione, C.; Boularot, A.; Meinnel, T. Cell. Mol. Life Sci. 2004, 61, 1455.
2. Bradshaw, R. A.; Brickey, W. W.; Walker, K. W. Trends Biochem. Sci. 1998, 23,
263.
3. Chang, S. Y.; McGary, E. C.; Chang, S. J. Bacteriol. 1989, 171, 4071.
4. Miller, C. G.; Kukral, A. M.; Miller, J. L.; Movva, N. R. J. Bacteriol. 1989, 171, 5215.
5. Li, X.; Chang, Y. H. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 12357.
6. Vaughan, M. D.; Sampson, P. B.; Honek, J. F. Curr. Med. Chem. 2002, 9, 385.
7. Lowther, W. T.; Matthews, B. W. Chem. Rev. 2002, 102, 4581.
8. Li, J. Y.; Chen, L. L.; Cui, Y. M.; Luo, Q. L.; Li, J.; Nan, F. J.; Ye, Q. Z. Biochem.
Biophys. Res. Commun. 2003, 307, 172.
9. D’Souza, V. M.; Holz, R. C. Biochemistry 1999, 38, 11079.
10. Lowther, W. T.; Matthews, B. W. Biochim. Biophys. Acta 2000, 1477, 157.
11. Ye, Q. Z.; Xie, S. X.; Huang, M.; Huang, W. J.; Lu, J. P.; Ma, Z. Q. J. Am. Chem. Soc.
2004, 126, 13940.
12. Huang, Q. Q.; Huang, M.; Nan, F. J.; Ye, Q. Z. Bioorg. Med. Chem. Lett. 2005, 15,
5386.
13. Luo, Q. L.; Li, J. Y.; Liu, Z. Y.; Chen, L. L.; Li, J.; Qian, Z.; Shen, Q.; Li, Y.;
Lushington, G. H.; Ye, Q. Z.; Nan, F. J. J. Med. Chem. 2003, 46, 2631.
14. Schiffmann, R.; Heine, A.; Klebe, G.; Klein, C. D. Angew. Chem., Int. Ed. 2005, 44,
3620.
15. Douangamath, A.; Dale, G. E.; D’Arcy, A.; Almstetter, M.; Eckl, R.; Frutos-
Hoener, A.; Henkel, B.; Illgen, K.; Nerdinger, S.; Schulz, H.; Mac Sweeney, A.;