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References and notes
HO
N
CO2Et
N
CO2Et
N
Cl
H2N
NH•HCl
a, b
1. Projan, S. J. Current Opinion Pharmacol. 2002, 2, 513–522.
2. Viable pfs-null mutants of Haemophilus influenzae, Strep-
tococcus pneumoniae, and Staphylococcus aureus could not
be generated. The pfs gene is not essential in Enterococcus
faecalis and maytherefore not be essential in other Gram-
positive strains where efflux pumps maybe upregulated.
Grant, C. and Levin, J., Quorex Pharmaceuticals, unpub-
lished results.
N
N
N
c
d
N
18
N
19
N
20
N
21
H2N
N
N
NH
N
3. Mao, C.; Cook, W. J.; Zhou, M.; Federov, A. A.; Almo,
S. C.; Ealick, S. E. Biochemistry 1998, 37, 7135–7146.
4. Koellner, G.; Luic, M.; Shugar, D.; Saenger, W.;
Bzowska, A. J. Mol. Biol. 1998, 280, 153–166.
N
N
e, f
g
N
N
N
H
N
5. Li, X.; Chu, S.; Feher, V. A.; Khalili, M.; Nie, Z.;
Margosiak, S.; Nikulin, V.; Sprankle, K. G.; Tedder, M.
E.; Almassy, R.; Levin, J.; Appelt, K.; Yager, K. M. J.
Med. Chem. 2003, 46, 5663–5673.
N
22
23
Ki =0.0170 µM
Scheme 4. (a) Diethyl ethoxymethylenemalonate, KOEt, EtOH, re-
i
flux; (b) SOCl2, cat. DMF, reflux; (c) H2, 20% Pd(OH)2/C, Pr2NEt,
6. (a) Della Ragione, F.; Porcelli, M.; Carteni-Farina, M.;
Zappia, V.; Pegg, A. E. Biochem. J. 1985, 232, 335–341; (b)
Cornell, K. A.; Swarts, W. E.; Barry, R. D.; Riscoe, M. K.
Biochem. Biophys. Res. Comm. 1996, 228, 724–732; (c)
Allart, B.; Gatel, M.; Guillerm, D.; Guillerm, G. Eur. J.
Biochem. 1998, 256, 155–162; (d) Cornell, K. A.; Riscoe,
M. K. Biochim. Biophys. Acta 1998, 1396, 8–14; (e) Lee,
J. E.; Cornell, K. A.; Riscoe, M. K.; Howell, P. L.
Structure 2001, 9, 941–953; (f) Lee, J. E.; Corrnell, K. A.;
Riscoe, M. K.; Howell, P. L. J. Biol. Chem. 2003, 278,
8761–8770.
7. (a) Surette, M. G.; Miller, M. B.; Bassler, B. L. Proc. Natl.
Acad. Sci. U.S.A. 1999, 96, 1639–1644; (b) Schauder, S.;
Shokat, K.; Surette, M. G.; Bassler, B. L. Mol. Biol. 2001,
41, 463–476.
8. Details of the enzymatic assays used in this study may be
found in Ref. 5.
9. (a) Lipinski, C. A.; Lombardo, F.; Dominy, B. W.;
Feeney, P. F. Adv. Drug Delivery Rev. 1997, 23; (b) Unity
and Selector software Tripos, Inc. St. Louis, MO;
(c) Sheridan, R. P.; Nachbar, R. B.; Bush, B. L.
J. Comp-Aided Mol. Des. 1994, 8, 323–340.
10. (a) Seyama, F.; Akahori, K.; Sakata, Y.; Misumi, S.; Aida,
M.; Nagata, C. J. Am. Chem. Soc. 1988, 110, 2192–2201;
(b) Jacobsen, K. A.; Siddiqi, S. M.; Olah, M. E.; Ji, X.-D.;
Melman, N.; Bellamkonda, K.; Meshulam, Y.; Stiles, G.
L.; Kim, H. O. J. Med. Chem. 1995, 38, 1720–1735; (c)
Baker, B. F.; Dervan, P. B. J. Am. Chem. Soc. 1989, 111,
2700–2712; (d) Shadid, B.; van der Plas, H. C.; Boesten,
W. H. J.; Kamphuis, J.; Meijer, E. M.; Schoemaker, H. E.
Tetrahedron 1990, 46, 913–920.
EtOH; (d) DIBAL-H, toluene, THF; (e) PPh3, NaN3, CCl4, DMF; (f)
H2, 20% Pd(OH)2/C, MeOH; (g) 14; R ¼ (CH2)2c-C5H9, iPr2NEt,
nBuOH, 95 °C.
maintain a charge- and dipole-neutral proximal ring
system. Inhibitor 23 was prepared according to Scheme
4. Thus condensation of 4-amidinopyridine (18) with
diethyl ethoxymethylenemalonate provided an interme-
diate hydroxy pyrimidine that was converted directly to
chloro ester 19.13 Sequential reductions provided benzyl
alcohol derivative 21.
Rather than a gain in affinity, a 6-fold drop in apparent
Ki was observed. There are at least two plausible, and
not necessarilymutuallyexclusive explanations for this
result. One is that the acute dihedral angle is an artifact
of protein crystal packing forces. Another is that the
recovered system energy is outweighed by energetic
penalties associated with desolvation of the inhibitor
upon binding.
A series of purine and deaza purine-based inhibitors of
MTA nucleosidase has been developed. Structure-based
modification of lead structure 2a, led to the discoveryof
16 and 17, low molecular weight inhibitors with
nanomolar potencyin an enzyme inhibition assay. These
compounds were also active in antimicrobial assays,
inhibiting the growth of three important pathogenic
genera.14
11. Itoh, T.; Ono, K.; Sugawara, T.; Mizuno, Y. J. Hetero-
cycl. Chem. 1982, 19, 513–517.
12. MTA nucleosidase crystallizes with two molecules per
asymmetric unit. Periodically, small differences in side-
chain and inhibitor conformations were observed between
subunits.
13. Palanki, M. S.; Erdman, P. E.; Manning, A. M.; Ow, A.;
Ransone, L. J.; Spooner, C.; Suto, C.; Suto, M. Bioorg.
Med. Chem. Lett. 2000, 10, 1645–1648.
Acknowledgements
The authors thank Drs. Carol Dammel and James Levin
of our Preclinical MicrobiologyDepartment for MIC
determinations and fruitful discussions.
14. Minimum inhibitoryconcentration (MIC) values were
typically P30 lM (ꢀ12 lg/mL).