T. Lu¨bbers et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4708–4714
4713
O
O
N
a,b,c
H2N
O
O
HO
H2N
+
+
N+
19
20
21a
OH
OH
1
O
X
X
d
HO
O
O
6
R1
N
R1
5
H2N
O
O
4
O
R
O
R
4a,b
21
22
Scheme 6. Reagents and conditions: (a) pyridine, EtOH, reflux, 6 h, 60%; (b) pyrrolidine, EtOH, reflux, 1 h, 83%; (c) DIBAH, THF, 0 °C, 75%; (d)
NaOMe, MeOH, reflux, 3–5 h, 17–84%.
2. Reece, R. J.; Maxwell, A. CRC Crit. Rev. Biochem. Mol.
Biol. 1991, 26, 335.
holds also true for the pair 22d,e, now at a more moder-
ate ratio of a roughly 2- to 4-fold lower MIC values when
moving from methyl to bromine as it was generally seen
for cyclothialidine derivatives. The reason for this obser-
vation might be a better permeability of the bromine
derivative, which is due either to a higher lipophilicity
or to an increased acidity of the phenol moiety. Com-
pounds 22f,g exhibited good activities against Gram-po-
sitive bacteria being often as active as novobiocin 1
although permeability of these compounds seems not
to be optimal. Since the pyridine and quinoline deriva-
tives 22f,g are probably interacting similarly with gyrase
B as novobiocin 1 we observed as well lower antibacterial
activity of 22g against the novobiocin resistant S. aureus
strain. Interestingly the pyridine derivative 22g did not
show this resistance. This might be due to its smaller size.
3. (a) Garrod, L. P.; Lambert, H. P.; O’Grady, F. In
Antibiotic and Chemotherapy, 5th ed.; Churchill Living-
stone: Edinburgh, 1981; pp 225–229; (b) Kawaguchi, H.;
Tsukiura, M.; Okanishi, T.; Miyaki, T.; Ohmori, K.;
Fujisawa, K.; Koshiyama, J. J. Antibiot. 1965, 18, 1; (c)
Linet, L.; Benazet, F.; Chapentie, Y.; Dubost, M.;
Florent, J.; Nancy, D.; Preud‘Homme, J.; Threlfall, T.
L.; Vuillenain, B.; Wright, D. E.; Abraham, A.; Cartier,
M.; De Chezelles, N.; Godard, C.; Theilleux, J. C.R. Acad.
Sci. Ser. C. 1972, 275, 455.
4. Boehm, H.-J.; Boehringer, M.; Bur, D.; Gmuender, H.;
Huber, W.; Klaus, W.; Kostrewa, D.; Kuehne, H.;
Luebbers, T.; Meunier-Keller, N.; Mueller, F. J. Med.
Chem. 2000, 43, 2664.
5. Watanabe, J.; Nakada, N.; Sawairi, S.; Shimada, H.;
Ohshima, S.; Kamiyama, T.; Arisawa, M. J. Antibiot.
1994, 47, 32.
In conclusion, we explored the chemical space around
the biased needle screening hit 3a. By applying our
knowledge about the SAR of the cyclothialidines and
by using the information from the X-ray structures from
novobiocin 1 and cyclothialidine 2 complexed to gyrase
B we could optimize this compound class. The forma-
tion of a tetracyclic core structure and the introduction
of a pyridine or quinoline moiety led to derivatives
22f,g, which are potent inhibitors of DNA gyrase and
which exhibit promising antibacterial activity against
Gram-positive bacterial strains.
6. (a) Wigley, D. B.; Davies, G. J.; Dodson, E. J.; Maxwell,
A.; Dodson, G. Nature 1991, 351, 624; (b) Lewis, R. J.;
Singh, O. M. P.; Smith, C. V.; Skarzynski, T.; Maxwell,
A.; Wonacott, A. J.; Wigley, D. B. J. EMBO 1996, 15,
1412; (c) Tsai, F. T. F.; Singh, O. M. P.; Skarzynski, T.;
Wonacott, A.; Weston, S.; Tucker, A.; Pauptit, R. A.;
Breeze, A. L.; Poyser, J. P.; O’Brien, R.; Ladbury, J. E.;
Wigley, D. B. Proteins: Struct. Funct. Genet. 1997, 28, 41;
(d) Holdgate, G. A.; Tunnicliffe, A.; Ward, W. H. J.;
Weston, S. A.; Rosenbrock, G.; Barth, P. T.; Taylor, I. W.
F.; Pauptit, R. A.; Timms, D. Biochemistry 1997, 36, 9663;
(e) Poyser, J. P.; Telford, B.; Timms, D.; Block, M. H.;
Hales, N. J.; WO Patent 99/01442, 1999; (f) Block, M. H.
9th RSC-SCI Medicinal Chemistry Symposium, Churchill
College, Cambridge, UK, 7, September 1997; (g) Pauptit,
R.; Weston, S.; Breeze, A.; Derbyshire, D.; Tucker, A.;
Hales, N.; Hollinshead, D.; Timms, D. In Structure-Based
Drug Design; Codding, P. W., Ed.; Kluwer Academic
Publishers: Dordrecht, The Netherlands, 1998; pp 225–
270.
Acknowledgments
We thank our colleagues in the analytical department
for spectral data, Mrs. Karin Kuratli, Mrs. Veronique
Schirmer, and Mrs. Ulrike Weis for technical assistance
in performing the DNA gyrase supercoiling assay and
the antibacterial tests.
7. (a) Geiwiz, J.; Go¨tschi, E.; Hebeisen, P.; Link, H.;
Lubbers, T. EP Patent 675122, 1995;; (b) Goetschi, E.;
¨
Angehrn, P.; Gmuender, H.; Hebeisen, P.; Link, H.;
Masciadri, R.; Nielsen, J. Pharmacol. Ther. 1993, 60, 367;
(c) Goetschi, E.; Angehrn, P.; Gmuender, H.; Hebeisen,
P.; Link, H.; Masciadri, R.; Reindl, P.; Ricklin, F. In
Medicinal Chemistry: Today and Tomorrow (Proceedings
of AIMECIS 95—Tokyo, September 1995); Yamazaki,
M., Ed.; Blackwell Science Ltd: Oxford, 1996; pp 263–270;
References and notes
1. (a) Niccolai, D.; Tarsi, L.; Thomas, R. J. Chem. Commun.
1997, 2333; (b) Chu, D. T. W.; Plattner, J. J.; Katz, L.
J. Med. Chem. 1996, 39, 3853.