R. P. Tangallapally et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6638–6642
6641
R' =
10a
10b
N
O2N
O
N
OH
R'
N
R'
H
N
b
N
10
N
N
N
9
a
N
+
10c
10d
N
N
Br
1
O
O
c
8
O
N
O
OH
N
Cl
O
N
12
11
Scheme 2. Synthesis of Isoxazoline compounds by altering the nitrofuran motif. Reagents and conditions: (a) PdCl2[P(o-tol)3], NaOtBu, toluene,
100 ꢂC, 3 h; (b) oxime, 5% NaOCl, cat. Et3N, CH2Cl2, rt, (c) Et3N, CH2Cl2, rt.
2. Boshoff, H. I. M.; Barry, C. E., 3rd Nat. Rev. Microbiol.
Table 2. Anti-tuberculosis activity of isoxazolines 10a–d and 12
2005, 3, 70.
Compound Structure
MIC90
3. Barry, C. E.; Boshoff, H. I.; Dowd, C. S. Curr. Pharm.
Des. 2004, 10, 3239.
(lg/mL)
4. (a) Tangallapally, R. P.; Yendapally, R.; Lee, R. E.;
Hevener, K.; Jones, V. C.; Lenaerts, A. J. M.; McNeil, M.
R.; Wang, Y.; Franzblau, S.; Lee, R. E. J. Med. Chem.
2004, 47, 5276; (b) Tangallapally, R. P.; Yendapally, R.;
Lee, R. E.; Lenaerts, A. J. M.; Lee, R. E. J. Med. Chem.
2005, 48, 8261; Tangallapally, R. P.; Lee, R. E. B.;
Lenaerts, A. J. M.; Lee, R. E. Bioorg. Med. Chem. Lett.
2006, 16, 2584; For a review, see: (d) Tangallapally, R. P.;
Yendapally, R.; Daniels, A. J.; Lee, R. E. B.; Lee, R. E.
Curr. Top. Med. Chem. 2007, 7, 509.
O
N
N
N
10a
O2N
N
>200
N
O
10b
>200
50
N
N
O
N
10c
N
5. For recent reviews related to oxazolidinone and oxazoli-
dine antibacterial agents, see: (a) Renslo, A. R.; Luehr, G.
W.; Gordeev, M. F. Bioorg. Med. Chem. 2006, 14, 4227;
(b) Sood, R.; Bhadauriya, T.; Rao, M.; Gautam, R.;
Malhotra, S.; Barman, T. K.; Upadhyay, D. J.; Rattan, A.
Infect. Disord. Drug Targets 2006, 6, 343; (c) Zappia, G.;
Menendez, P.; Delle Monache, G.; Misiti, D.; Nevola, L.;
Botta, B. Mini Rev. Med. Chem. 2007, 7, 389; For a paper
regarding glycoprotein IIb/IIIa receptor antagonists, see:
(d) Sielecki, T. M.; Liu, J.; Mousa, S. A.; Racanelli, A. L.;
Hausner, E. A.; Wexler, R. R.; Olson, R. E. Bioorg. Med.
Chem. Lett. 2001, 11, 2201; For papers regarding factor
Xa inhibitors, see: (e) Quan, M. L.; Liauw, A. Y.; Ellis, C.
D.; Pruitt, J. R.; Carini, D. J.; Bostrom, L. L.; Huang, P.
P.; Harrison, K.; Knabb, R. M.; Thoolen, M. J.; Wong, P.
C.; Wexler, R. R. J. Med. Chem. 1999, 42, 2752; (f) Lam,
P. Y. S.; Adams, J. J.; Clark, C. G.; Calhoun, W. J.;
Luettgen, J. M.; Knabb, R. M.; Wexler, R. R. Bioorg.
Med. Chem. Lett. 2003, 13, 1795; For a paper regarding
human leukocyte elastase (HLE) inhibitors, see: (g)
Groutas, W. C.; Venkataraman, R.; Chong, L. S.; Yoder,
J. E.; Epp, J. B.; Stanga, M. A.; Kim, E.-H. Bioorg. Med.
Chem. 1995, 3, 125; For papers regarding antibacterials,
see: (h) Pirrung, M. C.; Tumey, L. N.; Raetz, C. R. H.;
Jackman, J. E.; Snehalatha, K.; McClerren, A. L.; Fierke,
C. A.; Gantt, S. L.; Rusche, K. M. J. Med. Chem. 2002,
45, 4359; (i) Barbachyn, M. R.; Cleek, G. J.; Dolak, L. A.;
Garmon, S. A.; Morris, J.; Seest, E. P.; Thomas, R. C.;
Toops, D. S.; Watt, W.; Wishka, D. G.; Ford, C. W.;
Zurenko, G. E.; Hamel, J. C.; Schaadt, R. D.; Stapert, D.;
Yagi, B. H.; Adams, W. J.; Friis, J. M.; Slatter, J. G.;
Sams, J. P.; Oien, N. L.; Zaya, M. J.; Wienkers, L. C.;
Wynalda, M. A. J. Med. Chem. 2003, 46, 284.
N
N
O
N
10d
>200
N
N
O
N
12
1.56
N
O
N
O
As the nitrofuranyl isoxazole series was so potent
in vitro, we explored if the core isoxazoline had any
intrinsic anti-tuberculosis activity. This led to the dis-
covery of a novel isoxazoline compound 12 with
MIC90 value of 1.56 lg/mL. This is a new chemotype
though less potent than the nitrofurans it does offer
some significant potential advantages including in-
creased solubility as the compounds are less crystalline
and lower potential side effects as no nitro group is pres-
ent. Further optimization of this series is ongoing and
will be reported subsequently.
Acknowledgment
We thank National Institutes of Health Grant AI062415
for financial support.
References and notes
6. Guram, A. A.; Rennels, R. A.; Buchwald, S. L. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1348.
7. 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.;
Wiley: New York, 1984.
1. ‘Tuberculosis’ WHO Fact Sheet No. 104. Health Com-