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C. M. Yeung et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2275–2278
Reagents and conditions: (a) 60 °C, i-PrOH, 79%; (b) (i)
ethanolamine, 16 h, rt, 73%, (ii) Boc2O, 97%; (c) (i) oxalyl
chloride, DMSO, (ii) L-ValOMe, NaCNBH3, 1 h, rt, 63%,
(iii) 50% TFA, 70%; (d) (i) CDI, THF, reflux, 3 h, 68%, (ii)
LiOH, 59%.
An X-ray crystal structure of oxime 20 bound in the
HIV protease active site (Fig. 2)6 revealed the potential
interaction of the oxime hydroxyl group to form a favor-
able hydrogen bond with the Asp 30 side chain carbonyl
with a distance of 2.66 A. This interaction may be
responsible for the excellent potency against both the
WT and A17 resistant viruses.
˚
4. A17 strain was generated by in vitro 17 passages with
Lopinavir/Ritonavir and contains 6 mutations (L10F/
V32I/M46I/I47V/Q58E/I84V). For assay procedure, see
Ref. 11.
In summary, we have discovered a novel series of hybrid
arylsulfonamide HIV PIs that exhibit good in vitro
potency against both the WT and A17 resistant viruses.
The oximino group was identified as the optimal moiety
in terms of resistant profile, and this activity may be
attributed to its constructive hydrogen bonding with
the Asp 30 side chain of the protease as shown by the
X-ray crystallographic study. Further modifications on
the left-hand side of the molecule are being pursued as
a way to further enhance the antiviral and pharmacoki-
netic properties of this series.
5. Kim, E. E.; Baker, C. T.; Dwyer, M. D.; Murcko, M. A.;
Rao, B. G.; Tung, R. D.; Navia, M. A. J. Am. Chem. Soc.
1995, 117, 1181.
6. HIV protease was purified and crystallized in the presence
of compound 21 according to the procedures described by
Stoll et al.7 Data were collected on a Rigaku RU200 X-ray
generator using a Mar 165 CCDdetector. Data were
processed using HKL2000.8 The co-crystals of HIV
protease and compound X belong to the orthorhombic
space group P21212 with unit cell dimensions
˚
˚
˚
a = 58.041 A, b = 85.954 A, c = 46.033 A. Calculation of
initial electron density maps and refinement were done
using CNX9,10 and refined to a final Rwork = 27.75 and
˚
Rfree = 35.31 to 3.0 A resolution. Coordinates for the
References and notes
crystal structure of protease complexed with 21 have
been deposited in the RCSB protein data bank, PDB ID
1YT9.
1. For a recent review of HIV protease inhibitors in therapy,
see: Randolph, J. T.; DeGoey, D. Curr. Top. Med. Chem.
2004, 4, 1079.
2. (a) Boden, D.; Markowitz, M. Antimicrob. Agents Che-
mother. 1998, 42, 2775; (b) Miller, Vernica J. Acq. Immun.
Def. Synd. 2001, 26, S34; (c) Shafer, R. W. Clin. Microbiol.
Rev. 2002, 15, 247.
7. Stoll, V.; Qin, W.; Stewart, K. D.; Jakob, C.; Park, C.;
Walter, K.; Simmer, R. L.; Helfrich, R.; Bussiere, D.;
Kao, J.; Kempf, D. J.; Sham, H. L.; Norbeck, D. W.
Bioorg. Med. Chem. 2002, 10, 2803.
8. Otwinowski, K. Z.; Minor, W. Methods in Enzymology.
In Macromolecular Crystallography, Part A; Carter, C.
W., Jr., Sweet, R. M., Eds.; Academic: New York, 1997;
Vol. 276, p 307.
9. Brunger, A. T.; Adams, P. D.; Clore, G. M.; DeLano,
J.-S.; Kuszewski, J.; Nilges, M.; Pannu, N. S.; Read, R. J.;
Rice, L. M.; Simonson, T.; Warren, G. L. Acta Crystal-
logr. Sect. D 1998, D54, 905.
10. Badger, J.; Berard, D.; Kumar, R. A.; Szalma, S.; Yip, P.;
Griesinger, C.; Junker, J. CNX software manual; Mole-
cular Simulations Inc.: San Diego, CA, USA, 1999
3. Unpublished results.
Cl
Cl
S
N
Cl
b
a
+
NH2
S
O
O
H
N
Boc
c
N
N
H
OMe
N
N
OH
S
S
O
11. Mo, H.; Lu, L.; Dekhtyar, T.; Stewart, K. D.; Sun, E.;
Kempf, D. J.; Molla, A. Antiviral Res. 2003, 59,
173.
OH
d
N
N
N
O
6
S