Z. Wang et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4174–4177
4177
Table 2. Antiviral activities of sulfanyltriazoles against HIV-1 NNRTI
resistant mutants11
studies led to the identification of inhibitors of single
digit nM potency. Despite the fact that no optimization
was directed toward the NNRTI resistant mutants, sul-
fanyltriazoles 4e, 4o, 4t, and 12d exhibited good activity
against Y181C, K103N, and L100I, and promise great
potential in overcoming these and other NNRTI resis-
tant mutants. Future studies shall focus on optimizing
the inhibitory activities against the NNRTI resistant
mutants.
Compound
EC50
(lM)
WT
EC50
(lM)
Y188L
EC50
(lM)
Y181C
EC50
(lM)
K103N
EC50
(lM)
L100I
EFV
NVP
4d
0.001
0.050
0.068
0.003
0.072
0.022
0.001
0.020
0.037
0.059
0.079
0.018
0.313
>10
>10
0.001
>10
0.019
5.053
3.273
0.065
1.511
0.082
0.006
0.577
1.045
1.123
0.913
0.565
0.013
0.164
1.376
0.182a
0.488
0.031
0.024a
0.186
0.835
0.100
1.234
0.170
4.028
0.023
1.377
0.161
0.016
0.440
0.769
1.051
1.429
0.219
4e
4.306
>10
4j
4o
2.191
3.595
>3.333
>10
4t
4y
References and notes
4z
1. De Clercq, E. Med. Chem. Res. 2004, 13, 439.
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C. T. Curr. Pharm. Des. 2005, 11, 1805.
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1991, 63, 966.
12b
12c
12d
>1.654
>3.333
>3.333
a Activity against K103N/L100I; for EFV: EC50 = 2526 nM.
4. Freimuth, W. W. Adv. Exp. Med. Biol. 1996, 394, 279.
5. Young, S. D.; Britcher, S. F.; Tran, L. O.; Payne, L. S.;
Lumma, W. C.; Lyle, T. A.; Huff, J. R.; Anderson, P. S.;
Olsen, D. B.; Carroll, S. S.; Pettibone, D. J.; O’Brien, J. A.;
Ball, R. G.; Balani, S. K.; Lin, J. H.; Chen, I.-W.; Schleif, W.
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11. Jiang, T.; Kuhen, K. L.; Wolff, K.; Yin, H.; Bieza, K.;
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that RT is the target of these sulfanyltriazoles. Several
of these analogs (4e, 4o, 4t, 4y, 12b, and 12d) exhibited
good activity against L100I mutant with varying activ-
ities observed for the Y181C and K103N mutants.
However, none of these analogs were effective in inhib-
iting the Y188L mutant virus. Among these analogs,
4e, 4o, 4t, and 12d exhibited good overall antiviral pro-
file. In particular, the EC50’s for 4o (82 nM, ꢀ4-fold
shift from that of the WT virus) and 4t (6 nM, 6-fold
shift) against the K103N mutant are of interest consid-
ering that K103N is a key mutation associated with the
current NNRTI resistance. Double mutants containing
K103N are generally problematic for efavirenz. For
example, the EC50 of efavirenz against K103/L100I is
only 2.5 lM. On the other hand, sulfanyltriazoles 4e
and 4t exhibited EC50’s of 182 and 24 nM, respectively
(Table 2), suggesting the potential of these sulfanyl-
triazoles to overcome the K103 related NNRTI resis-
tant mutants.
12. Wu, B.; Kuhen, K.; Nguyen, T. N.; Ellis, D.; Anaclerio,
B.; He, X.; Yang, K.; Karanewsky, D.; Yin, H.; Wolff, K.;
Bieza, K.; Caldwell, J.; He, Y. Bioorg. Med. Chem. Lett.
2006, 16, 3430.
Modeling studies were carried out to understand how 4e
interacts with the reverse transcriptase (Fig. 3). Our re-
sults suggest that the carbonyl oxygen forms a hydrogen
bond with the K103 backbone NH, which is consistent
with the good activity of these sulfanyltriazoles against
the K103 mutants. The chlorophenyl moiety sits be-
tween P236 and V106, and points toward the solvent ex-
posed region. The triazole moiety stays in the middle of
the binding pocket, anchoring the three substituents on
the ring into the optimal space for interactions with the
enzyme. Finally the tolyl moiety fits into another impor-
tant hydrophobic pocket, where many key resistant
mutations take place, which include Y188L, Y181C,
F227C, and L100I. Our studies suggest that this class
of compounds shares the same pharmacophore with
pyrrolidinone-12 and benzophenone-based NNRTIs.19
13. Ellis, D.; Kuhen, K. L.; Anaclerio, B.; Wu, B.; Wolff, K.;
Yin, H.; Bursulaya, B.; Caldwell, J.; Karanewsky, D.; He,
Y. Bioorg. Med. Chem. Lett. 2006, 16, doi:10.1016/j.bmcl.
2006.05.073.
14. El-Kerdawy, M.; Eisa, H.; Barghash, A.; Marouf, A.
Sulfur Lett. 1989, 9, 209.
15. Shrimali, M.; Dixit, K. S.; Barthwal, J. P. J. Ind. Chem.
Soc. 1991, 68, 466.
16. Soliman, L. N.; Abdou, N. A.; Abou Sier, A. H.; Attia, A.
S. Bull. Faculty Pharm. (Cairo Univ.) 1990, 28, 53.
17. (a) Two patents covering related compounds were dis-
closed during our studies: Girardet, J.-L.; Zhang, Z.;
Hamatake, R.; de la Rosa Hernandez, M. A.; Gunic, E.;
Hong, Z.; Kim, H.; Koh, Y.-H.; Nilar, S.; Shaw, S.; Yao,
N. 2004, WO 2004030611.; (b) Simoneau, B.; Thavonek-
ham, B.; Landry, S.; O’Meara, J.; Yoakim, C.; Faucher,
A.-M. 2004, WO 2004050643.
18. HATU: (2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetrameth-
yl uronium hexafluorophosphate Methanaminium).
19. Chan, J. H.; Freeman, G. A.; Tidwell, J. H.; Romines, K.
R.; Schaller, L. T.; Cowan, J. R.; Gonzales, S. S.; Lowell,
G. S.; Andrews, C. W., III; Reynolds, D. J.; St. Clair, M.;
Hazen, R. J.; Ferris, R. G.; Creech, K. L.; Roberts, G. B.;
Short, S. A.; Weaver, K.; Koszalka, G. W.; Boone, L. R.
J. Med. Chem. 2004, 47, 1175.
In summary, a series of sulfanyltriazoles was discovered
as novel NNRTIs, and their preliminary SAR has been
established via chemical modifications. Molecular
modeling studies were employed to understand the
interactions between these inhibitors and the reverse
transcriptase, and to guide the SAR studies. These