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Bioorganic & Medicinal Chemistry Letters 18 (2008) 554–559
Novel indole-3-sulfonamides as potent HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs) Zhijian Zhao,a,* Scott E. Wolkenberg,a Meiqing Lu,b Vandna Munshi,b Gregory Moyer,b Meizhen Feng,b Anthony V. Carella,b Linda T. Ecto,b Lori J. Gabryelski,b Ming-Tain Lai,b Sridar G. Prasad,a Youwei Yan,a Georgia B. McGaughey,c Michael D. Miller,b Craig W. Lindsley,a, George D. Hartman,a Joseph P. Vaccaa and Theresa M. Williamsa a
Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA b Department of Antiviral Research, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA c Department of Molecular Systems, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA Received 10 October 2007; revised 20 November 2007; accepted 20 November 2007 Available online 28 November 2007
Abstract—This Letter describes the design, synthesis, and biological evaluation of novel 3-indole sulfonamides as potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) with balanced profiles against common HIV RT mutants K103N and Y181C. Ó 2007 Published by Elsevier Ltd.
HIV reverse transcriptase (HIV-RT) plays an essential role in the life cycle of HIV replication. Three nonnucleoside reverse transcriptase inhibitors (NNRTIs) have been introduced as a key class of drugs for the treatment of HIV infection (ViramuneÒ, RescriptorÒ, and SustivaÒ) in highly active antiretroviral therapy (HAART).1 However, the emergence of drug-resistant mutations in HIV-RT from NNRTI treatment raises an urgent need to discover and develop new agents with improved resistance profiles.2 In this letter, we wish to report our efforts in the discovery of novel NNRTIs based on an indole core through an iterative analogue library approach. In 1993, Williams and co-workers reported that 5chloro-3-(phenylsulfonyl)indole-2-carboxamide (1, Fig. 1) was a potent NNRTI against wild-type enzyme.3 Compound 1 also displays sub-micromolar activity against K103N and Y181C, two HIV-RT mutants observed clinically with high frequency. It has been demonstrated that the two oxygen atoms on the sulfone moiety are critical to maintain both the enzymatic and cellular Keywords: HIV; Antiviral; Indole; Sulfonamide. * Corresponding author. E-mail:
[email protected] Present address: VICB Program in Drug Discovery, Department of Pharmacology, Vanderbilt Medical Center, Nashville, TN 37232, USA. 0960-894X/$ - see front matter Ó 2007 Published by Elsevier Ltd. doi:10.1016/j.bmcl.2007.11.085
WT RT IC50 3 nM
O S O Cl
O
K103N RT IC50 116 nM Y181C RT IC50 71 nM
N H
NH2
1
Figure 1. Structure and HIV-RT inhibitory activity of 1.
activity of 1. In recent years, other groups have reported the discovery of indole derivatives as NNRTIs.4,5 In light of these encouraging results, we undertook an effort to identify NNRTIs from this series with an improved mutant profile. Our initial attempt was to replace the sulfone group in 1 with a sulfonamide group to generate compounds of general structure 7. This change was motivated by docking studies of 1 and HIV-RT in which the indole 3-phenylsulfonyl group occupies a hydrophobic pocket formed by Y181, Y188, and W229;5 we hypothesized that due to its close contact with Y181, the indole 3-substituent may affect activity versus the Y181C mutant. Earlier results demonstrated the necessity for substitution at the indole 5-position for optimal potency;3 because of this requirement, and to provide a handle for further derivatization, 5-bromoindole analogues 7 were prepared in parallel.
Z. Zhao et al. / Bioorg. Med. Chem. Lett. 18 (2008) 554–559 Br
O
Br
O
a N H
OEt
3
4 SO2Cl O
Br
N Ts
c
N Ts
Br
OEt
N Ts
Table 1. Anti-HIV activities of indole sulfonamide amide library 7 b
O
OEt
SO2NR1R2 O
NR1R2 O NH2
N H
O
7
d
OEt
Compound
SO2NR1R2 NH2 N H
S
Br
–NR1R2
6
5 Br
555
O
WT RT IC50a (nM)
SPREAD CIC95b (nM)
7a
H N
19
160
7b
HN
0.5
125
7c
H N
18
125
7d
HN
14
125
3.6
20-fold improvement in K103N enzyme inhibition was observed (7e versus 13a). A more modest 5-fold improvement was observed in Y181C RT potency (7e versus 13a), although Y181C potency was strongly dependent on substitution on the imidazole ring with a trend toward decreasing activity with increasing steric bulk of the substituent (compare
Z. Zhao et al. / Bioorg. Med. Chem. Lett. 18 (2008) 554–559
557
Table 3. Antiviral activities of indole sulfonamide amide library 10 O
S
Br N H 10
Compound
–NHR
7e
NH2
10a
H N
10b
N H
OH
N O
NHR O
WT RT IC50a (nM)
SPREAD CIC95b (nM)
K103N RT IC50a (nM)
Y181C RT IC50a (nM)
3.6
