Bioorganic & Medicinal Chemistry Letters 20 (2010) 3534–3536
Bioorganic & Medicinal Chemistry Letters
Anti HIV-1 agents 5: Synthesis and anti-HIV-1 activity of some
N-arylsulfonyl-3-acetylindoles in vitro
b
a,
b,
*
Jun-Qiang Ran a,1, Ning Huang b,1, Hui Xu a, , Liu-Meng Yang , Min Lv , Yong-Tang Zheng
*
*
a Laboratory of Pharmaceutical Design & Synthesis, College of Sciences, Northwest A&F University, Yangling 712100, China
b Key Laboratory of Animal Models and Human Diseases Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology,
Chinese Academy of Sciences, Kunming 650223, China
a r t i c l e i n f o
a b s t r a c t
Article history:
In continuation of our program aimed at the discovery and development of compounds with superior
anti-human immunodeficiency virus type 1 (HIV-1) activity, 21N-arylsulfonyl-3-acetylindole analogs
(2a–u) were synthesized and preliminarily evaluated as HIV-1 inhibitors in vitro. Among of all the ana-
logs, several compounds exhibited significant anti-HIV-1 activity, especially N-phenylsulfonyl-3-acetyl-
6-methylindole (2j) and N-(p-ethyl)phenylsulfonyl-3-acetyl-6-methylindole (2n) showed the most
Received 12 November 2009
Revised 18 April 2010
Accepted 28 April 2010
Available online 18 May 2010
potent anti-HIV-1 activity with EC50 values of 0.36 and 0.13 lg/mL, and TI values of >555.55 and
Keywords:
791.85, respectively. It demonstrated that introduction of the acetyl group at the 3-position of N-aryl-
sulfonyl-6-methylindoles could generally lead to the more potent analogs.
Ó 2010 Elsevier Ltd. All rights reserved.
N-Arylsulfonyl-3-acetylindole
Acquired immune-deficiency syndrome
Human immunodeficiency virus-1
Inhibitor
Since the first case of acquired immunodeficiency syndrome
(AIDS) was reported in 1981, the human immunodeficiency virus
(HIV)/AIDS has always been a global health threat and the leading
cause of deaths.1 Therefore, the rapid worldwide spread of AIDS
has prompted an intense research effort to discover compounds
that could effectively inhibit HIV. In the past two decades, 25
drugs, including nucleoside/nucleotide viral reverse transcriptase
(RT) inhibitors (NRTIs), non-nucleoside RT inhibitors (NNRTIs),
protease inhibitors (PIs), integrase inhibitors (INIs) and fusion (or
entry) inhibitors (FIs), were approved for clinical use in the world.2
However, these drugs have only limited or transient clinical benefit
due to their severe side effects and the emergence of viral variants
resistant to HIV-1 inhibitors.3 Consequently, it is imperative that
the design and development of new, selective and safe drugs for
the treatment of HIV-1.4,5
Recently, a series of N-arylsulfonylindole derivatives showed
the selective affinity on the human serotonin 5-HT6 receptor,6–8
and especially some single N-arylsulfonylindoles (1, Fig. 1) dis-
played potent anti-HIV-1 activity.9 Meanwhile, much attention
has been paid in recent years to the chemistry of 3-acetylindole
derivatives, because some compounds derived from 3-acetylin-
doles exhibited the diverse biological activities, for example, anti-
cancer activity10,11 and antiinflammatory activity.12 Inspired by
these previous observations, and as part of our continuing studies
on the indoles as anti-HIV-1 agents, in this Letter we synthesized
some N-arylsulfonyl-3-acetylindole analogs (2a–u, Fig. 1) by intro-
duction of the acetyl group at the 3-position of N-arylsulfonylin-
doles, and wanted to investigate whether the anti-HIV-1 activity
of the target compounds 2a–u could be improved to some extent.
As outlined in Scheme 1, a series of N-arylsulfonyl-3-acetylin-
dole analogs (2a–u) were synthesized from the commercially
available indoles. Firstly, indoles reacted with arylsulfonyl
chlorides in the presence of sodium hydroxide (NaOH) and trieth-
ylbenzylammonium chloride (TEBA) at room temperature to give
N-arylsulfonylindoles (1a–u),13 which were used directly for the
next step reaction without further purification. Subsequently,
treatment of 1a–u with acetic anhydride by a regioselective Fri-
edel–Crafts acylation reaction led to N-arylsulfonyl-3-acetylin-
doles (2a–u) in 51–89% yields,14 which were well characterized
by 1H NMR, MS, and mp (see Supplementary data).
Target compounds 2a–u were evaluated for their inhibitory
activity against HIV-1 replication in acutely infected C8166 cells
in vitro according to the previously described method,9,15 and
AZT was used as a positive control. In the meantime, in order to
investigate the influence of 3-acetyl group of 2a–u on the anti-
HIV-1 activity, intermediates 1a–u without 3-acetyl group were
also tested for their anti-HIV-1 activity. The assay results of com-
pounds 1a–u and 2a–u are presented in Table 1. Among of all
the target compounds, 2c, 2j–l, and 2n–o exhibited the significant
* Corresponding authors. Tel./fax: +86 29 87091952.
1
These authors contributed equally to this work.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
Ran, Jun-Qiang
