Anti human immunodeficiency virus-1 (HIV-1) agents 3. Synthesis and in vitro anti-HIV-1 activity of some N-arylsulfonylindoles

Article abstract of DOI:10.1248/cpb.57.797

In order to find compounds with superior anti human immunodeficiency virus type 1 (HIV-1) activity, twelve simple N-arylsulfonylindoles (3a-l) were synthesized and preliminarily evaluated as HIV-1 inhibitors in vitro for the first time. Several compounds demonstrated significant anti-HIV-1 activity, especially N-(3-nitrobenzene) sulfonyl-6-methylindole (3h) and N-(3-nitrobenzene)sulfonylindole (3i) showed the highest anti-HIV-1 activity with EC₅₀ values of 0.26 and 0.74 μg/ml, and TI values of 543.78 and >270.27, respectively.

Full text of DOI:10.1248/cpb.57.797

August 2009
Chem. Pharm. Bull. 57(8) 797—800 (2009)
797
Anti Human Immunodeficiency Virus-1 (HIV-1) Agents 3. Synthesis and
in Vitro Anti-HIV-1 Activity of Some N-Arylsulfonylindoles
Ling-Ling FAN,a,# Wu-Qing LIU,b,c,# Hui XU,*,a Liu-Meng YANG,b Min LV,a and Yong-Tang ZHENG*,b
a Laboratory of Pharmaceutical Design & Synthesis, College of Sciences, Northwest A&F University; Yangling 712100,
China: b Laboratory of Molecular Immunopharmacology, Key Laboratory of Animal Models and Human Diseases
Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences; Kunming 650223, China: and c Graduate
School of the Chinese Academy of Sciences; Beijing 100039, China.
Received September 20, 2008; accepted May 14, 2009; published online May 14, 2009
In order to find compounds with superior anti human immunodeficiency virus type 1 (HIV-1) activity,
twelve simple N-arylsulfonylindoles (3a—l) were synthesized and preliminarily evaluated as HIV-1 inhibitors
in vitro for the first time. Several compounds demonstrated significant anti-HIV-1 activity, especially N-(3-ni-
trobenzene)sulfonyl-6-methylindole (3h) and N-(3-nitrobenzene)sulfonylindole (3i) showed the highest anti-HIV-1
activity with EC50 values of 0.26 and 0.74 mg/ml, and TI values of 543.78 and ꢁ270.27, respectively.
Key words N-arylsulfonylindole; human immunodeficiency virus type 1; inhibitor
According to World Health Organization (WHO)/Joint our previous paper, we have synthesized some single N-
United Nations Programme on human immunodeficiency arylindoles and benzyl phenyl ethers evaluated as HIV-1 in-
virus (HIV)/acquired immunodeficiency syndrome (AIDS) hibitors, and found some compounds demonstrated signifi-
(UNAIDS) estimates published in December 2007, 33.2 mil- cant anti-HIV-1 activity.12,13) In continuation of our program
lion people are living with HIV, 2.5 million people have been aimed at the discovery and development of bioactive mole-
newly infected in 2007, and 2.1 million died from AIDS in cules,12—18) herein we report the synthesis and anti-HIV-1 ac-
2007.1) Consequently, the rapid worldwide spread of AIDS tivity of some single N-arylsulfonylindoles bearing various
has prompted an intense research effort to discover com- functional groups. Furthermore, the preliminary structure–
pounds that can effectively inhibit HIV. In the past two activity relationships (SARs) were also discussed.
decades, twenty-five drugs, including nucleoside/nucleotide
viral reverse transcriptase (RT) inhibitors (NRTIs), non-nu- Results and Discussion
cleoside RT inhibitors (NNRTIs), protease inhibitors (PIs),
Synthesis of N-Arylsulfonylindoles 3a—l N-Arylsul-
integrase inhibitor and fusion (or entry) inhibitors (FIs), were fonylindoles 3a—l (Fig. 1) were synthesized as shown in
approved for clinical use in the world.2) However, these drugs Chart 1. Arylsulfonyl chlorides (1) reacted with indoles (2)
have only limited or transient clinical benefit due to their se- in the presence of NaOH and triethylbenzylammonium chlo-
vere side effects and the emergence of viral variants resistant ride (TEBA) under ultrasonic irradiation at 40 °C, and com-
to HIV-1 inhibitors.3) Therefore, the development of new, se- pounds 3a—l were obtained in 83—99% yields and identi-
lective and safe HIV-1 inhibitors still remains a high priority fied by satisfactory 1H-NMR and mass spectra.
for medical research.4—8) Although a series of N-arylsul-
Anti-HIV-1 Activity of N-Arylsulfonylindoles 3a—l
fonylindole derivatives were found to be potent and selective Compounds 3a—l were evaluated in vitro for their inhibitory
ligands for the human serotonin 5-HT6 receptor,9—11) to the activity against HIV-1 replication in acutely infected C8166
best of our knowledge, little attention has been paid to the cells. 3ꢀ-Azido-3ꢀ-deoxythymidine (AZT) was used as a pos-
anti-HIV-1 activity of the single N-arylsulfonylindoles. In itive control. As shown in Table 1, among the tested com-
Fig. 1. Structures of Different N-Arylsulfonylindoles 3a—l
∗ To whom correspondence should be addressed. e-mail: orgxuhui@nwsuaf.edu.cn; zhengyt@mail.kiz.ac.cn
© 2009 Pharmaceutical Society of Japan
#
These authors contributed equally to this work.

798
Vol. 57, No. 8
introducing electron-withdrawing group (e.g., nitro group)
on the benzenesulfonyl ring, would give compound possess-
ing more potent anti-HIV-1 activity than the corresponding
one having electron-donating group (e.g., methyl group) (3f
vs. 3b; 3g vs. 3c; 3h vs. 3d). The same results were also
found on 3i (having nitro group on the benzenesulfonyl ring),
and 3j or 3k (having methyl or ethyl group on the benzene-
sulfonyl ring), for example, the TI values of 3i, 3j and
3k were ꢁ270.27, ꢁ14.94, and 19.05, respectively. On the
contrary, when the electron-withdrawing group (e.g., nitro
group) was introduced on the indole’s ring of 3j to give 3a,
the anti-HIV-1 activity of which was decreased as compared
with 3j. For example, the EC50 and TI values of 3a and 3j
were 26.31/13.38 mg/ml, and ꢁ6.68/ꢁ14.94, respectively.
While the electron-donating group (e.g., methyl group) intro-
duced on the 6-position of the indole’s ring of 3j to give more
potent compound 3d (TIꢁ14.94 for 3j vs. TIꢂ26.01 for 3d).
In the meantime, it was found that the position of methyl
group on the indole’s ring was very important to anti-HIV-1
activity of the corresponding compound. (1) When the
methyl group was introduced on the 3- or 6-position of the
indole’s ring of 3j to yield more potent compounds 3b and
3d, the corresponding EC50 and TI values of which were
11.38/3.00 mg/ml, and ꢁ17.57/26.01, respectively; however,
when the methyl group was introduced on the 4-position of
the indole’s ring of 3j to yield less potent compound 3c
(TIꢁ14.94 for 3j vs. TIꢁ8.08 for 3c). (2) When the methyl
group was introduced on the 3- or 4-position of the indole’s
Chart 1. The Synthetic Route of N-Arylsulfonylindoles 3a—l
Table 1. Anti-HIV-1 Activity of N-Arylsulfonylindoles (3a—l) in Vitroa)
Compounds
CC50b) (mg/ml)
EC50c) (mg/ml)
TId)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
ꢁ175.77
ꢁ200
ꢁ200
26.31
11.38
24.73
3.00
12.33
1.03
1.69
0.26
0.74
13.38
5.31
ꢁ6.68
ꢁ17.57
ꢁ8.08
26.01
ꢁ14.81
121.61
ꢁ118.34
543.78
ꢁ270.27
ꢁ14.94
19.05
78.04
ꢁ182.71
125.87
ꢁ200
141.38
ꢁ200
ꢁ200
100.91
47.14
3k
3l
0.93
0.0024
50.68
544745.83
AZTe)
1307.39
a) Values are means of two separate experiments; b) CC50 (50% cytotoxic concentra-
tion), concentration of drug that causes 50% reduction in total C8166 cell number; c)
EC50 (50% effective concentration), concentration of drug that reduces syncytia forma-
tion by 50%; d) therapeutic index (TI) is a ratio of the CC50 value/EC50 value; e) AZT
was used as a positive control.
pounds, 3d, 3f, 3g, 3h, 3i and 3l exhibited the more potent ring of 3i, the corresponding compound 3f or 3g showed the
anti-HIV-1 activity with EC50 values of 3.00, 1.03, 1.69, less potent anti-HIV-1 activity than 3i (TIꢁ270.27 for 3i vs.
0.26, 0.74 and 0.93 mg/ml, and therapeutic index (TI) values TIꢂ121.61 for 3f or TIꢁ118.34 for 3g); but when the methyl
of 26.01, 121.61, ꢁ118.34, 543.78, ꢁ270.27 and 50.68, re- group was introduced on the 6-position of the indole’s ring of
spectively. Especially 3h and 3i showed the highest anti-HIV- 3i, the corresponding compound 3h showed the more potent
1 activity with EC50 values of 0.26 and 0.74 mg/ml, and TI anti-HIV-1 activity than 3i, for example, the EC50 and TI val-
values of 543.78 and ꢁ270.27, respectively. Interestingly, the ues of 3i and 3h were 0.74/0.26 mg/ml, and ꢁ270.27/543.78,
anti-HIV-1 activities of many N-arylsulfonylindoles were respectively.
more potent than those of our previously reported N-arylin-
Consequently, based upon the above investigation, the
doles and benzyl phenyl ethers. For example, the TI value of nitro group on the benzenesulfonyl ring and the methyl
3h was more than 22 times of that of N-(2-nitrophenyl)indole group on the 6-position of the indole’s ring certainly were
(TIꢂ24.61), which exhibited the highest anti-HIV-1 activity two important functional groups for 3h being good HIV-1 in-
of eight synthesized N-arylindoles, while the EC50 value of hibitory activity. Additionally, in order to find more potent
3h was significantly decreased 30 times compared with N-(2- molecules containing these kind structures, the mechanisms
nitrophenyl)indole (EC50ꢂ7.88 mg/ml).12) Similarly, the TI of the anti-HIV-1 function of these compounds need to be
value of 3h was nearly 30 times of that of 4-nitrobenzyl studied further.
phenyl ether (TIꢂ18.32), which exhibited the highest anti-
HIV-1 activity of ten synthesized benzyl phenyl ethers, while Conclusion
the EC50 value of 3h was significantly decreased 23 times
compared with 4-nitrobenzyl phenyl ether (EC50ꢂ5.96 mg/ synthesized and preliminarily evaluated as HIV-1 inhibitors
ml).13)
in vitro. Six compounds 3d, 3f, 3g, 3h, 3i and 3l demon-
In conclusion, twelve simple N-arylsulfonylindoles were
As it can be seen in Table 1, it was possible to draw some strated significant anti-HIV-1 activity. Especially compounds
structure–activity relationships from the comparative study. 3h and 3i showed the highest anti-HIV-1 activity with EC50
Firstly, it was shown that the electronic effect of substituted values of 0.26 and 0.74 mg/ml, and TI values of 543.78 and
groups on the N-arylsulfonylindoles was related to anti-HIV- ꢁ270.27, respectively.
1 activity. For example, the EC50 and TI values of 3b and 3f
Experimental
were 11.38/1.03 mg/ml, and ꢁ17.57/121.61, respectively; the
General All the solvents were of analytical grade and the reagents were
used as purchased. Thin-layer chromatography (TLC) and preparative thin-
layer chromatography (PTLC) were performed with silica gel plates using
silica gel 60 GF254 (Qingdao Haiyang Chemical Co., Ltd.). Melting points
EC50 and TI values of 3c and 3g were 24.73/1.69 mg/ml, and
ꢁ8.08/ꢁ118.34, respectively; the EC50 and TI values of 3d
and 3h were 3.00/0.26 mg/ml, and 26.01/543.78, respectively.
Accordingly, the TI value of 3f was nearly 7 times of that of
3b; the TI value of 3g was more than 14 times of that of 3c;
were determined on a digital melting-point apparatus and were uncorrected.
1H-NMR spectra were recorded on a Bruker Avance DMX 400 MHz instru-
ment using TMS as internal standard and CDCl3 as solvent. EI-MS was car-
the TI value of 3h was nearly 21 times of that of 3d. That is, ried out with Thermo DSQ GC/MS instrument. Sonication was performed in

August 2009
799
Ningbo SB-5200DT ultrasonic cleaner with the frequency of 40 kHz and an
output power of 200 W.
fectious dose (TCID50) in C8166 cells was determined and calculated by the
Reed and Muench method. Virus stocks were stored in small aliquots at
General Procedure for the Synthesis of N-Arylsulfonylindoles 3a—l ꢄ70 °C.25)
The mixture of arylsulfonyl chlorides (1, 0.55 mmol), indoles (2, 0.5 mmol),
MTT-Based Cytotoxicity Assay Cellular toxicity of compounds 3a—l
NaOH (0.875 mmol), and triethylbenzylammonium chloride (TEBA, 0.05 on C8166 cells was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-
mmol) in dichloromethane (2 ml) in 25 ml round-bottomed flask was
reacted under ultrasonic irradiation at 40 °C. When the reaction was com-
tetrazolium bromide (MTT) method as described previously.26) Briefly, cells
were seeded on 96-well microtiter plate in the absence or presence of vari-
plete according to TLC analysis, the reaction mixture was filtered, and the ous concentrations of compounds in triplicate and incubated at 37 °C in a
filtrate was concentrated in vacuo and purified by PTLC to give the pure N- humid atmosphere of 5% CO2 for 3 d. The supernatants were discarded and
arylsulfonylindoles.
MTT reagent (5 mg/ml in PBS) was added to each well, then incubated for
N-Tosyl-5-nitroindole 3a: 142.0 mg, 90% yield, white solid, mp 156— 4 h, 100 ml of 50% N,N-dimethylformamide (DMF)–20% SDS was added.
157 °C; 1H-NMR (400 MHz, CDCl3) d: 2.37 (3H, s), 6.80 (1H, d, Jꢂ3.6 After the formazan was dissolved completely, the plates were read on a Bio-
Hz), 7.26 (2H, m), 7.73 (1H, d, Jꢂ3.6 Hz), 7.78 (2H, d, Jꢂ8.0 Hz), 8.07
Tek Elx 800 ELISA reader at 595/630 nm. The cytotoxic concentration that
(1H, d, Jꢂ9.2 Hz), 8.19 (1H, dd, Jꢂ2.4 Hz, Jꢂ8.8 Hz), 8.46 (1H, d, Jꢂ2.0 caused the reduction of viable C8166 cells by 50% (CC50) was determined
Hz); EI-MS m/z: 316 (Mꢃ, 30).
from dose–response curve.
N-Tosyl-3-methylindole 3b: 141.4 mg, 99% yield, white solid, mp 102—
Syncytia Assay In the presence of 100 ml various concentrations of
compounds, C8166 cells (4ꢅ105/ml) were infected with virus HIV-1IIIB at a
multiplicity of infection (M.O.I) of 0.06. The final volume per well was
200 ml. Control assays were performed without the testing compounds in
1
104 °C (lit.,19) 112—114 °C); H-NMR (400 MHz, CDCl3) d: 2.23 (3H, s),
2.32 (3H, s), 7.18 (5H, m), 7.43 (1H, d, Jꢂ7.2 Hz), 7.73 (2H, d, Jꢂ8.4 Hz),
7.97 (1H, d, Jꢂ8.0 Hz); EI-MS m/z: 285 (Mꢃ, 42).
N-Tosyl-4-methylindole 3c: 121.3 mg, 85% yield, white solid, mp 99— HIV-1IIIB infected and uninfected cultures. After 3 d of culture, the cyto-
1
101 °C (lit.,20) 107—108 °C); H-NMR (400 MHz, CDCl3) d: 2.23 (3H, s),
pathic effect (CPE) was measured by counting the number of syncytia. Per-
centage inhibition of syncytia formation was calculated and 50% effective
2.46 (3H, s), 6.67 (1H, d, Jꢂ4.0 Hz), 7.00 (1H, d, Jꢂ7.2 Hz), 7.19 (3H, m),
7.55 (1H, d, Jꢂ3.6 Hz), 7.75 (2H, d, Jꢂ8.0 Hz), 7.80 (1H, d, Jꢂ8.4 Hz); EI- concentration (EC50) was calculated. AZT (Sigma) was used as a positive
MS m/z: 285 (Mꢃ, 53).
control. Therapeutic index (TI)ꢂCC50/EC50.27)
N-Tosyl-6-methylindole 3d: 118.5 mg, 83% yield, white solid, mp 95—
96 °C (lit.,20) syrup); 1H-NMR (400 MHz, CDCl3) d: 2.23 (3H, s), 2.46 (3H,
s), 6.58 (1H, d, Jꢂ3.6 Hz), 7.03 (1H, d, Jꢂ8.0 Hz), 7.19 (2H, d, Jꢂ8.4 Hz),
7.37 (1H, d, Jꢂ8.0 Hz), 7.47 (1H, d, Jꢂ3.6 Hz), 7.74 (2H, d, Jꢂ8.4 Hz),
7.79 (1H, s); EI-MS m/z: 285 (Mꢃ, 49).
Acknowledgments This work has been supported by the program for
New Century Excellent University Talents, State Education Ministry of
China (NCET-06-0868), and the Key Project of Chinese Ministry of Educa-
tion (No. 107105). We also would like to acknowledge Key Scientific and
N-(4-Chlorobenzene)sulfonylindole 3e: 142.9 mg, 98% yield, white solid, Technological projects of Yunnan province (2004NG12), National 973 proj-
mp 106—107 °C (lit.,21) 78.5—79.9 °C); 1H-NMR (400 MHz, CDCl3) d: ect of China (2006CB504200), and the Knowledge Innovation Program of
6.67 (1H, d, Jꢂ3.6 Hz), 7.22 (1H, m), 7.30 (1H, t, Jꢂ7.6 Hz), 7.38 (2H, d, CAS (KSCX1-YW-R-24).
Jꢂ8.4 Hz), 7.53 (2H, m), 7.79 (2H, d, Jꢂ8.4 Hz), 7.96 (1H, d, Jꢂ8.4 Hz);
EI-MS m/z: 291 (Mꢃ, 40), 293 (Mꢃ, 15).
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