Identification of the novel N-phenylbenzenesulfonamide derivatives as potent HIV inhibitors

Article abstract of DOI:10.1016/j.cclet.2014.11.004

Searching for more safe and effective agents for HIV treatments is still an urgent topic worldwide. Based on our continuous modifications on the benzophenone derivatives as HIV-1 reverse transcriptase (RT) inhibitors, a new template bearing N-phenylbenzenesulfonamide (PBSA) structure was designed to enhance the interactions with HIV-1 RT. In this manuscript, a series of PBSA derivatives were synthesized and evaluated for their anti-HIV-1 activity. The preliminary test showed that these compounds were potent to inhibit wild-type HIV-1 with EC₅₀ values ranging of 0.105-14.531 μmol/L. In particular, compound 13f not only has high anti-HIV-1 activity (0.108 μmol/L), but also possesses low toxicity with a TI value of 1816.6. Furthermore, the major interactions of the inhibitor 13f with HIV-1 RT were also investigated using the molecular modelling. Our discovered structure-activity relationships (SARs) of these analogues may serve as an important clue for further optimizations.

Full text of DOI:10.1016/j.cclet.2014.11.004

Chinese Chemical Letters 26 (2015) 243–247
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Identification of the novel N-phenylbenzenesulfonamide derivatives
as potent HIV inhibitors
Yong Sun a,1, Cui-Lin Lu b,c,1, Chang-Yuan Wang a, Rui-Rui Wang b, Ke-Xin Liu a,
*
Liu-Meng Yang b, Yu-Hong Zhen a, Hou-Li Zhang a, Chao Wang a, Yong-Tang Zheng b,
,
Xiao-Dong Ma a,
*
a College of Pharmacy, Dalian Medical University, Dalian 116044, China
b Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology,
Chinese Academy of Sciences, Kunming 650223, China
c Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming 650204, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Searching for more safe and effective agents for HIV treatments is still an urgent topic worldwide. Based
on our continuous modifications on the benzophenone derivatives as HIV-1 reverse transcriptase (RT)
inhibitors, a new template bearing N-phenylbenzenesulfonamide (PBSA) structure was designed to
enhance the interactions with HIV-1 RT. In this manuscript, a series of PBSA derivatives were synthesized
and evaluated for their anti-HIV-1 activity. The preliminary test showed that these compounds were
Received 2 September 2014
Received in revised form 1 October 2014
Accepted 23 October 2014
Available online 10 November 2014
potent to inhibit wild-type HIV-1 with EC50 values ranging of 0.105–14.531
mmol/L. In particular,
Keywords:
compound 13f not only has high anti-HIV-1 activity (0.108 mol/L), but also possesses low toxicity with
m
Benzophenone
a TI value of 1816.6. Furthermore, the major interactions of the inhibitor 13f with HIV-1 RT were also
investigated using the molecular modelling. Our discovered structure-activity relationships (SARs) of
these analogues may serve as an important clue for further optimizations.
N-Phenylbenzenesulfonamide
Structure modification
Anti-HIV activity
ß 2014 Yong-Tang Zheng and Xiao-Dong Ma. Published by Elsevier B.V. on behalf of Chinese Chemical
Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. All rights reserved.
1. Introduction
GW678248 (7, Fig. 2) [15,16] were the most active inhibitors, and
dramatically improved the drug resistance issues. In particular,
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are
important part of certain multidrug regimens used in the
treatment of HIV infection [1–4]. Till now, five NNRTIs (Fig. 1):
nevirapine (1, NVP) [5], delavirdine (2, DLV) [6], efavirenz (3, EFE)
[7] etravirine (4, ETV) [8], and rilpivirine (5, RPV) [9–11] have been
approved for the clinical use, and significantly reduced the deaths
from AIDS. However, for the rapid emergence of drug resistance,
more effective NNRTIs, in particular those with new chemotypes
are still required in order to allow continued suppression of the
viral infection [12,13].
GW678248, which was progressed to the clinical II studies, also
possesses excellent pharmacokinetic property. As our great interest,
we have carried out some modifications on this scaffold, and
obtained Ami-BPs [18], Naph-BPs [19], Eth-BPs [20], and Hyd-BPs
[21] as new potent BP inhibitors. Previous SAR explorations revealed
that the flexible linker between A- and B-rings could not only
improve the adaptation of the inhibitor to RT, but also promote the
H-bond bindings with Tyr188 or Tyr181 [18]. To further enhance
these actions, we designed a series of phenylbenzenesulfonamide
derivatives (PBSAs, Fig. 2), in which the A-ring was more flexible. In
this manuscript, these compounds were synthesized, and evaluated
for their preliminary biological activity against wild-type HIV-1
virus. Moreover, applying the molecular stimulations, the actions of
the potent inhibitor 13f with HIV-1 RT was also investigated.
Recently, the novel benzophenone derivatives aroused great
attention due to their broad spectrum activity against several key
mutant HIV-1 strains, such as Tyr188, Tyr181, Trp229, and so on
[14–17]. Of these compounds, GW4511 (6, Fig. 2) [14] and
2. Experimental
*
Corresponding authors.
E-mail addresses: zhengyt@mail.kiz.ac.cn (Y.-T. Zheng), xiaodong.ma@139.com
All chemicals were purchased from commercial sources,
analytical grade and used without further purification. Melting
(X.-D. Ma).
1
These authors contributed equally to this work.
http://dx.doi.org/10.1016/j.cclet.2014.11.004
1001-8417/ß 2014 Yong-Tang Zheng and Xiao-Dong Ma. Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy
of Medical Sciences. All rights reserved.

244
Y. Sun et al. / Chinese Chemical Letters 26 (2015) 243–247
Fig. 1. Structures of currently marketed NNRTIs.
points were measured on a SGW X-4 microscopic melting-point
apparatus and were uncorrected. Mass spectra were obtained on a
Waters Quattro Micromass instrument using electrospray ioniza-
tion (ESI) techniques. 1H NMR and 13C NMR spectra on a Brucker
AV 400 MHz spectrometer were recorded in DMSO-d6. Chemical
mixture of 12 (0.01 mol) and pyridine (3.36 g, 0.04 mol) in acetone
(50 mL) was cooled to 0 8C in an ice bath, then aryl sulfonyl
chloride (0.02 mol) was added dropwise slowly. The resulting
mixture was allowed to warm to room temperature and stirred for
another 10 min. After the reaction was complete, the mixture was
poured into water (150 mL), filtered and washed with ethyl
ester to give crude product as beige solid, which was purified by
crystallization from acetonitrile to provide the target compounds
13a–t as off-white solids.
shifts were reported in
d (ppm) units relative to the internal
standard tetramethylsilane (TMS). Elemental analyses were
performed on a Carlo Erba 1106 instrument and the results of
elemental analyses for C, H, Cl, Br, F and N were within Æ0.4% of the
theoretical values.
Applying our previously reported procedure [18], all these
newly designed compounds were first synthesized. The following
are general procedure and structure datas of typical inhibitors. A
N-[4-(Aminosulfonyl)-2-methylphenyl]-2-[4-chloro-2-(4-
methylbenzenesulfonyl)aminophenoxy]acetamide (13a): Yield
66.1%; off-white solid, mp 132.2–134.1 8C; 1H NMR (DMSO-d6):
d
2.22 (s, 3H, CH3), 2.31 (s, 3H, CH3), 4.35 (s, 2H, CH2), 7.32 (s, 2H, NH2),
6.95–7.82(m, 10H, PhH), 9.57(br, 1H, NH), 9.71 (s, 1H, NH); 13C NMR
(DMSO-d6):
d 18.5, 22.3, 68.1, 114.1, 121.7, 122.8, 125.9, 126.1,
126.4, 126.8, 127.2 (2C), 128.2, 130.1 (2C), 134.2, 137.3, 139.9, 142.1,
144.4, 150.1, 166.8; MS (ESIÀ) m/z 523 [MÀH]À; Anal. Calcd. for
C22H22ClN3O6S2: C 50.43, H 4.23, Cl 6.77, N 8.02, O 18.32, S 12.24,
found: C 50.47, H 4.21, Cl 6.76, N 8.01, O 18.30, S 12.26.
N-[4-(Aminosulfonyl)phenyl]-2-[4-chloro-2-(4-methylbenze-
nesulfonyl)aminophenoxy]acetamide (13f): Yield 71.1%; off-white
solid, mp 201.1–202.9 8C; 1H NMR (DMSO-d6):
d
2.27 (s, 3H, CH3),
4.26 (s, 2H, CH2), 7.33(s, 2H, NH2), 6.67–7.93 (m, 11H, PhH), 9.59 (s,
1H, NH), 9.88 (br, 1H, NH); 13C NMR (DMSO-d6):
18.5, 68.1, 113.5,
d
121.9 (2C), 122.3, 126.1, 126.3, 127.1(2C), 127.5 (2C), 128.1, 129.3
(2C), 135.1, 138.6, 140.3, 142.8, 151.3, 166.4; MS (ESIÀ) m/z
509 [MÀH]À; Anal. Calcd. for C21H20ClN3O6S2: C 49.46, H 3.95,
Cl 6.95, N 8.24, O 18.82, S 12.57, found: C 49.50, H 3.93, Cl 6.93, N 8.23,
O 18.81, S 12.59.
Fig. 2. Designing strategy of the title compounds.
N-[4-(Aminosulfonyl)phenyl]-2-[4-chloro-2-(4-methoxyben-
zenesulfonyl)aminophenoxy]acetamide (13j): Yield 53.9%; white
solid, mp 243.1–244.6 8C; 1H NMR (DMSO-d6):
d 3.68 (s, 3H, OCH3),
Fig. 3. (a) Model of 13f docked into the non-nucleoside binding site of RT; (b) Model of GW678248 docked into the non-nucleoside binding site of RT.

Y. Sun et al. / Chinese Chemical Letters 26 (2015) 243–247
245
4.35 (s, 2H, CH2), 7.35 (s, 2H, NH2), 6.85–7.80 (m, 11H, PhH), 9.57 (s,
1H, NH), 9.91 (s, 1H, NH); 13C NMR (DMSO-d6):
55.9, 58.3, 114.2,
with the appropriately substituted of aryl sulfonyl chloride under
the action of base, the title compounds 13a–t were furnished in
53%–74% yields (Scheme 1).
To explore the biological activity of these newly obtained
analogues, the activity against wild-type HIV-1 strain IIIB was
tested [22]. For comparison, lead compound GW678248 and the
FDA-approved drug zidovudine (AZT) were also evaluated as
reference compounds. The activity data is interpreted in CC50
(cytotoxicity), EC50 (anti-HIV activity) and TI (therapeutic index,
given by the CC50/EC50 ratio).
d
115.3 (2C), 121.1 (2C), 123.2, 125.9, 126.7, 127.9 (2C), 128.3, 127.0
(2C), 133.4, 140.6, 142.5, 152.9, 162.5, 167.8; MS (ESIÀ) m/z
525 [MÀH]À; Anal. Calcd. for C21H20ClN3O7S2: C 47.95, H 3.83, Cl
6.74, N 7.99, O 21.29, S 12.19, found: C 47.98, H 3.82, Cl 6.72, N 7.97,
O 21.30, S 12.20.
N-[4-(Aminosulfonyl)-2-methylphenyl]-2-[2-(4-methylbenze-
nesulfonyl)aminophenoxy]acetamide (13k): Yield 56.4%; white
solid, mp 119.0–120.1 8C; 1H NMR (DMSO-d6):
d 2.25 (s, 3H, CH3),
2.32 (s, 3H, CH3), 4.37 (s, 2H, CH2), 7.33 (s, 2H, NH2), 6.97–7.75 (m,
The assay results for 13a–t are summarized in Table 1,
apparently, most of these compounds exhibit moderate activity
against the wild-type HIV-1 strain IIIB with EC50 values ranging
11H, PhH), 9.65 (br, 1H, NH), 9.73 (s, 1H, NH); 13C NMR (DMSO-d6):
d
18.7, 21.8, 68.5, 114.3, 122.7, 124.8, 126.4, 126.1, 126.8, 126.9,
127.5(2C), 128.6, 130.2(2C), 134.5, 138.1, 139.2, 142.4, 144.0,
from 0.105 mmol/L to 14.531 mmol/L, along with the TI values
ranging from 12.90 to 1816.55. The most active inhibitor 13f with a
TI value of 1816.55 could able to inhibit the wild-type HIV-1 at very
150.8, 167.2; MS (ESIÀ) m/z 488 [MÀH]À; Anal. Calcd. for
C22H23N3O6S2: C 53.97, H 4.74, N 8.58, O 19.61, S 13.10, found:
C 53.94, H 4.73, N 8.59, O 19.60, S 13.14.
low concentrations with an EC50 value of 0.108 mmol/L. It is no
N-[4-(Aminosulfonyl)phenyl]-2-[2-(4-chlorobenzenesulfonyl)-
aminophenoxy] acetamide (13t): Yield 68.1%; off-white solid, mp
doubt that the PBSA derivatives were able to form binding affinity
with HIV-1 RT. However, the actions were so weak that they
conferred an anti-HIV activity about 100-fold lower than
GW678248.
By placing various substituents on the A-, B-, and C-rings, a
series of PBSAs were synthesized to explore their SARs. For the
benzenesulfonamide section, which closed to the top hydrophobic
pocket lined by the important aromatic residues Tyr181, Tyr188
and Trp229, a number of C-4 substituents (H, Me, NO2, Cl, MeO)
were introduced (compounds 13a–e). Among 13a–e, most of them
137.7–138.9 8C; 1H NMR (DMSO-d6):
d
4.38 (s, 2H, CH2), 7.30 (s, 2H,
NH2), 6.70–7.87 (m, 12H, PhH), 9.87 (s, 1H, NH), 10.04 (br, 1H, NH);
13C NMR (DMSO-d6):
68.8, 114.7, 120.8 (2C), 122.9, 127.2, 127.5,
d
127.6(2C), 127.8, 129.3 (2C), 129.8 (2C), 134.4, 138.3, 140.2, 141.7,
151.5, 167.5; MS (ESIÀ) m/z 495 [MÀH]À; Anal. Calcd. for
C20H18ClN3O6S2: C 48.43, H 3.66, Cl 7.15, N 8.47, O 19.36, S
12.93, found: C 48.40, H 3.63, Cl 7.17, N 8.46, O 19.40, S 12.94.
Cytotoxicity assay: The cytotoxicities of compounds on C8166
cells were assessed by MTT colorimetric assay as described
previously [22]. The absorbance at 570 nm/630 nm (A570/630) was
read in an ELISA reader (Elx1000, Bio-Tek Instrument Inc., USA). The
minimumcytotoxicconcentration that caused the reduction of viable
cells by 50% (CC50) was determined from the dose response curve.
have similar level of anti-HIV activity (1.607–3.667
well as the higher cytopathogenicity (>123.11 mol/L). Interest-
ingly, just removing the methyl group at C-2 position of the C-ring,
the inhibition abilities of analogues 13f–i (<1 mol/L) were
tremendously improved. The notable example was compound 13f
(0.108 mol/L), which almost displayed 20 times stronger potency
compared with 13b (2.010 mol/L). Another series of compounds
mmol/L), as
m
m
Syncytium reduction assay: In the presence of 100
m
L of various
m
concentrations of compounds, C8166 cells (4 Â 105/mL) were
m
infected with virus (HIV-1 IIIB) at a multiplicity of infection (M.O.I)
13k–o, with the removal of the chlorine atom on the B-ring, also
exhibit weak anti-HIV activity, except for analogues 13k and m
of 0.06. The final volume per well was 200
mL. AZT and GW678248
were used for drug control. After 3 days of culture, the number of
syncytia (multinucleated giant cells) was scored under an inverted
microscope; 50% effective concentration to blocking syncytia
formation (EC50) was calculated [22].
(0.552 mmol/L and 0.667 mmol/L, respectively). Furthermore,
compounds 13p–t were also synthesized to explore the affect of
the methyl group on the C-ring. Apparently, this modification was
more favourable, and resulted in the identification of a very potent
compound 13t, exhibiting 0.161
mmol/L anti-wild-type HV-1
activity and 1246.50 selectivity.
3. Results and discussion
Overall, our previous SAR studies implied that installing
substituents on the B-ring would decrease the anti-HIV activity.
In terms of B- and C-rings, more substituents were needed to
establish their SARs. Although the obtained PBSAs were not as
potent as GW678248, they provided a new potentia anti-HIV
template for further optimizations.
According to the established methodology [18], treatment of
2-nitrophenol (8a,b) with ethyl bromoacetate, and subsequent
hydrolysis provides the acid derivative 10a,b. After chlorination of
10, and then coupling with 4-amino-benzenesulfonamide in basic
condition, intermediates 11a–t were prepared in good yields
(66%–86%). Next, reducing reaction in the presence of Fe–NH4Cl
was carried out to obtain the amino 12a–t. Then by coupling 12
In addition, using the program AutoDock 4.0.1 [23], a modelling
study was performed to explore the possible action mechanism of
Scheme 1. Synthesis of N-phenylbenzenesulfonamide analogues 13a–t. Reagents and conditions: (a) BrCH2COOEt, K2CO3, KI, acetonitrile, 2 h, 80 8C, 72%–90%; (b) NaOH, H2O,
60 8C, 2 h, 68%–84%; (c) SOCl2, 80 8C, 1 h; (d) 4-aminobenzenesulfonamide, NaHCO3, acetone, 80 8C, 2 h, 66%–86%; (e) Fe, NH4Cl, acetone-H2O, 80 8C, 12 h, 58%–76%; (f)
RSO2Cl, Py, acetonitrile, r.t, 30 min, 53%–74%.

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Y. Sun et al. / Chinese Chemical Letters 26 (2015) 243–247
Table 1
Biological activity of compounds 13a–t against HIV-1 in C8166 cells.a
Compound
R1
R2
R3
EC50
(
m
mol/L)b
CC50
(
m
mol/L)c
TId
13a
13b
13c
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
Me
Me
Me
Me
Me
H
4-Me-
H
1.231 Æ 0.506
2.010 Æ 0.049
1.607 Æ 0.340
3.667 Æ 0.676
2.454 Æ 0.157
0.108 Æ 0.010
0.686 Æ 0.161
0.452 Æ 0.226
3.124 Æ 0.869
0.105 Æ 0.010
0.552 Æ 0.286
14.531 Æ 5.846
0.667 Æ 0.216
9.519 Æ 0.548
26.644
>381.67
>219.8
>190.5
104.7
46.9
>392.17
4-Cl
168.19 Æ 23.01
171.84 Æ 4.89
123.11 Æ 2.97
195.91 Æ 44.95
152.51 Æ 31.91
126.78 Æ 6.70
179.42 Æ 24.14
75.61 Æ 31.66
180.88 Æ 41.64
208.62 Æ 11.61
183.87 Æ 34.26
212.99 Æ 8.53
172.40
13d
13e
13f
4-NO2
4-MeO
4-Me
H
50.2
1816.6
222.5
280.2
57.4
13g
13h
13i
H
H
4-Cl
H
4-NO2
4-MeO
4-Me
H
13j
H
723.1
328.0
14.4
13k
13l
Me
Me
Me
Me
Me
H
H
13m
13n
13o
13p
13q
13r
H
4-Cl
275.8
22.4
H
4-NO2
4-MeO
4-NO2
4-MeO
H
H
6.47
H
4.482 Æ 1.066
208.52 Æ 7.15
>406.88
46.5
–
H
H
>203.442
H
H
8.407 Æ 3.164
0.610 Æ 0.273
0.161 Æ 0.060
0.002
216.59 Æ 1.13
192.51 Æ 25.40
201.07 Æ 7.81
4651.22
25.8
13s
H
H
4-Me
4-Cl
315.7
1246.5
13t
H
H
AZT
GW678248
2,325,610.0
0.0014 Æ 0.0001
>386.8
>257,866.7
a
Data represent the mean of at least two separate experiments.
b
c
Compound concentration required to protect C8166 cells against viral cytopathogenicity by 50%.
Compound concentration that decreases the uninfected C8166 cell viability by 50%.
Therapeutic index: CC50/EC50 ratio.
d
the PBSAs with HIV-1 RT. According to the basis of the protocols,
the most active inhibitor 13f was chosen to be docked into the
nonnucleoside inhibitor binding pocket (NNIBP) of RT (PDB code:
3DOK). The default AutoDock 4.0.1 parameters were used. For
comparison, GW678248 was also docked to NNIBP with the same
protocols.
Acknowledgments
This work was supported in part by grants from the National
Natural Science Foundation of China (No. 81402788), and the Ph.D.
Start-up Fund of Natural Science Foundation of Liaoning Province,
China (No. 20141115).
It was clear to indicate that the binding conformations of
compound 13f and GW678248 were very similar, especially in the
hydrophilic section (Fig. 3). Of this template, the sulfonamide
group on the C-ring reached the top of the cavity and formed strong
actions with Ser105, Val105, Val106 and Pro225, while the NH part
that linked the B- and C-rings formed a direct hydrogen bond with
the backbone OH group of Asn103, in which the oxygen atom
serves as hydrogen-bond acceptor (average O. . .H distan-
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that long distance between A-ring and HIV-1 RT BBINP was the
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PBSAs as HIV inhibitors, various substitutes installed in the A-ring
will be beneficial.

Y. Sun et al. / Chinese Chemical Letters 26 (2015) 243–247
247
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