Synthesis and biological activity of naphthyl-substituted (B-ring) benzophenone derivatives as novel non-nucleoside HIV-1 reverse transcriptase inhibitors

Article abstract of DOI:10.1016/j.bmc.2011.06.007

A novel series of benzophenone derivatives with B-ring substituted by naphthyl ring has been synthesized and evaluated as non-nucleoside HIV-1 reverse transcriptase inhibitors. Most of these compounds showed good to moderate activity against wild-type HIV

Full text of DOI:10.1016/j.bmc.2011.06.007

Bioorganic & Medicinal Chemistry 19 (2011) 4601–4607
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Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and biological activity of naphthyl-substituted (B-ring)
benzophenone derivatives as novel non-nucleoside HIV-1 reverse
transcriptase inhibitors
Xiao-Dong Ma a, Xuan Zhang d,e, Hui-Fang Dai c, Shi-Qiong Yang a, Liu-Meng Yang d, Shuang-Xi Gu a,
Yong-Tang Zheng d, Qiu-Qin He a, Fen-Er Chen a,b,
⇑
a Department of Chemistry, Fudan University, Shanghai 200433, PR China
b Institute of Biomedical Science, Fudan University, Shanghai 200433, PR China
c School of Pharmacy, Fudan University, Shanghai 200031, PR China
d Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology,
Chinese Academy of Sciences, Kunming 650223, PR China
e Faculty of Pharmacy, Kunming Medical University, Kunming 650031, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of benzophenone derivatives with B-ring substituted by naphthyl ring has been synthe-
sized and evaluated as non-nucleoside HIV-1 reverse transcriptase inhibitors. Most of these compounds
showed good to moderate activity against wild-type HIV-1 and mutated viruses. In particular, the ana-
logue 10i demonstrated the most potent activity against wild-type HIV-1 with an EC50 value of 4.8 nM,
and with a high selectivity index up to 10347.9, it also proved to be active against the HIV-1 double
Received 9 May 2011
Revised 2 June 2011
Accepted 2 June 2011
Available online 14 June 2011
mutant strain A17 (K103N+Y181C) with an EC50 value of 2.1 lM. In addition, the molecular modeling
Keywords:
HIV
NNRTIs
Benzophenone derivatives
Naphthyl
SAR
study was used to explore the major interactions between the potent inhibitors with the HIV-1 RT.
The investigation of the structure–activity relationships may serve as an important lead for the further
optimization.
Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
1. Introduction
Since their first discovery in the early 1990s, non-nucleoside re-
verse transcriptase inhibitors (NNRTIs) have been shown to be a
key component of highly active anti-retroviral therapy
(HAART).1–4 To date, four NNRTIs have been approved for clinical
use (1–4, Fig. 1): nevirapine (1, NVP),5 delavirdine (2, DLV),6 efavi-
renz (3, EFE)7 and etravirine (4, ETV).8,9 In spite of the achieve-
ments of combination therapy in reducing the deaths from AIDS,
the emergence of resistance to current anti-HIV drugs in clinical
use means that further entities with broadened spectrum of activ-
ity are required in order to allow continued suppression of the viral
infection.10,11
As novel NNRTIs, benzophenone derivatives (BPs, Fig. 2), such as
6 (GW451112) and 7 (GW67824813,14), which were derived from 5
(GF12859015) showed a greatly improved profile of activity against
both wild-type and clinically relevant NNRTI-resistant mutant
strains of HIV-1. Recent crystallographic studies of HIV-1 RT in
complexes with 5 and 6 have indicated that it was possible to
H3C
N
CH3
NH
CH3
CH3
N
H
N
O
N
HN
S
O
O
N
N
N
N
H
O
2
1
Delavirdine
Nevirapine
F3C
CN
CN
H3C
CH3
N
O
NH
Cl
O
N
Br
N
H
O
NH2
3
4
Etravirine
Efavirenz
⇑
Corresponding author. Tel./fax: +86 21 65643811.
E-mail address: rfchen@fudan.edu.cn (F.-E. Chen).
Figure 1. Structures of currently marketed NNRTIs.
0968-0896/$ - see front matter Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2011.06.007

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X.-D. Ma et al. / Bioorg. Med. Chem. 19 (2011) 4601–4607
chloride, which conveniently removed the methoxy group to re-
H
N
lease the naphthol for the subsequent alkylation step. The cyana-
tion13 of 9k, 9l, 9q and 9d with CuCN at 160 °C for 8 h in
anhydrous DMF gave the corresponding 6-cyano intermediates
9s–v in 32–43% yield, respectively. Subsequent alkylation of 9a–v
with 1113 yielded the desired analogues 10a–v in a slightly conver-
gent route (Scheme 1).
O
B
O
C
O
A
Cl
5
H
N
O
O
R1
2.2. Biological activity
O
SO2NH2
The biological activity of naphthyl-substituted (B-ring) benzo-
phenone analogues 10a–v against wild-type HIV-1 strain in
C8166 cells are summarized in Table 1.19,20 Lead compound
GW678248 and the FDA-approved drug, zidovudine (AZT) were
also evaluated as reference compounds. The activity data are inter-
preted in CC50 values (cytotoxicity), EC50 (anti-HIV activity) and SI
(selectivity, given by the CC50/EC50 ratio).
R2
Cl
6, R1 = F, R2 = CF3 ( GW 4511)
7, R1 = Cl, R2 = CN ( GW 678248)
Figure 2. Structures of potent benzophenones.
As seen from the results in Table 1, clearly, the analogues 10a–i,
without any substitutions at the C-6 position on the naphthyl ring,
were much more potent against wild-type HIV-1 virus than that
with C-6-bromo (10j–r) or cyano (10s–v) substitution. Generally,
most of the compounds 10a–i were highly potent, with the EC50
values ranging from 4.8 nM (10i) to 608.9 112.6 nM (10g) and
selectivity index (SI) values ranging from 54.2 (10g) to 10347.9
(10i). In particular, compound 10d (EC50 = 7.8 3.3 nM) and 10i
(EC50 = 4.8 nM) exhibited more anti-HIV-1 potency than zidovu-
dine, whereas less than the leading compound GW678248. Appar-
ently, the sharp decline in biological activity of the derivatives
10j–v indicated that the introduction of a bromo or cyano group
in the naphthyl ring of the title molecules resulted the bulky or
electron-withdrawing group at the C-6 position, which may only
introduce further substituents on the B-ring of the benzophenone
template, such increase in bulk will result in strong interactions
with Leu100, Val106 and Tyr188, and thus the tighter packing with
the binding pocket of RT gave high level inhibitions.16 On this basis,
we replaced B-ring with the bulky naphthyl moiety and synthe-
sized a series of naphthyl-substituted (B-ring) benzophenone
derivatives 10a–y for their potential anti-HIV activity. Additionally,
the preliminary structure–activity relationships (SARs) and molec-
ular modeling study of these compounds are also described in this
manuscript.
2. Results and discussion
2.1. Chemistry
weakly improve the
p–p stacking interaction between inhibitors
and amino acid residues with Leu100, Val106 and Tyr188 within
the binding pocket of RT.
The synthesis of target compounds 10a–v is shown in Scheme 1.
Starting from 6-substituted-2-methoxynaphthalene (8a–b), the 2-
benzoyl-1-naphthol (9a–r) were prepared by Friedel–Crafts acyla-
tion17,18 with aryl chloride in the presence of catalytic aluminium
To investigate the potential SAR of these compounds, the im-
pact on the potency by moving a small substituent around the A-
ring was further explored. Clearly, placement of a methyl group
H
N
O
O
OH
O
O
c
Ar
O
Ar
SO2NH2
a
H
N
Br
O
SO2NH2
R
R
11
R
9a-v
10a-v
8a-b
9k, 9l, 9q, 9d R = Br
9s-v R = CN
b
10 Ar
R
H
H
H
H
H
H
H
H
10 Ar
R
10 Ar
R
a
b
c
d
e
f
Ph
i
3,5-Cl,CN-Ph
Ph
H
q
r
s
3,4-Me2-Ph
3,5-Cl,Br-Ph
3-Me-Ph
Br
3-Me-Ph
j
Br
Br
Br
Br
Br
Br
Br
Br
3-Cl-Ph
k
l
3-Me-Ph
3-Cl-Ph
CN
CN
CN
CN
3,5-Me2-Ph
2,5-Me2-Ph
2,4-Me2-Ph
3,4-Me2-Ph
3,5-Cl,Br-Ph
t
3-Cl-Ph
m
n
o
p
3-F-Ph
u
v
3,4-Me2-Ph
3,5-Me2-Ph
3,5-Me2-Ph
2,4-Me2-Ph
2,5-Me2-Ph
g
h
Scheme 1. Synthesis of naphthyl-substituted (B-ring) benzophenone analogues10a–v. Reagents and conditions: (a) AlCl3, ArCOCl, CS2, reflux, 2 h, 50–76%; (b) CuCN, DMF,
160 °C, 32–43%; (c) K2CO3, NaI, N-[4-(Aminosulfonyl)-2-methylphenyl]-2-bromoacetamide (11), acetone, 2 h, 50 °C, 57–67%.

X.-D. Ma et al. / Bioorg. Med. Chem. 19 (2011) 4601–4607
4603
Table 1
Biological activity of compounds 10a–v against HIV-1 in C8166 cells
a
c
Compd
EC50
CC50
(l
M)
SId
b
IIIB (nM)
A17 (lM)
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
10m
10n
10o
10p
10q
10r
52.7 22.0
13.5
33.8 9.3
7.8 3.3
11.6
139.3 33.8
608.9 112.6
27.1
4.8
4607.7
9.6
2.4
9.5
8.4
7.6
7.9
12.3
7.5
2.1
25.8
3.4
3.9
9.7
7.8
33.1
20.7
28.2
10.2
10.4
20.6
97.3
16.3
33.8 4.7
40.4 0.5
37.4 0.8
39.1 2.1
47.5
25.5 7.2
33.0 2.0
36.6 12.6
49.4 0.8
29.2 12.5
6.8 0.3
641.8
2992.0
1106.5
5038.4
4093.5
183.1
54.2
1348.9
10347.9
6.3
2.9
4.1
2.7
7.0
2.6
5.3
2.7
3.8
2299.8 563.3
1672.1 348.9
9170.3
6.8 0.2
31.0 6.3
24.5 5.1
61.4 23.3
14.0 2.2
85.2 27.4
28.5 15.1
15.2 3.0
>374.5
4419.8
23605.3 2196.4
2644.1 949.7
31946.1 9353.8
7573.8
790.6 140.0
2046.0 341.8
86348.3 2456.0
1777.9 226.2
0.69 0.43
12.82 3.12
10s
10t
10u
10v
GW678248
AZT
19.2
>183.1
>4.4
72.0
>563380.2
422068.8
>379.1
128.1 17.6
>386.8
0.0014 0.0001
0.023
5401.4 345.5
a
b
c
EC50: effective concentration of compound required to protect the cell against viral cytopathogenicity by 50% in C8166 cells.
A17: HIV-1 mutated strain bearing both K103N and Y181C mutations.
CC50: cytotoxic concentration of compound that reduces the normal uninfected C8166 cell viability by 50%.
SI: selectivity index: ratio CC50/EC50(HIV-1 IIIB).
d
Table 2
Biological activity of compounds 10b–e, 10i, 10j, 10m, 10n and 10r against HIV-2
ROD in C8166 cells
SIc
a
b
Compd
EC50
(l
M)
CC50
(l
M)
10b
10c
10d
10e
10i
10j
10m
10n
10r
28.3
34.5
45.4
30.3
23.6
27.7
6.0
29.8
11.1
2.1
40.4 0.5
37.4 0.8
39.1 2.1
47.5 0.03
49.4 0.8
29.2 12.5
24.5 5.1
31.0 6.3
28.5 15.1
>386.8
0.7
0.9
1.2
0.6
0.5
0.9
0.2
1.0
0.4
GW678248
AZT
>176.7
133354.1
39.0
5201.1
a
EC50: effective concentration of compound required to protect the cell against
viral cytopathogenicity by 50% in C8166 cells.
b
CC50: cytotoxic concentration of compound that reduces the normal uninfected
C8166 cell viability by 50%.
c
SI: selectivity index: ratio CC50/EC50
.
at meta-position was more favorable than that with hydrogen or
chloro at the same position. Nevertheless, for the dimethyl substi-
tuent at different positions, the activity was vastly different, with
the EC50 values ranging from 7.8 3.3 nM (10d, 3,5-dimethyl-sub-
stitued) to 608.9 112.6 nM (10g, 3,4-dimethyl-substitued).
Although addition of another methyl group (10d) at the second
meta-position on the A-ring did prove to be beneficial, it was 1.6-
fold less potent than the chloro, cyano di-substituted analogue
10i (EC50 = 4.8 nM, SI = 10347.9). In fact, in the case of the ana-
logues 10a–i, a polar aprotic and sterically small meta-substituent,
such as cyano, would reach into the hydrophobic region adjacent
to the side chains of Tyr181 and Tyr188, and thus favoured to en-
chance the interactions with HIV-1 RT.
Figure 3. Binding model of 10i with HIV-1 RT (PDB code: 3DOK).16
ranging from 2.1 lM to 97.3 lM were obtained (Table 1). Further-
more, some analogues (10b–e, 10i, 10j, 10m, 10n and 10r) were
also evaluated the potency against the HIV-2 ROD virus (Table 2).
Unfortunately, these naphthyl-substituted derivatives almost only
exhibited mediocre inhibitory activity against HIV-2 with EC50 val-
ues in a range from 6.0
lM to 45.4 lM.
2.3. Molecular modeling analysis
In addition, all of the synthesized compounds (10a–v) were
tested the anti-HIV activity against the double mutant strain A17
(103N+181C) and the moderate inhibitory activity with EC50 values
To understand how our newly synthesized compounds interact
with the reverse transcriptase, a modeling study was carried out

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X.-D. Ma et al. / Bioorg. Med. Chem. 19 (2011) 4601–4607
using the program FLEX-DOCK SYBYL-X 1.2 (the default SYBYL-X
1.2 parameters were used).21 The most potent compound 10i
was chosen to be docked into non-nucleoside inhibitor binding
pocket (NNIBP) of HIV-1 RT. As shown in Figure 3, apparently,
3.3. General procedure for the synthesis of 9s–v13
To a solution of 9k, 9l, 9q, 9d (21.00 mmol) in DMF (20 mL),
copper cyanide (3.76, 42.00 mmol) was added and the resulting
mixture was heated to 160 °C and stirred for 2 h. The mixture
was then cooled, and water was added. The resulting solid was fil-
tered and washed with EtOAc. The filtrate was dried over MgSO4
and concentrated in vacuo. Column chromatography on silica gel
using hexane/EtOAc (15:1) gave 9s–v as a light yellow solid in
32–43% yield.
the naphthyl ring enhances the
residues Tyr188, Trp229 and Phe227. In addition, there is also a
strong interactions between the phenyl (A-ring) and the ami-
p–p interactions with amino acid
p–p
no acid residues Tyr181 and Leu100. Moreover, the cyano substitu-
ent of A-ring makes a hydrogen bond with the NH group of Tyr181.
All these interactions support our initial design, however, the low
sensitivity of the title compounds to the drug-resistant strain
(K103+Y181) may due to the lack of effective interaction with
the key mutant amino acid Asn103, which plays an important role
in generating drug-resistance of HIV.
3.4. General procedure for the synthesis of 10a–v
A mixture of 9a–v (10.00 mmol), 11 (3.06 g, 10.00 mmol), NaI
(0.15 g, 1.00 mmol) and K2CO3 (4.97 g, 36.00 mmol) in acetone
(20 mL) was warmed to reflux for 2 h. The reaction mixture was
then poured into water (30 mL) and extracted twice with 30 mL
of EtOAc. The combined organic layers were dried over MgSO4, fil-
tered, and concentrated in vacuo to give crude product. Purification
by flash chromatography using hexane/EtOAc (10:1) gave 10a–v.
2.4. Conclusion
In the present study, a series of BP derivatives with B-ring
substituted by the naphthyl ring were discovered as potent NNR-
TIs, and their preliminary SARs have been established via chemical
modifications. The newly synthesized derivatives 10a–i exhibited
excellent potency against HIV-1 wild-type virus, in particular,
compound 10i displayed the best activity with an EC50 value of
4.8 nM and selective index value of 10347.9. Also, compound 10i
showed good potency against the double mutant strain A17
3.4.1. N-[4-(Aminosulfonyl)-2-methylphenyl]-2-(1-benzoyl-2-
naphenoxy)acetamide (10a)
Yield 66.9%; white solid, mp 181.2–182.1 °C; 1H NMR (DMSO-
d6) d (ppm): 2.16 (s, 3H, CH3), 4.92 (s, 2H, CH2), 7.28 (s, 2H, NH2),
7.38–8.16 (m, 14H, PhH, NaphH), 9.26 (s, 1H, NH); 13C NMR
(DMSO-d6) d: 17.5, 67.8, 114.6, 122.3, 122.4, 123.4, 123.5, 123.8,
124.4, 127.6, 128.3, 128.7, 129.0 (2C), 129.2 (2C), 130.8, 130.9,
131.3, 134.0, 137.1, 138.4, 140.2, 152.3, 168.4, 196.9; MS (ESIÀ)
m/z 473 [MÀH]À; Anal. Calcd for C26H22N2O5S: C 65.81, H 4.67, N
5.90, S 6.76. Found: C 65.79, H 4.65, N 5.93, S 6.78.
(K103N+Y181C) with EC50 value of 2.1
ing model of 10i with RT was also simulated and indicated that the
naphthyl ring enchanced the interactions with RT as initial de-
lM. Furthermore, the bind-
p–p
sign. Overall, this compound may serve as the basis for further
modification in searching for more potent candidates for anti-HIV
chemotherapy.
3.4.2. N-[4-(Aminosulfonyl)-2-methylphenyl]-2-[1-(3-
methylbenzoyl)-2-naphenoxy]acetamide (10b)
3. Experimental section
3.1. Chemistry
Yield 65.4%; white solid, mp 200.2–201.3 °C; 1H NMR (DMSO-
d6) d (ppm): 2.16 (s, 3H, CH3), 2.29 (s, 3H, CH3), 4.92 (s, 2H, CH2),
7.29 (s, 2H, NH2), 7.35–8.15 (m, 13, PhH, NaphH), 9.22(s, 1H,
NH); 13C NMR (DMSO-d6) d: 17.5, 20.8, 67.8, 114.6, 122.6, 123.5,
123.6, 123.8, 124.5, 126.8, 127.9, 128.4, 128.7, 128.9, 129.4,
130.9, 131.3, 134.8, 137.3, 138.5, 140.3, 152.3, 166.5, 196.8; MS
(ESIÀ) m/z 487 [MÀH]À; Anal. Calcd for C27H24N2O5S: C 66.38, H
4.95, N 5.73, S 6.56. Found: C 66.37, H 4.98, N 5.74, S 6.55.
All chemicals used were purchased from commercial sources,
were of analytical grade and were used without further purifica-
tion. Melting points were measured on a SGW X-1 microscopic
melting-point apparatus and were uncorrected. Mass spectra were
obtained on a Waters Quattro Micromass instrument using electro-
spray ionization (ESI) techniques. 1H NMR and 13C NMR spectra on
a Brucker AV 400 MHz spectrometer were recorded in DMSO-d6.
Chemical shifts were reported in d (ppm) units relative to the inter-
nal standard tetramethylsilane (TMS). Elemental analyses were
performed on a Carlo Erba 1106 instrument and the results of ele-
mental analyses for C, H, Cl, Br, F and N were within 0.4% of the
theoretical values. Flash chromatography separations were ob-
tained on Silica gel (300–400 mesh) using EtOAc/hexane as
eluents.
3.4.3. N-[4-(Aminosulfonyl)-2-methylphenyl]-2-[1-(3-
chlorobenzoyl)-2-naphenoxy]acetamide (10c)
Yield 65.4%; white solid, mp 180.1–181.2 °C; 1H NMR (DMSO-
d6) d (ppm): 2.19 (s, 3H, CH3), 4.94 (s, 2H, CH2), 7.29 (s, 2H, NH2),
7.39–8.17 (m, 13, PhH, NaphH), 9.38(s, 1H, NH); 13C NMR
(DMSO-d6) d: 17.6, 67.6, 114.5, 121.4, 123.3, 123.7, 123.8, 124.6,
127.7, 127.9, 128.1, 128.5 (2C), 128.7, 130.8, 131.0, 131.1, 131.8,
133.7, 134.0, 138.6, 139.1, 140.3, 152.7, 166.5, 195.5; MS (ESI–)
m/z 507 [MÀH]À; Anal. Calcd for C26H21ClN2O5S: C 61.35, H 4.16,
Cl 6.97, N 5.50, S 6.30. Found: C 61.33, H 4.17, Cl 6.98, N 5.52, S
6.29.
3.2. General procedure for the synthesis of 9a–r17,18
.
Anhydrous AlCl3 (1.85 g, 13.90 mmol) was added to a solution
of 2-methoxynaphthalene 10a–b (6.32 mmol) and substituted
benzoyl chloride (7.51 mmol) in CS2 (30 mL), carefully holding
the temperature under 5 °C. After completion, the mixture was
heated to reflux and stirred for additional 2 h. Then the reaction
mixture was poured to a beaker containing ice water (45 mL)
and concd HCl (15 mL), and stirred for 30 min. The organic layer
was separated and the aqueous layer was extracted with dichloro-
methane three times. The organic layers were combined, dried
with anhydrous sodium sulfate and concentrated. The residue
was purified by silica gel column chromatography using hexane/
EtOAc (20:1) to afford 9a–r as a light yellow solid.
3.4.4. N-[4-(Aminosulfonyl)-2-methylphenyl]-2-[1-(3,5-
dimethylbenzoyl)-2-naphenoxy]acetamide (10d)
Yield 58.9%; white solid, mp 191.3–192.4 °C; 1H NMR (DMSO-
d6) d (ppm): 2.16 (s, 3H, CH3), 2.24 (s, 6H, 2CH3), 4.93 (s, 2H,
CH2), 7.28 (s, 2H, NH2), 7.26–8.14 (m, 12H, PhH, NaphH), 9.16 (s,
1H, NH); 13C NMR (DMSO-d6) d: 17.4, 20.6 (2C), 67.8, 114.6,
122.7, 123.5, 123.8, 124.4, 126.9 (2C), 127.6 (3C), 128.3, 128.7,
130.8, 130.9, 131.1, 136.4, 137.4, 138.2 (2C), 138.4, 140.2, 152.2,
166.4, 196.8; MS (ESI–) m/z 501 [MÀH]À; Anal. Calcd for
C28H26N2O5S: C 66.91, H 5.21, N 5.57, S 6.38. Found: C 66.89, H
5.20, N 5.57, S 6.40.

X.-D. Ma et al. / Bioorg. Med. Chem. 19 (2011) 4601–4607
4605
3.4.5. N-[4-(Aminosulfonyl)-2-methylphenyl]-2-[1-(2,5-
dimethylbenzoyl)-2-naphenoxy]acetamide (10e)
125.6, 127.5, 129.0, 129.3 (2C), 129.4 (2C), 129.8, 130.2, 130.6
(2C), 131.0, 134.2, 137.0, 138.5, 140.2, 152.8, 166.3, 196.1; MS
(ESI–) m/z 552 [MÀH]À; Anal. Calcd for C26H21BrN2O5S: C 56.43,
H 3.82, Br 14.44, N 5.06, S 5.79. Found: C 56.44, H 3.83, Br 14.46,
N 5.04, S 5.80.
Yield 63.5%; white solid, mp 199.9–200.8 °C; 1H NMR (DMSO-
d6) d (ppm): 2.10 (s, 3H, CH3), 2.17 (s, 3H, CH3), 2.58 (s, 3H, CH3),
4.88 (s, 2H, CH2), 7.25 (s, 2H, NH2), 7.25–8.13 (m, 12H, PhH,
NaphH), 9.26(s, 1H, NH); 13C NMR (DMSO-d6) d: 17.6, 20.3, 20.9,
67.9, 114.8, 123.4, 123.7, 123.8, 124.4 (2C), 127.6, 127.7, 128.4,
128.7, 130.8, 131.1, 131.3, 131.9, 132.0, 133.2, 135.2, 135.7,
137.1, 138.5, 140.3, 152.3, 166.5, 198.9; MS (ESI–) m/z 502
[MÀH]À; Anal. Calcd for C28H26N2O5S: C 66.91, H 5.21, N 5.57, S
6.38. Found: C 66.90, H 5.20, N 5.59, S 6.39.
3.4.11. N-[4-(Aminosulfonyl)-2-methylphenyl]-2-[6-bromo-1-
(3-methylbenzoyl)-2-naphenoxy]acetamide (10k)
Yield 59.5%; white solid, mp 207.7–208.9 °C; 1H NMR (DMSO-
d6) d (ppm): 2.17 (s, 3H, CH3), 2.30 (s, 3H, CH3), 4.94 (s, 2H, CH2),
7.28 (s, 2H, NH2), 7.31–8.29 (m, 12H, PhH, NaphH), 9.25 (s, 1H,
NH); 13C NMR (DMSO-d6) d: 17.5, 20.8, 67.8, 115.8, 117.3, 122.5,
123.5, 123.8, 125.6, 126.8, 127.6, 128.9, 129.4, 129.5, 129.8,
130.1, 130.4, 130.5, 130.9, 134.8, 137.0, 138.4, 138.5, 140.2,
152.7, 166.3, 196.2; MS (ESI–) m/z 567 [MÀH]À; Anal. Calcd for
3.4.6. N-[4-(Aminosulfonyl)-2-methylphenyl]-2-[1-(2,4-
dimethylbenzoyl)-2-naphenoxy]acetamide (10f)
Yield 64.8%; white solid, mp 197.4–198.5 °C; 1H NMR (DMSO-
d6) d (ppm): 2.08 (s, 3H, CH3), 2.15 (s, 3H, CH3), 2.27 (s, 3H, CH3),
4.81 (s, 2H, CH2), 7.30 (s, 2H, NH2), 7.03–8.13 (m, 12H, PhH,
NaphH), 9.15(s, 1H, NH); 13C NMR (DMSO-d6) d: 16.2, 17.5, 20.0,
68.1, 115.0, 123.4, 123.7, 123.8, 124.5, 124.8, 125.4, 127.7, 127.8,
128.4, 128.7, 128.8, 130.9, 131.2, 131.5, 133.9, 136.7, 138.2,
138.4, 138.7, 140.4, 152.6, 166.4, 199.4; MS (ESI–) m/z 502
[MÀH]À; Anal. Calcd for C28H26N2O5S: C 66.91, H 5.21, N 5.57, S
6.38. Found: C 66.93, H 5.23, N 5.56, S 6.37.
C27H23N2O5S: C 57.15, H 4.09, N 4.94, Br 14.08, S 5.65. Found: C
57.13, H 4.11, N 4.96, Br 14.09, S 5.64.
3.4.12. N-[4-(Aminosulfonyl)-2-methylphenyl]-2-[6-bromo-1-
(3-chlorobenzoyl)-2-naphenoxy]acetamide (10l)
Yield 61.2%; white solid, mp 199.5–200.4 °C; 1H NMR (DMSO-
d6) d (ppm): 2.19 (s, 3H, CH3), 4.96 (s, 2H, CH2), 7.28 (s, 2H, NH2),
7.35–8.30 (m, 12H, PhH, NaphH), 9.41 (s, 1H, NH); 13C NMR
(DMSO-d6) d: 17.6, 67.5, 115.7, 117.4, 121.3, 123.7 (2C), 123.8,
125.5, 127.7, 128.2, 128.5, 129.4, 129.8, 130.2, 130.7, 131.0,
131.1, 133.8, 134.0, 138.5, 138.8, 140.3, 153.2, 166.3, 194.9; MS
(ESI–) m/z 586 [MÀH]À; Anal. Calcd for C26H20ClBrN2O5S: C 53.12,
H 3.43, N 4.77, Cl 6.03, Br 13.59, S 5.45. Found: C 53.10, H 3.44,
N 4.78, Cl 6.02, Br 13.60, S 5.46.
3.4.7. N-[4-(Aminosulfonyl)-2-methylphenyl]-2-[1-(3,4-
dimethylbenzoyl)-2-naphenoxy]acetamide (10g)
Yield 67.1%; white solid, mp 209.8–210.7 °C; 1H NMR (DMSO-
d6) d (ppm): 2.15 (s, 3H, CH3), 2.26 (s, 3H, CH3), 2.64 (s, 3H, CH3),
4.88 (s, 2H, CH2), 7.29 (s, 2H, NH2), 6.96–8.11 (m, 12H, PhH,
NaphH), 9.17(s, 1H, NH); 13C NMR (DMSO-d6) d: 17.5, 21.0, 21.5,
67.9, 114.8, 123.5, 123.7, 123.8, 124.4, 124.5, 126.7, 127.6, 127.7,
128.3, 128.7, 130.8, 131.0, 131.1, 132.5, 132.8, 134.2, 138.5,
139.2, 140.3, 143.1, 152.0, 166.5, 198.2; MS (ESI–) m/z 502
[MÀH]À; Anal. Calcd for C28H26N2O5S: C 66.91, H 5.21, N 5.57, S
6.38. Found: C 66.89, H 5.20, N 5.59, S 6.37.
3.4.13. N-[4-(Aminosulfonyl)-2-methylphenyl]-2-[6-bromo-1-
(3-fluorobenzoyl)-2-naphenoxy]acetamide (10m)
Yield 57.5%; white solid, mp 258.8–259.5 °C; 1H NMR (DMSO-
d6) d (ppm): 2.19 (s, 3H, CH3), 4.95 (s, 2H, CH2), 7.28 (s, 2H, NH2),
7.34–8.29 (m, 12H, PhH, NaphH), 9.40 (s, 1H, NH); 13C NMR
(DMSO-d6) d: 17.6, 67.6, 115.2 (JCF = 22.1 Hz), 115.7, 117.4, 121.1
(JCF = 21.1 Hz), 121.6, 123.8 (2C), 125.5, 125.8 (JCF = 2.2 Hz), 127.7,
129.4, 129.9, 130.3, 130.8, 131.0, 131.2, 131.3 (JCF = 7.4 Hz),,
138.5, 139.3 (JCF = 6.1 Hz), 140.3, 153.1, 162.4 (JCF = 243.9 Hz),
166.4, 195.1 (JCF = 2.1 Hz); MS (ESI–) m/z 569 [MÀH]À; Anal. Calcd
for C26H20BrFN2O5S: C 54.65, H 3.53, Br 13.98, F 3.32, N 4.90, S 5.61.
Found: C 54.63, H 3.54, Br 13.99, F 3.30, N 4.91, S 5.60.
3.4.8. N-[4-(Aminosulfonyl)-2-methylphenyl]-2-[1-(3-chloro-5-
bromobenzoyl)-2-naphenoxy]acetamide (10h)
Yield 57.9%; light yellow solid, mp 242.3–243.3 °C; 1H NMR
(DMSO-d6) d (ppm): 2.21 (s, 3H, CH3), 4.97 (s, 2H, CH2), 7.27 (s,
2H, NH2), 7.43–8.19 (m, 12H, PhH, NaphH), 9.46 (s, 1H, NH); 13C
NMR (DMSO-d6) d: 17.7, 67.4, 114.3, 120.3, 123.0, 123.1, 123.7
(2C), 124.5, 127.6, 127.9, 128.0, 128.4, 128.6, 130.4, 130.8, 131.0,
132.1, 135.1, 135.7, 138.5, 140.2, 140.3, 153.0, 166.3, 194.2; MS
(ESI–) m/z 586 [MÀH]À; Anal. Calcd for C26H20BrN2O5S: C 53.12,
H 3.43, Cl 6.03, Br 13.59, N 4.77, S 5.45. Found: C 53.10, H 3.45,
Cl 6.02, Br 13.57, N 4.78, S 5.44.
3.4.14. N-[4-(Aminosulfonyl)-2-methylphenyl]-2-[6-bromo-1-
(3,5-dimethylbenzoyl)-2-naphenoxy]acetamide (10n)
Yield 57.9%; white solid, mp 207.7–208.6 °C; 1H NMR (DMSO-
d6) d (ppm): 2.16 (s, 3H, CH3), 2.34 (s, 6H, 2CH3), 4.92 (s, 2H,
CH2), 7.30 (s, 2H, NH2), 7.28–8.14 (m, 11H, PhH, NaphH), 9.17 (s,
1H, NH); 13C NMR (DMSO-d6) d: 17.4, 20.6 (2C), 67.8, 114.6,
122.7, 123.4, 124.4, 126.9 (2C), 127.6 (3C), 128.3, 128.7, 130.8,
130.9, 131.1, 135.4, 136.7, 137.4, 138.2 (2C), 138.4, 140.2, 152.2,
166.4, 196.8; MS (ESI–) m/z 580 [MÀH]À; Anal. Calcd for
3.4.9. N-[4-(Aminosulfonyl)-2-methylphenyl]-2-[1-(3-chloro-5-
cyanobenzoyl)-2-naphenoxy]acetamide (10i)
Yield 58.6%; off-white solid, mp 223.4–224.5 °C; 1H NMR
(DMSO-d6) d (ppm): 2.23 (s, 3H, CH3), 4.99 (s, 2H, CH2), 7.29 (s,
2H, NH2), 7.44–8.31 (m, 12H, PhH, NaphH), 9.62 (s, 1H, NH); 13C
NMR (DMSO-d6) d: 17.8, 67.2, 114.1, 114.2, 116.8, 119.9, 123.2,
123.7, 123.8, 124.6, 127.7, 128.1, 128.5, 128.7, 130.8, 131.2,
131.9, 132.4, 133.0, 134.9, 136.5, 138.6, 139.6, 140.2, 153.4,
166.5, 194.0; MS (ESI–) m/z 532 [MÀH]À; Anal. Calcd for
C28H25BrN2O6S: C 57.84, H 4.33, N 4.82, S, Br 13.74. Found: C
57.83, H 4.35, N 4.80, S, Br 13.73.
3.4.15. N-[4-(Aminosulfonyl)-2-methylphenyl]-2-[6-bromo-1-
(2,4-dimethylbenzoyl)-2-naphenoxy]acetamide (10o)
C27H20ClN3O5S: C 60.73, H 3.78, N 7.57, S 6.00. Found: C 60.72, H
Yield 63.7%; white solid, mp 209.8–210.5 °C; 1H NMR (DMSO-
d6) d (ppm): 2.16 (s, 3H, CH3), 2.26 (s, 3H, CH3), 2.63 (s, 3H, CH3),
4.90 (s, 2H, CH2), 7.28 (s, 2H, NH2), 6.97–8.27 (m, 11H, PhH,
NaphH), 9.19 (s, 1H, NH); 13C NMR (DMSO-d6) d: 17.5, 21.0, 21.5,
67.8, 116.0, 117.3, 123.7, 123.8, 124.5, 125.7, 126.7, 127.6, 129.4,
129.9, 130.1, 130.3, 130.5, 131.0, 132.5, 132.9, 134.0, 138.4,
139.3, 140.3, 143.2, 152.5, 166.3, 197.5; MS (ESI–) m/z 580
[MÀH]À; Anal. Calcd for C28H25BrN2O5S: C 57.84, H 4.33, N 4.82,
Br 13.74, S 5.51. Found: C 57.85, H 4.34, N 4.80, Br 13.72, S 5.50.
3.79, N 7.55, S 6.01.
3.4.10. N-[4-(Aminosulfonyl)-2-methylphenyl]-2-(6-bromo-1-
benzoyl-2-naphenoxy)acetamide (10j)
Yield 60.3%; light yellow solid, mp 213.3–214.5 °C; 1H NMR
(DMSO-d6) d (ppm): 2.17 (s, 3H, CH3), 4.94 (s, 2H, CH2), 7.28 (s,
2H, NH2), 7.31–8.30 (m, 13H, PhH, NaphH), 9.30 (s, 1H, NH); 13C
NMR (DMSO-d6) d: 17.6, 67.9, 115.8, 117.3, 122.3, 123.6, 123.8,

4606
X.-D. Ma et al. / Bioorg. Med. Chem. 19 (2011) 4601–4607
3.4.16. N-[4-(Aminosulfonyl)-2-methylphenyl]-2-[6-bromo-1-
(2,5-dimethylbenzoyl)-2-naphenoxy]acetamide (10p)
PhH, NaphH), 9.24 (s, 1H, NH); 13C NMR (DMSO-d6) d: 16.2, 17.6,
20.0, 67.8, 106.6, 116.5, 119.0, 123.8 (2C), 124.6, 124.8, 125.4,
127.4, 127.9, 128.1, 128.8, 131.2, 132.3, 132.4, 133.9, 134.9,
136.9, 138.1, 138.3, 138.4, 140.4, 156.1, 166.0, 198.3; MS (ESI–)
m/z 527 [MÀH]À; Anal. Calcd for C29H25N3O5S: C 66.02, H 4.78, N
7.96, S 6.08. Found: C 66.01, H 4.79, N 7.95, S 6.06.
Yield 65.8%; white solid, mp 205.5–206.3 °C; 1H NMR (DMSO-
d6) d (ppm): 2.17 (s, 3H, CH3), 2.28 (s, 3H, CH3), 2.52 (s, 3H, CH3),
4.83 (s, 2H, CH2), 7.31 (s, 2H, NH2), 7.05–8.29 (m, 11H, PhH,
NaphH), 9.18 (s, 1H, NH); 13C NMR (DMSO-d6) d: 16.3, 17.6, 20.0,
68.0, 116.3, 117.4, 123.8 (2C), 124.8, 125.4, 125.7, 127.7, 128.7,
129.5, 130.0, 130.2, 130.7, 130.8, 131.2, 133.8, 136.8, 138.2,
138.4, 138.5, 140.4, 153.0, 166.3, 198.7; MS (ESI–) m/z 580
[MÀH]À; Anal. Calcd for C28H25BrN2O5S: C 57.84, H 4.33, N 4.82,
Br 13.74, S 5.51. Found: C 57.86, H 4.34, N 4.80, Br 13.73, S 5.50.
3.4.22. N-[4-(Aminosulfonyl)-2-methylphenyl]-2-[6-cyano-1-
(3,5-dimethylbenzoyl)-2-naphenoxy]acetamide (10v)
Yield 58.2%; off-white solid, mp 258.7–259.5 °C; 1H NMR (DMSO-
d6) d (ppm): 2.16 (s, 3H, CH3), 2.24 (s, 6H, 2CH3), 5.01 (s, 2H, CH2), 7.28
(s, 2H, NH2), 7.28–8.64 (m, 11H, PhH, NaphH), 9.30 (s, 1H, NH); 13
C
3.4.17. N-[4-(Aminosulfonyl)-2-methylphenyl]-2-[6-bromo-1-
(3,4-dimethylbenzoyl)-2-naphenoxy]acetamide (10q)
NMR (DMSO-d6) d: 17.6, 20.6 (2C), 67.4, 106.6, 116.2, 119.0, 122.6,
123.5, 123.8, 124.8, 127.0 (2C), 127.4, 127.8, 127.9, 130.9, 132.0,
132.1, 134.9, 135.7, 137.0, 138.3, 138.4 (2C), 140.2, 154.9, 166.1,
195.9; MS (ESI–) m/z 526 [MÀH]À; Anal. Calcd for C29H25N3O5S: C
66.02, H 4.78, N 7.96, S 6.08. Found: C 66.00, H 4.10, N 7.97, S 6.09.
Yield 63.7%; white solid, mp 210.4–211.9 °C; 1H NMR (DMSO-
d6) d (ppm): 2.10 (s, 3H, CH3), 2.17 (s, 3H, CH3), 2.57 (s, 3H, CH3),
4.88 (s, 2H, CH2), 7.25 (s, 2H, NH2), 7.28–8.27 (m, 11H, PhH,
NaphH), 9.27 (s, 1H, NH); 13C NMR (DMSO-d6) d: 17.6, 20.3, 20.9,
67.8, 116.1, 117.3, 123.8 (2C), 124.4, 125.7, 127.7, 129.4, 129.9,
130.2, 130.6 (2C, 130.55, 130.62), 131.1, 132.0 (2C, 132.00,
132.03), 133.3, 135.3, 135.8, 136.8, 138.5, 140.3, 152.8, 166.4,
198.2; MS (ESI–) m/z 580 [MÀH]À; Anal. Calcd for C28H25BrN2O5S:
C 57.84, H 4.33, N 4.82, Br 13.74, S 5.51. Found: C 57.83, H 4.32,
N 4.81, Br 13.72, S 5.52.
3.5. Anti-HIV activity
3.5.1. Cytotoxicity assay
The cytotoxicities of compounds on C8166 cells were assessed
by MTT colorimetric assay as described previously.19 The absor-
bance at 570 nm/630 nm (A570/630) was read in an ELISA reader
(Elx1000, Bio-Tek Instrument Inc., USA). The minimum cytotoxic
concentration that caused the reduction of viable cells by 50%
(CC50) was determined from dose response curve.
3.4.18. N-[4-(Aminosulfonyl)-2-methylphenyl]-2-[6-bromo-1-
(3-chloro-5-bromobenzoyl)-2-naphenoxy]acetamide (10r)
Yield 59.1%; white solid, mp 227.3–228.2 °C; 1H NMR (DMSO-
d6) d (ppm): 2.22 (s, 3H, CH3), 4.98 (s, 2H, CH2), 7.27 (s, 2H, NH2),
7.40–8.30 (m, 11H, PhH, NaphH), 9.48 (s, 1H, NH); 13C NMR
(DMSO-d6) d: 17.7, 67.3, 115.6, 117.4, 120.4, 123.1, 123.7(2C),
125.4, 127.6, 128.0, 129.3, 129.8, 130.2, 130.4, 130.8, 131.1,
131.4, 135.1, 135.9, 138.5, 140.1, 140.2, 153.5, 166.2, 193.7; MS
(ESI–) m/z 666 [MÀH]À; Anal. Calcd for C26H19Br2N2O5S: C 46.83,
H 2.87, Cl 5.32, Br 23.97, N 4.20, S 4.81. Found: C 46.80, H 2.88,
Cl 5.35, Br 23.96, N 4.22, S 4.80.
3.5.2. Syncytium reduction assay
In the presence of 100 lL various concentrations of compounds,
C8166 cells (4 Â 105/mL) were infected with viruses (HIV-1IIIB
,
HIV-1A17, and HIV-2ROD) at a multiplicity of infection (M.O.I) of
0.06. The final volume per well was 200 lL. 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 for-
mation (EC50) was calculated.20
3.4.19. N-[4-(Aminosulfonyl)-2-methylphenyl]-2-[6-cyano-1-
(3-methylbenzoyl)-2-naphenoxy]acetamide (10s)
Acknowledgments
Yield 56.9%; off-white solid, mp 228.9–230.8 °C; 1H NMR
(DMSO-d6) d (ppm): 2.18 (s, 3H, CH3), 2.29 (s, 3H, CH3), 5.00 (s,
2H, CH2), 7.27 (s, 2H, NH2), 7.35–8.29 (m, 12H, PhH, NaphH), 9.35
(s, 1H, NH); 13C NMR (DMSO-d6) d: 17.7, 20.8, 67.5, 106.7, 116.3,
119.1, 122.6, 123.8, 123.9, 124.9, 125.8, 126.9, 127.6, 127.8,
128.1, 129.1, 129.5, 129.6, 130.6, 132.3, 132.6, 135.0, 135.1,
137.0, 138.6, 138.7, 156.0, 166.3, 196.0; MS (ESI–) m/z 513
[MÀH]À; Anal. Calcd for C29H23N3O5S: C 65.48, H 4.51, N 8.18, S
6.24. Found: C 65.51, H 4.50, N 8.18, S 6.25.
This work was supported in part by grants from the National
Natural Science Foundation of China (Nos. 20872018 and
30672536), the National Natural Science Foundation of Shanghai
(No. 10ZR1401900), the Knowledge Innovation Program of CAS
(KSCX2-YW-R-185), 973 program (2009CB522306) and Eleventh
Five-Year Key Scientific and Technological Program of China
(2009ZX09501–029).
Reference and notes
3.4.20. N-[4-(Aminosulfonyl)-2-methylphenyl]-2-[6-cyano-1-
(3-chlorobenzoyl)-2-naphenoxy]acetamide (10t)
1. Schaefer, W.; Friebe, W. G.; Leinert, H.; Mertens, A.; Poll, T.; Von der Saal, W.;
Zilch, H.; Nuber, B.; Ziegler, M. L. J. Med. Chem. 1993, 36, 726.
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Yield 57.1%; off-white solid, mp 184.7–185.5 °C; 1H NMR
(DMSO-d6) d (ppm): 2.21 (s, 3H, CH3), 5.03 (s, 2H, CH2), 7.28 (s,
2H, NH2), 7.52–8.65 (m, 12H, PhH, NaphH), 9.48 (s, 1H, NH); 13C
NMR (DMSO-d6) d: 17.7, 67.3, 106.7, 116.1, 119.0, 121.3, 123.7
(2C), 124.6, 127.4, 127.9, 128.1, 128.2, 128.5, 131.0, 131.1, 132.4,
132.6, 133.9, 134.0, 134.9, 138.5, 138.6, 140.3, 156.3, 166.1,
194.6; MS (ESI–) m/z 533 [MÀH]À; Anal. Calcd for C27H20ClN3O5S:
C 60.73, Cl 6.64, H 3.78, N 7.87, S 6.00. Found: C 60.72, Cl 6.65, H
3.79, N 7.88, S 6.01.
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3.4.21. N-[4-(Aminosulfonyl)-2-methylphenyl]-2-[6-cyano-1-
(3,4-dimethylbenzoyl)-2-naphenoxy]acetamide (10u)
Yield 56.2%; off-white solid, mp 220.7–221.9 °C; 1H NMR
(DMSO-d6) d (ppm): 2.17 (s, 3H, CH3), 2.28 (s, 3H, CH3), 2.52 (s,
3H, CH3), 4.91 (s, 2H, CH2), 7.28 (s, 2H, NH2), 7.04–8.63 (m, 11H,

X.-D. Ma et al. / Bioorg. Med. Chem. 19 (2011) 4601–4607
4607
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