Synthesis and biological evaluation of N-acetyl-β-aryl-1,2-didehydroethylamines as new HIV-1 RT inhibitors in vitro

Article abstract of DOI:10.1016/j.bmcl.2007.06.008

A variety of N-acetyl-β-aryl-1,2-didehydroethylamines were synthesized by direct reduction-acetylation of β-aryl-nitroolefins and assayed as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) for the first time. Compound 7a exhibited a TI value of >13.2 with CC₅₀ value of >0.787 mM in C8166 cells. This structure-activity relationship (SAR) study provided a new lead for design and discovery of more potent and selective analogues act as NNRTIs.

Full text of DOI:10.1016/j.bmcl.2007.06.008

Bioorganic & Medicinal Chemistry Letters 17 (2007) 4476–4480
Synthesis and biological evaluation of N-acetyl-b-aryl-1,2-
didehydroethylamines as new HIV-1 RT inhibitors in vitro
Pi Cheng,a,d Zhi-Yong Jiang,a,c Rui-Rui Wang,b Xue-Mei Zhang,a,c Qian Wang,b
a,c
Yong-Tang Zheng,b,* Jun Zhou and Ji-Jun Chena,c,
*
aState Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany,
The Chinese Academy of Sciences, Kunming, Yunnan 650204, PR China
bLaboratory of Molecular Immunopharmacology, Key Laboratory of Animal Models and Human Diseases Mechanisms,
Kunming Institute of Zoology, The Chinese Academy of Sciences, Kunming, Yunnan 650223, PR China
cThe Joint-Laboratory of Antiviral Natural Medicines, Kunming Branch, The Chinese Academy of Sciences,
Kunming, Yunnan 650204, PR China
dGraduate School of the Chinese Academy of Sciences, Beijing 100039, PR China
Received 17 January 2007; revised 18 May 2007; accepted 2 June 2007
Available online 8 June 2007
Abstract—A variety of N-acetyl-b-aryl-1,2-didehydroethylamines were synthesized by direct reduction–acetylation of b-aryl-nitro-
olefins and assayed as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) for the first time. Compound 7a exhibited a
TI value of >13.2 with CC50 value of >0.787 mM in C8166 cells. This structure–activity relationship (SAR) study provided a new
lead for design and discovery of more potent and selective analogues act as NNRTIs.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Due to the AIDS crisis, development of new, selective
and safe non-nucleoside reverse transcriptase inhibitors
(NNRTIs) still remains a high priority for medical
research.1 Structure simplification of natural product
has provided us an efficient way to find new and less
toxic anti-HIV lead compounds.2 N-Acetyl-b-aryl-1,2-
didehydroethylamine (Fig. 1) is the characteristic and
basic structure unit present in some b-aryl-1,2-didehy-
droethylamine alkaloids isolated from marine species,
some alkaloids of this family display a wide spectrum
of biological activities.3 For example, ziziphines
(Fig. 1) possessing this skeleton are a series of cylopep-
tide alkaloids isolated from marine species Ziziphus
oenophila,4 among which ziziphines N and Q show sig-
nificant in vitro activities against Plasmodium falciparum
with IC50 values of 3.9 and 3.5 lg/mL, respectively.
Hamigeroxalamic acid, an alkaloid isolated from Medi-
terranean sponge Hamigera hamigera, shows deterrent
activity in a fish feeding assay.5 Although there has been
no report about the anti-HIV-1 activity of the b-aryl-
1,2-didehydroethylamine alkaloids, they have the simi-
lar biological source as the anti-HIV-1 RT tetrahydro-
isoquinoline alkaloid.6 In our previous work, we
discovered that simple tetrahydroisoquinonine alkaloid
possessed moderate activity against HIV-1 RT.7 Thus,
we were interested in the study of the anti-HIV-1 activity
of b-aryl-1,2-didehydroethylamine. N-Acetyl-b-aryl-1,2-
didehydroethylamine can be viewed as a simplified b-
aryl-1,2-didehydroethylamine alkaloid. Therefore, to
explore the range of biological activities of N-acetyl-b-
aryl-1,2-didehydroethylamines, we have synthesized a
series of title compounds which were evaluated as NNR-
TIs of HIV-1 in vitro.
N-Acetyl-b-aryl-1,2-didehydroethylamines have been
the subject of intensive synthetic studies for long time.8
Among these synthetic strategies are the Beckmann
rearrangement of benzylideneacetone oxime9 and the
addition reaction of arylvinylisocyanates.10 However,
these two methodologies are limited to the special oxi-
mes or the water-sensitive isocyanates, furthermore,
strong acid or basic treatment is generally required.
Laso and colleagues found that the conjugated nitro
group can be reduced to amine and further acetylated
by refluxing a mixture of nitroalkene, acetic acid, acetic
Keywords: N-Acetyl-b-aryl-1,2-didehydroethylamine; b-Aryl-nitroole-
fin; NNRTIs; Anti-HIV-1 RT activity.
*
Corresponding authors. Tel.: +86 871 5223265; fax: +86 871
5223265; e-mail: chenjj@mail.kib.ac.cn
0960-894X/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.06.008

P. Cheng et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4476–4480
4477
OMe
H
O
OH
H
HN
Me HN
HN
O
N
N
O
R
Ar
O
O
H
N
O
HN
Me
O
HN
HN
CH3
OH
N
Me
O
O
ziziphine N: R = CH2CH(CH3)2 hamigeroxalamic
ziziphine Q: R = CH(CH3)2
fragilamide A
β
N
-acetyl- -aryl-1,2-
acid
didehydroethylamine
Figure 1. Structures of some naturally occurring bioactive b-aryl-1,2-didehydroethylamine alkaloids and their basic structure unit.
anhydride and iron powder under nitrogen in a one-pot
procedure.11 b-Aryl-nitroolefin (1, Scheme 1) contains a
conjugated nitro group and can be prepared by treating
aromatic aldehyde with ammonium acetate in boiling
nitromethane.
the first report about the anti-HIV-1 RT activity of
the cytotoxic nitroolefin. These findings, therefore,
urged us to prepare its analogues with a variety of sub-
stituents and with other aromatic moieties to explore the
structure–activity relationship (SAR). The activities of
nitroolefin intermediates against HIV-1 RT (IC50 val-
ues) are given in Table 1. The potency of inhibition
against HIV-1 RT was dependent on the positions of
the substituents on the phenyl for compounds 1a–1s, it
clearly appeared that the ortho monosubstituted-phenyl
compounds possessed higher enzymatic activity. For
example, ortho bromo substituted compound 1b exhib-
ited 95.74% inhibitory ratio against HIV-1 RT at
200 lg/mL (IC50 = 0.2024 mM), while its meta and para
substituted analogues 1c and 1d were inactive. ortho
chloro substituted compound 1e exhibited 99.28% inhib-
itory ratio (IC50 = 0.3609 mM), but its analogues 1f and
1g were significantly less active. The bulkier 2,4,5-trim-
ethylsubstituted compound 1l only showed 31.53%
inhibitory ratio, significantly lower than that of the
ortho methyl substituted analogue 1j (IC50 = 0.2614
mM). The ortho methoxy substituted compound 1o pos-
sessed 99.69% inhibitory ratio (IC50 = 0.2246 mM),
while the bulkier 2,4,5-trimethoxylsubstituted com-
pound 1r only exhibited 49.12% inhibitory ratio
(IC50 > 0.8368 mM). Compared to those ortho mono-
substituted phenyl compounds, naphthyl analogues (1t
Therefore, we decided to synthesize N-acetyl-b-aryl-1,2-
didehydroethylamines (4, Scheme 1) through selective
direct reduction–acetylation of b-aryl-nitroolefin deriva-
tives based on Laso’s method and assessed the enamides
(4, Scheme 1) as inhibitors of HIV-1 RT. As outlined in
Scheme 1, b-aryl-nitroolefin 1 was first reduced to com-
pound 3 and/or compound 2. Compound 3 would be
trapped in the presence of acetic anhydride to form
oxime acetate 5, and so would be compound 2 to yield
the desired N-acetyl-b-aryl-1,2-didehydroethylamine 4.
Oxime acetate 5 should be in turn reduced to 4 in the
reaction condition. Compound 4 might be further acet-
ylated to the N-acetyl-arylvinylacetamide 6, which could
be reversed by treatment with methanolic potassium
hydroxide. In this procedure, target compounds 4 were
obtained in moderate yields.12
Surprisingly, the trans-conformational b-phenylnitro-
olefin (1a, Table 1) displayed 99.67% inhibitory ratio
against HIV-1 RT at 200 lg/mL with a CC50 value of
13.6 lM against C8166 cells. To our knowledge, this is
NH2
Ar
NH4OAc
CHO
Fe
NO2
2
Ar
Ar
CH3NO2
AcOH
Ac2O
NHOH
Ar
1
3
OH-
Ac2O
N(COCH3)2
NHCOCH3
4
Ar
Ar
Ar
6
Ac2O
Fe
AcOH
Ac2O
NHOCOCH3
5
Scheme 1. Synthesis of N-acetyl-b-aryl-1,2-didehydroethylamine 4.

4478
P. Cheng et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4476–4480
Table 1. Structures, anti-HIV-1 RT activities and cytotoxicities of b-aryl-nitroolefin 1a
HIV-1 RT % inhibitionb
c
IC50 (mM)
d
CC50 (mM)
Compound
Ar
1a
1b
1c
1d
1e
1f
(E)-Phenyl
99.67
95.74
13.42
20.30
99.28
49.76
19.83
95.42
22.87
99.24
36.86
31.53
98.22
96.38
99.69
93.51
86.35
49.12
29.38
81.41
58.84
86.23
91.84
96.46
0.0879
0.2024
nte
0.0136
0.00057
nt
(E)-2-Bromophenyl
(E)-3-Bromophenyl
(E)-4-Bromophenyl
(E)-2-Chlorophenyl
(E)-3-Chlorophenyl
(E)-4-Chlorophenyl
(E)-2-Fluorophenyl
(E)-4-Fluorophenyl
(E)-2-Methylphenyl
(E)-4-Methylphenyl
(E)-2,4,5-Trimethylphenyl
(E)-2-Hydroxyphenyl
(E)-4-Hydroxyphenyl
(E)-2-Methoxyphenyl
(E)-4-Methoxyphenyl
(E)-2,4-Dimethoxyphenyl
(E)-2,4,5-Trimethoxyphenyl
(E)-4-Trifluoromethylphenyl
(E)-1-Naphthyl
nt
nt
0.3609
>1.093
nt
0.003
0.0046
nt
1g
1h
1i
0.3646
nt
0.0028
nt
1j
0.2614
nt
0.0074
0.0152
0.0069
0.0188
0.0158
0.005
0.0063
0.0054
0.0047
nt
1k
1l
nt
0.54
1m
1n
1o
1p
1q
1r
0.5533
0.2246
0.5612
0.5534
>0.8368
nt
1s
1t
0.786
0.9347
0.7092
0.4652
0.0013
0.0396
0.0406
0.0255
0.0289
nt
1u
1v
1w
PFA
(E)-2-Naphthyl
(E)-3-Thienyl
(E)-2-Furyl
a All data represent mean values for at least two separate experiments.
b Compounds were tested at 200 lg/mL, the positive control agent phosphonoformic acid (PFA) was tested at 20 lg/mL, the inhibition of recom-
binant HIV-1 RT activity was performed with a commercially available ELISA kit (Boechringer Mannheim, Germany) according to the
instructions of the manufacturer.13
c IC50 = effective concentration that inhibited 50% HIV-1 RT.
d CC50 = toxic concentration in C8166 cells that caused the reduction of viable cells by 50%.
e nt, not tested.
Table 2. Structures and anti-HIV-1 RT activities of N-acetyl-b-aryl-
1,2-didehydroethylamine 4a
and 1u), thienyl (1v) and furyl (1w) analogues were less
Compound Ar
Yield HIV-1 RT %
b
active. However, nitroolefin intermediates were quite
cytotoxic, for example, 1b showed a CC50 value of
0.57 lM in C8166 cells.
(%)
inhibition
4a
4b
4c
4d
4e
4f
(E)-Phenyl
45
51
43
50
43
43
49
45
44
50
64
52
47
33
46
56
44
22.25
54.35
41.48
nac
(E)-2-Bromophenyl
(E)-3-Bromophenyl
(E)-4-Bromophenyl
(E)-2-Chlorophenyl
(E)-3-Chlorophenyl
(E)-4-Chlorophenyl
(E)-2-Fluorophenyl
(E)-4-Fluorophenyl
(E)-2-Methylphenyl
(E)-4-Methylphenyl
(E)-2,4,5-Trimethylphenyl
(E)-2-Hydroxyphenyl
(E)-4-Hydroxyphenyl
(E)-2-Methoxyphenyl
(E)-4-Methoxyphenyl
(E)-2,4-Dimethoxyphenyl
Nitroolefins were converted to amides 4, the structures
and enzymatic activities of 4 are summarized in Table 2.
Compounds with ortho substituted bromo (4b), chloro
(4e), fluoro (4h), methyl (4j) and meta substituted bromo
groups (4c) displayed stronger activity than unsubstitut-
ed analogue 4a. However, the ortho hydroxyl or meth-
oxy substituted compounds 4m and 4o exhibited no
activity. Naphthyl compounds 4t and 4u showed higher
inhibitory ratio against HIV-1 RT than 4a. Compounds
(4v–x), containing the heterocycles, exhibited no
activity.
34.02
10.74
na
4g
4h
4i
36.19
na
4j
40.15
16.62
25.45
10.10
na
4k
4l
4m
4n
4o
4p
4q
4r
na
na
Interestingly, the SAR of compounds 4 against RT is
similar to that of nitroolefins 1: the ortho monosubsti-
tuted-phenyl compounds possess higher enzymatic
activity. This suggests that compounds 1 and 4 probably
have similar mechanism of action with RT. In some
newly developed NNRTIs such as the oxindole14 and
benzimidazole-2-one15 derivatives, NH unit was a pro-
ton-donating group in the hydrogen bond formation
process between the inhibitor and HIV-1 RT based on
detailed docking studies, N-alkyl analogues would suffer
dramatic loss of activities. In our experiment, com-
pounds 4a–x were less active compared with their syn-
thetic precursors b-phenylnitroolefins 1a–w, indicating
na
na
(E)-2,4,5-Trimethoxyphenyl 35
(E)-4-Trifluoromethylphenyl 49
4s
na
4t
(E)-1-Naphthyl
(E)-2-Naphthyl
(E)-3-Thienyl
(Z)-3-Thienyl
(E)-2-Furyl
40
50
26
12
38
26.47
30.05
na
4u
4v
4wd
4x
12.02
na
a All data represent mean values for at least two separate experiments.
b Compounds were tested at 200 lg/mL.
c na, not active.
d 4w was produced combined with 4v by reduction of (E)-3-(2-nitro-
vinyl)thiophene (1v).

P. Cheng et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4476–4480
4479
CH3
N
R
R
H
N
CH3
CH3
NaH
O
O
MeI, dry THF
7a
: R = 2-Br
4b
: R = 2-Br
7b: R = 2-Cl
7c
4e
4h
: R = 2-Cl
: R = 2-F
: R = 2-F
7d: R = 2-Me
4j
: R = 2-Me
7e
: R = 3-Br
: R = 4-Br
4c
: R = 3-Br
7f
4d
: R = 4-Br
Scheme 2. Synthesis of N-methyl analogues 7a–f.
Table 3. Enzymatic activities (IC50), syncytium reduction (EC50) and cytotoxicity (CC50) assay of selected compoundsa
HIV-1 RT % inhibitionb
TIf
c
IC50 (mM)
d
EC50 (mM)
e
CC50 (mM)
Compound
4b
4c
54.35
41.48
34.02
36.19
40.50
30.05
85.27
75.22
61.69
79.80
45.42
na
nt
0.1338
0.0893
0.1238
0.3830
0.3790
0.0497
0.0598
0.0959
0.1191
0.1158
0.1284
nt
0.241
0.134
0.297
0.341
0.385
0.154
>0.787
0.441
0.667
0.609
0.409
nt
1.8
1.5
2.4
<1
nt
4e
nt
4h
4j
nt
nt
1.0
3.1
>13.2
4.6
5.6
5.2
3.2
nt
4u
7a
7b
7c
nt
0.339
0.434
0.477
0.487
0.838
nt
7d
7e
7f
AZTg
nt
nt
1.08 · 10À5
>5.092
>471,481
a All data represent mean values for at least two separate experiments.
b Compounds were tested at 200 lg/mL.
c IC50 = effective concentration that inhibited 50% HIV-1 RT.
d EC50 = effective concentration required to protect C8166 cells against the cytopathogenicity of HIV-1IIIB by 50%.16
e CC50 = cytostatic concentration required to reduce C8166 cell proliferation by 50%.17
f Therapeutic index: CC50/EC50 ratio.
g AZT was used as positive control.
that the hydrogen atom of NH unit was probably not
crucial to potent activity. To examine whether there is
hydrogen bond between 4 and the enzyme, the N-methyl
analogues of 4b, 4e, 4hand4jweresynthesized(Scheme 2).
Compounds 7a–d showed 85.27%, 75.22%, 61.69%
and 79.80% inhibitory ratio (Table 3) against HIV-1
RT at 200 lg/mL, respectively, increased nearly onefold
from 4b, 4e, 4h and 4j. This suggested that NH unit in
compounds 4 was not involved to form a hydrogen bond
with HIV-1 RT. On the contrary, the N-methyl ana-
logues were proved to have stronger interaction with
the HIV-1 RT active site and increased enzymatic activ-
ity accordingly. Furthermore, N-methyl analogues (7e,
7f) of 4c and 4d were prepared (Scheme 2) and evaluated
for their inhibitory abilities to RT, respectively. As out-
lined in Table 3, 7e and 7f lost significant enzymatic
activity compared with 7a, which gave us an informa-
tion that ortho-substituted N-methyl derivatives still
possessed higher enzyme activities.
noted regarding the anti-HIV-1 activity data with the
tested compounds: (i) the cytotoxicities of selected com-
pounds significantly decreased compared with nitroole-
fin intermediates; (ii) compounds 4h and 4j were
inactive (EC50 > 200.0 lM, TI 6 1), whereas the other
compounds exhibited weak (4b, 4c, 4e, 4u), moderate
(7b–e) activity; (iii) the most active compound was (E)-
N-(2-bromostyryl)-N-methylacetamide (7a, TI > 13.2);
(iv) compound 7a showed higher enzymatic activity
(IC50) and TI value than its isomer 7e, which suggested
that higher enzymatic inhibitory ratio would lead to
increased anti-HIV activity in cell-based assay.
Although the TI values of the tested compounds are
suboptimal, they possess a naturally occurring structure
unit and the SAR exploration provided us a guide on
further anti-HIV-1 study of the derivatives in this fam-
ily. Furthermore, the anti-HIV-1 assay of the natural
b-aryl-1,2-didehydroethylamine alkaloids can be initi-
ated based on our findings. In summary, we have
described a convenient synthesis of the N-acetyl-b-aryl-
1,2-didehydroethylamine derivatives, this class of com-
pounds were studied as inhibitors of HIV-1 replication
against RT for the first time, representing a new lead
for the design and synthesis of more potent and selective
analogues that act as NNRTIs. Further structure mod-
ification on the nitrogen atom of compounds 4 is
underway.
Compounds 4b, 4c, 4e, 4h, 4j, 4u and 7a–e with HIV-1
RT inhibitory ratio above 30% were tested for their
anti-HIV-1 activities (EC50) and cytotoxicties (CC50) in
cell-based assays, in addition the therapeutic index
(TI) was calculated (Table 3). The antiviral assay was
performed based on a protocol described in our previous
reports.16,17 Besides, enzymatic activities (IC50) of com-
pounds 7a–e were evaluated. The following is to be

4480
P. Cheng et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4476–4480
11. Laso, N. M.; Quiclet-Sire, B.; Zard, S. Z. Tetrahedron
Lett. 1996, 37, 1605.
Acknowledgments
12. Procedure for preparing compound 4a: a suspension of iron
powder (120 mmol) in acetic acid (1.2 mL) and acetic
anhydride (12 mL) was heated to reflux for 30 min under a
nitrogen atmosphere, then the b-phenylnitroolefin (1a,
6 mmol) was added to the mixture in half hour and the
reaction system was kept refluxing for another 4 h until the
disappearance of starting material monitored by TLC
check. The mixture was then cooled and poured to ice
cooled water and filtered, the filtrate was evaporated to give
a residue which was dissolved in 10 mL methanol, the pH
was adjusted to about 12 using the methanolic KOH.
Filtration through Celite followed by evaporation of
methanol and purification on silica gel chromatography
afforded the target compounds. In this procedure, (E)-N-
(styryl)acetamide 4a was obtained as white solid, mp 104–
106 ꢁC; 1H NMR (CDCl3) d: 7.52 (d, J = 14.4 Hz, 1H,
NCH), 7.32–7.16 (m, 5H, Ar–H), 6.09 (d, J = 14.4 Hz, 1H,
Ar–CH), 2.11 (s, 3H, COCH3); IR mmax (KBr) cmÀ1: 3287
(NH) 1669 (CO); EI-MS m/z (%): 161 [M]+ (35), 147 (49),
118 (100), 105 (85), 91 (77), 77 (47).
The authors are grateful to the analytical group of the
State Key Laboratory of Phytochemistry and Plant
Resources in West China, Kunming Institute of Botany,
the Chinese Academy of Sciences, for measurements of
all spectra. The work was partly supported by the 863
Program, Ministry of Science and Technology, PR Chi-
na (2003AA2Z3512).
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