Synthesis of aryl semicarbazone of 4-aminoacetophenone and their anti- HIV activity

Article abstract of DOI:10.1016/S0031-6865(98)00028-4

The thioureido derivative of 4-aminoacetophenone aryl semicarbazone have been prepared. These derivatives have been characterised on the basis of different physicochemical evidences. The anti-HIV-1 (HTLV-III(B)) and -HIV-2 (ROD) activity and cytotoxicity

Full text of DOI:10.1016/S0031-6865(98)00028-4

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Pharmaceutica Acta Helvetiae 73 1998 215–218
Synthesis of aryl semicarbazone of 4-aminoacetophenone and their
anti-HIV activity
a
c
c
Vibha Mishra , S.N. Pandeya b,), E. DeClercq , Christophe Pannecouque ,
c
Myriam Witvrouw
a
Department of Applied Chemistry, Institute of Technology, Banaras Hindu UniÕersity, Varanasi 221 005, India
b Department of Pharmaceutics, Institute of Technology, Banaras Hindu UniÕersity, Varanasi 221 005, India
c
Rega Institute for Medical Research, Katholieke UniÕersiteit LouÕain, Minderbroedersstraat 10, B-3000 LouÕain, Belgium
Received 2 July 1998; revised 30 July 1998; accepted 19 August 1998
Abstract
The thioureido derivative of 4-aminoacetophenone aryl semicarbazone have been prepared. These derivatives have been characterised
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.
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on the basis of different physicochemical evidences. The anti-HIV-1 HTLV-IIIB and -HIV-2 ROD activity and cytotoxicity of the
compounds were tested. The compound VII and VIII showed maximum protection among the series. q 1998 Elsevier Science B.V. All
rights reserved.
Keywords: Thioureido; Semicarbazone; Anti-HIV
1. Introduction
tive of isatin is used in clinical practice to treat influenza
virus. Further some urea derivatives )N–CO–N- have
been found to be potent compounds for the inhibition of
Human immunodeficiency virus is the causative agent
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HIV-protease Wilkerson et al., 1997 . The present series
of compounds possess these moieties.
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of acquired immunodeficiency syndrome AIDS , which is
one of the world’s most serious health problems, with
current protocols being inadequate for either prevention or
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successful long term treatment DeClercq, 1995 . Several
non-nucleoside inhibitors of the HIV-1 RT include niver-
2. Experimental
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.
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apina Merluzzi et al., 1990 and R82913 Pauwels et al.,
.
1990 these two drugs contain at benzodiazipine nucleus.
In this study an attempt has been made to synthesize
bioisosteric open chain analogs of the benzodiazipines. In
compound number R82913 there is a )N–CS–NH phar-
macophore also methsazone, a thiosemicarbazone deriva-
2.1. Preparation of 4-methyl phenyl semicarbazide
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4-Methyl phenyl urea 0.1 M was dissolved in ethanol
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30 ml . With constant stirring a solution of hydrazine
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hydrate 0.01 M in ethanol was added, whole content was
refluxed for several hours. The precipitate was collected
and washed with ether. Recrystallization from ethanol gave
)
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4-methylphenyl semicarbazide m.p. 1808C, yield 62%
Corresponding author. Tel.: q91-54231680150; Fax: q91-
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Sah, 1934 .
542316427
0031-6865r98r$ - see front matter q 1998 Elsevier Science B.V. All rights reserved.
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PII: S0031-6865 98 00028-4

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V. Mishra et al.rPharmaceutica Acta HelÕetiae 73 1998 215–218
2.2. Preparation of 4-aminoacetophenone 3-methyl phenyl
semicarbazone
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4-Methyl phenyl semicarbazide 0.01 M was dissolved
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in ethanol 10 ml and added slowly to a ethanolic solution
.
of acetophenone 0.01 M . The reaction mixture was stirred
at room temperature for 1 h. The precipitate was collected,
washed with ether and water and dried. Recrystallization
X
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Ž .
Ž .
Fig. 2. RsC6 H4 –CH3 p , C6 H4 –Cl p ; R sH, C6 H4 –Cl p , C6 H4 –
Ž .
Ž .
CH3 p , C6 H4 –OCH3 p .
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from ethanol gave semicarbazone m.p. 1688C, yield 65% .
MT-4 cells from cell death brought on by infection with
HIV-1 and HIV-2.
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2.3. Synthesis of 4- 4-methyl phenyl thioureido aceto-
phenone 4-methyl phenyl semicarbazone
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4-Methyl phenyl isothiocyanate 0.01 M was added to
the solution of 4-aminoacetophenone-4-methylphenyl
3. Results and discussion
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semicarbazone 0.01 M in ethanol 40 ml . The reaction
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The structures of the prepared compounds see Figs. 1
mixture was refluxed for 4 h. The solvent was evaporated
and solid was washed with petroleum ether 40–608C .
Recrystallization from ethanol gave a product m.p. 1358C,
yield 71% . Similarly other 4-thioureido derivatives were
1
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and 2 were confirmed on the basis of H NMR data and
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the data in Table 1.
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1
3.1. H NMR data
prepared.
Melting points were determined by open capillary
method. Elemental analysis were done on Perkin-Elmer
Model 240 C analyser. IR spectra were recorded on Jasco
FT-IR 5300 using KBr disc 1H NMR spectra were recorded
on Jeol FX90Q multinuclear spectrometer in DMSO-d6
with TMS as an internal standard.
3.1.1. For 4-aminoacetophenone 4-methyl phenyl semicar-
bazone
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2
Ž .
3
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.
1
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1.6
2.51
4.1
d-singlet C–CH3 3H
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.
d-singlet Ar–CH3 3H
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d-singlet ArNH2 2H, disappeared in
.
.
D2O exchange
2.4. Anti-HIV testing
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1H, disappeared in
4
4.65
d-singlet
D2O exchange
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The method of Pauwels et al. 1987 was followed. The
screen involved testing a compound’s ability to inhibit the
Ž .
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.
5
6.7
d-doublet aromatic protons 2H
d-multiplet aromatic protons 4H
d-doublet aromatic protons 2H
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Ž .
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.
cytopathic effects of HIV-1 strain HTLV-IIIB LAI,
6
7.1–7.3
7.85
8.4
.
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Ž .
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.
Popovic et al., 1984 and HIV-2 strain LAV-2ROD,
Clavel et al., 1986 in MT-4 cells. These cells were
7
.
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8
d-singlet NNH 1H, disappeared in
.
infected with HIV-1 and HIV-2 incubated in the presence
of various concentrations of the test compounds. The
number of viable cells was then determined 5 days after
D2O exchange
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3.1.2. For 4- 4-methyl phenyl thioureido acetophenone
4-methyl phenyl semicarbazone
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infection by staining with 3- 4,5-dimethyl thiazol-2 yl -2,5
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diphenyl tetrazolium bromide Pauwels et al., 1987 . The
reported values shown in Table 2 are the concentrations of
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2
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1
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1.6
2.4
d-singlet C–CH3 3H
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each compound required to protect 50% IC50 of the
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.
d-singlet Ar–CH3 3H
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2H, disappeared in
3
4.2
d-singlet
D2O exchange
.
.
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4
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2H, disappeared in
4.6
d-singlet
D2O exchange
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.
5
6.9–7.8
9.2
d-multiplet aromatic protons 12H
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.
6
d-singlet NNH 1H, disappeared in
D2O exchange
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Fig. 1. RsCH3 p , Cl p .

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V. Mishra et al.rPharmaceutica Acta HelÕetiae 73 1998 215–218
217
Table 1
Structural and physicochemical details of 4-thioureidoderivatives of acetophenone arylsemicarbazone
X
y1
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.
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No.
I
R
R
Yield
M.p.
Elements %
Infrared cm
TLC
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Rf
Ž .
%
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8C
Calculated
Found
NH
C50
C5S
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CH3
p
65
71
78
61
81
62
69
66
168
135
215
190
174
130
135
163
C: 68.04
H: 6.43
N: 19.86
55.91
4.06
68.33
6.66
20.22
56.27
4.45
15.19
60.78
4.68
15.82
60.69
4.23
15.63
59.32
4.95
15.28
66.34
5.89
16.55
66.91
5.80
16.64
64.78
5.81
3320
1690
–
0.87
0.83
0.95
0.91
0.96
0.89
0.91
0.80
Ž .
Cl p
Ž .
II
Cl p
CH3
H
3428
3280
3400
3450
3280
3420
3250
1685
1695
1690
1680
1685
1670
1680
1050
1120
1120
1020
1020
1110
1080
14.83
61.10
4.91
15.50
60.32
4.61
16.00
59.01
4.74
14.97
66.14
5.56
16.78
66.78
5.84
16.24
64.39
5.63
Ž .
Cl p
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p
III
IV
V
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Cl p
Ž .
Cl p
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p
OCH3
H
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p
VI
VII
VIII
CH3
CH3
CH3
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p
Ž .
p
CH3
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p
Ž .
p
OCH3
15.66
15.38
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.
TLC was performed with silica gel in chloroform:methanol 8:2 system.
The anti-HIV results are given in Table 2. The initial
studies show that compound VIII exhibited maximum 40%
protection against strain IIIB and 35% protection against
ROD. Compound VII has shown maximum protection
20% against IIIB and 18% against ROD. Rest of the
compounds exhibited very little protection. Thus these
studies give an indication that further manipulation of this
series may yield more potent compound.
Table 2
Anti-HIV activity of 4-thioureido derivatives of acetophenone arylsemicarbazone
No.
I
Strain
Exp.-nr
Concentration
EC50
EC90
CC50
S
Maximum protection
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
P3.1441
P3.1442
P3.1441
P3.1442
P3.1441
P3.1442
P3.1441
P3.1442
P3.1441
P3.1442
P3.1441
P3.1442
P3.1441
P3.1442
P3.1441
P3.1442
ugrml
ugrml
ugrml
ugrml
ugrml
ugrml
ugrml
ugrml
ugrml
ugrml
ugrml
ugrml
ugrml
ugrml
ugrml
ugrml
)125
)125
)59
)56
)125
)125
)75
)59
)59
)125
)74
)58
)74
)79
)81
)86
)125
)125
)59
)56
)125
)125
)75
)59
)59
)125
)74
)58
)74
)79
)81
)86
)125
)125
s58.6
s56.4
)125
)125
s75
s59.5
s59.4
)125
s74.2
s58.5
s74.5
s79.5
s81.4
s85.8
=1
=1
-1
-1
=1
=1
-1
-1
-1
=1
-1
-1
-1
-1
-1
-1
11
7
2
6
1
2
0
2
4
6
2
4
20
18
40
35
II
III
IV
V
VI
VII
VIII
ROD

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V. Mishra et al.rPharmaceutica Acta HelÕetiae 73 1998 215–218
Merluzzi, V.J., Hargrave, K.D., Labadia, M., Grozinger, K., Skoog, M.,
Acknowledgements
Wu, J.C., Shin, C.K., Eckner, K., Hattox, S., Adams, J., Rosenthal,
A.S., Faanes, R., Eckner, R.J., Koup, R.A., Sullivan, J.L., 1990.
Science 250, 1411.
The authors are grateful to the Head, Department of
Applied Chemistry and Department of Pharmaceutics, In-
stitute of Technology, Banaras Hindu University, Varanasi
221 005, India, for facilities and Prof. E. DeClercq, Rega
Institute for Medical Research, Belgium for anti-HIV
screening.
Pauwels, R., DeClercq, E., Desmyter, J., Balzarini, J., Goubau, P.,
Herdewijn, P., Vandeputte, M., 1987. J. Virol. Methods 16, 171.
Pauwels, R., Andries, K., Desmeyter, J., Schols, D., Kukla, M.J., Breslin,
H.J., Raeymaeckers, A., Van Gelder, J., Woestenborghs, R., Heykants,
J., Schellekens, K., Janssen, M.A.C., DeClercq, E., Janssen, P.A.,
1990. Nature 343, 470.
Popovic et al., 1984.
Sah, Ma., 1934. J. Chinese Chem. Soc. 2, 32.
Wilkerson, W.W., Dax, S., Cheathem, W.W., 1997. J. Med. Chem. 40,
4079.
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