Synthesis of 3-nitrosoimidazo[1,2-a]pyridine derivatives as potential antiretroviral agents

Article abstract of DOI:10.1002/1521-4184(200107)334:7<224::AID-ARDP224>3.0.CO;2-7

Ten 2-aryl or heteroaryl-3-nitrosoimidazo[1,2-a]pyridine derivatives were synthesised as potential antiretroviral agents. The new compounds were characterized by elemental analysis, ¹H NMR, and by crystallography for (14). The compounds were devoid of any activity against HIV-1 or HIV-2.

Full text of DOI:10.1002/1521-4184(200107)334:7<224::AID-ARDP224>3.0.CO;2-7

224
Gueiffier and co-workers
Synthesis of 3-Nitrosoimidazo[1,2-a]pyridine Derivatives as Potential
Antiretroviral Agents
a,b)
a)
c)
b)
d)
Aziz Chaouni-Benabdallah , Christophe Galtier , Hassan Allouchi , Abdelhak Kherbeche , Jean-Claude Debouzy ,
e)
e)
f)
f)
f)
f)
Jean-Claude Teulade , Olivier Chavignon , Myriam Witvrouw , Christophe Pannecouque , Jan Balzarini , Erik de Clercq ,
a)
a)
Cécile Enguehard , and Alain Gueiffier
a) E.A. 3247 Groupe de Recherche en Chimie Hétérocyclique et Thérapeutique, Laboratoire de Chimie Thérapeutique, Faculté de Pharmacie,
31 Avenue Monge, 37200 Tours, France
b) Laboratoire de Catalyse et Environnement, Université Sidi Mohamed Ben Abdellah, Ecole Supérieure de Technologie de Fès, B.P. 2427,
Route d’Imouzzer, Fès, Maroc
c) Laboratoire de Chimie Physique, Faculté de Pharmacie, 31 Avenue Monge, 37200 Tours, France
d) CRSSA/BCM, 24 Av. des Maquis du Grésivaudan, B.P. 87, 38702 La Tronche, Cedex, France
e) Laboratoire de Chimie Organique, Faculté de Pharmacie, 28 Place Henri Dunant, 63001 Clermont-Ferrand, France
f) Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium
Key Words: Imidazo[1,2-a]pyridine; nitrosation; antiretroviral; NCp7; crystal data
Since it was then demonstrated that NOBA acts through its
nitroso function, we were interested in continuation of our
Summary
studies on imidazo[1,2-a]pyridine derivatives as antiviral
Ten 2-aryl or heteroaryl-3-nitrosoimidazo[1,2-a]pyridine deriva-
[11]
agents
, in the preparation of 3-nitroso derivatives as
tives were synthesised as potential antiretroviral agents. The new
1
antiretroviral agents acting as potential zinc ejectors. It has
been demonstrated that 2-phenylimidazo[1,2-a]pyridine de-
compounds were characterized by elemental analysis, H NMR,
and by crystallography for (14). The compounds were devoid of
rivatives could be nitrosated in the 3-position using sodium
any activity against HIV-1 or HIV-2.
[12]
nitrite in acetic acid media at room temperature
. We now
report the preparation and the activity of various 2-aryl or
heteroaryl-3-nitrosoimidazo[1,2-a]pyridine derivatives as
antiretroviral agents.
Introduction
Since the demonstration of possible evasion to multidrug
therapy with reverse transcriptase and protease inhibitors in
HIV infection , the development of novel antiretroviral
[1]
Results and Discussion
agents with other targets has been mandatory in the long-term
therapy of AIDS.
Chemistry
From the different approaches investigated, the two retrovi-
Substituted 2-aminopyridine 1a–e were reacted with phen-
acyl bromide to give the desired imidazo[1,2-a]pyridines
2a–e (Scheme 1). As a second alternative, influence of the
ral Zn finger motifs of the HIV-1 nucleocapsid p7 (NCp7)
[2]
protein appear to be of great interest . Among all the known
retroviruses, the spacing and metal chelating residues of the
Cys-X -Cys-X -His-X -Cys (CCHC) Zn fingers are abso-
2
4
4
Table 1. Compounds synthesized and their mp and yields.
——————————————————————————————
[3]
[4]
lutely conserved , except for the spumaretroviruses
.
Different families of compounds have been shown to be able
to eject zinc from the two CCHC Zn fingers as a consequence
of chemical modification at the sulfur atom of the Zn-coordi-
nating Cys residues. From these compounds, C-nitrosoderi-
Compounds
R
Ar
Mp (°C) Yield (%)
——————————————————————————————
5
H
phenyl
165a
136
202b
199c
203d
245
237
208
245
197
71
73
70
74
76
78
82
90
67
87
6
8-CH3
7-CH3
6-CH3
8-OCH2C6H5
7-CH3
7-CH3
7-CH3
7-CH3
7-CH3
phenyl
[5]
vatives [3-nitrosobenzamide (NOBA)] , disulfide benz-
7
phenyl
[6]
amides [2,2′-dithiobisbenzamides (DIBAS)] , dithiane and
[7]
[8]
8
phenyl
dithiolane derivatives , azodicarbonamide (ADA)
and
[9]
9
phenyl
pyridinoalkanoyl thiolesters (PATE)
have been docu-
10
11
12
13
14
naphth-2-yl
biphen-4-yl
thien-2-yl
fur-2-yl
mented. Recently, nucleomimetic strategy for the inhibition
[10]
of HIV-1 nucleocapsid protein NCp7 was investigated
.
———
Correspondence: E.A. 3247 Groupe de Recherche en Chimie Hétérocy-
clique et Thérapeutique, Laboratoire de Chimie Thérapeutique, Faculté de
Pharmacie, 31 Avenue Monge, 37200 Tours, France.
E-mail: enguehard@univ-tours.fr
pyridin-2-yl
——————————————————————————————
a mp 162–164°C[24] b mp 188°C[24], 194–196°C[12] c mp 180–182°C[24]
d mp 193°C[25]
,
,
,
Fax : +33 247367288
.
Arch. Pharm. Pharm. Med. Chem.
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0365-6233/01/0707/0224 $17.50 +.50/0

3-Nitrosoimidazo[1,2-a]pyridine Derivatives
225
NH2
COCH2Br
N
EtOH
Reflux
R
+
R
N
N
1a-e
2a-e
a : R = H
b : R = 3-CH
3
c : R = 4-CH
3
d : R = 5-CH
3
e : R = 3-OCH C H
2 6
5
H3C
NH2
H3C
N
EtOH
Reflux
Ar
+
ArCOCH2Br
N
N
3a-e
1c
4a-e
a : Ar = pyridin-2-yl
b : Ar = napht-2-yl
c : Ar = biphen-2-yl
d : Ar = thien-2-yl
e : Ar = Fur-2-yl
N
NaNO2
2a-e
4a-e
Ar
R
N
AcOH
NO
5-14
Scheme 1. Synthesis of 2-aryl or heteroaryl-3-nitrosoimidazo[1,2-a]pyridines 5–14.
2-substituent was investigated. Thus, 2-amino-4-picoline 1c
was reacted with aryl or heteroaryl-α-bromoethanone 3a–e in
[13]
refluxing ethanol according to Roe’s procedure
to give
the 2-substituted-7-methylimidazo[1,2-a]pyridines 4a–e.
Then nitrosation was achieved in a usual manner using so-
dium nitrite in acetic acid at room temperature to give the
nitroso derivatives 5–14. Slow addition rate of sodium nitrite
in dilute solution prevented the formation of a red tar and thus
exempted us from doing chromatography. Proof of the struc-
1
ture was easily given by H NMR spectra with an upfield shift
[14]
of H-5 in position peri from the NO group
. Finally, the
Figure 1. Ellipsoid representation of 14 and atomic labelling (X-Ray num-
bering).
crystal structure for compound 14 was investigated.
Figures 2 and 3a,b. There are numerous weak Van der Waals
interactions so that the crystal packing is rather loose in
ageement with the low observed density.
Crystallographic Data
The thermal ellipsoid representation and the labelling of
[15]
non-hydrogen atoms
of both conformations are presented
Antiviral Activities
in Figure 1. The bond lengths and bond angles agree quite
well with literature data.
All the synthesised compounds were inactive against HIV-1
The imidazo[1,2-a]pyridine rings 1 (atoms N1 to C8A) and
(strain III ) and HIV-2 (strain ROD)in MT-4 cells at subtoxic
B
the pyridinic moiety 2 (atoms C1′ to C6′) are planar with the concentrations. Since the mechanistic pathway of NCp7 pro-
following dihedral angle : 2/1 = 26.4(1)°.
tein Zinc fingers of VIH is not completely established, inter-
The packing of the molecule and the projection of the pretation of these results appears difficult. However, from the
structure on the (x0z) and the (y0z) planes are shown in steric hinderance of the substituent in position 2, the nitroso
Arch. Pharm. Pharm. Med. Chem. 334, 224–228 (2001)

226
Gueiffier and co-workers
Figure 2. Packing representation of 14.
group could not be located in the close vicinity of the thiolate
group of the zinc finger cysteine. In order to verify this
hypothesis, the synthesis of 2-unsubstituted derivatives
would be of interest.
Figure 3a. Projections of 14 on the (x0y) plane.
Acknowledgments
We thank Kristien Erven and Cindy Heens for excellent technical assis-
tance. These investigations were supported by grants from the Fonds voor
Wetenschappelijk Onderzoek (FWO) – Vlaanderen, the Geconcerteerde
Onderzoeksacties (GOA) – Vlaamse Gemeenschap, and ISEP/FORTIS.
Experimental Part
Chemistry
Melting points were determined on a Totolli capillary apparantus and are
uncorrected. Elemental analyses for C, H, N were performed by the Mi-
croanalytical Center, ENSCM, Montpellier, France and were in the range of
0.4% of the theoretical values. NMR spectra were recorded on a Bruker DPX
200 spectrometer. Chemical shifts are expressed from TMS using residual
CHCl3 at δ 7.30 ppm, and from the central resonance of CDCl3 at δ 77.1
ppm. The following compounds were obtained according to described pro-
cedures: 2-phenylimidazo[1,2-a]pyridine 2a [16], 8-methyl-2-phenylimid-
Figure 3b. Projections of 14 on the (x0z) plane.
7-Methyl-2-(pyridin-2-yl)imidazo[1,2-a]pyridine 4a
This compound was obtained from 2-amino-4-picoline 1c and 3a in 48%
yield ; mp 183–185 °C; 1H NMR (CDCl3, 200 MHz); δ = 8.63 (d, J5′,6′ = 4.8
Hz, 1H, H-6′), 8.19 (d, J3′,4′ = 7.6 Hz, 1H, H-3′), 8.18 (s, 1H, H-3), 8.03 (d,
azo[1,2-a]pyridine 2b [17], 7-methyl-2-phenylimidazo[1,2-a]pyridine 2c [17]
,
6-methyl-2-phenylimidazo[1,2-a]pyridine 2d [17], 8-benzyloxy-2-phenyl-
J5,6 = 6.9 Hz, 1H, H-5), 7.78 (td, J3′,4′ = J4′,5′ = 7.6 Hz, J4′,6′ = 1.8 Hz, 1H,
imidazo[1,2-a]pyridine 2e [18], 2-bromoacetylpyridine 3a [19], 2-bromo-1-
H-4′), 7.40 (br.s, 1H, H-8), 7.22 (ddd, J4′,5′ = 7.6 Hz, J5′,6′ = 4.8 Hz, J3′,5′
=
[20], 7-methyl-2-(biphen-4-yl)imidazo-
1 Hz, 1H, H-5′), 6.63 (dd, J5,6 = 6.9 Hz, J6,8 = 1.4 Hz, 1H, H-6), 2.44 (s, 3H,
CH3) ; 13C NMR (CDCl3, 50 MHz); d = 153.1 (C-2′), 149.4 (C-6′), 146.1
(C-2*), 145.9 (C-8a*), 136.8 (C-4′), 133.8 (C-7), 125.1 (C-5), 122.5 (C-5′),
120.4 (C-3′), 116.1 (C-8), 115.4 (C-6), 110.3 (C-3), 21.4 (CH3).
(naphth-2-yl)ethanone 3b
[1,2-a]pyridine 4c [21], 7-methyl-2-(thien-2-yl)imidazo[1,2-a]pyridine 4d
[22], 7-methyl-2-(fur-2-yl)imidazo[1,2-a]pyridine 4e [23], 3-nitroso-2-
phenylimidazo[1,2-a]pyridine 5 [24], 7-methyl-3-nitroso-2-phenylimi-
dazo[1,2-a]pyridine 7 [12], and 8-benzyloxy-3-nitroso-2-phenyl-
imidazo[1,2-a]pyridine 9 [25]. Original 1H NMR for previously reported
compounds are given in Table 2.
7-Methyl-2-(naphth-2-yl)imidazo[1,2-a]pyridine 4b
This compound was obtained from 2-amino-4-picoline 1c and 3b in 54%
yield ; mp 200°C ; 1H NMR (CDCl3, 200 MHz); δ = 8.50 (br.s, 1H, H-1′),
7.96 (dd, J3′,4′ = 8.6 Hz, J1′,3′ = 1.7 Hz, 1H, H-3′), 7.87 (m, 4H, H-5, 4′, 5′,
8′), 7.80 (s, 1H, H-3), 7.49 (m, 2H, H-6′, 7′), 7.42 (br.s, 1H, H-8), 6.54 (dd,
J5,6 = 6.9 Hz, J6,8 = 1.6 Hz, 1H, H-6), 2.38 (s, 3H, CH3) ; 13C NMR (CDCl3,
50 MHz); = 146.2 (C-8a*), 145.2 (C-2*), 135.9 (C-8a′), 133.7 (C-4a′), 133.1
(C-7), 131.2 (C-2′), 128.3 (C-5′*), 128.2 (C-8′*), 127.7 (C-4′), 126.2 (C-7′*),
125.9 (C-6′*), 124.8 (C-5), 124.5 (C-1′), 124.1 (C-3′), 115.7 (C-8), 115.1
(C-6), 108.0 (C-3), 21.4 (CH3).
General Procedure for Cyclisation
Mixtures of 2-aminopyridine or substituted derivatives (10 mmol) and
phenacylbromide (1.99 g, 10 mmol) or aryl/heteroaryl-α-bromoethanone
(10 mmol) in ethanol (90 mL) were refluxed for 5 (4a) or 8 hours (4b). After
cooling, the mixtures were evaporated to dryness, the residues taken up in
water, made basic with sodium carbonate and extracted with dichlo-
romethane. The organic layers were dried over calcium chloride, evaporated
to dryness and chromatographed.
Arch. Pharm. Pharm. Med. Chem. 334, 224–228 (2001)

3-Nitrosoimidazo[1,2-a]pyridine Derivatives
227
Table 2. Original 1H NMR for previously reported compounds.
Compounds
H-3
7.83
s
H-5
8.02
dd
H-6
6.68
t
H-7
6.96
dd
H-8
–
CH3 or CH2
Others
7.99
m
2b
2.70
s
7.40
m
J5,6 = 6.8 Hz
J5,6 = 6.8 Hz
J6,7 = 6.8 Hz
H-3',4',5'
H-2',6'
J5,7 = 1 Hz J6,7 = 6.8 Hz J5,7 = 1 Hz
2c
2d
4c
4d
7.81
s
7.97
d
J5,6 = 6.8 Hz
6.64
dd
5,6 = 6.8 Hz
–
7.47
br.s
2.43
s
7.43
m
H-3',4',5'
8.02
m
H-2',6'
J
J6,8 = 1.6 Hz
7.81
s
7.97
d
J5,7 = 1.7 Hz
–
7.05
dd
7,8 = 9.2 Hz
7.56
d
7,8 = 9.2 Hz
2.36
s
7.40
m
H-3',4',5'
7.93
m
H-2',6'
J
J
J5,7 = 1.7 Hz
7.85
s
8.04
m
6.65
dd
J5,6 = 7 Hz
J6,8 = 1.8 Hz
6.62
dd
5,6 = 7 Hz
J6,8 = 1.6 Hz
–
7.53
br.s
2.44
s
7.53
m
H-3",4",5"
7.70
m
H-3',5',2",6"
8.04
m
H-2',6'
7.70
s
7.96
d
J5,6 = 7 Hz
–
–
–
7.39
br.s
2.40
s
7.11
dd
H-4'
7.31
dd
H-5'
7.47
dd
H-3'
J
J
4',5' = 5 Hz
J
4',5' = 5 Hz
J3',4' = 3.6 Hz
J3',4' = 3.6 Hz J3',5' = 1.2 Hz J3',5' = 1.2 Hz
4e*
7.58
s
7.80
d
5,6 = 6.9 Hz
6.42
dd
5,6 = 6.9 Hz
7.29
br.s
2.28
s
6.51
dd
H-4'
6.90
d
H-3'
7.48
d
H-5'
J
J
J6,8 = 1.5 Hz
J
3',4' = 3.3 Hz
J4',5' = 1.8 Hz
J
3',4' = 3.3 Hz J4',5' = 1.8 Hz
7
–
9.84
d
7.10
dd
7.58
m
2.56
s
7.58
m
8.68
m
J5,6 = 6.8 Hz J5,6 = 6.8 Hz
J6,8 = 1.4 Hz
H-3',4',5'
H-2',6'
9*
7.80
s
7.69
dd
6.55
dd
6.43
dd
–
5.42
s
7.40
m
7.55
m
8.05
m
J5,6 = 6.6 Hz
J5,7 = 1 Hz J5,6 = 6.6 Hz J5,7 = 1 Hz
J
6,7 = 7.6 Hz
J
6,7 = 7.6 Hz
H-3',4',5'
H-3'',4'',5''
H-2'',6''
H-2',6'
* reported in DMSO-D6.
General Procedure for Nitrosation
H-8), 7.43–7.56 (m, 3H, H-3′′, 4′′, 5′′), 7.11 (dd, J5,6 = 6.8 Hz, J6,8 = 1.4 Hz,
1H, H-6), 2.58 (s, 3H, CH3).
To a solution of imidazo[1,2-a]pyridine derivative 2a–e or 4a–e
(2.5 mmol) in acetic acid was slowly added a solution of sodium nitrite (25
mmol) in water (7 mL). The mixture was stirred for 30 minutes. The green
precipitate was collected to give the pure nitroso derivative which was dried
in an oven. In some cases chromatography on neutral alumina eluted with
dichloromethane was necessary.
7-Methyl-3-nitroso-2-(thien-2-yl)imidazo[1,2-a]pyridine 12
1H NMR (CDCl3, 200 MHz); δ = 9.74 (d, 1H, J5,6 = 6.8 Hz, H-5), 8.46
(dd, J3′,4′ = 3.8 Hz, J3′,5′ = 1.2 Hz, 1H, H-3′), 7.73 (dd, J4′,5′ = 5 Hz, J3′,5′
1.2 Hz, 1H, H-5′), 7.52 (br.s, 1H, H-8), 7.27 (dd, J4′,5′ = 5 Hz, J3′,4′ = 3.8 Hz,
1H, H-4′), 7.02 (dd, J5,6 = 6.8 Hz, J6,8 = 1.5 Hz, 1H, H-6), 2.52 (s, 3H, CH3).
=
8-Methyl-3-nitroso-2-phenylimidazo[1,2-a]pyridine 6
1H NMR (CDCl3 , 200 MHz); δ = 9.83 (d, J5,6 = 7 Hz, 1H, H-5), 8.72 (m,
2H, H-2′, 6′), 7.60 (m, 4H, H-7, 3′, 4′, 5′), 7.17 (t, J5,6 = J6,7 = 7 Hz, 1H, H-6),
2.78 (s, 3H, CH3).
2-(Fur-2-yl)-7-methyl-3-nitrosoimidazo[1,2-a]pyridine 13
1H NMR (CDCl3, 200 MHz); δ = 9.80 (d, J5,6 = 6.8 Hz, 1H, H-5), 7.88
(dd, J4′,5′ = 1.7 Hz, J3′,5′ = 0.7 Hz, 1H, H-5′), 7.85 (d, J3′,4′ = 3.5 Hz, 1H, H-3′),
7.61 (br.s, 1H, H-8), 7.11 (dd, J5,6 = 6.8 Hz, J6,8 = 1.5 Hz, 1H, H-6), 6.72
(dd, J3′,4′ = 3.5 Hz, J4′,5′ = 1.7 Hz, 1H, H-4′), 2.58 (s, 3H, CH3).
6-Methyl-3-nitroso-2-phenylimidazo[1,2-a]pyridine 8
1H NMR (CDCl3 , 200 MHz); δ = 9.89 (br.s, 1H, H-5), 8.66 (m, 2H,
H-2′,6′), 7.77 (m, 2H, H-7, 8), 7.62 (m, 3H, H-3′,4′,5′), 2.49 (s, 3H, CH3).
7-Methyl-3-nitroso-2-(pyridin-2-yl)imidazo[1,2-a]pyridine 14
1H NMR (CDCl3, 200 MHz); δ = 9.84 (d, J5,6 = 6.9 Hz, 1H, H-5), 8.98 (d,
7-Methyl-2-(naphth-2-yl)-3-nitrosoimidazo[1,2-a]pyridine 10
J5′,6′ = 4.6 Hz, 1H, H-6′), 8.90 (d, J3′,4′ = 7.8 Hz, 1H, H-3′), 7.94 (td, J4′,5′
=
1H NMR (CDCl3, 200 MHz); δ = 9.91 (d, 1H, J5,6 = 6.8 Hz, H-5), 9.32
(br.s, 1H, H-1′), 8.76 (dd, J3′,4′ = 8.7 Hz, J1′,3′ = 1.7 Hz, 1H, H-3′), 7.91–8.09
(m, 3H, H-4′, 5′, 8′), 7.66 (br.s, 1H, H-8), 7.57–7.63 (m, 2H, H-6′, 7′), 7.10
(dd, J5,6 = 6.8 Hz, J6,8 = 1.6 Hz, 1H, H-6), 2.57 (s, 3H, CH3).
J3′,4′ = 7.8 Hz, J4′,6′ = 1.9 Hz, 1H, H-4′), 7.76 (br.s, 1H, H-8), 7.54 (ddd, J4′,5′
= 7.8 Hz, J5′,6′ = 4.6 Hz, J3′,5′ = 1 Hz, 1H, H-5′), 7.19 (dd, J5,6 = 6.9 Hz, J6,8
= 1.5 Hz, 1H, H-6), 2.61 (s, 3H, CH3).
X-Ray Diffraction
2-(Biphen-4-yl)-7-methyl-3-nitrosoimidazo[1,2-a]pyridine 11
Green plate crystals were grown by slow evaporation of ethanol/chloro-
form solutions. The crystal used for X-ray measurement was lamellar, with
dimensions: 0.025×0.1×0.2 mm. The studied compound, C13H10N4O, Mx =
1H NMR (CDCl3, 200 MHz); δ = 9.88 (d, J5,6 = 6.8 Hz, 1H, H-5), 8.79 (d,
J = 8.6 Hz, 2H, H-2′, 6′), 7.71–7.84 (m, 4H, H-3′, 5′, 2′′, 6′′), 7.65 (br.s, 1H,
Arch. Pharm. Pharm. Med. Chem. 334, 224–228 (2001)

228
Gueiffier and co-workers
228.25 g.mole–1, crystallized in the monoclinic system, space group P21/a
(Z = 4). The unit cell parameters were obtained by a least-squares fit of the
setting angles of 25 reflections with θ between 15 and 35° and are as follows :
a = 7.155(3), b = 12.106(3), c = 13.022(4), and β = 101.37(3) with a cell
volume of 1105.8(6) Å3.The calculated density is equal to 1.431 g.cm–3. The
linear absorption coefficient was µ = 0.7585 mm–1 for the CuKα radiation
and an ω–2θ scan.
The diffracted intensities were collected with a CAD-4 Enraf-Nonius
diffractometer equipped with a graphite monochromator for θmax = 60: 0 ≤
h ≤ 7, 0 ≤ k ≤13, –14 ≤ l ≤ 14. Three standard reflections were used to monitor
the data and to detect any decrease of intensity (–4 3 1, –1 –4 5, 1 4 5). There
were 1598 independent reflections of which 797 were considered as observed
(I>2σ (I) and Rint = 0.0206).
The crystal structure was solved and refined using the SHELX97 program
[26]. Scattering factors were taken from the International Tables for Crystal-
lography [27]. The hydrogen atoms were introduced in their theoretical
positions and allowed to ride with the atoms to which they are attached; the
refinement was then resumed. The final reliability factors were: R = 0.059,
wR = 0.129 and the goodness of fit was equal to 0.967. The weight was equal
to: w = 1/[σ2(Fo2) + (0.0787P)2 + 0.1435P] where P = (Fo2 +2Fc2)/3. The
minimum and maximum residual density were equal –0.231 and 0.239 e.Å–3
respectively.
P. Harvey, D. Hupe, L. Sharmeen, D. Mack, J. Scholten, J. Saunders,
T. McQuade, Drug Design Discov., 1997, 15, 49–61 ; [d] J. V. N. Vara
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Inhibition of HIV-1-Induced Cytopathicity in MT-4 and CEM Cells
The methodology of the anti-HIV assays has been described previously.
Briefly, human MT-4 (ca. 4 × 105 cell mL–1) cells were infected with 100
CCID50 of HIV-1 (IIIB)/mL or HIV-2(ROD)/mL and seeded in 200-µl wells
of a microtiter plate, containing appropriate concentrations of the test com-
pounds. After 5 days of incubation at 37°C, the number of viable (MT-4)
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Received: May 7, 2001 [FP572]
Arch. Pharm. Pharm. Med. Chem. 334, 224–228 (2001)