Chemistry Reference
In-Depth Information
TABLE 9-4. Structures and Anti-HIV Activities of Khelthiolactone Analogs (73-84)
36
R
3
R
2
R
4
R
1
S
O
O
O
O
O
O
O
O
O
O
H9 Lymphocytes
a
CEM-SS Cell Line
b
Compound
Structure
EC
50
(mM)
TI
EC
50
(mM)
TI
73
R
1
¼
R
2
¼
R
3
¼
R
4
¼
H
0.029
>
5,390
0.307
13.7
Mono-substitution
74
R
1
¼
CH
3
,R
2
¼
R
3
¼
R
4
¼
H
0.0119
>
12,900
*
75
R
2
¼
CH
3
,R
1
¼
R
3
¼
R
4
¼
H
0.00718
>
21,300
0.0635
>
3,150
76
R
2
¼
C
3
H
7
,R
1
¼
R
3
¼
R
4
¼
H
0.128
>
1,153
0.128
>
1,153
R
2
¼
phenyl, R
1
¼
R
3
¼
R
4
¼
H
>
56.6
>
56.6
77
2.48
2.48
R
3
¼
CH
3
,R
1
¼
R
2
¼
R
4
¼
H
>
7,690
78
0.0199
*
79
R
3
¼
OCH
3
,R
1
¼
R
2
¼
R
4
¼
H
1.28
>
117
*
80
R
4
¼
OCH
3
,R
1
¼
R
2
¼
R
3
¼
H
N/S
*
Di-substitution
81
R
2
¼
R
3
¼
CH
3
,R
1
¼
R
4
¼
H
0.262
>
571
*
82
R
2
¼
CH
3
,R
3
¼
OCH
3
,R
1
¼
R
4
¼
H
1.46
>
1000
*
83
R
1
¼
R
2
,CH
3
,R
3
¼
R
4
¼
H
0.0334
>
4490
*
84
R
1
¼
C
6
H
5
,R
2
¼
CH
3
,R
3
¼
R
4
¼
H
4.95
6.24
*
AZT
0.045
41,667
0.0038
>
263
2
:
56
10
4
>
1
:
37
10
5
DCK (2)
0
:
14
0
:
26 100
1
:
57
10
7
>
10
9
53
0.0635
>
3,150
a
Screened in H9 lymphocytes by Panacos, Inc.
b
Screened in CEM-SS cells by the National Institutes of Health.
9.2.3.2.2 DCK-Lactam Analogs The DCK lactam analogs (85-88) were also
synthesized asymmetrically and evaluated for antiviral activity against HIV-1 repli-
cation in H9 lymphocyte cells. As shown in Figure 9-5, the interchange of O and its
similar-sized bioisostere NH retains the anti-HIV activity in DCK series derivatives
because 87 and 88 had comparable activity with corresponding DCKs (53 and 63).
Thus, the hydrogen bond acceptor ability of NH or O at position-1 is likely involved
in receptor binding. Too bulky to fit and bind target, the N-t-BOC (butoxycarbonyl)
intermediates (85 and 86) did not inhibit HIV-1 replication.
38
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