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the 6-position [6-methyl (61) and 6-methoxy (62)] dramatically decreased activity;
thus, C-6 is not favorable for modification. More analogs with various substituents
at C-4 were also synthesized. 4-Propyl (55), isopropyl (56), phenyl (57), and
trifluoromethyl (58) DCK analogs were less potent or inactive (Table 9-2).
25
The larger volume of the propyl and isopropyl groups could interfere with target
binding, whereas the phenyl substituent may affect compound planarity and not
fit into the binding site. Although similar in size and shape to a methyl group, an
electron-withdrawing trifluoromethyl group was unfavorable, based on the low activity
of 58. The extremely high anti-HIV potency of 4-methyl DCK (53) and 5-methyl DCK
(59) indicates that a methyl group probably fits well into a hydrophobic cleft on the
target's active surface and greatly increases both the agent'stargetaffinity and the
desired pharmacological response.
25
9.2.3.1.2 Disubstituted Analogs Disubstituted DCK analogs were also developed
and screened for inhibition of HIV replication in H9 lymphocytes (Table 9-3).
24
4-Methyl-5-methoxy DCK (69) was the most promising compound and was
similar to 4-methyl DCK (53) and much better than DCK (2) in the same assay.
Dimethyl DCKs 63 (3,4-dimethyl), 67 (3,5-dimethyl), 68 (4,5-dimethyl), and 72
(4,6-dimethyl) showed about 20-fold lower activity compared with 2. Among
other 3,4-disubstituted compounds, 3-chloro-4-methyl (64) and 3,4-cyclohexano
TABLE 9-3. Structures and Anti-HIV Activities of Disubstituted DCK Analogs (63-72)
a,24
5
4
6
3
O
O
O
O-camp
No.
IC
50
(mM)
b
EC
50
(mM)
c
TI
d
O-camp
3,4-di-substitution
1
:
92
10
3
>
8
:
02
10
4
63
3-CH
3
4-CH
3
>
154
2
:
01
10
3
5
:
17
10
4
64
Cl
CH
3
104
65
C
6
H
5
CH
3
>
140
43.7
>
3.20
2
:
12
10
3
>
6
:
98
10
4
66
-CH
2
CH
2
CH
2
CH
2
-
>
148
3,5-di-substitution
9
:
10
10
3
>
1
:
69
10
4
67
3-CH
3
5-CH
3
>
154
4,5-di-substitution
>
154
4
:
19
10
3
>
3
:
68
10
4
68
4-CH
3
5-CH
3
69
CH
3
OCH
3
>
150
7
:
21
10
6
>
2
:
08
10
7
70
CH(CH
3
)
2
CH
3
>
147
No
suppression
71
CH
3
OCH
2
C
6
H
5
>
135
1.54
87.7
4,6-di-substitution
4
:
69
10
3
72
4-CH
3
6-CH
3
3.75
1
:
25
10
3
a
Inhibitory of HIV-1 IIIB in H9 lymphocytes.
b
Concentration that inhibits uninfected H9 cell growth by 50%.
c
Concentration that inhibits viral replication by 50%.
d
Therapeutic Index, TI
ΒΌ
IC
50
=
EC
50
.
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