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O
R
2
O
O
R
1
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
125
126
IC
50
> 166 µM
EC
50
= 0.76 µM
TI > 218
IC
50
= 41 µM
EC
50
= 1.25 µM
TI = 33
127
R
1
= CH
3
, R
2
= COCH
3
, NS
128
R
1
= OCH
2
C
6
H
5
, R
2
= H, NS
129
R
1
= OCH
2
COC
6
H
5
, R
2
=H, NS
(DCI)
Figure 9-7. Structures and activity of DCK related compounds 125-129.
structurally in the A ring.
44,45
The naphthalene compound 125 and indanone analog
126 showed only slight activity against a non-drug-resistant HIV strain in H9 lym-
phocytes with EC
50
values of 0.76 and 1.25 mM, respectively, whereas opened ring
compounds 127-129 were inactive (Figure 9-7). These results suggested that a bi-
ring system is a requirement for anti-HIV activity.
45
9.2.4
SAR Conclusions
The following conclusions were drawn from the SAR studies of DCK and DCP ana-
logs and derivatives: (1) A bi-ring system is a requirement, and a planar system is
probably an essential feature for potent anti-HIV activity. Steric compression
between DCK C-4 and C-5 substituents or phenyl substituents on the skeleton
can reduce the overall planarity and, thus, resonance of the system, which results
in decreased or completely lost activity. (2) The stereochemistry at the 3
0
and 4
0
positions should be R-configured, and an isovaleryl structural feature is essential
on these positions. Camphanoyl moieties are the most potent substituents.
(3) Methyl or other aliphatic substitutions on the DCK C-3, C-4, and C-5 are favor-
able for anti-HIV activity against the non-drug-resistant strain, whereas aromatic
substituents and 6-substitution are not. The DCK C-3 can tolerate polar but not
charged or electron withdrawing substituents. (4) The bioisosteric isomers, thio-
DCK, and DCK lactam retain activity. (5) The positional isomer, DCP, is even
more promising because most DCP analogs are active against a multiple RT inhi-
bitor resistant strain, whereas most DCK derivatives are ineffective against this RT
inhibiter resistant strain. An appropriate alkyl substituent at position 2 is critical for
the anti-HIV activity of DCP analogs against both viral strains. In addition, most
2-substituted DCP analogs are less toxic to the cells compared with DCP.
43,46
9.2.5
Mechanism of Action
The preliminary mechanism of action studies indicated that DCK inhibits HIV after
viral entry but before viral DNA integration.
22
To further elucidate the mechanism
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