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O
O
5
R
6
R
3
6
3
2
O
O
R
2
O
O
2
4′
3′
O
O
O
RO
O
O
O
O
O
O
O
O
O
O
107
. R
2
=R
3
=R
6
=H, DCP
108
R
2
=R
6
=H, R
3
=CH
3
109
. R
2
=R
6
=H, R
3
=C
6
H
5
110
. R
2
=CH
3
, R
3
=R
6
=H
111
. R
2
=CH
2
CH
3
, R
3
=R
6
=H
112
. R
2
= CH
2
CH
2
CH
3
, R
3
=R
6
=H
113
. R
2
= CH(CH
3
)
2
, R
3
=R
6
=H
114
. R
2
= CH
2
OCH
2
CH
3
, R
3
=R
6
=H
115
. R
2
=C
6
H
5
, R
3
=R
6
=H
116
. R
2
=R
3
=CH
3
, R
6
=H
117
. R
2
=CH
2
CH
3
, R
3
=H, R
6
=C(CH
3
)
3
118
. R
2
=CH
3
, R=
O
119
. R
2
=CH
3
, R=
O
120
. R
2
=CH
3
, R=
O
121
. R
2
=CH
2
CH
3
, R=
O
122
. R
2
=CH
2
OCH
2
CH
3
, R=
O
123
. R
2
=ph, R=
O
124
. R
2
=ph, R=
Figure 9-6. Substituted DCP derivatives 107-124.
introducing a small alkyl substituent (one or two carbons) at the chromone 2- and/or
3-position retained anti-HIV activity, whereas a large substitution (over three car-
bons) at these positions significantly decreased activity against non-drug-resistant
HIV in H9 lymphocytes, and substitution at 6-position is not favorable.
Interestingly, these compounds showed different SAR against the HIV-1
RTMDR1 strain. Analogs with a C-2 substituent showed activity. Among them,
compound 111 (2-ethyl) exhibited the most promising antiviral activity, whereas
112 (2-propyl) and 113 (2-isopropyl) were slightly less potent. Compounds 110
(2-methyl), 115 (2-phenyl), and 116 (2,3-dimethyl) showed moderate activity.
Compound 117, with 6-t-butyl and 2-ethyl substitution, lost almost all activity;
thus, similar to the SAR of DCK analogs, 6-substitution is not favorable. Interest-
ingly, the DCP C-3 position is also not favorable against the resistant strain as the
previous most potent compound in non-drug-resistant strain, 108, showed only
slight activity; and 109 (3-phenyl) was inactive at the testing concentration.
The unsubstituted parent 107 lost potency against the resistant strain, as did 2
(DCK) and 53 (4-methyl DCK). Analogs with a 3
0
-isobutyryl or isovaleryl
substituent exhibited comparable or slightly weaker potency than corresponding
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