Abstract
A series of new natural product skeleton based 3-(halobenzyl)isocarbostyrils (
2a
–
2i
), were designed and synthesized to examine the effect of position of different halide substituents on anti-inflammatory activity. The structure–activity relationship shows a significant influence of position of halide substituents on in vitro anti-inflammatory activity. 3-(
o
-halobenzyl)isocarbostyrils (
2a
,
2d,
and
2g
) showed the lowest activity most probably due to the closure of pharmacophore site by intramolecular hydrogen bond between halides and N–H of amide. In contrast, 3-(
p
-halobenzyl)isocarbostyrils
2c
,
2f
, and
2i
exhibited moderate to very good inflammatory activity. Compound
2c
(IC
50
=
251.002 ± 2.910) was found to have comparable activity with the standard drug (Indomethacin, IC
50
=
271.210 ± 2.127). To further understand the effect of position of halide substituents on 3-(halobenzyl)isocarbostyrils, computational POM was carried out. The study with constructive propositions may be helpful for the design of more potent analogs.
Graphical Abstract