Inhibition of the enzymes in the leukotriene and prostaglandin pathways in inflammation by 3-aryl isocoumarins

The biosynthesis of leukotrienes in one of the arachidonic acid pathways and PGE₂ in the Other by 5-LOX and mPGES1 respectively, play pivotal roles in augmenting inflammatory responses. PGE₂ is known to participate in Cancer pathological processes as well. Isocoumarins are natural compounds with a wide range of biological activities. In this study, 3-aryl isocoumarin derivatives are synthesized and tested against 5-LOX enzyme in vitro and PGE₂ production in HeLa cells. Most of the compounds show high activity, and 1c is identified as a dual inhibitor with an IC₅₀ of 4.6 ± 0.26 μM and 6.3 ± 0.13 μM against 5-LOX and PGE₂ production respectively. Another compound 7f, exhibits an IC₅₀ of 12.4 ± 0.14 μM against 5-LOX. Further investigations reveal that the mechanism of action of 1c and 7f against 5-LOX is mixed and competitive modes of action respectively. Thunberginol A (7c) exhibits IC₅₀ of 15.8 ± 0.03 μM against PGE₂ production. 1c and 7c inhibit the mRNA expression of mPGES1 and COX-2. The study has identified a novel scaffold, 1c with a dual inhibitory activity which can be further optimized to compete against Licofelone which is under clinical trials (with IC₅₀ of 6.0 μM for mPGES1 & 0.2 μM for 5-LOX). To conclude, 3-aryl isocoumarin derivatives appears as promising tools to fight against inflammatory diseases as well as Cancer.