Design, synthesis, biological evaluation and computational studies of novel phthalimides as dual COX-2/5-LOX inhibitors

Aiming to find effective anti-inflammatory agents, two new series of phthalimide derivatives 4a-h and 7a-f were synthesized and evaluated as inhibitors of COX and 5-LOX enzymes. The structures of all of the new compounds were confirmed by different spectroscopic analyses. The compounds in this study were designed with the intention of being moderately selective COX-2 inhibitors to avoid the negative effects of both highly selective COX-2 and non-selective COX inhibitors. The results of the in vitro screening showed that compounds 4c and 7a are the most potent compounds on COX-2 isoenzyme with moderate selectivity indices lower than that of celecoxib but higher than meloxicam. The two compounds also demonstrated powerful 5-LOX inhibitory activity with IC50 values less than 1 µM which is comparable to that of the reference drug zileuton. In addition all of the compounds under investigation could inhibit the nitric oxide production in LPS-induced RAW 264.7 macrophages. Furthermore, compounds 4c and 7a caused a reduction of the inflammatory mediators PGE-2, IL-6 and TNF-α supporting their anti-inflammatory effect in macrophages. Finally, molecular docking studies as well molecular dynamic simulations were carried out to investigate the binding pattern of the most potent compounds into the active site of both COX-2 and 5-LOX. Consequently, the achieved findings of this study suggest that those novel phthalimide derivatives could be promising leads for further optimization and the development of new anti-inflammatory drugs. New phthalimide derivatives were synthesized as anti-inflammatory agents. Compound 4c inhibited both COX-2 and LOX enzymes and production of NO. Also, it decreased the levels of PGE-2, IL-6 and TNF-α.