Multitarget drugs: synthesis and preliminary pharmacological characterization of zileuton analogues endowed with Dual 5-LOinhibitor and NO-dependent activities

A novel class of NO-donor/5-lipooxygenase (5-LO) inhibitory agents was designed by joining Zileuton, a well known 5-LO inhibitor belonging to the family of hydroxyureas, to NO-donor nitrooxy or furoxan moieties. The products displayed a pharmacological profile both of NO-donor drugs and 5-LO inhibitors. Inhibition of LTB4 production, induced in heparinized human whole blood by calcium ionophore A 23187, was observed, and the inhibitory potencies of the compounds were near that of the lead. In addition the products were capable of relaxing rat tracheal rings precontracted with 1 μM carbachol, with a mechanism NO-mediated, myorelaxing potencies lying in the μM range. According to their NOdonor nature, they were also able to relax rat aorta strips precontracted with phenylephrine, with varying potencies in a large concentration range. Finally compounds 18 and 25, namely those with the lead substituted at 6-position with an alkoxy chain bearing a nitrooxy or a 3-carbamoylfuroxan moiety respectively, displayed anti-inflammatory activity when tested on carrageenan-induced paw edema in conscious rats. The family of the products described represents the first class of dual drugs with 5-LO inhibitor/NO-dependent activities.