5-(4H)-Oxazolones and Their Benzamides as Potential Bioactive Small Molecules

The five membered heterocyclic oxazole group plays an important role in drug discovery. Oxazolones present a wide range of biological activities. In this article the synthesis of 4-substituted-2-phenyloxazol-5(4H)-ones from the appropriate substituted aldehydes via an Erlenmeyer-Plochl reaction is reported. Subsequently, the corresponding benzamides were produced via a nucleophilic attack of a secondary amine on the oxazolone ring applying microwave irradiation. The compounds are obtained in good yields up to 94% and their structures were confirmed using IR,H-1-NMR,C-13-NMR and LC/MS data. The in vitro anti-lipid peroxidation activity and inhibitory activity against lipoxygenase and trypsin induced proteolysis of the novel derivatives were studied. Inhibition of carrageenin-induced paw edema (CPE) and nociception was also determined for compounds4aand4c. Oxazolones2aand2cstrongly inhibit lipid peroxidation, followed by oxazolones2band2dwith an average inhibition of 86.5%. The most potent lipoxygenase inhibitor was the bisbenzamide derivative4c, with IC(50)41 mu M. The benzamides3c,4a-4eand5cwere strong inhibitors of proteolysis. The replacement of the thienyl moiety by a phenyl group does not favor the protection. Compound4cinhibited nociception higher than4a. The replacement of thienyl groups by phenyl ring led to reduced biological activity. Docking studies of the most potent LOX inhibitor highlight interactions through allosteric mechanism. All the potent derivatives present good oral bioavailability.