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

Abstract

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, 1H-NMR, 13C-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 compounds 4a and 4c. Oxazolones 2a and 2c strongly inhibit lipid peroxidation, followed by oxazolones 2b and 2d with an average inhibition of 86.5%. The most potent lipoxygenase inhibitor was the bisbenzamide derivative 4c, with IC50 41 μM. The benzamides 3c, 4a–4e and 5c were strong inhibitors of proteolysis. The replacement of the thienyl moiety by a phenyl group does not favor the protection. Compound 4c inhibited nociception higher than 4a. 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.

Pyrazoles and Pyrazolines as Anti-Inflammatory Agents

“…For the lipid peroxidation study, 2,2′-azobis(2-amidinopropane) hydrochloride (AAPH) was used for the generation of peroxyl radicals. The generation of the conjugated diene hydroperoxide derived from the oxidation of sodium linoleate in an aqueous solution was recorded at 234 nm [ 43 , 44 ]. The compounds presented high anti-lipid peroxidation activity (78–100%) ( Table 4 ).…”

“…The ability of the compounds to prevent the oxidation of linoleic acid sodium salt from alkylperoxyl radicals was recorded at 234 nm. Trolox was used as reference (93%) ( Table 4 ) [ 43 , 44 ].…”

“…The results are recorded immediately after the mixing solutions at 734 nm. The results were compared to the appropriate standard inhibitor Trolox ( Table 4 ) [ 44 ].…”

Pain Control by Targeting Oxidized Phospholipids: Functions, Mechanisms, Perspectives

“…Based on the idea that proalgesic OxPL are preferentially produced locally and non-enzymatically, OxPL neutralization was thought to be a feasible strategy to target the proalgesic function of OxPL, at least in rodent pain models ( 10 , 14 , 15 ). Targeting enzymatic OxPL production with small molecule inhibitors, for instance oxazolone-derived compounds for lipoxygenase inhibition, is antinociceptive ( 50 ). It could well be that co-treatment with OxPL scavengers together with small molecule lipoxygenase blockers can synergistically even enhance the efficiency of pain control.…”

Exploring the 2′-Hydroxy-Chalcone Framework for the Development of Dual Antioxidant and Soybean Lipoxygenase Inhibitory Agents

“…Evaluation of Site Score, indicate Site 1 (site score 1.113) as a putative allosteric site for further docking studies. Interestingly, Site 1 has been previously identified and utilized for docking studies on LOX-1, as presented in recent publications [ 67 , 72 ].…”