5-(4 H)-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 μΜ. 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.

Keywords: anti-inflammatory activities; antioxidant activities; benzamides; docking studies; lipid peroxidation; lipoxygenase inhibition; oxazolones.

Figure 1

Representative biologically active oxazole-derivatives.

Figure 2

Structure of benzamides A and 4-substituted-2-phenyloxazol-5(4H)-ones B.

Scheme 1

Synthetic route for target compounds 2a–2f, 3a, 3c, 3d, 4a–e, 5b and 6b. Reagents and conditions: (i) (1) 10% NaOH, 80 °C, 30 min; (2) HCl, H₂O (ii) Method A: ArCHO, Ac₂O, AcONa, reflux; Method B: ArCHO, Ac₂O, AcONa, MW, 100 °C, 15 min; Method C: ArCHO, Ac₂O, 5 mol.% I₂, MW, 90 °C, 20 min; (iii) Method D: morpholine, toluene, reflux; Method E: morpholine, AcOEt, MW, 80 °C, 15 min; (iv) Method F: piperazine, toluene, reflux; Method G: piperazine, toluene, TEA, MW, 110 °C, 10–20 min; Method H: piperazine, EtOH, rt; Method I: piperazine, MEG, MW, 120 °C, 5 min; (v) piperidine, toluene, MW, 100 °C, 15 min; (vi) EtOH, 75 °C, 30 min.

Figure 3

% Anti-nociception measured every 5 min for 4a, 4c and aspirin.

Figure 4

Suggested modifications—Compound 7.

Figure 5

Preferred docking pose of 4c (depicted in grey) bound to soybean lipoxygenase (LOX-1).