New 2-(4-(4-bromophenylsulfonyl)phenyl)-4-arylidene-oxazol-5(4H)-ones: analgesic activity and histopathological assessment

Abstract

This paper reports the synthesis, analgesic activity, acute toxicity and histopathological (HP) assessment of four new compounds from oxazol-5(4H)-ones class that contain in their molecule a diarylsulfone moiety. The new 2-(4-(4-bromophenylsulfonyl)phenyl)-4-arylidene-oxazol-5(4H)-ones were obtained by reaction of 2-(4-(4-bromophenyl-sulfonyl)benzamido)acetic acid intermediate with aromatic aldehydes (benzaldehyde, 4-methoxy, 4-nitro or 4-bromobenzaldehyde), in acetic anhydride and in the presence of anhydrous sodium acetate. The new compounds have been characterized by spectral techniques, such as: Fourier-transform infrared spectroscopy (FT-IR), mass spectrometry (MS), proton nuclear magnetic resonance (1H-NMR) and by elemental analysis. The acute toxicity of the new oxazol-5(4H)-ones in mice was assessed through "acute toxic class" method, according to Organization for Economic Co-operation and Development (OECD) Guidelines. The HP assessment of some preserved organs collected from mice has been performed. The analgesic activity of all new synthesized compounds was carried out with two pharmacological tests: the writhing test and the hot plate test. In order to predict the binding affinities of the synthesized oxazol-5(4H)-ones derivatives against molecular targets involved in pain and inflammation, molecular docking simulations were performed. The results of the writhing test indicated that the most active compound was the oxazolone that contains in the molecule a methoxy group. The acute oral toxicity study revealed no lethal effect of new compounds. The HP assessment of the preserved organs collected from mice did not indicate any cytohistopathological aspects that can be linked to any inflammatory, neoplastic or cytotoxic process, demonstrating the low toxicity of new compounds.

Figure 1

Benzylidene-oxazolones (I), (II) and (III) with analgesic/anti-inflammatory activity

Figure 2

The new 2-(4-(4-bromophenylsulfonyl)phenyl)-4-arylidene-oxazol-5(4H)-ones 2a–d synthesis

Figure 3

Average change in body weight (b.w.) of animals treated by gavage, with the tested substances: (A) Stage I, 300 mg/kg b.w.; (B) Stage II, 2000 mg/kg b.w.

Figure 4

Cerebellum. Normal appearance of the topohistological elements which form the cerebellar hemispheres. Mouse treated with compound 2a. HE staining, ×40

Figure 5

Heart. Normal aspects of cardiomyocytes in the left ventricle. Mouse treated with compound 2b. HE staining, ×200.

Figure 6

Kidneys. Normal aspects of the proximal renal tubules; hyperemia in the mesangial and interstitial capillaries. Similar aspects with control group and compound 2a. Mouse treated with compound 2b. HE staining, ×200

Figure 7

Lungs. Histological modifications similar to the control group and compounds 2a, 2b and 2c; hyperemia and microhemorrhages in the interstitial areas and in the interalveolar spaces. Mouse treated with compound 2d. HE staining, ×100

Figure 8

Spleen. Lymphoid tissue well represented in the lymphocyte sheaths and in the paracortical areas. No toxic changes. Mouse treated with compound 2c. HE staining, ×200

Figure 9

Liver. Capillaries and venules with peri-vascular lymphoid infiltrations; hepatocyte vacuolar degeneration of higher intensity compared to control group and compounds 2a, 2b and 2c. Mouse treated with compound 2d. HE staining, ×100

Figure 10

Three-dimensional docked conformation of the protein–ligand complex (A) and two-dimensional depiction of molecular interactions between compound 2b and TRPA1 crystal structure (B). TRPA1: Transient receptor potential cation channel, subfamily A, member 1

Figure 11

Three-dimensional docked conformation of the protein-ligand complex (A) and two-dimensional depiction of molecular interactions between compound 2b and TRPV1 crystal structure (B). TRPV1: Transient receptor potential cation channel subfamily V member 1