Novel N-phenylcarbamothioylbenzamides with anti-inflammatory activity and prostaglandin E₂ inhibitory properties

A number of 2-((4-ethylphenoxy)methyl)-N-(substituted-phenylcarbamothioyl)benzamides (1a-h) were synthesized via reaction of 2-((4-ethylphenoxy)methyl)benzoyl isothiocyanate (2) as a key intermediate with several substituted primary aromatic amines. The new compounds were characterized by proton nuclear magnetic resonance (¹H-NMR), carbon-13 nuclear magnetic resonance (¹³C-NMR), infrared spectrometry (IR), mass spectrometry (MS), and elemental analysis. The anti-inflammatory activity of 1a-h was investigated by acute carrageenan-induced paw edema in mice using the reference drug indomethacin. The results obtained indicated that, of the derivatives developed, 1a and 1d-h exhibited significantly higher anti-inflammatory activity (26.81%-61.45%) when compared with the reference drug indomethacin (22.43%) (P = 0.0490 for 1a, 0.0015 for 1d, 0.0330 for 1f, and P < 0.001 for 1e and 1h). Moreover, the ulcer incidence of 20% for 1e and 1h was clearly lower when compared with the indomethacin group (in which the ulcer incidence was 80%). Of particular note, the ulcer index of 0.2 for 1e was significantly less than that in the indomethacin group (0.6, P = 0.014). Additionally, prostaglandin E₂ (PGE₂) inhibitory properties were found to be high with 1e (68.32 pg/mL), significantly different from those of the placebo group (530.13 pg/mL, P < 0.001), and equipotent to the effect observed in the indomethacin-pretreated group (96.13 pg/mL, P > 0.05). Moreover, the PGE₂ level of 54.15 pg/mL with 1h was also significantly different from that of the placebo group (P > 0.001) and of the indomethacin group (P > 0.05). The significant inhibition of PGE₂ observed with 1e (68.32 pg/mL) and 1h (54.15 pg/mL) agree with their observed ulcer incidences. Our overall findings for N-phenylcarbamothioylbenzamides 1a-h clearly suggest that the compounds exhibit an anti-inflammatory effect, potently inhibit PGE₂ synthesis, and markedly demonstrate low ulcer incidence.