Anti-inflammatory and antinociceptive effects of LQFM275 − A new multi-target drug

Abstract

Compound (4-(3,5-di-tert-butyl-4-hydroxybenzylamine)benzenesulfonamide) (LQFM275) was designed and synthesized from darbufelone and sulfanilamide as a new multi-target for the treatment of inflammatory diseases. LQFM275 showed a great range of safe cytotoxicity profile (100–400 μM) evaluated by MTT assay, preventing damage induced by lipopolysaccharide (LPS) in EA.hy926 cell line. In mice, the acute oral treatment with LQFM275 (57, 114, and 228 mg/kg) reduced the number of writhing by 26, 37, and 49 %, respectively. LQFM275 (114 mg/kg) also presented an antinociceptive effect, reducing by 57 % the nociceptive response in the second phase of the formalin test and by 47 % the Carrageenan(Carra)-induced hyperalgesia. That effect was dependent on its anti-inflammatory activity. LQFM275 (114 mg/kg) also reduced 42 % and 31 % of the Carra and LPS-induced edema, respectively. The pleurisy test attenuated the leukocyte migration induced by Carra and LPS by reducing the number of polymorphonuclear cells (by 39 and 36 %, respectively). The production of reactive oxygen species in the pleural exudate was reduced, which is shown by a decrease in myeloperoxidase (MPO) activity (Carra = 35 % and LPS = 40 %) and in levels of pro-inflammatory cytokines TNF-α and IL-1β (Carra = 48 % and LPS = 47 e 36 %). On the other hand, it increased the levels of anti-inflammatory cytokines, IL-4, and IL-10 (Carra = 50 % and LPS = 21 and 53 %). Moreover, LQFM275 demonstrated to be a dual COX-2 and 5-LOX inhibitor (IC50 = 81 and 167 μM, respectively). Therefore, the promising anti-inflammatory and antinociceptive effects of LQFM275 provide an opportunity for a new multi-target drug development.