RESUMEN
We describe herein the discovery of LASSBio-881 (3c) as a novel in vivo antinociceptive, anti-inflammatory, and in vitro antiproliferative and antioxidant compound, with a cannabinoid ligand profile. We observed that LASSBio-881 (3c) was able to bind to CB1 receptors (71% at 100microM) and also to inhibit T-cell proliferation (66% at 10microM) probably by binding to CB2 receptors, in a non-proapoptotic manner, different from anandamide (1). It was also demonstrated that LASSBio-881 (3c) had an important antioxidant profile toward free radicals (DPPH and hydroxyl), probably due to its particular redox behavior, which reflects the presence of both nitro and 3,5-di-tert-butyl-4-hydroxyphenyl sub-units, as demonstrated by cyclic voltammetry studies. In addition, we showed that these structural sub-units are essential for the observed pharmacological activity.
Asunto(s)
Analgésicos/farmacología , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Depuradores de Radicales Libres/farmacología , Hidrazinas/síntesis química , Hidrazinas/farmacología , Hidrazonas/síntesis química , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismo , Analgésicos/síntesis química , Analgésicos/química , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Antioxidantes/síntesis química , Antioxidantes/química , Ácido Araquidónico/toxicidad , Ácidos Araquidónicos/farmacología , Compuestos de Bifenilo/metabolismo , Encéfalo/efectos de los fármacos , Moduladores de Receptores de Cannabinoides/farmacología , Carragenina/toxicidad , Proliferación Celular/efectos de los fármacos , Edema/inducido químicamente , Edema/prevención & control , Endocannabinoides , Femenino , Formaldehído/toxicidad , Depuradores de Radicales Libres/síntesis química , Depuradores de Radicales Libres/química , Hidrazinas/química , Hidrazinas/metabolismo , Hidrazonas/química , Hidrazonas/farmacología , Ligandos , Masculino , Ratones , Modelos Moleculares , Dolor/tratamiento farmacológico , Picratos , Alcamidas Poliinsaturadas/farmacología , Piridinas/toxicidad , Ratas , Ratas Wistar , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB2/agonistas , Relación Estructura-Actividad , Superóxidos/metabolismo , Linfocitos T/efectos de los fármacosRESUMEN
In this work, we reported the synthesis and evaluation of the analgesic, anti-inflammatory, and antipyretic properties of new 2-(6-nitro-benzo[1,3]dioxol-5-yloxy)-acetylhydrazone derivatives (3), designed exploring molecular hybridization and isosteric replacement approaches between nimesulide (1) and carbanalogue NAH series (2) developed at LASSBio. Target compounds were synthesized in very good yields exploiting abundant Brazilian natural product safrole (4) as starting material. The evaluation of the antinociceptive properties of this series led us to discover a new potent prototype of analgesic and antipyretic agent, that is, NAH derivative 3c, named LASSBio-891, which showed to be more potent than dipyrone used as standard.
