RESUMEN
The present study includes design and synthesis of new molecular hybrids of 2-methylthiobenzimidazole linked to various anti-inflammatory pharmacophores through 2-aminothiazole linker, to investigate the effect of such molecular variation on cyclooxygenase (COX) and 15-lipoxygenase (15-LOX) enzymes inhibition as well as in vivo anti-inflammatory activity. The chemical structures of new hybrids were confirmed using different spectroscopic tools and elemental analyses. Benzimidazole-thiazole hybrids linked to acetyl moiety 13, phenyl thiosemicarbazone 14, 1,3-thiazolines 15a-c and 4-thiazolidinone 16 exhibited significant COX-2 inhibition (IC50 = 0.045-0.075 µM) with significant COX-2 selectivity indices (SI = 142-294). All hybrids revealed potent 15-LOX inhibitory activity (IC50 = 1.67-6.56 µM). Benzimidazole-thiazole hybrid 15b was the most potent dual COX-2 (IC50 = 0.045 µM, SI = 294) inhibitor approximate to celecoxib (COX-2; IC50 = 0.045 µM, SI = 327), with double inhibitory activity versus 15-LOX enzyme (IC50 = 1.67 µM) relative to quercetin (IC50 = 3.34 µM). Three hybrids (14, 15b &16) were selected for in vivo screening using carrageenan-induced paw edema method. Benzimidazole-thiazole hybrid linked to 4-thiazolidinone 16 showed the maximum edema inhibition at both 3 h and 4 h intervals as well (~119% and 102% relative to indomethacin, respectively). The gastric ulcerogenic effect of benzimidazole-thiazole hybrid 16 was estimated compared with indomethacin showing superior gastrointestinal safety profile. In bases of molecular modeling; all new active hybrids were subjected to docking simulation into active sites of COX-2 and 15-LOX enzymes to study the binding mode of these novel potent dual COX-2/15-LOX inhibitors.
Asunto(s)
Araquidonato 15-Lipooxigenasa/metabolismo , Bencimidazoles/química , Inhibidores de la Ciclooxigenasa 2/farmacología , Ciclooxigenasa 2/metabolismo , Tiazoles/química , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Bencimidazoles/farmacología , Carragenina/toxicidad , Inhibidores de la Ciclooxigenasa 2/química , Diseño de Fármacos , Edema/inducido químicamente , Edema/tratamiento farmacológico , Inhibidores de la Lipooxigenasa/química , Inhibidores de la Lipooxigenasa/farmacología , Masculino , Estructura Molecular , Ratas , Relación Estructura-Actividad , Tiazoles/farmacologíaRESUMEN
Genetic and epigenetic factors contribute equally to the pathogenesis of type 1 diabetes mellitus. Sodium butyrate (NaB) has been reported to improve glucose homeostasis by modulation of the p38/ERK MAPK pathway. This work aims to evaluate the effect of NaB on the ultrastructure of pancreatic ß-cells and the PI3/AKT pathway. Juvenile albino male rats were used to establish a type 1 diabetes model using streptozotocin injection and NaB in a pre- and post-treatment schedule. Plasma glucose, insulin levels, and glucose tolerance were evaluated. Light and electron microscopy and immunohistochemistry were performed using Ki-67, caspase-3, and insulin. NaB treatment resulted in a significant improvement in plasma glucose levels, plasma insulin levels/expression, and ameliorated diabetes-induced histological alternations. Additionally, it increased the expression of phosphorylated AKT. These findings provide evidence that NaB may be useful in the treatment of juvenile diabetes.