RESUMEN
Some novel indolizine derivatives were synthesized by bioisosteric modification of imidazo[1,2-a]pyridine for anti-inflammatory activity. The physicochemical characterization and structure of compounds were elucidated by state of the art spectroscopic technique. Induced fit docking was performed for initial screening to elucidate the interactions with corresponding amino acids of cyclooxygenase (COX-1, COX-2) and lipoxygenase (LOX) enzymes. The target compounds 53-60 were then evaluated against in vivo carrageenan and arachidonic acid induced rat paw edema models for anti-inflammatory activity. Amongst all the synthesized derivatives, compound 56 showed the significant anti-inflammatory activity in both rat paw edema models with very less ulcerogenic liability in comparison to standard diclofenac, celecoxib, and zileuton. The compounds 56 was further assessed to observe in vitro enzyme inhibition assay on both cyclooxygenase and lipoxygenase enzyme where it showed a preferential and selective non-competitive enzyme inhibition towards the COX-2 (IC50=14.91µM, Ki=0.72µM) over COX-1 (IC50>50µM) and a significant non-competitive inhibition of soybean lipoxygenase enzyme (IC50=13.09µM, Ki=0.92µM). Thus, in silico, in vivo, and in vitro findings suggested that the synthesized indolizine compound 56 has a dual COX-2 and LOX inhibition characteristic and parallel in vivo anti-inflammatory activity in comparison to the standard drugs.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Indolizinas/farmacología , Inhibidores de la Lipooxigenasa/farmacología , Lipooxigenasa/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Ácido Araquidónico , Carragenina , Inhibidores de la Ciclooxigenasa/síntesis química , Inhibidores de la Ciclooxigenasa/química , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Edema/inducido químicamente , Edema/tratamiento farmacológico , Femenino , Indolizinas/síntesis química , Indolizinas/química , Inhibidores de la Lipooxigenasa/síntesis química , Inhibidores de la Lipooxigenasa/química , Masculino , Ratones , Estructura Molecular , Ratas , Relación Estructura-Actividad , Úlcera/inducido químicamente , Úlcera/tratamiento farmacológicoRESUMEN
Bioisosteres are integral components of modern pharmaceutical research that allow structural optimization to maximize in vivo efficacy and minimize adverse effects by selectively modifying pharmacodynamic, pharmacokinetic and physicochemical properties. A recent medicinal chemistry campaign focused on identifying small molecule inhibitors of prolylcarboxypeptidase (PrCP) initiated an investigation into the use of pyrazoles as bioisosteres for amides. The results indicate that pyrazoles are suitable bioisosteric replacements of amide functional groups. The study is an example of managing bioisosteric replacement by incorporating subsequent structural modifications to maintain potency against the selected target. A heuristic model for an embedded pharmacophore is also described.