RESUMEN
Inflammation is a hallmark of many metabolic diseases. We previously showed that ferrocene-appended 1H-1,2,3-triazole hybrids inhibit nitric oxide (NO) production in in vitro models of lipopolysaccharide-induced inflammation in the BV-2 cell. In the present study, we explored the viability, anti-inflammatory, and antioxidant potential of ferrocene-1H-1,2,3-triazole hybrids using biochemical assays in rat mesangial cells (RMCs). We found that, among all the ferrocene-1H-1,2,3-triazole hybrids, X2-X4 exhibited an antioxidant effect on mitochondrial free radicals. Among all the studied compounds, X4 demonstrated the best anti-inflammatory effect on RMCs. These results were supplemented by in silico studies including molecular docking with human cytosolic phospholipase A2 (cPLA2) and cyclooxygenase 2 (COX-2) enzymes as well as absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling. Besides, two new crystal structures of the compounds have also been reported. In addition, combining the results from the inducible nitric oxide synthase (iNOS), cPLA2, COX-2, and matrix metalloproteinase-9 (MMP-9) enzymatic activity analysis and NO production also confirmed this argument. Overall, the results of this study will be a valuable addition to the growing body of work on biological activities of triazole-based compounds.
Asunto(s)
Antiinflamatorios/farmacología , Antioxidantes/farmacología , Enfermedades Renales/tratamiento farmacológico , Células Mesangiales/efectos de los fármacos , Triazoles/farmacología , Animales , Antioxidantes/metabolismo , Supervivencia Celular/efectos de los fármacos , Celobiosa/análogos & derivados , Cristalografía por Rayos X , Ciclooxigenasa 2/metabolismo , Radicales Libres , Fosfolipasas A2 Grupo IV/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Lipopolisacáridos/farmacología , Metaloproteinasa 9 de la Matriz/metabolismo , Células Mesangiales/metabolismo , Mitocondrias/metabolismo , Simulación del Acoplamiento Molecular , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , RatasRESUMEN
Keeping in view the interesting chemistry and pharmacological importance of harmine series of bases -- the beta-carboline alkaloids, a number of new derivatives of tetrahydroharmine and harmalol have been prepared and characterized through spectral studies. Some of these derivatives showed spasmolytic activity. It was observed that all the N-acyl tetrahydroharmine derivatives are stable, not labile and no ring opening occurs in these compounds, as reported recently.