Antiparasitic, structural, pharmacokinetic, and toxicological properties of riparin derivatives

作者：Mafud Ana C; Silva Marcos P N; Nunes Geandra B L; de Oliveira Milene A R; Batista Larissa F; Rubio Thiago I; Mengarda Ana C; Lago Eloi M; Xavier Rogerio P; Gutierrez Stanley J C; Pinto Pedro L S; da Silva Filho Ademar A; Mascarenhas Yvonne P; de Moraes Josue^*

来源：Toxicology in Vitro, 2018, 50: 1-10.

DOI：10.1016/j.tiv.2018.02.012

• Riparin derivatives
• Structural analysis
• Theoretical calculations
• ADMET
• Antischistosomal compounds

Schistosomiasis, caused by helminth flatworms of the genus Schistosoma, is one of the most important parasitic diseases in the world, affecting over 200 million people in developing countries. Riparins are natural alkamides found in Aniba riparia (Lauraceae) fruits that possess several pharmacological properties. In this study, we reported the synthesis, characterization and structural analysis of six riparin derivatives (A-F), as well as their schistosomicidal activity against S. mansoni worms together with a biological, pharmacokinetic and toxicological in silico evaluation. Firstly, these compounds were synthesized, purified and characterized by elemental analysis, FT-IR spectroscopy, X-ray diffraction and theoretical calculations to evaluate their stability and conformation. Next, the schistosomicidal activity of the riparins was tested against S. mansoni worms. Bioassays revealed that Riparins E and F were the most active compounds, showing half-maximum inhibitory concentration at low micromolar ranges (IC50 values similar to 10 mu M). Also, confocal laser scanning microscopy studies revealed tegumental damage in parasites after exposition with Riparins B, E and F. Additionally, based on MTT assay, all tested riparins showed no cytotoxic potential toward mammalian cells. Finally, in silico analyses were used to predict the absorption, distribution, metabolism, elimination and toxicity (ADMET) of the compounds. Taken together, the results revealed a promising ADMET profile and suggested that riparins could be starting points for lead optimization programs for natural products with antischistosomal properties.

• 出版日期2018-8