CONICET | Buscador de Institutos y Recursos Humanos

Introduction. Since Domagk et al described the activity of thiosemicarbazones (TSCs) against experimental tuberculosis, the antineoplastic, antibacterial, antifungal, antiprotozoal and antiviral activity of a great number of TSCs has been extensively investigated. Moglioni et al have designed, synthesized and characterized different TSCs derivatives from 1-indanones. The activity of these novel compounds is being currently investigated in vitro against a broad variety of viruses. However, TSCs are extremely poorly water soluble and precipitate very rapidly during the in vitro assays, leading to erratic, non-reproducible and unreliable antiviral half maximal inhibitory concentration (IC50) data. Thus, the extremely low aqueous solubility remains a key hurdle towards their biological evaluation. In this context, it is important to design an appropriate vehicle to improve the solubility of these new drug candidates as an essential stage prior to the exhaustive analysis of the antiviral activity. The present work investigated for the first time the mechanisms governing the self-aggregation of TSCs [1] and the effect of hydroxy-propyl-β-cyclodextrin (HPβCD) on their solubility and physical stability in water. Goals v To determine experimental and theoretical log P values of TSCs. v To study the aqueous solubility and the thermal properties. v To characterize the aggregation process of TSCs in water. v To investigated the HPβCD effect on TSC solubility and stability in water. Methods. Preparation of TSC-CD complexes: HPβCD and an excess of TSC were dissolved in methanol:aceton. The organic solvent was removed by rotoevaporation (15 min, 70ºC). The solid white powder obtained was re-dissolved in water (according to the final CD desired concentration). The solution was stirred (30 min) and then filtered (0,45 μm nylon membrane filter) to remove insoluble TSC. The filtrate was analyzed by UV-spectroscopy. The size, size distribution and zeta potential of the aggregates was measured by dynamic light scattering (DLS). Results. 1-indanone TSC molecules combine a bulky hydrophobic aromatic ring and a highly hydrophilic thiosemicarbazone group. This structure confers the molecule an amphiphilic character and might account for their aggregation in water [1]. The formation of nano-aggregates in water was suggested by the appearance of a new strong absorption peak at 233-239 nm in the UV spectra and visualized by transmission electron microscopy [1]. Regardless of the relatively low lipophilicity predicted by the theoretical calculations, these compounds displayed extremely low water solubility [1]. DLS confirmed the early formation of nanoscopic particles (120-300 nm) that undergo a gradual size growth to generate larger submicron-structures [1]. The negatively-charged character of the surface was established by zeta potential measurements. Cyclodextrins (CDs) are cyclic oligosaccharides of α-D-glucopyranose containing a relatively hydrophobic nano-cavity and a hydrophilic outer surface. The hydrophobic cavity enables the partial or total incorporation of lipophilic molecules into the cavity. Phase-solubility studies indicated that the solubility of TSCs was dramatically improved by the formation of inclusion complexes with HPβCD. Moreover, HPβCD decreased the self-aggregation of TSCs in solution, and improved the physical stability of the solutions over time. Conclusions. Overall results support that the complexation of TSC with CDs is an efficient strategy to improve the solubility and their stability in water towards a reliable biological evaluation. Acknowledgements: RJG thanks a PhD scholarship of the CONICET. [1] RJ Glisoni, DA Chiappetta, LM Finkielsztein, AG Moglioni, A Sosnik. Self-aggregation behaviour of novel thiosemicarbazone drug candidates with potential antiviral activity. New J Chem. 2010, 34, 20472058

enviar mensaje