Complexation of new thiosemicarbazone based anti-viral agents for the evaluation of the biological activity

GLISONI R.J.; CHIAPPETTA D.A.; MOGLIONI A.; SOSNIK A.

Rosario

Taller; 1er Taller de Órganos Artificiales, Biomateriales e Ingeniería de Tejidos (BIOOMAT 2009); 2009

Centro Binacional (Argentina – Italia) de Criobiología Clínica y Aplicada (CAIC), Facultad de Ciencias Bioquímicas y Farmacéuticas de la Universidad Nacional de Rosario y Sociedad Latinoamericana de Biomateriales, Ingeniería de Tejidos y Órganos Artificia

Thiosemicarbazones (TSCs) have been evaluated since 1946, when their antibacterial activity against Mycobacterium tuberculosis was reported for the first time. Since then, this and other biological properties of TSC derivatives such as antibacterial, antitumoral, antiprotozoal, and antiviral have been described. Some TSCs like ambazone, metisazone and triapine have been approved by FDA to treatment of different diseases such as viral infections and leukemias. Our investigation group has reported the inhibitory activity of TSCs synthesized from aromatic ketones and terpenones against Junin virus (JUNV), the causative agent of Argentine hemorrhagic fever (AHF). In this context, the evaluation of the antiviral activity of a series of 1-indanone TSCs with different patterns of substitution in the aromatic ring has been conducted. Also, novel TSCs were synthesized and evaluated against bovine viral diarrhoea virus (BVDV), a surrogate model for evaluation of anti-Hepatitis C virus (HCV) activity in vitro, of difficult culture and replication in vitro. However, the poor solubility in aqueous media displayed by these drugs that decreases over time, dramatically constrained biological tests in vitro. These studies were carried out by solubilizing TSCs in dimethyl sulfoxide (DMSO). Therefore, the maximal TSCs concentration attainable in the culture media was determined by the cytotoxicity of DMSO. 1-indanone thiosemicarbazone derivatives are poorly water-soluble and show an amphiphilic character that would result in their gradual aggregation in water. Based on this, the study of the behaviour of these molecules in water and the design of an appropriate vehicle to improve the solubility and to prevent aggregation appears as an essential stage prior to the exhaustive analysis of the antibacterial activity in culture. In this framework, we are investigating the possible self-aggregation of TSCs in water and the formation of nano-aggregates that would remind the structure of micelles and serve as nuclei for the crystallization and precipitation drug candidate crystals. Cyclodextrins are cyclic