Novel 1-indanone thiosemicarbazones and their inclusion complexes with hydroxypropyl-â-cyclodextrin are effective antivirals against the hepatitis C virus (HCV)

GLISONI R; CUESTAS M; MATHET V; OUBIñA J; MOGLIONI A; ALEJANDRO SOSNIK

Congreso; VII Congresso Latino Americano de Órgãos Artificiais e Biomateriais, VII COLAOB.; 2012

Abstract The hepatitis C virus (HCV) is a major cause of acute and chronic hepatitis in humans. Approximately 5% of the infected people die from cirrhosis or hepatocellular carcinoma. The current gold-standard therapy comprises a combination of pegylated-interferon and ribavirin. Due to the relatively low effectiveness, the prohibitive costs and the extensive side effects of the treatment, an intense research for new anti-HCV agents is taking place. Thiosemicarbazones (TSCs) have shown antiviral activity against a wide range of DNA and RNA viruses. However, their extremely low aqueous solubility and high self-aggregation tendency often preclude their reliable biological evaluation in vitro1. In this work, we investigated and compared for the first time the anti- HCV activity of two novel 1-indanone TSCs, 5,6-dimethoxy-1-indanone TSC and 5,6-dimethoxy-1-indanone N4-allyl TSC, and their inclusion complexes with hydroxypropyl-â-CD (HP-b-CD)2 in Huh7.5 cells containing the full-length and the subgenomic subgenotype 1b HCV replicon system. Studies of physical stability in culture medium showed that free TSCs precipitated rapidly and formed submicron aggregates. Conversely, TSC complexation with HP-b-CD led to were more stable systems with minimal size growth and concentration loss due to drug precipitation2. More importantly, both TSCs and their inclusion complexes displayed a potent suppression of the HCV replication in both cell lines with no cytotoxic effects. The mechanism would involve the inhibition of non-structural proteins of the virus. In addition, findings suggested that the cyclodextrin released the drug to the culture medium over time. This platform could be exploited for the development of TSC formulations and delivery systems with improved features towards the evaluation of the drug pharmacokinetics in animal models.     References 1 Glisoni, R.J., Chiappetta, D.A., Finkielsztein, L.M., Moglioni, A.G., Sosnik, A., 2010. Self-aggregation behaviour of novel thiosemicarbazone drug candidates with potential antiviral activity. New J. Chem. 34, 2047-2058. 2 Glisoni, R.J., Chiappetta, D.A., Moglioni, A.G., Sosnik, A., 2012. Novel 1- Indanone thiosemicarbazone antiviral candidates: Aqueous solubilization and physical stabilization by means of cyclodextrins. Pharm. Res. 29, 739-755.