Complexes of Cyclodextrin/1-Indanone Thiosemicarbazone Derivatives: A Molecular Dynamics Approach

MARTINI M.F.; GLISONI R.J.; MOGLIONI A.G.; SOSNIK A. ; PICKHOLZ M.

San Javier-Tucumán, Argentina

Congreso; XLI Reunión Anual de la Sociedad Argentina de Biofísica; 2012

Sociedad Argentina de Biofísica

Since the potential therapeutic activity of thiosemicarbazones (TSCs) against Mycobacterium tuberculosis has emerged, many other activities as antineoplastic, antibacterial, antifungal, antiprotozoal and antiviral activity have been reported. In particular, 5,6-dimethoxy-1-indanone TSC was more effective than ribavirin against the virus of the bovine viral diarrhea, the surrogate model of the hepatitis C virus (HCV) [1]. However, TSCs display extremely low aqueous solubility and a relatively high tendency to selfaggregate in water [2]. This behavior hampered the reproducible and reliable evaluation of the biological activity in vitro [1,2]. Cyclodextrins (CDs) are macrocyclic oligosaccharides that combine a hydrophobic nano-sized cavity with a hydrophilic surface. The cavity enables the partial or total incorporation of lipophilic molecules. Thus, CDs are extensively used to increase the water solubility, physicochemcial stability and bioavailability of lipophilic drugs. To circumvent the critical biopharmaceutic drawbacks of TSCs, Glisoni et al [3] thoroughly investigated the development of complexes between hydroxypropylB-CD (HPB-CD) and different TSCs of 1-indanone. Then, the activity against HCV was demonstrated in vitro [4]. In this work, we analyzed the formation of complexes between HPB-CD and two types of TSCs (1-indanone TSC and 5,6-dimethoxy-1-indanone TSC) at an atomic level, using molecular dynamics techniques. The systems studied include collective properties, through the study of 8 CDs and 8 molecules of TSCs. We have also investigated in detail the generation of inclusion complexes by analyzing CD:TSC (1:1) systems at different initial positions. The results showed a single preferential orientation of 5,6-dimethoxy-1-indanone TSC in the inclusion complexes formed, while 1-indanone TSC had two possible orientations, in relation to the portion of the molecule that is located within the cavity of HP-BCD.