Insights on self-aggregation phenomena of 1-indanone thiosemicarbazones and the formation of inclusion complexes with hydroxypropyl-β-cyclodextrin by Molecular Dynamics simulations

• Published in: Journal of molecular liquids 2016-10, Vol.222, p.963-971
• Main Authors: Martini, M. Florencia, Glisoni, Romina J., Sosnik, Alejandro, Moglioni, Albertina, Pickholz, Mónica
• Format: Article
• Language: English
• Subjects: Complex formation; Cyclodextrins; Molecular Dynamics; Thiosemicarbazones of 1-indanone
• ISSN: 0167-7322; 1873-3166
• DOI: 10.1016/j.molliq.2016.07.109

1-Indanone thiosemicarbazones (TSCs) display a broad spectrum of pharmacological activities. However, their extremely poor solubility and self-aggregation tendency in water hurdles the reliable evaluation of the activity in vitro. To overcome these drawbacks, the formation of complexes with different natural and chemically modified cyclodextrins (CDs) has been investigated. Aiming to gain further insight into the molecular mechanisms involved in the interaction of these new chemical entities with CDs, this work investigated for the first time the interaction of two types of 1-indanone TSCs with hydroxyl-propyl-β-CD (HPβ-CD) by Molecular Dynamics (MD) simulations. Results were in good agreement with the experimental work and revealed the fundamental contribution of the substituents in the 1-indanone aromatic ring not only to the intrinsic aqueous solubility but also more importantly to the self-aggregation and the ability of the TSC to form stable complexes with the CD. In the particular case of the 5,6-dimethoxy-1-indanone derivative, the increase of the solubility in presence of HPβ-CD stems from a considerable decrease of the TSC-TSC intermolecular interactions and the formation of inclusion complexes that are stable for a short time. Then, the high self-aggregation tendency of this TSC destabilizes the complex and leads to the initial TSC insolubilization and subsequent precipitation. •Complexation of 1-indanone thiosemicarbazone derivatives with hydroxyl-propyl-β-CD•Cooperative effects investigated by Molecular Dynamics simulations.•Fundamental contribution of the substituents in the 1-indanone aromatic ring•Simulation results were in good agreement with the experimental work.