Hybrid Design as a Strategy for Development of Trypanocidal Drugs

Author(s)

Freitas, Marcelo da Silva ^[1] ; Torrecilhas, Ana Claudia ^[1] ; Xander, Patricia ^[1] ; Vasconcelos, Camilla Ioshida ^[1] ; Menegon, Renato Farina ^[1]

Affiliation

^[1] Univ Fed Sao Paulo UNIFESP, Dept Ciencias Farmaceut, Diadema, SP - Brazil

• Document type: Journal article
• Source: JOURNAL OF PHARMACEUTICAL RESEARCH INTERNATIONAL; v. 25, n. 2 2018.
• Web of Science Citations: 0

Abstract

Aims: We performed an initial in vitro study with a single molecule to evaluate the possibility to develop a larger series of hybrid compounds active in Chaga's disease. Hybridization is an important approach to confer to a single molecule the biological activity of two distinct molecules. We proposed thiosemicarbazone (TS9) hybridization with beta-citronellol through carbamate linkage. Methodology: The cytotoxicity of the hybrid compound was evaluated against human THP-1 cells and all forms of Trypanosoma cruzi (T. cruzi). IC50 value was determined against amastigotes and the selectivity index (SI) was estimated based on toxicity against THP-1 cells. Lipinski analysis was performed in order to estimate the hybrid drug-like properties. Results: The hybrid presented substantially less cytotoxicity against THP-1 cells than TS9 and biological similarities to both matrix moieties. The hybrid SI (3.9) was better than for TS9 (0.6) and similar to that found for benznidazole (BZN) (4.7), but with a higher drug-like score performed by Lipinski analysis. Conclusion: In face of its relevant trypanocidal action against T. cruzi amastigotes, it's an important concept proof to pursue in developing of hybrid or prodrug derivatives of TS9 and antiprotozoal terpenes. (AU)

• FAPESP's process: 14/25093-4 - Synthesis and non-clinical studies of potentially antiprotozoal reciprocal prodrugs
• Grantee: Renato Farina Menegon
• Support Opportunities: Regular Research Grants