Síntese e otimização guiada por estrutura de fragmentos ligantes da enzima tiorredoxina glutationa redutase de Schistosoma mansoni

Abstract

Schistosomiasis is part of a group of diseases known as neglected tropical diseases and affects over 250 million people worldwide, especially children living in tropical and subtropical regions with limited access to basic sanitation. It is caused by trematodes of the Schistosoma genus, with Schistosoma mansoni being the only species involved in Brazil. The current treatment relies exclusively on Praziquantel, a drug in use for over 40 years, which presents limitations, being the most concerning, the potential emergence of drug-resistant parasites. Given this scenario, the search for new molecular targets and bioactive compounds is extremely important. One molecular target that has been studied for years is the Schistosoma mansoni Thioredoxin-Glutathione Reductase (SmTGR), an essential enzyme for the parasite’s survival, as it plays a key role in maintaining redox balance and protecting against oxidative stress. Inhibiting this enzyme impairs the parasite’s ability to survive within the host. In this work, fragment-based drug discovery (FBDD) strategies were employed, using both fragment linking and fragment growing approaches for the rational design of SmTGR inhibitors. A total of 48 compounds were synthesized, including 39 novel molecules and 9 compounds previously described in the literature. The compounds were characterized by spectroscopic techniques, and some were submitted to drug metabolism and pharmacokinetic (DMPK) evaluation assays, including permeability, solubility, and metabolic stability tests. Additionally, all compounds were tested for their ability to inhibit SmTGR in vitro enzymatic assays. However, none of the fragments or optimized compounds had inhibition against the enzyme. The results obtained contribute to a better understanding of this enzyme, support the rational design of new molecules targeting SmTGR, and provide a basis for the development of novel therapeutic strategies.