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- Targeting trypanothione synthetase and Trypanothione reductase: development of common inhibitors to tackle Trypanosomatid diseasePublication . Augusto, André; Costa, Inês; Conceição, Jaime; Cristiano, Maria de LurdesNeglected Tropical Diseases (NTDs) encompass a range of disorders, including infectious diseases caused by viruses, bacteria, parasites, fungi, and toxins, mainly affecting underprivileged individuals in developing countries. Among the NTDs, those caused by parasites belonging to the Trypanosomatidae family are particularly impacting and require attention, since the lack of financial incentives has led to constraints on the development of novel drugs to tackle them effectively. To circumvent the minor advances in drug discovery in this area, academic research emerges as a crucial player, namely through the identification and validation of new drug targets, thereby contributing to the development of more efficient, safe, and less expensive therapies against Trypanosomatidae infections. Noteworthy, this is a matter of utmost urgency since these diseases are endemic in countries with low socioeconomic standards. This review provides a comprehensive understanding of the current paradigm of NTDs caused by parasites belonging to the Trypanosomatidae family, addressing the ongoing limitations and challenges associated to the current chemotherapy solutions for these diseases and discussing the opportunities unravelled by recent research that led to the identification of new biomolecular targets that are common to Trypanosomatidae parasites. Among these, the unique properties of Trypanothione Synthetase (TryS) and Trypanothione Reductase (TryR), two key protozoan enzymes that are essential for the survival of Trypanosoma and Leishmania parasites, will be emphasised. In addition to a critical analysis of the latest advances in the discovery of novel molecules capable of inhibiting TryS and TryR, the possibility of dual targeting through a combination of TryS and TryR inhibitors will be addressed.
- Synthesis and structure of novel pyrimidine‐thioethers: structural effects on reactivity along with an unpredicted dimethylamination reactionPublication . Costa, Inês; Frija, Luís M. T.; Augusto, André; Paixão, José A.; Cristiano, Maria de LurdesBuchwald–Hartwig reactions have been in the spotlight over the past years due to their usefulness in creating a wide range of chemical skeletons applied in drug discovery. Aminopyrimidines are heterocyclic structures with significant biological relevance and compounds bearing the amino- and diaminopyrimidine motifs have been associated with antiviral, antibacterial, antiparasitic, antifungal, anticancer, and anti-inflammatory properties. Given the notable status of aminopyrimidines in the design of target-specific drug candidates, the synthesis and structure of four aminopyrimidine-arylsulfide conjugates (3, 4, 5, and 6) are reported that are designed to inhibit trypanothione reductase, a key enzyme in the redox pathway of trypanosomatids. When applying the Buchwald–Hartwig synthetic approach, the formation of different products is witnessed by altering the reaction conditions, observing that regioselectivity is conditioned by reaction time and by Boc-protection of the starting 2,6-dichloropyrimidin-4-amine. The electron-withdrawing character of the protecting group appears to increase the susceptibility of the pyrimidine at C2 for further reaction with the solvent, DMF, yielding the corresponding diaminopyrimidine-based conjugates. The crystal structures of the novel aminopyrimidine-arylsulfide conjugate and their Boc-protected 2,6-dichloropyrimidin-4-amine precursors are disclosed and discussed.