摘要：Leishmaniasis is a neglected vector-born disease caused by a protozoan of the genus Leishmania and affecting more than 1.300.000 people worldwide. The couple tryparedoxin/tryparedoxin peroxidase is essential for parasite survival in the host since it neutralizes the hydrogen peroxide produced by macrophages during the infection. Herein we report a study aimed at discovering the first class of compounds able to non-covalently inhibit tryparedoxin peroxidase. We have solved the high-resolution structure of Tryparedoxin peroxidase I from Leishmania major (Lm TXNPx) in the reduced state and in fully folded conformation. A first series of compounds able to inhibit Lm TXNPx was identified by means of the high throughput docking technique. The inhibitory activity of these compounds was validated by a Horseradish peroxidase-based enzymatic assay and their affinity for Lm TXNPx calculated by surface plasmon resonance experiments. On the basis of these results, the analysis of the enzyme-inhibitor docked models allowed us to rationally design and synthesize a series of N , N -disubstituted 3-aminomethyl quinolones. These compounds showed an inhibitory potency against Lm TXNPx in the micromolar range. Among them, compound 12 represents the first non-covalent Lm TXNPx inhibitor reported to date and could pave the way to the discovery of a new class of drugs against leishmaniasis.
