Leishmania spp. are responsible for up to 1 million new cases each year. The current therapeutic arsenal against Leishmania is largely inadequate, and there is an urgent need for better drugs. Trypanothione reductase (TR) represents a druggable target since it is essential for the parasite and not shared by the human host. Here, we report the optimization of a novel class of potent and selective LiTR inhibitors realized through a concerted effort involving X-ray crystallography, synthesis, structure-activity relationship (SAR) investigation, molecular modeling, and in vitro phenotypic assays. 5-Nitrothiophene-2-carboxamides 3, 6e, and 8 were among the most potent and selective TR inhibitors identified in this study. 6e and 8 displayed leishmanicidal activity in the low micromolar range coupled to SI > 50. Our studies could pave the way for the use of TR inhibitors not only against leishmaniasis but also against other trypanosomatidae due to the structural similarity of TR enzymes.

Optimization of potent and specific trypanothione reductase inhibitors. A structure-based drug discovery approach / Battista, T.; Federico, S.; Brogi, S.; Pozzetti, L.; Khan, T.; Butini, S.; Ramunno, A.; Fiorentino, E.; Orsini, S.; Di Muccio, T.; Fiorillo, A.; Exertier, C.; Di Risola, D.; Colotti, G.; Gemma, S.; Ilari, A.; Campiani, G.. - In: ACS INFECTIOUS DISEASES. - ISSN 2373-8227. - 8:8(2022), pp. 1687-1699. [10.1021/acsinfecdis.2c00325]

Optimization of potent and specific trypanothione reductase inhibitors. A structure-based drug discovery approach

Battista T.;Fiorillo A.;Exertier C.;Di Risola D.;Colotti G.;Campiani G.
2022

Abstract

Leishmania spp. are responsible for up to 1 million new cases each year. The current therapeutic arsenal against Leishmania is largely inadequate, and there is an urgent need for better drugs. Trypanothione reductase (TR) represents a druggable target since it is essential for the parasite and not shared by the human host. Here, we report the optimization of a novel class of potent and selective LiTR inhibitors realized through a concerted effort involving X-ray crystallography, synthesis, structure-activity relationship (SAR) investigation, molecular modeling, and in vitro phenotypic assays. 5-Nitrothiophene-2-carboxamides 3, 6e, and 8 were among the most potent and selective TR inhibitors identified in this study. 6e and 8 displayed leishmanicidal activity in the low micromolar range coupled to SI > 50. Our studies could pave the way for the use of TR inhibitors not only against leishmaniasis but also against other trypanosomatidae due to the structural similarity of TR enzymes.
2022
leishmania; sulfonamides; trypanothione; trypanothione reductase
01 Pubblicazione su rivista::01a Articolo in rivista
Optimization of potent and specific trypanothione reductase inhibitors. A structure-based drug discovery approach / Battista, T.; Federico, S.; Brogi, S.; Pozzetti, L.; Khan, T.; Butini, S.; Ramunno, A.; Fiorentino, E.; Orsini, S.; Di Muccio, T.; Fiorillo, A.; Exertier, C.; Di Risola, D.; Colotti, G.; Gemma, S.; Ilari, A.; Campiani, G.. - In: ACS INFECTIOUS DISEASES. - ISSN 2373-8227. - 8:8(2022), pp. 1687-1699. [10.1021/acsinfecdis.2c00325]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1669499
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