Free Radical Production Induced by Nitroimidazole Compounds Lead to Cell Death in Leishmania infantum Amastigotes

• Published in: Molecules (Basel, Switzerland) Vol. 29; no. 17; p. 4041
• Main Authors: Andrés-Rodríguez, Julia, González-Montero, María-Cristina, García-Fernández, Nerea, Calvo-Álvarez, Estefanía, Pérez-Pertejo, María-Yolanda, Reguera-Torres, Rosa-María, Balaña-Fouce, Rafael, García-Estrada, Carlos
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 26.08.2024
• Subjects: Animals; Antiparasitic agents; Antiprotozoal Agents - chemistry; Antiprotozoal Agents - pharmacology; Cell death; Cell Death - drug effects; Cell Survival - drug effects; Chagas disease; Cytotoxicity; Drug development; Drug dosages; drug repurposing; Free Radicals - metabolism; Hep G2 Cells; High-Throughput Screening Assays; Humans; Leishmania infantum; Leishmania infantum - drug effects; Leishmania infantum - metabolism; Leishmaniasis, Visceral - drug therapy; Leishmaniasis, Visceral - parasitology; Mice; NADH, NADPH Oxidoreductases; neglected tropical diseases; nitroaromatic compounds; Nitroimidazoles - chemistry; Nitroimidazoles - pharmacology; Parasites; Parasitic diseases; pretomanid; Protozoa; RAW 264.7 Cells; Reactive Oxygen Species - metabolism; Toxicity; Tropical diseases; visceral leishmaniais; Leishmania infantum; nitroaromatic compounds; drug repurposing; fexinidazole; neglected tropical diseases; visceral leishmaniais; trypanothione reductase; pretomanid
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules29174041

Leishmania infantum is the vector-borne trypanosomatid parasite causing visceral leishmaniasis in the Mediterranean basin. This neglected tropical disease is treated with a limited number of obsolete drugs that are not exempt from adverse effects and whose overuse has promoted the emergence of resistant pathogens. In the search for novel antitrypanosomatid molecules that help overcome these drawbacks, drug repurposing has emerged as a good strategy. Nitroaromatic compounds have been found in drug discovery campaigns as promising antileishmanial molecules. Fexinidazole (recently introduced for the treatment of stages 1 and 2 of African trypanosomiasis), and pretomanid, which share the nitroimidazole nitroaromatic structure, have provided antileishmanial activity in different studies. In this work, we have tested the in vitro efficacy of these two nitroimidazoles to validate our 384-well high-throughput screening (HTS) platform consisting of L. infantum parasites emitting the near-infrared fluorescent protein (iRFP) as a biomarker of cell viability. These molecules showed good efficacy in both axenic and intramacrophage amastigotes and were poorly cytotoxic in RAW 264.7 and HepG2 cultures. Fexinidazole and pretomanid induced the production of ROS in axenic amastigotes but were not able to inhibit trypanothione reductase (TryR), thus suggesting that these compounds may target thiol metabolism through a different mechanism of action.