Image-Based In Vitro Screening Reveals the Trypanostatic Activity of Hydroxymethylnitrofurazone against Trypanosoma cruzi

Author(s)

Scarim, Caue Benito ^{[1, 2]} ; Olmo, Francisco ^[2] ; Ferreira, Elizabeth Igne ^[3] ; Chin, Chung Man ^{[1, 4]} ; Kelly, John M. ^[2] ; Fortes Francisco, Amanda ^[2]

Affiliation

^[1] Sao Paulo State Univ UNESP, Sch Pharmaceut Sci, BR-14800903 Araraquara, SP - Brazil

^[2] London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Infect Biol, Keppel St, London WC1E 7HT - England

^[3] Univ Sao Paulo, Sch Pharmaceut Sci, Dept Pharm, LAPEN Lab Design & Synth Chemotherapeut Agents Po, BR-05508900 Sao Paulo - Brazil

^[4] Union Coll Great Lakes UNILAGO, Adv Res Ctr Med, Sch Med, BR-15030070 Sao Jose Do Rio Preto, SP - Brazil

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 22, n. 13 JUL 2021.
• Web of Science Citations: 0

Abstract

Hydroxymethylnitrofurazone (NFOH) is a therapeutic candidate for Chagas disease (CD). It has negligible hepatotoxicity in a murine model compared to the front-line drug benznidazole (BZN). Here, using Trypanosoma cruzi strains that express bioluminescent and/or fluorescent reporter proteins, we further investigated the in vitro and in vivo activity of NFOH to define whether the compound is trypanocidal or trypanostatic. The in vitro activity was assessed by exploiting the fluorescent reporter strain using wash-out assays and real-time microscopy. For animal experimentation, BALB/c mice were inoculated with the bioluminescent reporter strain and assessed by highly sensitive in vivo and ex vivo imaging. Cyclophosphamide treatment was used to promote parasite relapse in the chronic stage of infection. Our data show that NFOH acts by a trypanostatic mechanism, and that it is more active than BZN in vitro against the infectious trypomastigote form of Trypanosoma cruzi. We also found that it is more effective at curing experimental infections in the chronic stage, compared with the acute stage, a feature that it shares with BZN. Therefore, given its reduced toxicity, enhanced anti-trypomastigote activity, and curative properties, NFOH can be considered as a potential therapeutic option for Chagas disease, perhaps in combination with other trypanocidal agents. (AU)

• FAPESP's process: 16/10847-9 - Hydroxymethylnitrofurazone (NFOH): activity study in chronic phase of Chagas' Disease in an animal model and synthesis of soluble derivatives
• Grantee: Cauê Benito Scarim
• Support Opportunities: Scholarships in Brazil - Doctorate