Mechanistic, in-silico and in vitro studies with nitrofurans reveal potent leishmanicidal activity and inhibition of trypanothione reductase
Visceral leishmaniasis caused by Leishmania infantum and Leishmania donovani is one of the neglected tropical diseases (NTDs) caused by trypanosomatids with treatment options limited to outdated drugs often causing adverse effects and promoting drug resistance. Previous antileishmanial drug discover...
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Elsevier
2025-08-01
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| Series: | International Journal for Parasitology: Drugs and Drug Resistance |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211320725000284 |
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| author | Julia Andrés-Rodríguez María-Cristina González-Montero Nerea García-Fernández Juan-José Galano-Frutos Maria-Cristina de Rosa Patricia Ferreira María-Yolanda Pérez-Pertejo Rosa M. Reguera Rafael Balaña-Fouce Carlos García-Estrada |
| author_facet | Julia Andrés-Rodríguez María-Cristina González-Montero Nerea García-Fernández Juan-José Galano-Frutos Maria-Cristina de Rosa Patricia Ferreira María-Yolanda Pérez-Pertejo Rosa M. Reguera Rafael Balaña-Fouce Carlos García-Estrada |
| author_sort | Julia Andrés-Rodríguez |
| collection | DOAJ |
| description | Visceral leishmaniasis caused by Leishmania infantum and Leishmania donovani is one of the neglected tropical diseases (NTDs) caused by trypanosomatids with treatment options limited to outdated drugs often causing adverse effects and promoting drug resistance. Previous antileishmanial drug discovery campaigns have identified nitroheterocyclic molecules with high efficacy and a high selectivity index. Therefore, we have evaluated on our screening platform of fluorescent L. donovani amastigotes, the antileishmanial activity of seven nitrofuran derivatives: furazolidone, nitrofurazone, nitrofurantoin, nifurtimox, 5-nitro-2-furaldehyde diacetate, PYZD-4409 and 5-nitro-2-furonitrile. These compounds showed good efficacy against axenic and intramacrophage amastigotes, most of them showing low cytotoxicity in mammalian cell lines. These nitrofuran derivatives induced reactive oxygen species production in axenic amastigotes and inhibited trypanothione reductase (TryR) either in uncompetitive or competitive manner, thus suggesting that their mechanism of action involves increased oxidative stress caused by an imbalance in redox metabolism. Furazolidone exhibited the most promising antileishmanial profile, and molecular docking analysis revealed consistency with the strongest TryR uncompetitive inhibitory effect, demonstrating its high affinity for an alternative binding site near the substrate (oxidized trypanothione) pocket. Docking results also highlighted PYZD-4409 as the compound with the highest binding affinity, and showed consistency with its competitive inhibition mechanism. Furthermore, similar binding modes identified across L. donovani TryR and other homologous proteins suggest the potential broad-spectrum activity of these nitrofuran derivatives, thus underscoring their importance as promising candidates for the development of novel antileishmanial therapies with broad-spectrum applications. |
| format | Article |
| id | doaj-art-598bb293ee214424bf981baa42e383f0 |
| institution | Kabale University |
| issn | 2211-3207 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
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| series | International Journal for Parasitology: Drugs and Drug Resistance |
| spelling | doaj-art-598bb293ee214424bf981baa42e383f02025-08-20T04:01:48ZengElsevierInternational Journal for Parasitology: Drugs and Drug Resistance2211-32072025-08-012810060510.1016/j.ijpddr.2025.100605Mechanistic, in-silico and in vitro studies with nitrofurans reveal potent leishmanicidal activity and inhibition of trypanothione reductaseJulia Andrés-Rodríguez0María-Cristina González-Montero1Nerea García-Fernández2Juan-José Galano-Frutos3Maria-Cristina de Rosa4Patricia Ferreira5María-Yolanda Pérez-Pertejo6Rosa M. Reguera7Rafael Balaña-Fouce8Carlos García-Estrada9Departamento de Ciencias Biomédicas, Facultad de Veterinaria, Universidad de León, Campus de Vegazana s/n, 24007, León, SpainDepartamento de Ciencias Biomédicas, Facultad de Veterinaria, Universidad de León, Campus de Vegazana s/n, 24007, León, SpainDepartamento de Ciencias Biomédicas, Facultad de Veterinaria, Universidad de León, Campus de Vegazana s/n, 24007, León, SpainIstituto di Scienze e Tecnologie Chimiche “Giulio Natta” (SCITEC) — National Research Council (CNR), Via Largo Francesco Vito 1, 00168, Rome, ItalyIstituto di Scienze e Tecnologie Chimiche “Giulio Natta” (SCITEC) — National Research Council (CNR), Via Largo Francesco Vito 1, 00168, Rome, ItalyDepartamento de Bioquímica y Biología Molecular y Celular — Universidad de Zaragoza, C/ Pedro Cerbuna 12, 50009, Zaragoza, SpainDepartamento de Ciencias Biomédicas, Facultad de Veterinaria, Universidad de León, Campus de Vegazana s/n, 24007, León, Spain; Instituto de Biomedicina (IBIOMED), Universidad de León, Campus de Vegazana s/n, 24007, León, SpainDepartamento de Ciencias Biomédicas, Facultad de Veterinaria, Universidad de León, Campus de Vegazana s/n, 24007, León, Spain; Instituto de Biomedicina (IBIOMED), Universidad de León, Campus de Vegazana s/n, 24007, León, SpainDepartamento de Ciencias Biomédicas, Facultad de Veterinaria, Universidad de León, Campus de Vegazana s/n, 24007, León, Spain; Instituto de Biomedicina (IBIOMED), Universidad de León, Campus de Vegazana s/n, 24007, León, Spain; Corresponding author. Departamento de Ciencias Biomédicas, Facultad de Veterinaria, Universidad de León, Campus de Vegazana s/n, 24007, León, Spain.Departamento de Ciencias Biomédicas, Facultad de Veterinaria, Universidad de León, Campus de Vegazana s/n, 24007, León, Spain; Instituto de Biomedicina (IBIOMED), Universidad de León, Campus de Vegazana s/n, 24007, León, Spain; Corresponding author. Departamento de Ciencias Biomédicas, Facultad de Veterinaria, Universidad de León, Campus de Vegazana s/n, 24007, León, Spain.Visceral leishmaniasis caused by Leishmania infantum and Leishmania donovani is one of the neglected tropical diseases (NTDs) caused by trypanosomatids with treatment options limited to outdated drugs often causing adverse effects and promoting drug resistance. Previous antileishmanial drug discovery campaigns have identified nitroheterocyclic molecules with high efficacy and a high selectivity index. Therefore, we have evaluated on our screening platform of fluorescent L. donovani amastigotes, the antileishmanial activity of seven nitrofuran derivatives: furazolidone, nitrofurazone, nitrofurantoin, nifurtimox, 5-nitro-2-furaldehyde diacetate, PYZD-4409 and 5-nitro-2-furonitrile. These compounds showed good efficacy against axenic and intramacrophage amastigotes, most of them showing low cytotoxicity in mammalian cell lines. These nitrofuran derivatives induced reactive oxygen species production in axenic amastigotes and inhibited trypanothione reductase (TryR) either in uncompetitive or competitive manner, thus suggesting that their mechanism of action involves increased oxidative stress caused by an imbalance in redox metabolism. Furazolidone exhibited the most promising antileishmanial profile, and molecular docking analysis revealed consistency with the strongest TryR uncompetitive inhibitory effect, demonstrating its high affinity for an alternative binding site near the substrate (oxidized trypanothione) pocket. Docking results also highlighted PYZD-4409 as the compound with the highest binding affinity, and showed consistency with its competitive inhibition mechanism. Furthermore, similar binding modes identified across L. donovani TryR and other homologous proteins suggest the potential broad-spectrum activity of these nitrofuran derivatives, thus underscoring their importance as promising candidates for the development of novel antileishmanial therapies with broad-spectrum applications.http://www.sciencedirect.com/science/article/pii/S2211320725000284Leishmania donovaniVisceral leishmaniasisCyclic nitrofuransTrypanothioneTrypanothione reductaseMolecular docking |
| spellingShingle | Julia Andrés-Rodríguez María-Cristina González-Montero Nerea García-Fernández Juan-José Galano-Frutos Maria-Cristina de Rosa Patricia Ferreira María-Yolanda Pérez-Pertejo Rosa M. Reguera Rafael Balaña-Fouce Carlos García-Estrada Mechanistic, in-silico and in vitro studies with nitrofurans reveal potent leishmanicidal activity and inhibition of trypanothione reductase International Journal for Parasitology: Drugs and Drug Resistance Leishmania donovani Visceral leishmaniasis Cyclic nitrofurans Trypanothione Trypanothione reductase Molecular docking |
| title | Mechanistic, in-silico and in vitro studies with nitrofurans reveal potent leishmanicidal activity and inhibition of trypanothione reductase |
| title_full | Mechanistic, in-silico and in vitro studies with nitrofurans reveal potent leishmanicidal activity and inhibition of trypanothione reductase |
| title_fullStr | Mechanistic, in-silico and in vitro studies with nitrofurans reveal potent leishmanicidal activity and inhibition of trypanothione reductase |
| title_full_unstemmed | Mechanistic, in-silico and in vitro studies with nitrofurans reveal potent leishmanicidal activity and inhibition of trypanothione reductase |
| title_short | Mechanistic, in-silico and in vitro studies with nitrofurans reveal potent leishmanicidal activity and inhibition of trypanothione reductase |
| title_sort | mechanistic in silico and in vitro studies with nitrofurans reveal potent leishmanicidal activity and inhibition of trypanothione reductase |
| topic | Leishmania donovani Visceral leishmaniasis Cyclic nitrofurans Trypanothione Trypanothione reductase Molecular docking |
| url | http://www.sciencedirect.com/science/article/pii/S2211320725000284 |
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