5-Nitroindazole-based compounds: further studies for activity optimization as anti-Trypanosoma cruzi agents

Fonseca-Berzal, Cristina; Ibáñez‐Escribano, Alexandra; Castro, Sonia de; Escario, José Antonio; Gómez‐Barrio, Alicia; Arán, Vicente J.

doi:10.1016/j.actatropica.2022.106607

Cited by 3 publications

(2 citation statements)

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“…These results indicated that halogens or methoxy groups as substituents in nitroisoxazole derivatives modulated trypanocidal activity. This is consistent with studies by Fonseca-Berzal et al [ 38 ], who determined that 5-nitroindazole derivatives with halogen substituents showed the best activity against epimastigotes, as the electron-attracting characteristics of these substituents modify the physicochemical properties of molecules to improve their pharmacological properties.…”

Section: Resultssupporting

confidence: 92%

“…Despite the epimastigote form not being a clinical form present in mammals, its easy handling has allowed screening for the trypanocidal activity of various compounds. It is worth noting that, during the intracellular life cycle of the parasite, a form similar to the epimastigote, which is biochemically and morphologically identical to the form present in the vector, has been described [ 38 ]. Table 3 shows the percentage of toxic effects of nitroisoxazole derivatives and precursors of the compounds under study.…”

Section: Resultsmentioning

confidence: 99%

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Assessment of the Activity of Nitroisoxazole Derivatives against Trypanosoma cruzi

Moncada-Basualto,

Saavedra-Olavarría,

Rivero-Jerez

et al. 2024

Molecules

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The development of new compounds to treat Chagas disease is imperative due to the adverse effects of current drugs and their low efficacy in the chronic phase. This study aims to investigate nitroisoxazole derivatives that produce oxidative stress while modifying the compounds’ lipophilicity, affecting their ability to fight trypanosomes. The results indicate that these compounds are more effective against the epimastigote form of T. cruzi, with a 52 ± 4% trypanocidal effect for compound 9. However, they are less effective against the trypomastigote form, with a 15 ± 3% trypanocidal effect. Additionally, compound 11 interacts with a higher number of amino acid residues within the active site of the enzyme cruzipain. Furthermore, it was also found that the presence of a nitro group allows for the generation of free radicals; likewise, the large size of the compound enables increased interaction with aminoacidic residues in the active site of cruzipain, contributing to trypanocidal activity. This activity depends on the size and lipophilicity of the compounds. The study recommends exploring new compounds based on the nitroisoxazole skeleton, with larger substituents and lipophilicity to enhance their trypanocidal activity.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Assessment of the Activity of Nitroisoxazole Derivatives against Trypanosoma cruzi

Moncada-Basualto,

Saavedra-Olavarría,

Rivero-Jerez

et al. 2024

Molecules

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3-Alkoxy-1-Benzyl-5-Nitroindazole Derivatives Are Potent Antileishmanial Compounds

Mollineda-Diogo,

Sifontes-Rodríguez,

Aguirre-García

et al. 2024

IJMS

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Indazoles have previously been identified as molecules with antiprotozoal activity. In this study, we evaluate the in vitro activity of thirteen 3-alkoxy-1-benzyl-5-nitroindazole derivatives (series D) against L. amazonensis, L. infantum, and L. mexicana. In vitro, cytotoxicity against mouse peritoneal macrophages and growth inhibitory activity in promastigotes were evaluated for all compounds, and those showing adequate activity and selectivity were tested against intracellular amastigotes. Transmission and scanning electron microscopy were employed to study the effects of 3-alkoxy-1-benzyl-5-nitroindazole and 2-benzyl-5-nitroindazolin-3-one derivatives on promastigotes of L. amazonensis. Compounds NV6 and NV8 were active in the two life stages of the three species, with the latter showing the best indicators of activity and selectivity. 3-alkoxy-1-benzyl-5-nitroindazole derivatives (series D) showed in vitro activity comparable to that of amphotericin B against the promastigote stage of Leishmania spp. Two compounds were also found to be active the amastigote stage. Electron microscopy studies confirmed the antileishmanial activity of the indazole derivatives studied and support future research on this family of compounds as antileishmanial agents.

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In Vitro Evaluation of New 5-Nitroindazolin-3-one Derivatives as Promising Agents against Trypanosoma cruzi

Pozo-Martínez,

Arán,

Zúñiga-Bustos

et al. 2024

IJMS

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Chagas disease is a prevalent health problem in Latin America which has received insufficient attention worldwide. Current treatments for this disease, benznidazole and nifurtimox, have limited efficacy and may cause side effects. A recent study proposed investigating a wide range of nitroindazole and indazolone derivatives as feasible treatments. Therefore, it is proposed that adding a nitro group at the 5-position of the indazole and indazolone structure could enhance trypanocidal activity by inducing oxidative stress through activation of the nitro group by NTRs (nitroreductases). The study results indicate that the nitro group advances free radical production, as confirmed by several analyses. Compound 5a (5-nitro-2-picolyl-indazolin-3-one) shows the most favorable trypanocidal activity (1.1 ± 0.3 µM in epimastigotes and 5.4 ± 1.0 µM in trypomastigotes), with a selectivity index superior to nifurtimox. Analysis of the mechanism of action indicated that the nitro group at the 5-position of the indazole ring induces the generation of reactive oxygen species (ROS), which causes apoptosis in the parasites. Computational docking studies reveal how the compounds interact with critical residues of the NTR and FMNH2 (flavin mononucleotide reduced) in the binding site, which is also present in active ligands. The lipophilicity of the studied series was shown to influence their activity, and the nitro group was found to play a crucial role in generating free radicals. Further investigations are needed of derivatives with comparable lipophilic characteristics and the location of the nitro group in different positions of the base structure.

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5-Nitroindazole-based compounds: further studies for activity optimization as anti-Trypanosoma cruzi agents

Cited by 3 publications

References 50 publications

Assessment of the Activity of Nitroisoxazole Derivatives against Trypanosoma cruzi

Assessment of the Activity of Nitroisoxazole Derivatives against Trypanosoma cruzi

3-Alkoxy-1-Benzyl-5-Nitroindazole Derivatives Are Potent Antileishmanial Compounds

In Vitro Evaluation of New 5-Nitroindazolin-3-one Derivatives as Promising Agents against Trypanosoma cruzi

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