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. 2024 Jun 11;29(12):2762.
doi: 10.3390/molecules29122762.

Assessment of the Activity of Nitroisoxazole Derivatives against Trypanosoma cruzi

Affiliations

Assessment of the Activity of Nitroisoxazole Derivatives against Trypanosoma cruzi

Mauricio Moncada-Basualto et al. Molecules. .

Abstract

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.

Keywords: Chagas disease; ROS; Trypanosoma cruzi; cruzipain enzyme; nitroisoxazoles.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Serie of nitroisoxazoles derivatives in the study.
Scheme 1
Scheme 1
Synthetic methodology for obtaining compounds 117. (A) Synthesis of derivates of nitroisoxazoles 23. (B) Synthesis of nitroisoxazoles 417.
Figure 2
Figure 2
(a) Cyclic voltammogram of compound 2 with a potential sweep between −1.7 and −0.8 V and sweep speeds between 0.05 and 2.5 V/s. (b) Cyclic voltammogram of compound 8 with a potential sweep between −1.7 and −0.6 V and sweep speeds between 0.05 and 2.5 V/s contains labile protons. (c) Cyclic voltammogram of compound 8 using speed 2.0 V/s, (i) the first black line without NaOH; (ii) the purple line, in the presence of NaOH 1 M. (d) Cyclic voltammogram of compound 9 with a potential sweep between −1.5 and 0.0 V and sweep speeds between 0.05 and 2.5 V/s. (e) Experimental (upper) and WimSIM 9 (down) simulated the ESR spectrum of compound 7 at room temperature in DMSO.
Figure 3
Figure 3
Ratio area of the ROS generation of the series of nitroisoxazoles on T. cruzi. The significant difference compared to the control CN (trypomastigotes without compound) (one-way ANOVA with Dunnett’s post-test, * p < 0.05, *** p < 0.001 statistical difference signific with CN).
Figure 4
Figure 4
(a) Superposition between native crystallographic ligand and native docked structure, (b) Binding modes of compound 8, (c) 9, and (d) 11 through docking.

References

    1. Souza W. Basic Cell Biology of Trypanosoma Cruzi. Curr. Pharm. Des. 2002;8:269–285. doi: 10.2174/1381612023396276. - DOI - PubMed
    1. Estani S.S., Segura E.L. Protozoan Diseases: Chagas Disease. Int. Encycl. Public Health. 2017:70–78. doi: 10.1016/B978-0-12-803678-5.00357-X. - DOI
    1. World Health Organization . Control of Chagas Disease: Second Report of the WHO Expert Committee. World Health Organization; Geneva, Switzerland: 2002.
    1. Chatelain E. Chagas Disease Drug Discovery: Toward a New Era. J. Biomol. Screen. 2015;20:22–35. doi: 10.1177/1087057114550585. - DOI - PubMed
    1. Forsyth C.J., Hernandez S., Olmedo W., Abuhamidah A., Traina M.I., Sanchez D.R., Soverow J., Meymandi S.K. Safety Profile of Nifurtimox for Treatment of Chagas Disease in the United States. Clin. Infect. Dis. 2016;63:1056–1062. doi: 10.1093/CID/CIW477. - DOI - PMC - PubMed

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