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. 2021 Aug 17;26(16):4960.
doi: 10.3390/molecules26164960.

Synthesis and Evaluation of Biological Activities of Bis(spiropyrazolone)cyclopropanes: A Potential Application against Leishmaniasis

Olalla Barreiro-Costa  1 , Gabriela Morales-Noboa  2 , Patricio Rojas-Silva  1 , Eliana Lara-Barba  2 , Javier Santamaría-Aguirre  2 , Natalia Bailón-Moscoso  3 , Juan Carlos Romero-Benavides  4 , Ana Herrera  3 , Cristina Cueva  3 , Lenin Ron-Garrido  2 , Ana Poveda  2 , Jorge Heredia-Moya  1
Affiliations

Synthesis and Evaluation of Biological Activities of Bis(spiropyrazolone)cyclopropanes: A Potential Application against Leishmaniasis

Olalla Barreiro-Costa et al. Molecules. .

Abstract

This work focuses on the search and development of drugs that may become new alternatives to the commercial drugs currently available for treatment of leishmaniasis. We have designed and synthesized 12 derivatives of bis(spiropyrazolone)cyclopropanes. We then characterized their potential application in therapeutic use. For this, the in vitro biological activities against three eukaryotic models-S. cerevisiae, five cancer cell lines, and the parasite L. mexicana-were evaluated. In addition, cytotoxicity against non-cancerous mammalian cells has been evaluated and other properties of interest have been characterized, such as genotoxicity, antioxidant properties and, in silico predictive adsorption, distribution, metabolism, and excretion (ADME). The results that we present here represent a first screening, indicating two derivatives of bis(spiropyrazolone)cyclopropanes as good candidates for the treatment of leishmaniasis. They have good specificity against parasites with respect to mammalian cells.

Keywords: ADME; bis(spiropyrazolone)cyclopropanes; drugs; leishmaniasis cytotoxicity.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Scheme 1
Scheme 1
Synthesis of bis(pyrazol-5-oles) 2 and bis(spiropyrazolone)cyclopropanes 4.
Figure 1
Figure 1
Comet assay of Leishmania mexicana cells exposed to bis(spiropyrazolone)cyclopropanes 4 including Violin plots of tail length measurements from a comet population. Black traits indicate the median and dashed traits including highest and lowest quartiles of each population. DMSO: dimethylsulfoxide; Dox: doxorubicin. The tests for significance were limited to the Kruskal–Wallis one-way ANOVA. Post hoc tests were done via Fisher’s least significant difference. Treatments with the same letter are not significantly different. Significance codes: **** p-value < 0.0001; *** p-value < 0.001.
Figure 2
Figure 2
Comet assay of de CHO-K1 cells exposed to bis(spiropyrazolone)cyclopropanes 4. Violin plots of tail length measurements from a comet population, are represented. Black traits indicate the median and dashed traits the highest and lowest quartiles of each population. DMSO: dimethyl sulfoxide; Dox: doxorubicin. The tests for significance were limited to the Kruskal–Wallis one-way ANOVA. Post hoc tests were done by using the criterium Fisher’s least significant difference. Treatments with the same letter are not significantly different. Significance codes: **** p < 0.0001; *** p < 0.001; ** p < 0.01.
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