Trypanocidal and Anti-Inflammatory Effects of Three ent-Kaurane Diterpenoids from Gymnocoronis spilanthoides var. subcordata (Asteraceae)

Selener, Mariana G.; Borgo, Jimena; Sarratea, Maria Belen; Delfino, Maria Alicia; Laurella, Laura C.; Cerny, Natacha; Gomez, Jessica; Coll, Mauro; Malchiodi, Emilio L.; Bivona, Augusto E.; Barrera, Patricia; Redko, Flavia C.; Catalán, César A. N.; Alberti, Andrés Sánchez; Sülsen, Valeria P.

doi:10.3390/pharmaceutics16030415

Open AccessArticle

Trypanocidal and Anti-Inflammatory Effects of Three ent-Kaurane Diterpenoids from Gymnocoronis spilanthoides var. subcordata (Asteraceae)

by

Mariana G. Selener

^1,2,†,

Jimena Borgo

^1,2,†,

Maria Belen Sarratea

³

,

Maria Alicia Delfino

⁴,

Laura C. Laurella

^1,2,

Natacha Cerny

⁵,

Jessica Gomez

⁶,

Mauro Coll

⁶,

Emilio L. Malchiodi

^3,4

,

Augusto E. Bivona

^3,4

,

Patricia Barrera

⁶,

Flavia C. Redko

^1,2

,

César A. N. Catalán

⁷,

Andrés Sánchez Alberti

^3,5,*,‡

and

Valeria P. Sülsen

^1,2,*,‡

¹

Cátedra de Farmacognosia, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, Piso 2, Buenos Aires C1113AAD, Argentina

²

Instituto de Química y Metabolismo del Fármaco (IQUIMEFA), CONICET-Universidad de Buenos Aires, Junín 956, Piso 2, Buenos Aires C1113AAD, Argentina

³

Instituto de Estudios de la Inmunidad Humoral (IDEHU), CONICET-Universidad de Buenos Aires, Junín 956, Piso 4, Buenos Aires C1113AAD, Argentina

⁴

Cátedra de Inmunología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, Piso 4, Buenos Aires C1113AAD, Argentina

⁵

Departamento de Microbiología, Parasitología e Inmunología-IMPAM (UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, Buenos Aires C1121ABG, Argentina

⁶

Facultad de Ciencias Médicas, Instituto de Histología y Embriología “Dr. Mario H. Burgos” (IHEM), Universidad Nacional de Cuyo-CONICET, CC 56, Mendoza 5500, Argentina

⁷

Instituto de Química Orgánica, Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán, Ayacucho 471, San Miguel de Tucumán T4000INI, Argentina

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

^‡

The work was co-directed by both authors.

Pharmaceutics 2024, 16(3), 415; https://doi.org/10.3390/pharmaceutics16030415

Submission received: 3 January 2024 / Revised: 24 February 2024 / Accepted: 27 February 2024 / Published: 18 March 2024

(This article belongs to the Special Issue Natural Product Pharmaceuticals)

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Abstract

Chagas disease, caused by the protozoan Trypanosoma cruzi, affects 6–7 million people worldwide. The dichloromethane extract obtained from the aerial parts of Gymnocoronis spilanthoides var subcordata showed trypanocidal activity in vitro. The fractionation of the dewaxed organic extract via column chromatography led to the isolation of three diterpenoids: ent-9α,11α-dihydroxy-15-oxo-kaur-16-en-19-oic acid or adenostemmoic acid B, (16R)-ent-11α-hydroxy-15-oxokauran-19-oic acid and ent-11α-hydroxy-15-oxo-kaur-16-en-19-oic acid. These compounds showed IC₅₀ values of 10.6, 15.9 and 4.8 µM against T. cruzi epimastigotes, respectively. When tested against amastigotes, the diterpenoids afforded IC₅₀ values of 6.1, 19.5 and 60.6 µM, respectively. The cytotoxicity of the compounds was tested on mammalian cells using an MTT assay, resulting in CC₅₀s of 321.8, 23.3 and 14.8 µM, respectively. The effect of adenostemmoic acid B on T. cruzi was examined at the ultrastructural level using transmission microscopy. Treatment with 20 μM for 48 h stimulated the formation of abnormal cytosolic membranous structures in the parasite. This compound also showed an anti-inflammatory effect in murine macrophages stimulated with LPS and other TLR agonists. Treatment of macrophages with adenostemmoic acid B was able to reduce TNF secretion and nitric oxide production, while increasing IL-10 production. The combination of adenostemmoic acid B with benznidazole resulted in greater inhibition of NF-kB and a decrease in nitrite concentration. The administration of adenostemmoic acid B to mice infected with trypomastigotes of T. cruzi at the dose of 1 mg/kg/day for five days produced a significant decrease in parasitemia levels and weight loss. Treatment with the association with benznidazole increased the survival time of the animals. In view of these results, adenostemmoic acid B could be considered a promising candidate for further studies in the search for new treatments for Chagas disease.

Keywords: Gymnocoronis; diterpene; natural compounds; ent-kaurane; Trypanosoma cruzi; anti-inflammatory activity; antiparasitic

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MDPI and ACS Style

Selener, M.G.; Borgo, J.; Sarratea, M.B.; Delfino, M.A.; Laurella, L.C.; Cerny, N.; Gomez, J.; Coll, M.; Malchiodi, E.L.; Bivona, A.E.; et al. Trypanocidal and Anti-Inflammatory Effects of Three ent-Kaurane Diterpenoids from Gymnocoronis spilanthoides var. subcordata (Asteraceae). Pharmaceutics 2024, 16, 415. https://doi.org/10.3390/pharmaceutics16030415

AMA Style

Selener MG, Borgo J, Sarratea MB, Delfino MA, Laurella LC, Cerny N, Gomez J, Coll M, Malchiodi EL, Bivona AE, et al. Trypanocidal and Anti-Inflammatory Effects of Three ent-Kaurane Diterpenoids from Gymnocoronis spilanthoides var. subcordata (Asteraceae). Pharmaceutics. 2024; 16(3):415. https://doi.org/10.3390/pharmaceutics16030415

Chicago/Turabian Style

Selener, Mariana G., Jimena Borgo, Maria Belen Sarratea, Maria Alicia Delfino, Laura C. Laurella, Natacha Cerny, Jessica Gomez, Mauro Coll, Emilio L. Malchiodi, Augusto E. Bivona, and et al. 2024. "Trypanocidal and Anti-Inflammatory Effects of Three ent-Kaurane Diterpenoids from Gymnocoronis spilanthoides var. subcordata (Asteraceae)" Pharmaceutics 16, no. 3: 415. https://doi.org/10.3390/pharmaceutics16030415

APA Style

Selener, M. G., Borgo, J., Sarratea, M. B., Delfino, M. A., Laurella, L. C., Cerny, N., Gomez, J., Coll, M., Malchiodi, E. L., Bivona, A. E., Barrera, P., Redko, F. C., Catalán, C. A. N., Alberti, A. S., & Sülsen, V. P. (2024). Trypanocidal and Anti-Inflammatory Effects of Three ent-Kaurane Diterpenoids from Gymnocoronis spilanthoides var. subcordata (Asteraceae). Pharmaceutics, 16(3), 415. https://doi.org/10.3390/pharmaceutics16030415

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Trypanocidal and Anti-Inflammatory Effects of Three ent-Kaurane Diterpenoids from Gymnocoronis spilanthoides var. subcordata (Asteraceae)

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