Antileishmanial activity of 11α19βdihydroxy-7-acetoxy-7-deoxoichangin analogs against Leishmania Viannia panamensis
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1
Universidad Nacional Colombia, Facultad de Ciencias, Colombia
Leishmaniasis is a neglected tropical disease (NTDs) endemic in 98 countries, affecting more than 12 million people. Leishmaniasis have treatment, pentavalent antimony (First drug choice), pentamidine, miltefosine and amphotericin B (Second drugs choice). However, these current drugs are limited due to their toxicity, biological resistance, length of treatment and high cost. No safe and effective vaccine currently exists against any form of human leishmaniasis. For these reason numerous plant-derived natural compounds from different structural classes have been investigated as antileishmanial candidates, including terpenoids.
Since safety, efficacy and affordable chemotherapeutic agents for leishmaniasis is clearly needed, the identification of new antileishmanial drugs candidates should be an urgent priority. Numerous plant-derived natural products from different structural types have been investigated as antileishmanial candidates, including alkaloids and terpenoids.
In previous studies, we described the natural compound 11a-19b-dihydroxy-7-acetoxy-7-deoxoichangin (Terpenoid compound) as a potential treatment against leishmaniasis, because this compound has immunomodulatory effect given by the activation of immune response in infected cells. However, the heterogeneity of the extraction´s method and the low concentrations found in the plant material it makes necessary to find synthetic analogs of this compound through search tools.
The present study evaluated the in vitro antileishmanial activity of four analogs of 11α-19β-dihydroxy-7-acetoxy-7-deoxoichangin against Leishmania panamensis promastigotes and intracellular amastigotes.
The analogs of 11a-19b-dihydroxy-7-acetoxy-7-deoxoichangin were defined by the similarity of structure, through the Tanimoto index and literature reports of biological activity. The cytotoxic effects of compounds were assessed on macrophages of human volunteers by Alamar Blue assay. Concentration that induced the 50% of cytotoxicity on macrophages (CC50) was established by GraphPad Prism6. The effect of terpenoids compounds on the viability of infective forms of L. (V.) panamensis was determined using the alamar blue assay, also; Miltefosine and Pentamidine were used as standard drugs. The 50% inhibitory concentration (IC50) values for each compound were determined by GraphPad Prism6. The effect of compounds on intracellular amastigotes was carried out by flow cytometry in human macrophages infected with GFP -transfected L. panamensis UA 140 (Donated by Dr. Sara Robledo - Universidad de Antioquia). The selectivity index (SI) of the compounds was determined considering the following equation: CC50 on mammalian cells/IC50 on L. panamensis.
11a-19b-dihydroxy-7-acetoxy-7-deoxoichangin analogs were found with structure similarity 90% and bibliographic reports of biological activity: Nomilin, limonin, Glycyrrhizic acid and Oleanolic acid. The mammalian cells citotoxicity, given by the 50% cytotoxic concentration (CC50), was evaluated against human macrophages. Terpenoids compounds (Nomilin, Limonin, Glycyrrhizic acid and Oleanolic acid) were not toxic up to 100 uM. However, we demonstrated that Nomilin, Limonin, Glycyrrhizic acid and Oleanolic acid were able to kill the parasites in a concentration-dependent way. 11a-19b-dihydroxy-7-acetoxy-7-deoxoichangin analogs present inhibitory effects on L. panamensis promastigotes (50% inhibitory concentration range, 44.30 to 102.64 uM). For assays on promastigotes, compounds with selectivity index of 1 or more than 1 were considered selective. Preliminary results of intracellular amastigotes assay, demonstrated that terpenoids compounds (Nomilin and oleanolic acid) decreasing the intracellular parasites inside the macrophage; however in other terpenoids no activity is seen against infection. Thus, they do not present any potential risk of toxicity for the host cells.
Thus, they do not present any potential risk of toxicity for the host cells. This study has identified the terpenoids as prominent molecules in the development of new alternative therapies for leishmaniasis.
Acknowledgements
Thanks to Prof. Sara Maria Robledo, Universidad de Antioquia- Facultad de Medicina, PECET by her gentle donation of Leishmania panamensis GFP transfected strain.
Thanks to Ms. Rodrigo Ochoa, Universidad de Antioquia- PECET by his helpful colaboration in bioinformatic analysis
This project was financed Colciencias (project 1101-569-34446).
Keywords:
Terpenoid compounds,
Nomilin,
Limonin,
Glycyrrhizic Acid,
Oleanolic Acid,
Leishmania panamensis,
Leishmaniasis,
leishmanicidal activity
Conference:
IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología, Medellin, Colombia, 13 Oct - 16 Oct, 2015.
Presentation Type:
Oral Presentation
Topic:
Infectious and parasitic diseases
Citation:
Torres
FE,
Granados
DS and
Delgado
LG
(2015). Antileishmanial activity of 11α19βdihydroxy-7-acetoxy-7-deoxoichangin analogs against Leishmania Viannia panamensis.
Front. Immunol.
Conference Abstract:
IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología.
doi: 10.3389/conf.fimmu.2015.05.00323
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Received:
31 May 2015;
Published Online:
15 Sep 2015.
*
Correspondence:
Prof. Lucy G Delgado, Universidad Nacional Colombia, Facultad de Ciencias, Bogotá, Colombia, lgdelgadom@unal.edu.co