Wilmer Alcazar1, Sami Alakurtti2,3, Maritza Padrón-Nieves1, Maija Liisa Tuononen2,3, Noris Rodríguez4, Jari Yli-Kauhaluoma2, Alicia Ponte-Sucre1. 1. Laboratory of Molecular Physiology, Institute of Experimental Medicine, School of Medicine Luis Razetti, Faculty of Medicine, Universidad Central de Venezuela, P.O. Box 50587, Caracas 1050, Venezuela. 2. Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5 E, P.O. Box 56, FI-00014 Helsinki, Finland. 3. VTT Technical Research Centre of Finland, Biologinkuja 7, P.O. Box 1000, FI-02044 Espoo, Finland. 4. Laboratory of Genetic Engineering, Institute of Biomedicine, Universidad Central de Venezuela, P.O. Box 4043, Caracas 1010A, Venezuela.
Abstract
Herein, we evaluated in vitro the anti-leishmanial activity of betulin derivatives in Venezuelan isolates of Leishmania amazonensis, isolated from patients with therapeutic failure. METHODS: We analyzed promastigote in vitro susceptibility as well as the cytotoxicity and selectivity of the evaluated compounds. Additionally, the activity of selected compounds was determined in intracellular amastigotes. Finally, to gain hints on their potential mechanism of action, the effect of the most promising compounds on plasma and mitochondrial membrane potential, and nitric oxide and superoxide production by infected macrophages was determined. RESULTS: From the tested 28 compounds, those numbered 18 and 22 were chosen for additional studies. Both 18 and 22 were active (GI50 ≤ 2 µM, cytotoxic CC50 > 45 µM, SI > 20) for the reference strain LTB0016 and for patient isolates. The results suggest that 18 significantly depolarized the plasma membrane potential (p < 0.05) and the mitochondrial membrane potential (p < 0.05) when compared to untreated cells. Although neither 18 nor 22 induced nitric oxide production in infected macrophages, 18 induced superoxide production in infected macrophages. CONCLUSION: Our results suggest that due to their efficacy and selectivity against intracellular parasites and the potential mechanisms underlying their leishmanicidal effect, the compounds 18 and 22 could be used as tools for designing new chemotherapies against leishmaniasis.
Herein, we evaluated in vitro the anti-leishmanial activity of betulin derivatives in Venezuelan isolates of Leishmania amazonensis, isolated from patients with therapeutic failure. METHODS: We analyzed promastigote in vitro susceptibility as well as the cytotoxicity and selectivity of the evaluated compounds. Additionally, the activity of selected compounds was determined in intracellular amastigotes. Finally, to gain hints on their potential mechanism of action, the effect of the most promising compounds on plasma and mitochondrial membrane potential, and nitric oxide and superoxide production by infected macrophages was determined. RESULTS: From the tested 28 compounds, those numbered 18 and 22 were chosen for additional studies. Both 18 and 22 were active (GI50 ≤ 2 µM, cytotoxic CC50 > 45 µM, SI > 20) for the reference strain LTB0016 and for patient isolates. The results suggest that 18 significantly depolarized the plasma membrane potential (p < 0.05) and the mitochondrial membrane potential (p < 0.05) when compared to untreated cells. Although neither 18 nor 22 induced nitric oxide production in infected macrophages, 18 induced superoxide production in infected macrophages. CONCLUSION: Our results suggest that due to their efficacy and selectivity against intracellular parasites and the potential mechanisms underlying their leishmanicidal effect, the compounds 18 and 22 could be used as tools for designing new chemotherapies against leishmaniasis.
Authors: Maria Carolina Freitas Garcia; Deivid Costa Soares; Raissa Couto Santana; Elvira Maria Saraiva; Antonio Carlos Siani; Mônica Freiman S Ramos; Maria das Graças Miranda Danelli; Thaïs Cristina Souto-Padron; Lucia H Pinto-da-Silva Journal: Parasitology Date: 2018-01-21 Impact factor: 3.234
Authors: Daniel Spinks; Han B Ong; Chidochangu P Mpamhanga; Emma J Shanks; David A Robinson; Iain T Collie; Kevin D Read; Julie A Frearson; Paul G Wyatt; Ruth Brenk; Alan H Fairlamb; Ian H Gilbert Journal: ChemMedChem Date: 2010-12-29 Impact factor: 3.466
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