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Molecules 2019, 24(2), 268; https://doi.org/10.3390/molecules24020268

Potent Antitrypanosomal Activities of 3-Aminosteroids against African Trypanosomes: Investigation of Cellular Effects and of Cross-Resistance with Existing Drugs

1
Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Münster, Pharma Campus Corrensstraße 48, D-48149 Münster, Germany
2
Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Nigeria Nsukka, Enugu 410001, Nigeria
3
Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK
4
Department of Applied Biology, Kyoto Institute of Technology, Kyoto 606-8585, Japan
5
The Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK
6
Department of Cell and Molecular Biology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, Brazil
*
Author to whom correspondence should be addressed.
Received: 19 December 2018 / Revised: 7 January 2019 / Accepted: 8 January 2019 / Published: 12 January 2019
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Abstract

Treatment of animal African trypanosomiasis (AAT) requires urgent need for safe, potent and affordable drugs and this has necessitated this study. We investigated the trypanocidal activities and mode of action of selected 3-aminosteroids against Trypanosoma brucei brucei. The in vitro activity of selected compounds of this series against T. congolense (Savannah-type, IL3000), T. b. brucei (bloodstream trypomastigote, Lister strain 427 wild-type (427WT)) and various multi-drug resistant cell lines was assessed using a resazurin-based cell viability assay. Studies on mode of antitrypanosomal activity of some selected 3-aminosteroids against Tbb 427WT were also carried out. The tested compounds mostly showed moderate-to-low in vitro activities and low selectivity to mammalian cells. Interestingly, a certain aminosteroid, holarrhetine (10, IC50 = 0.045 ± 0.03 µM), was 2 times more potent against T. congolense than the standard veterinary drug, diminazene aceturate, and 10 times more potent than the control trypanocide, pentamidine, and displayed an excellent in vitro selectivity index of 2130 over L6 myoblasts. All multi-drug resistant strains of T. b. brucei tested were not significantly cross-resistant with the purified compounds. The growth pattern of Tbb 427WT on long and limited exposure time revealed gradual but irrecoverable growth arrest at ≥ IC50 concentrations of 3-aminosteroids. Trypanocidal action was not associated with membrane permeabilization of trypanosome cells but instead with mitochondrial membrane depolarization, reduced adenosine triphosphate (ATP) levels and G2/M cell cycle arrest which appear to be the result of mitochondrial accumulation of the aminosteroids. These findings provided insights for further development of this new and promising class of trypanocide against African trypanosomes. View Full-Text
Keywords: African trypanosomiasis; Trypanosoma brucei brucei; Trypanosoma congolense; mode of action; resistant strains African trypanosomiasis; Trypanosoma brucei brucei; Trypanosoma congolense; mode of action; resistant strains
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Nnadi, C.O.; Ebiloma, G.U.; Black, J.A.; Nwodo, N.J.; Lemgruber, L.; Schmidt, T.J.; de Koning, H.P. Potent Antitrypanosomal Activities of 3-Aminosteroids against African Trypanosomes: Investigation of Cellular Effects and of Cross-Resistance with Existing Drugs. Molecules 2019, 24, 268.

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