Potent antitrypanosomal activities of 3-aminosteroids against African trypanosomes: investigation of cellular effects and of cross-resistance with existing drugs

Nnadi, C., Ebiloma, G. U., Black, J. A., Nwodo, N., Lemgruber, L., Schmidt, T. J. and De Koning, H. P. (2019) Potent antitrypanosomal activities of 3-aminosteroids against African trypanosomes: investigation of cellular effects and of cross-resistance with existing drugs. Molecules, 24(2), 268. (doi:10.3390/molecules24020268) (PMID:30642032)

Nnadi, C., Ebiloma, G. U., Black, J. A., Nwodo, N., Lemgruber, L., Schmidt, T. J. and De Koning, H. P. (2019) Potent antitrypanosomal activities of 3-aminosteroids against African trypanosomes: investigation of cellular effects and of cross-resistance with existing drugs. Molecules, 24(2), 268. (doi:10.3390/molecules24020268) (PMID:30642032)

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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.

Item Type:Articles
Additional Information:This research was funded by a fellowship for C.O.N. from the Federal Government of Nigeria through the Tertiary Education Trust Fund (TETFund) and the University of Nigeria Nsukka to conduct his doctoral studies at WWU Münster and by a short-term scientific mission (STSM) grant from COST action CM1307 for C.O.N. to perform the studies described here at the University of Glasgow.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Black, Dr Jennifer and Nnadi, Mr Charles and De Koning, Professor Harry and Ebiloma, Godwin Unekwuojo and Lemgruber Soares, Dr Leandro
Authors: Nnadi, C., Ebiloma, G. U., Black, J. A., Nwodo, N., Lemgruber, L., Schmidt, T. J., and De Koning, H. P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Molecules
Publisher:MDPI
ISSN:1420-3049
ISSN (Online):1420-3049
Published Online:12 January 2019
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Molecules 24(2): 268
Publisher Policy:Reproduced under a Creative Commons License

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