Dataset Information

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

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 G?/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.

SUBMITTER: Nnadi CO

PROVIDER: S-EPMC6359104 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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

Nnadi Charles O CO Ebiloma Godwin U GU Black Jennifer A JA Nwodo Ngozi J NJ Lemgruber Leandro L Schmidt Thomas J TJ de Koning Harry P HP

Molecules (Basel, Switzerland) 20190112 2

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-dru ...[more]

PMID: 30642032

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Project description:African trypanosomiasis is a disease caused by the parasitic protozoa of the Trypanosoma genus. Despite several efforts at chemotherapeutic interventions, the disease poses serious health and economic concerns to humans and livestock of many sub-Saharan African countries. Zanthoxylum zanthoxyloides (Lam.) Zepern. & Timler (Z. zanthoxyloides LZT) is a plant species of important phytochemical and pharmacological relevance in the subtropical zones of the African continent. However, the mechanisms of its antitrypanosomal effects in African trypanosomes remain to be elucidated. The aim of the study was to determine the in vitro effects and mechanisms of action of Z. zanthoxyloides LZT (root) fractions against Trypanosoma brucei. T. brucei (GUTat 3.1 strain), L. donovani (D10 strain), P. falciparum (3D 7 strain), Jurkat cells, and Chang liver cells were cultivated in vitro to the log phase in their respective media at 37°C. Crude extracts and fractions were prepared from air-dried pulverized plant material of Z. zanthoxyloides LZT (root) using the modified Kupchan method of solvent partitioning. Half-maximal inhibitory concentrations (IC50) were determined through the alamar blue cell viability assay. Effects of fractions on cell death and cell cycle of T. brucei were determined using flow cytometry. Fluorescence microscopy was used to investigate the effects of fractions on the morphology and distribution of T. brucei. Antitrypanosomal compounds of fractions were characterized using high-performance liquid chromatography (HPLC) and attenuated total reflectance infrared (ATR-IR) spectroscopy. Methanol, butanol, and dichloromethane fractions were selectively active against T. brucei with respective IC50 values of 3.89, 4.02, and 5.70 μg/ml. Moreover, methanol, butanol, and dichloromethane fractions significantly induced apoptosis-like cell death with remarkable alteration in the cell cycle of T. brucei. Furthermore, dichloromethane and methanol fractions altered the morphology, induced aggregation, and altered the ratio of nuclei to kinetoplasts in the parasite. The HPLC chromatograms and ATR-IR spectra of the active fractions suggested the presence of aromatic hydrocarbons with hydroxyl, carbonyl, amine, or amide functional groups. The results suggest that Z. zanthoxyloides LZT have potential chemotherapeutic effects on African trypanosomes with implications for novel therapeutic interventions in African trypanosomiasis.

Dataset Information

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

Publications

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

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