Abstract
In the absence of vaccines, there is a need for alternative sources of effective chemotherapy for African trypanosomiasis (AT). The increasing rate of resistance and toxicity of commercially available antitrypanosomal drugs also necessitates an investigation into the mode of action of new antitrypanosomals for AT. In this study, furoquinoline 4, 7, 8-trimethoxyfuro (2, 3-b) quinoline (compound 1) and oxylipin 9-oxo-10, 12-octadecadienoic acid (compound 2) were isolated from the plant species Zanthoxylum zanthoxyloides (Lam) Zepern and Timler (root), and their in vitro efficacy and mechanisms of action investigated in Trypanosoma brucei (T. brucei), the species responsible for AT. Both compounds resulted in a selectively significant growth inhibition of T. brucei (compound 1, half-maximal effective concentration EC50 = 1.7 μM, selectivity indices SI = 74.9; compound 2, EC50 = 1.2 μM, SI = 107.3). With regards to effect on the cell cycle phases of T. brucei, only compound 1 significantly arrested the second growth-mitotic (G2-M) phase progression even though G2-M and DNA replication (S) phase arrest resulted in the overall reduction of T. brucei cells in G0-G1 for both compounds. Moreover, both compounds resulted in the aggregation and distortion of the elongated slender morphology of T. brucei. Analysis of antioxidant potential revealed that at their minimum and maximum concentrations, the compounds exhibited significant oxidative activities in T. brucei (compound 1, 22.7 μM Trolox equivalent (TE), 221.2 μM TE; compound 2, 15.0 μM TE, 297.7 μM TE). Analysis of growth kinetics also showed that compound 1 exhibited a relatively consistent growth inhibition of T. brucei at different concentrations as compared to compound 2. The results suggest that compounds 1 and 2 are promising antitrypanosomals with the potential for further development into novel AT chemotherapy.
Highlights
African trypanosomiasis (AT), a tsetse-transmitted disease of humans and livestock caused by the protozoan parasites of the genus Trypanosoma, is of serious health and economic concerns to humans and livestock of various sub-Saharan African countries [1,2]
Gas chromatography-mass spectrometric (GC-MS) identification of compounds occurred at m/z of approximately 259 (4,7,8-trimethoxyfuro (2, 3-b) quinoline: compound 1) and 294 (9-oxo-10, 12-octadecadienoic acid (9-oxo-ODA): compound 2), respectively (Figures 1A and 2A)
This study demonstrates the chemotherapeutic properties of 9-oxo-ODA and skimmianine against African trypanosomes
Summary
African trypanosomiasis (AT), a tsetse-transmitted disease of humans and livestock caused by the protozoan parasites of the genus Trypanosoma, is of serious health and economic concerns to humans and livestock of various sub-Saharan African countries [1,2]. To meet the need for novel, less toxic and more efficient chemotherapy in African trypanosomiasis, the urgency for alternative sources of potential antitrypanosomals remains considerably high. In this regard, plant-based natural products may hold significant potential as alternative chemotherapeutic agents for the control of AT [8,9,10,11]. Timler (Z. zanthoxyloides) in Trypanosoma brucei (T. brucei) have been reported [14] Even though these studies suggest that furoquinoline alkaloids may play critical roles in the antimicrobial properties of Rutaceae, furoquinolines responsible for the potential antitrypanosomal activities of Rutaceae have not been identified
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