Modulation of penile erection in rabbits by mondia whitei: possible mechanism of action

The plant Zanthoxylum zanthoxyloides (Lam.) Zepern. & Timler is one of the most important medicinal species of the genus Zanthoxylum on the African continent. It is used in the treatment and management of parasitic diseases in sub-Saharan Africa. These properties have inspired scientists to investigate species within the genus for bioactive compounds. However, a study, which details a spectroscopic, spectrometric and bioactivity guided extraction and isolation of antiparasitic compounds from the genus Zanthoxylum is currently non-existent. Tortozanthoxylamide (1), which is a derivative of the known compound armatamide was isolated from Z. zanthoxyloides and the full structure determined using UV, IR, 1D/2D-NMR and high-resolution liquid chromatography tandem mass spectrometry (HRESI-LC-MS) data. When tested against Trypanosoma brucei subsp. brucei, the parasite responsible for animal African trypanosomiasis in sub-Saharan Africa, 1 (IC₅₀ 7.78 µM) was just four times less active than the commercially available drug diminazene aceturate (IC₅₀ 1.88 µM). Diminazene aceturate is a potent drug for the treatment of animal African trypanosomiasis. Tortozanthoxylamide (1) exhibits a significant antitrypanosomal activity through remarkable alteration of the cell cycle in T. brucei subsp. brucei, but it is selectively non-toxic to mouse macrophages RAW 264.7 cell lines. This suggests that 1 may be considered as a scaffold for the further development of natural antitrypanosomal compounds.

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.