In-vivo antitrypanosomal effect and in-silico prediction of chronic toxicity of N-methylholaphyllamine in rats

Purpose: To determine the in-vivo anti-trypanosomal effect and sub-chronic toxicity of Nmethylholaphyllamine (MHA) isolated from H. africana against Trypanosoma brucei in rats and also to predict its toxicity by an in-silico method. Methods: Parasitemia was induced in rats with 1.5 x 105/mL trypanosomes and treatment commenced 5 days post-infection for 12 days. The rats were treated with MHA (3.5 μM/rat) for 5 days and with diminazene (3.5 mg/kg) for 2 days and were monitored every other day during and after treatment for the level of parasitemia and PCV. The chronic toxicity study was carried out with a 28-day sub-chronic toxicity cycle protocol while the toxicity was predicted in-silico with ProTox-II which is freely available on a web server. Results: MHA exhibited anti-trypanosomal effect in infected rats leading to the restoration of PCV to baseline values (≥ 40 %) on the 14th day and consequent disappearance of parasitemia on day 17 post-infection with no relapse. The slight changes in clinical observation, weight, feed consumption, clinical and histopathology of high-dose MHA rats were not significant (p < 0.05) and were not attributed to the treatment. Apart from MHA-induced immunotoxicity observed in in-silico prediction, no other predicted toxicities were significant; however, few undetected toxicities were found to be mediated by amine oxidase A, androgen and/or histamine, H1 receptors toxicophore fit. Conclusion: The high in-vivo antitrypanosomal effect and non-toxicity of MHA in this study further provide useful empirical data for lead optimization of MHA to combat sleeping sickness