In vitro investigation of clofazimine analogues for antiplasmodial, cytotoxic and pro-oxidative activities

Background: Tetramethyl-piperidine-substituted, B4119 and B4158 have been shown to exhibit antiplasmodial activity.Objectives: The in vitro antiplasmodial, cytotoxic and oxidative activities of clofazimine and its analogues, all TMP (tetramethylpiperidyl)- substituted phenazines except B669, were evaluated in this study.Methods: The antiplasmodial activity of the compounds against RB-1 and pfUP10 laboratory strains of Plasmodium falciparum was investigated by flow cytometry. The cytotoxic activity against HeLa cells and oxidative activity were studied employing colorimetric and cytochrome C reduction assays respectively.Results: The riminophenazine agents exhibited antiplasmodial action of varying degrees: B669, B4100 and B4103 showed the best activity while B4121 and B4169 exhibited significant activity at 2μg/ml. Clofazimine had no antiplasmodial activity. The compounds B4100, B4103, B4121 and B4169 exhibited significant cytotoxic activity against HeLa cells at concentrations of 0.5μg/ml and above while B669 was active at 2μg/ml. Clofazimine and B669 tested at a concentration of 0.5μg/ml caused enhancement (p ≤ 0.05) of neutrophil superoxide production when compared to the FMLP control while all the other TMP-derivatives had no effect (p ≥ 0.05).Conclusion: Tetramethylpiperidyl-subsituted phenazines may potentially be useful antimalarial/antitumor agents with no pro-oxidative properties. In vivo studies on the agents relative to these properties are recommended.Keywords: Riminophenazines, malaria, cytotoxicity and superoxide anion