Abstract
Tetramethyl-piperidine-substituted, B4119 and B4158 have been shown to exhibit antiplasmodial activity. 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. 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. 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). 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.
Highlights
The World Health Organization reported around 207 million cases of malaria in 20121.More than 80% of the world’s malaria casualties occur in Africa, involving mostly children under the age of five and pregnant women[2,3]
In an effort to minimize side-effects and to improve activity, derivatives of clofazimine, called TMP substituted phenazines were designed. They differ from clofazimine structurally as they contain the TMP group which have been extensively studied for a variety of biological activity among which are anti-tumor, antimicrobial, antimycobacterial and antimalarial activities
The anti-growth effect of chloroquine disulphate (0-250 ƞ M, final concentration) and TMP-phenazines (0.125-2 μg/ml) of the pfUP10 and RB-1 laboratory strains of Plasmodium falciparum was measured by a flow cytometric method
Summary
The World Health Organization reported around 207 million cases of malaria in 20121.More than 80% of the world’s malaria casualties occur in Africa, involving mostly children under the age of five and pregnant women[2,3]. In an effort to minimize side-effects and to improve activity, derivatives of clofazimine, called TMP (tertramethyl-piperidyl) substituted phenazines were designed. They differ from clofazimine structurally as they contain the TMP group which have been extensively studied for a variety of biological activity among which are anti-tumor, antimicrobial, antimycobacterial and antimalarial activities. 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. 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. In vitro investigation of clofazimine analogues for antiplasmodial, cytotoxic and pro-oxidative activities
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