Antitrypanosomal Activity of Novel Tryptophan Analogs

Abstract

A range of 16 novel tryptophan analogs designed as enzyme-activated inhibitors of FAD and Pyridoxal Phosphate - dependent enzymes containing acetylenic, alkenyl and/or dithiocarbamate moieties were tested for in vitro activity against Trypanosoma brucei brucei. Nine of these compounds, 1-(indole-2-y1)-2- piperazinomethyl ethyne, 1-(1-benzenesulphonylindo1-2-y1)-2-piperazinomethyl ethyne, 1-(1-benzenesulphonylido12-y1)-2-(4-methylpiperazinomethyl) ethyne, 5- (methoxyindo1-2-y1)-2-piperidino methylethyne, 1-(1-benzenesulphonylindo1-3- y1)-2-(4-methylpiperazinomethyl) ethyne, 1(1-benzenesulphony1-5-methoxyindo1- 3-y1)-2-(4-methylpiperazinomethyl) ethyne, bis [1-thiocarbonyl-4-(3-(1 -benzene-sulpholindol-2-yl} prop-2-ynyl) piperazine] disulphate, bis[' -thiocarbony1-4-(3- {indole-2-y1} prop-2-ynyl) piperazine] disulphide and bis(1 -thiocarbony1-4-(3- {5-methoxyindo1-2-yl)prop-2-ynyl) piperazine) disulphide were found to have a significant inhibitory activity at micromolar concentrations. The structure-biological activity relationships for the novel compounds is discussed with reference to the most active compound, 1-(1- benzenesulphonylindo1-2-y1)-2-(4-methylpiperazino methyl) ethyne. Possible chemical modifications on the most active "lead" compounds in order to modulate the antitrypanosomal activity and explore the possible modes of action are presented.