Novel 2,6-diketopiperazine-derived acetohydroxamic acids as promising anti-Trypanosoma brucei agents

Aim: Identification of new, effective and selective trypanocidal agents. Materials & methods: Twelve novel acetohydroxamic acid derivatives based on 2-alkyl-2-aryl-2,6-diketopiperazine scaffolds have been synthesized and evaluated in vitro for their growth inhibitory activity against bloodstream form Trypanosoma brucei. Results: All the analogs were remarkably potent inhibitors, with low micromolar to submicromolar activities. Structure-activity relationship studies demonstrated that the presence of an alkyl substituent at the N(4)-position of the 2,6-diketopiperazine ring portion was, in general, beneficial to trypanocidal activity in this series. Conclusion: The highest activity resulted from the introduction of a methyl, n-propyl or n-butyl substituent to the N(4)-position of the parent compound. Importantly, the most potent analogs were found to be highly selective against T. brucei with respect to mammalian cells.