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

George Fytas ORCID logo; Grigoris Zoidis; Martin C Taylor ORCID logo; John M Kelly ORCID logo; Alexandra Tsatsaroni; Andrew Tsotinis; (2019) Novel 2,6-diketopiperazine-derived acetohydroxamic acids as promising anti-Trypanosoma brucei agents. FUTURE MEDICINAL CHEMISTRY, 11 (11). pp. 1259-1266. ISSN 1756-8919 DOI: 10.4155/fmc-2018-0599
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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.


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