We have previously described a number of lipophilic conformationally constrained spiro carbocyclic 2,6-diketopiperazine (2,6-DKP)-1-acetohydroxamic acids as potent antitrypanosomal agents. In this report, we extend the SAR analysis in this class of compounds with respect to in vitro growth inhibition of Trypanosoma and Leishmania parasites. Introduction of bulky hydrophobic substituents at the vicinal position of the basic nitrogen atom in the spiro carbocyclic 2,6-DKP ring system can provide analogues which are potently active against bloodstream form Trypanosoma brucei and exhibit significant activities toward Trypanosoma cruzi epimastogotes and Leishmania infantum promastigotes and intracellular amastigotes. In particular, compounds possessing a benzyl or 4-chlorobenzyl substituent were found to be the most active growth inhibitors, with activities in the low nanomolar and low micromolar ranges for T. brucei and L. infantum, respectively. The benzyl-substituted (S)-enantiomer was the most potent derivative against T. brucei (IC = 6.8 nm), T. cruzi (IC = 0.21 μm), and L. infantum promastigotes (IC = 2.67 μm) and intracellular amastigotes (IC = 2.60 μm). Moreover, the (R)-chiral benzyl-substituted derivative and its racemic counterpart displayed significant activities against L. donovani. Importantly, the active compounds show high selectivity in comparison with two mammalian cell lines.
Graphical abstractAn explanation for the vast difference observed in the trypanocidal activity between the new secondary (N-methylated) hydroxamic acids 5 and 6, and their primary (nonmethylated) congeners 1a and 2, based on their E/Z conformational behaviour in DMSO, is presented.
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 T. brucei. Results: All the analogues were remarkably potent inhibitors, with low micromolar to submicromolar activities. Structureactivity 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. Conclusions: 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 analogues were found to be highly selective against T. brucei with respect to mammalian cells.
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