Novel lipophilic acetohydroxamic acid derivatives based on conformationally constrained spiro carbocyclic 2,6-diketopiperazine scaffolds with potent trypanocidal activity.

Fytas, Christos; Zoidis, Grigoris; Tzoutzas, Nikolaos; Taylor, Martin C; Fytas, George; Kelly, John M; (2011) Novel lipophilic acetohydroxamic acid derivatives based on conformationally constrained spiro carbocyclic 2,6-diketopiperazine scaffolds with potent trypanocidal activity. Journal of medicinal chemistry, 54 (14). pp. 5250-5254. ISSN 0022-2623 DOI: https://doi.org/10.1021/jm200217m

Abstract

We describe novel acetohydroxamic acid derivatives with potent activity against cultured bloodstream-form Trypanosoma brucei and selectivity indices of >1000. These analogues were derived from conformationally constrained, lipophilic, spiro carbocyclic 2,6-diketopiperazine (2,6-DKP) scaffolds by attaching acetohydroxamic acid moieties to the imidic nitrogen. Optimal activity was achieved by placing benzyl groups adjacent to the basic nitrogen of the 2,6-DKP core. S-Enantiomer 7d was the most active derivative against T. brucei (IC(50) = 6.8 nM) and T. cruzi (IC(50) = 0.21 μM).

Additional Information

Item Type	Article
Keywords	trypanosoma-brucei, inhibitors, design, protein
Faculty and Department	Faculty of Infectious and Tropical Diseases > Department of Infection Biology
PubMed ID	21542562
ISI	292892300028
Related URLs	OA Location