title: Novel lipophilic acetohydroxamic acid derivatives based on conformationally constrained spiro carbocyclic 2,6-diketopiperazine scaffolds with potent trypanocidal activity.
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).
authors.affiliation: Faculty of Pharmacy, Department of Pharmaceutical Chemistry, University of Athens, Panepistimioupoli-Zografou, GR-15771, Athens, Greece.
authors.forename: Christos
authors.initials: C
authors.lastname: Fytas
authors.forename: Grigoris
authors.initials: G
authors.lastname: Zoidis
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Tzoutzas
authors.forename: Martin C
authors.initials: MC
authors.lastname: Taylor
authors.forename: George
authors.initials: G
authors.lastname: Fytas
authors.forename: John M
authors.initials: JM
authors.lastname: Kelly
mesh_terms: D000818:Animals; D002460:Cell Line; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008968:Molecular Conformation; D021261:Parasitic Sensitivity Tests; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects; D014349:Trypanosoma cruzi / Q000187:drug effects
chemical_list: D006877:Hydroxamic Acids; D010879:Piperazines; D013141:Spiro Compounds; D014344:Trypanocidal Agents