New Lipophilic Hydroxamates as Promising Trypanocidal Agents: Design, Synthesis, SAR, and Conformational Behavior Studies

A series of novel hydroxamic acid derivatives was designed
and
synthesized, and their growth inhibitory activity against bloodstream
form Trypanosoma brucei was evaluated. These compounds
are based on conformationally constrained, lipophilic, spiro carbocyclic
2,6-diketopiperazine (2,6-DKP) scaffolds and bear a side pharmacophoric
functionality that contains an acetohydroxamic acid moiety (CH2CONHOH) linked with the imidic nitrogen atom of the 2,6-DKP
ring via an acetamido portion [CH2CON(R), R = H, CH3]. Most of these analogues were active in the midnanomolar
to low micromolar range against T. brucei. (S)-Isobutyl- or (S)-benzyl-substitution
on the methylene carbon located between the amine nitrogen atom and
carbonyl of the 2,6-DKP ring was studied. The effect of the methyl-substitution
on the nitrogen atom of the acetamido portion in the side pharmacophoric
functionality was also examined. Compounds 22 and 23, bearing an isobutyl- or benzyl-substituent, respectively,
and concurrently a methyl-substituent, were found to be the most potent
hydroxamates of this series (IC50 = 34 and 53 nM, respectively).
Both had promising selectivity over the parasite compared to mammalian
cells (SI = 940 and 470, respectively). Moreover, an E/Z conformational behavior study on hydroxamic acid 18 and its methyl-substituted counterpart 21 was undertaken
using NMR spectroscopy and theoretical calculations.