RESUMO
A series of isoxazole-3-hydroxamic acid derivatives has been identified as a new class of small, nonpeptidic inhibitors of peptide deformylase (PDF). The synthesis, enzyme inhibition and preliminary investigation of the binding mode of this potential antibacterial compounds are reported.
Assuntos
Amidoidrolases/antagonistas & inibidores , Antibacterianos/farmacologia , Ácidos Hidroxâmicos/farmacologia , Isoxazóis/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Escherichia coli/efeitos dos fármacos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/química , Isoxazóis/síntese química , Isoxazóis/química , Modelos Moleculares , Estrutura Molecular , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
A pyridoxamine equivalent, 9-aminothioxanthene 10,10-dioxide, has been designed that is capable of affording transamination in good to excellent yields of natural as well as artificial amino acids. Amidines and guanidines in catalytic amounts were capable of performing [1,3]-proton transfer in the imines under mild conditions, whereas various simple amines failed. The use of chiral catalysts resulted in modest asymmetric induction (ee < or = 45%). The electronic dependence in para-substituted phenyl glyoxylate imines, isotope effects, and computational studies support a stepwise, bifunctional mechanism for amidine and guanidine catalysts. Attempts toward an autocatalytic model system are described.