Metalloform-selective inhibition: Synthesis and structure–activity analysis of Mn(II)-form-selective inhibitors of Escherichia coli methionine aminopeptidase

Methionine aminopeptidase (MetAP) is a promising target for development of novel antibacterial, antifungal and anticancer agents. However, its physiologically relevant metal ion remains to be defined, and its inhibitors need to inhibit the in vivo metalloform. Based on the Mn(II)-form-selective inhibitors discovered by high throughput screening as leads, a series of analogs of 5-phenylfuran-2-carboxylic acid was prepared and subsequently evaluated on Co(II)-, Mn(II)-, Ni(II)-, and Fe(II)-forms of Escherichia coli MetAP, in order to define the structural elements responsible for their inhibitory potency and metalloform selectivity. Various substitutions on the phenyl ring changed their potency on the Mn(II)-form but not their metalloform selectivity. We conclude that the preferential coordination of the carboxyl group to Mn(II) ions is the major determinant for their superb selectivity toward the Mn(II)-form. Changing the carboxylate to hydroxamate alters its ability to bind and discriminate different metal ions, and the hydroxamate derivative becomes non-selective among the metalloforms tested.