Combinatorial multicomponent access to natural-products-inspired peptidomimetics: discovery of selective inhibitors of microbial metallo-aminopeptidases.

The development of selective inhibitors of microbial metallo-aminopeptidases is an important goal in the pursuit of antimicrobials for therapeutic applications. Herein, we disclose a combinatorial approach relying on two Ugi reactions for the generation of peptidomimetics inspired by natural metallo-aminopeptidase inhibitors. The library was screened for inhibitory activity against the neutral metallo-aminopeptidase of Escherichia coli (ePepN) and the porcine kidney cortex metallo-aminopeptidase (pAPN), which was used as a model of the M1-aminopeptidases of mammals. Six compounds showed typical dose-response inhibition profiles toward recombinant ePepN, with two of them being very potent and highly selective for ePepN over pAPN. Another compound showed moderate ePepN inhibition but total selectivity for this bacterial enzyme over its mammalian orthologue at concentrations of physiological relevance. This strategy proved to be useful for the identification of lead compounds for further optimization and development.