title: Combinatorial multicomponent access to natural-products-inspired peptidomimetics: discovery of selective inhibitors of microbial metallo-aminopeptidases.
abstract: 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.
authors.affiliation: Center for Natural Products Research, Faculty of Chemistry, University of Havana, Zapata y G, 10400, La Habana (Cuba).
authors.forename: Yanira
authors.initials: Y
authors.lastname: Méndez
authors.forename: Karell
authors.initials: K
authors.lastname: Pérez-Labrada
authors.forename: Jorge
authors.initials: J
authors.lastname: González-Bacerio
authors.forename: Gilberto
authors.initials: G
authors.lastname: Valdés
authors.forename: María Á
authors.initials: MÁ
authors.lastname: de los Chávez
authors.forename: Joel
authors.initials: J
authors.lastname: Osuna
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Charli
authors.forename: Isel
authors.initials: I
authors.lastname: Pascual
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Rivera
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D001688:Biological Products / Q000737:chemistry*; D008667:Metalloproteins / Q000037:antagonists & inhibitors*; D057786:Peptidomimetics / Q000737:chemistry*; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001688:Biological Products; D008667:Metalloproteins; D057786:Peptidomimetics; D011480:Protease Inhibitors; D000626:Aminopeptidases
keywords: aminopeptidases; combinatorial chemistry; medicinal chemistry; multicomponent reactions; protease inhibitors