RESUMO
Ruthenium(II) alkyne azide cycloaddition (RuAAC) is an attractive reaction to access 1,5-triazole derivatives and is applicable to internal alkynes. Here, we explore RuAAC to introduce molecular diversity on the diazabicyclooctane (DBO) scaffold of ß-lactamase inhibitors. The methodology presented is fully regioselective and enabled synthesis of a series of 1,5-triazole DBOs and trisubstituted analogues. Molecular modelling and biological evaluation revealed that the DBO substituents provided putative stabilizing interactions in the active site of broad-spectrum ß-lactamase KPC-2 and promising activity against a hyperpermeable strain of Escherichia coli producing KPC-2.
Assuntos
Rutênio , Inibidores de beta-Lactamases , Inibidores de beta-Lactamases/química , Rutênio/farmacologia , Rutênio/química , Reação de Cicloadição , Azidas , Triazóis/química , Catálise , AlcinosRESUMO
Treatment of multidrug-resistant tuberculosis with combinations of carbapenems and ß-lactamase inhibitors carries risks for dysbiosis and for the development of resistances in the intestinal microbiota. Using Escherichia coli producing carbapenemase KPC-2 as a model, we show that carbapenems can be modified to obtain drugs that are inactive against E. coli but retain antitubercular activity. Furthermore, functionalization of the diazabicyclooctanes scaffold provided drugs that did not effectively inactivate KPC-2 but retained activity against Mycobacterium tuberculosis targets.
