Identification and optimization of quinolone-based inhibitors against cytochrome bd oxidase using an electrochemical assay

Abstract A target-focused library of small molecules, containing a set of quinones, quinolones, coumarins, flavonoids and other diverse drugs was screened to identify potential inhibitors of the cytochrome bd-I oxidase from Escherichia coli by means of an electrochemical assay based on the immobilization of the proteins on gold nanoparticles. As primary hits, three quinolone fragments were identified with inhibition activity in this study. As a hit-to-lead optimization approach, a series of more complex natural product-based quinolones substituted in position 3 by an isoprenyl chain of various lengths were synthetized in order to increase the inhibitory efficiency of the initial hit fragments. We show that the efficiency of these molecules depends on the length of their isoprenyl side chain.