Towards catalytic fluoroquinolones: from metal-catalyzed to metal-free DNA cleavage

Abstract

A library of eight new fluoroquinolone–nuclease conjugates containing a guanidinoethyl or aminoethyl auxiliary pendant on the 1,4,7-triazacyclononane (TACN) moiety was designed and synthesized to investigate their potential as catalytic antibiotics. The Cu(II) complexes of the designer structures showed significant in vitro hydrolytic and oxidative DNA cleavage activity and good antibacterial activity against both Gram-negative and Gram-positive bacteria. The observed activity of all the Cu(II)–TACN–ciprofloxacin complexes was strongly inhibited in the presence of Cu(II)-chelating agents, thereby demonstrating “vulnerability” under physiological conditions. However, selected TACN–ciprofloxacin conjugates in their metal-free form efficiently cleaved plasmid DNA under physiological conditions. The lead compound 1 showed good DNase activity which was retained in the presence of strong metal chelators and exhibited excellent antibacterial activity against both Gram-negative and Gram-positive bacteria. Density functional theory calculations combined with quantum mechanics/molecular mechanics simulations suggest a general base–general acid mechanism for the hydrolytic DNA cleavage mechanism by compound 1.