Combined HQSAR method and molecular docking study on genotoxicity mechanism of quinolones with higher genotoxicity.

Using the hologram quantitative structure-activity relationship (HQSAR) method, a quantitative model of the structure-activity relationship between the genotoxicity of quinolones towards gram-negative bacteria and structure of quinolones is constructed. A series of novel quinolones are designed, and 4 environmentally friendly quinolone derivatives are finally selected, because of their enhanced genotoxicity towards gram-negative/positive bacteria, decreased bioconcentration and increased photodegradability and biodegradability. The mechanisms underlying the genotoxicity of quinolones and its derivatives are analysed based on amino acid residues and molecular interactions. Three hydrophilic amino acids [arginine (ARG), asparagine (ASN) and aspartic acid (ASP)] play important roles in the antibacterial effects of quinolones. The introduction of highly hydrophilic groups into the C-7 position of amifloxacin (AMI) not only improved the stability of the AMI derivative-topoisomerase IV-DNA complex but also improved the antibacterial activities of AMI derivatives.