Abstract
Most studies on adverse drug reactions (ADRs) of fluoroquinolones (FQs) have focused on the mechanisms of single ADRs, and no quantitative structure–activity relationship (QSAR) method studies have been carried out that combine several ADRs of FQs. In this study, an improved three-dimensional (3D) QSAR method was established using fuzzy comprehensive evaluation. This method could simultaneously consider three common ADRs of FQs using molecular parameters. The improved method could comprehensively predict three ADRs of FQs and provide direction for the development of new drugs with lower ADRs than the originals. According to the improved method, 48 derivatives with lower ADRs (decreased by 4.86% to 50.92%) were designed from pazufloxacin. Three derivatives with a higher genotoxicity, higher photodegradation, and lower bioconcentration than pazufloxacin were selected using the constructed QSAR methods of the FQs. Finally, three traditional 3D-QSAR methods of single ADR were constructed to validate the improved method. The improved method was reasonable, with a relative error range of 0.96% to 4.30%. This study provides valuable reference data and will be useful for the development of strategies to produce new drugs with few ADRs. In the absence of complementary biological studies of these adverse drug reactions, the results reported here may be quite divergent from those found in humans or experimental animals in vivo. One major reason for this is that many adverse drug reactions are dependent upon enzyme-catalyzed metabolic activation (toxication) or on non-enzymatic conversion to toxic products and are not due to the parent drug moiety.
Highlights
Quinolone antibiotics are a class of antibacterial agents with a wide range of activity.Fluoroquinolones (FQs, Figure 1) have broad-spectrum and strong antibacterial activity and good tissue distribution [1]
In the absence of complementary biological studies of these adverse drug reactions, the results reported here may be quite divergent from those found in humans or experimental animals in vivo
One major reason for this is that many adverse drug reactions are dependent upon enzyme-catalyzed metabolic activation or on non-enzymatic conversion to toxic products and are not due to the parent drug moiety
Summary
Quinolone antibiotics are a class of antibacterial agents with a wide range of activity. There are more than a dozen common FQs in clinical use These drugs target bacterial DNA gyrase and inhibit bacterial DNA helix-promoting enzymes so that DNA cannot control the transcription and translation of RNA and proteins. FQs antimicrobial widespread distribution in FQshave havebroad-spectrum broad-spectrumantimicrobial antimicrobialactivity, activity,widespread widespreaddistribution distributionin invivo, vivo,and andhigh high. They are widely used in human health, aquaculture, and animal husbandry. FQstructure structure similar thatofofantagonists antagonists thecentral central nervoussystem system inhibitor, γ-aminobutyric acid (GABA), it can interfere with binding to receptors, inhibit activity, produce central excitatory effects, release excitatory thresholds, and even induce convulsions.
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