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Nowadays, fluoroquinolones (FQs) constitute one of the most important classes of antibiotics. FQs are used to treat infections caused by Gram-positive and Gram-negative species. A set of fluoroquinolone–Safirinium dye hybrids has been synthesized in our laboratory as potential new dual-action antibacterial agents. In the present study we have evaluated how such a modification influences the affinity of FQs to phospholipids. The immobilized artificial membrane (IAM) high-performance liquid chromatography (IAM-HPLC) was used as a tool for the determination of phospholipids partitioning. The obtained results indicate that the fluoroquinolone–Safirinium dye hybrids, especially the SafiriniumP conjugates, display significantly lower affinity to phospholipids than the parent FQs. Despite the fact that the hybrid structures comprise a quaternary nitrogen atom and hence are permanently charged, the attractive electrostatic interactions between the solutes and negatively charged phospholipids do not occur or occur at a lesser extent than in the case of the unmodified FQs. Since affinity of FQs to phospholipids involves molecular mechanism, which is not entirely determined by lipophilicity, assessment of phospholipid partitioning should be considered at the early stage of the development of new FQ antibiotics.

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Currently, rapid evaluation of the physicochemical parameters of drug candidates, such as lipophilicity, is in high demand owing to it enabling the approximation of the processes of absorption, distribution, metabolism, and elimination. Although the lipophilicity of drug candidates is determined using the shake flash method (n-octanol/water system) or reversed phase liquid chromatography (RP-LC), more biosimilar alternatives to classical lipophilicity measurement are currently available. One of the alternatives is immobilized artificial membrane (IAM) chromatography. The present study is a continuation of our research focused on physiochemical characterization of biologically active derivatives of isoxazolo[3,4-b]pyridine-3(1H)-ones. The main goal of this study was to assess the affinity of isoxazolones to phospholipids using IAM chromatography and compare it with the lipophilicity parameters established by reversed phase chromatography. Quantitative structure–retention relationship (QSRR) modeling of IAM retention using differential evolution coupled with partial least squares (DE-PLS) regression was performed. The results indicate that in the studied group of structurally related isoxazolone derivatives, discrepancies occur between the retention under IAM and RP-LC conditions. Although some correlation between these two chromatographic methods can be found, lipophilicity does not fully explain the affinities of the investigated molecules to phospholipids. QSRR analysis also shows common factors that contribute to retention under IAM and RP-LC conditions. In this context, the significant influences of WHIM and GETAWAY descriptors in all the obtained models should be highlighted.

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