Abstract
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.
Highlights
Fluoroquinolones (FQs) are one of the most commonly prescribed classes of antibiotics and show a broad spectrum of antibacterial activity, including against both Gram-positive and Gram-negative bacterial species
immobilized artificial membrane (IAM)-HPLC was introduced by Pidgeon in 1989 [21], and it was proposed as an alternative for liposome’s partitioning
We have chosen the chromatographic hydrophobicity indices (CHIIAM ) approach proposed by Valko and co-workers [22], which involves gradient elution using an IAM column
Summary
Fluoroquinolones (FQs) are one of the most commonly prescribed classes of antibiotics and show a broad spectrum of antibacterial activity, including against both Gram-positive and Gram-negative bacterial species. FQs originate from the nalidixic acid structure, and their major modifications include the introduction of a fluorine atom at the position 6 and the addition of a piperazine moiety at the position 7 of the quinolone ring [1]. A number of research groups develop hybrid compounds based on FQs structures linked to other antibacterial agents [2]. This concept of “dual-action drugs” has been gaining popularity since such hybrid drugs show synergistic molecular action, which enhances affinity and efficacy when compared to parent drugs. The dual-drug conjugates demonstrate the capability to reduce cross-resistance, and one part of a hybrid may counterbalance the known side effects associated with the other part of the drug [2,3].
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