Synthesis and antimicrobial activity of ciprofloxacin and norfloxacin permanently bonded to polyethylene glycol by a thiourea linker

Abstract

C 2 -symmetric (divalent) biologically active molecules are an extensively studied field, as certain substances possessing a B-linker-B type structure (where B represents a bioactive molecule) have promising biological properties. 1 The synthesis and investigation of the dimers of the highly antibacterial quinolonecarboxylic acids were also carried out. However, the norfloxacin dimers linked with an alkyl chain, described by Coppel et al., 2 were very slightly active. Later Kerns et al. 3-5 synthesized the C 2 -symmetric and mixed dimers of ciprofloxacin and norfloxacin using 1,4-phenylenebis-methylene and 2-butene-1,4-diyl linkers. These derivatives possessed comparable activity with that of the monomers and, in a few cases, higher MIC values were found against certain drug-resistant strains.Polyethylene glycol (PEG), a cheap and nontoxic telechelic polymer diol of amphiphilic character is soluble both in water and organic solvents; therefore, it is often used as a carrier for drug molecules.Bioactive molecules linked covalently to PEG possess favorable pharmacodynamic properties due to high water solubility and lipophilicity of the polymer, and PEGylation usually results in an enhanced biological stability and the products are less immunogenic. The PEGylated drug conjugates are primarily used in a 'releasable' form (that is, in a form linked by means of bondings unstable in a biological milieu).In contrast, in the permanently bonded form, the drug molecule is attached to the polymer with covalent bondings stable in a biological milieu. The permanently bonded form is also advantageous, as numerous drug molecules introduced to therapy contains PEG in such a linkage. Related compounds are the PEGylated derivative of the bovine adenosyl deaminase enzyme ADAGEN, 6 the PEGylated L-asparagine-containing ONCASPAR, 7 PEG-INTRON, 8 which contains PEGylated interferon, and NEULASTA 9 carrying a PEGylated granulocyte-colony stimulating factor. Incorporation of the monofunctional PEG chain(s) to these protein-type bioactive molecules resulted in decreasing immunogenity of the parent compound, as well as in the increase of the circulation half-life time and the stability. There are few reports on permanently bonded drugs, but those compounds exhibit low biological activity. 10 Ciprofloxacin was encapsulated in PEG-coated, long-circulating sustained-release liposomes. 11,12 It is to be noted that Carraher et al. 13 reported the synthesis and biological activity of ciprofloxacin covalently bonded to organotin polymers of 1 and 2. Norfloxacin was also attached to methacrylate polymers. 14 The goal of this work was to investigate the antimicrobial effect of the quinolonecarboxylic acid dimers prepared with a PEG linker, and to study the effect of PEGylation on the antibacterial activity.To investigate the separate effect of the PEGylation and dimerization of 1 and 2 on the antimicrobial effect, both the mono-and bifunctional PEG derivatives of the antimicrobial agents were prepared.Monomethoxy-PEG (MW average ¼1132 Da) and PEG ...

Switchable Control of Antibiotic Activity: A Shape-Shifting “Tail” Strategy

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Antimicrobial and Antibiofilm Potential of PEGylated Chitosan-Based Nano-Antibiotics Against Multidrug-Resistant E Coli Strains

“…Moreover, PEG is a non-toxic polymer with having amphiphilic nature, as it can dissolve into both water and organic solvents. Biologically active materials when linked to PEG, can have enhanced properties of pharmacodynamics because of the amphiphilic nature of PEG (Pintér et al 2009). Surface modification with PEG-like PEGylated conjugates provides better stability, enhanced controlled release, low immunogenic response, and prolonged systemic circulation time (Ghitman et al 2018).…”

Polymer therapeutics in surgery: the next frontier

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