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Ciprofloxacin derivative – improvement of its solubility, permeability and antibacterial activity by deep eutectic solvent

Deep eutectic solvents (DES) have emerged as a promising option in the search for novel solvents that comply with green chemistry guidelines. As they are non-toxic, non-flammable, and non- volatile they represent a good replacement for standardly used organic solvents. They are made of two or more renewable compounds that are found in nature, which when combined in a specific moral ratio and heated become homogenized liquid, stable at room temperature. With more than a million options for their synthesis as well as proven antibacterial activity, in the present work, we have used them as a solvent to improve some of the pharmaceutically relevant characteristics of ciprofloxacin derivate. As it is known antibacterial resistance is a global problem in medicinal treatments and healthcare. It is pivotal to find new alternatives to commonly known antibiotics, in order to overpass this problem. Ciprofloxacin is a clinically used antibiotic, from a group of fluoroquinolones. To bridge the resistance problem N-acylated chiral derivate of ciprofloxacin with CH(CH3)CH2CH2CH3 group was synthesized (1-Cyclopropyl-6-fluoro-7-[4-(2- methyl-pentanoyl)- piperazin-1-yl]-4-oxo-1, 4- dihydroquinoline-3- carboxylic acid). To further improve potential of herein synthesized ciprofloxacin derivate we aimed to design it as a THEDES (Therapeutic Deep Eutectic Solvent), which is a mixture of chosen API and forming compounds commonly used for the synthesis of DES. Solubility of ciprofloxacin derivate in DES was tested in silico using Cosmo Therm program. Options with the lowest lnγ value, which indicates the best solubility, were tested experimentally. We also tested permeability by using in vitro model of passive permeation the Parallel Artificial Membrane Permeability Assay (PAMPA). The antimicrobial potential of this novel ciprofloxacin derivate formulation was assessed by disk diffusion assay on different microbial cultures. According to the obtained results, the chosen ciprofloxacin derivative in a form of THEDES shows many benefits and seemingly overpasses current problems in more than one way.

antimicrobial activity, ciprofloxacin derivative, DES, PAMPA, solubility

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