title: Fluoroquinolones: A micro-species equilibrium in the protonation of amphoteric compounds.
abstract: The knowledge of the speciation of fluoroquinolones is of great actuality for the implications on the activity, bioavailability and pharmacokinetics. Literature reports a number of contrasting evaluations on the existence of tautomeric forms of mono-protonated species, described by a set of protonation micro-constants. Here the protonation sequence and the related protonation constants of four representative molecules are evaluated by a combined potentiometric-spectrophotometric method. The experimental observations necessary to differentiate between a protonation scheme represented by macro-constants alone, and the one that requires the introduction of a micro-protonation scheme, are clearly delineated based on a careful analysis of experimental data and of simulated models. The role of the medium was investigated and UV-vis spectra in water- methanol solution were analyzed. The existence of the zwitterionic species alone at physiological pH in water, and an increase of the relative amount of the neutral species with the lipophilicity of the medium were remarked. This surely affects the bioavailability of FQs, with the increase of the neutral species when the molecules approach the local lipophilic environment close to the cellular membranes. NMR studies allowed the attribution of the protonation sites of the different forms. Quantum chemical evaluation of all the possible existent forms with different protonation degrees and in different sites strongly substantiates the experimental results. The study of the relevant frontier molecular orbitals completed the detailed theoretical characterization of the species.
authors: Dipartimento di Scienze Chimiche e Geologiche, Università di Cagliari, Cittadella Universitaria, 09042, Monserrato-Cagliari, Italy. Electronic address: nurchi@unica.it.
authors: Valeria M
authors: VM
authors: Nurchi
authors: Dipartimento di Scienze Chimiche e Geologiche, Università di Cagliari, Cittadella Universitaria, 09042, Monserrato-Cagliari, Italy.
authors: Guido
authors: G
authors: Crisponi
authors: Dipartimento di Scienze Chimiche e Geologiche, Università di Cagliari, Cittadella Universitaria, 09042, Monserrato-Cagliari, Italy.
authors: Joanna I
authors: JI
authors: Lachowicz
authors: Dipartimento di Chimica e Farmacia, Via Vienna 2, 07100 Sassari, Italy.
authors: Maria Antonietta
authors: MA
authors: Zoroddu
authors: Dipartimento di Chimica e Farmacia, Via Vienna 2, 07100 Sassari, Italy.
authors: Massimiliano
authors: M
authors: Peana
authors: Dipartimento di Chimica e Farmacia, Via Vienna 2, 07100 Sassari, Italy.
authors: Serenella
authors: S
authors: Medici
authors: Dipartimento Politecnico, Laboratori di Tecnologie Chimiche, Università di Udine, Via del Cotonificio 108, 33100 Udine, Italy.
authors: Daniele
authors: D
authors: Veclani
authors: Dipartimento Politecnico, Laboratori di Tecnologie Chimiche, Università di Udine, Via del Cotonificio 108, 33100 Udine, Italy.
authors: Marilena
authors: M
authors: Tolazzi
authors: Dipartimento Politecnico, Laboratori di Tecnologie Chimiche, Università di Udine, Via del Cotonificio 108, 33100 Udine, Italy. Electronic address: andrea.melchior@uniud.it.
authors: Andrea
authors: A
authors: Melchior
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry*; D024841:Fluoroquinolones / Q000737:chemistry*; D011199:Potentiometry; D011522:Protons; D013053:Spectrophotometry
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D011522:Protons
keywords: DFT computational study; Fluoroquinolones; NMR; Potentiometry; Protonation micro-constants; Spectrophotometry