Photophysics and Photochemistry of Nalidixic Acid†

Abstract

The photophysics and photochemistry of nalidixic acid (NA) were studied as function of pH and solvent properties. The ground state of NA exhibits different protonated forms in the range of pH 1.8-10.0. Fluorescence studies showed that the same species exist at the lowest singlet excited state. Absorption experiments were carried out with NA and with the methylated analog of nalidixic acid (MNE) in different organic solvents and water pH 3, where the main species corresponds to that protonated at the carboxylic group. These studies and the DFT calculation of torsional potential energy profiles suggest that the most stable conformation of the NA in nonprotic solvents corresponds to a closed structure caused by the existence of intramolecular hydrogen bond. Absorption and fluorescence spectra were studied in sulfuric acid solution. The pK value (Ho -1.0) found in these conditions was attributed to the protonation of the 4' keto oxygen atom of the heterocyclic ring. Theoretical calculations (DFT/B3LYP/6-311G*) of the energies of the different monoprotonated forms of the NA and Fukui indexes (f(x)-) showed that the species with the proton attached to 4' keto oxygen atom is the most stable of all the cationic forms. MNE and enoxacin also showed the protonation of the 4' keto oxygen atom with similar pK values. The photodecomposition of NA is dependent on the medium properties. Faster decomposition rates were obtained in strong acid solution. In nonprotic solvents, a very slow decomposition rate was observed.

Structure and Medium Effects on the Photochemical Behavior of Nonfluorinated Quinolone Antibiotics†

“…The pK 3 values are shown in Table 1. A similar protonation equilibrium was previously found for NA and its fluorinated analogous, enoxacin (6). This equilibrium could be assigned to the protonation of the carbonyl group at position 4.…”

“…Whereas, for norfloxacin that does not have N atom at position 8, U F increases at pH 3.5 (5,21,22). The fluorescence quenching under basic conditions has also been found for several quinolone derivatives (6,7,19,23). For fluoroquinolones bearing the piperazinyl group at the 7-carbon atom, this fact has been attributed to a decrease in the intrinsic radiative constant (7).…”

“…On the other hand, the decarboxylation products of NA in methanolic solution have been identified (8). We have reported that the photodecomposition rate of NA is strongly dependent on the medium properties (6). However, the effect of the different substituents in the heterocyclic ring on the photodecomposition rate has not been yet well determined.…”

“…The photochemical and photophysical behavior of nonfluorinated quinolone antibiotics has received less attention. Recently, we reported that the photophysical and photochemical properties of NA, a drug structurally related to naphthyridines, are strongly dependent on pH and medium properties (6). This dependence is undoubtedly caused by the presence of different sites for potential protonation processes.…”

Synthesis of 1,4‐Dihydropyridines and Their Fluorescence Properties

“…In less‐polar solvents, such as cyclohexane, 9e exhibited a hypochromic effect, and in other polar solvents (such as ethyl acetate, acetonitrile, and DMSO), it exhibited a bathochromic effect (Table 10 and Figure 4). These results suggest that the excitation state of 9e is stabilized by polar solvents 4e…”