Modeling the Photochemistry of the Reference Phototoxic Drug Lomefloxacin by Steady-State and Time-Resolved Experiments, and DFT and Post-HF Calculations

The irradiation in water of 1-ethyl-6,8-difluoro-7(3-methylpiperazino) 3-quinolone-2-carboxylic acid (lomefloxacin), a bactericidal agent whose use is limited by its serious phototoxicity (and photomutagenicity in the mouse), leads to formation of the aryl cation in position eight that inserts into the 1-ethyl chain. Trapping of the cation was examined and it was found that chloride and bromide straightforwardly add in position eight, but with iodide and with pyrrole the 1-(2-iodoethyl) and the 1-[2-(2-pyrrolyl)ethyl] derivatives are formed. DFT and post-HF methods have shown that the triplet is the lowest state of the cation and intersystem crossing to the singlet has no role because a less endothermic process occurs, that is, intramolecular hydrogen abstraction from the N-ethyl chain that finally leads to cyclization. These findings suggest that the mutagenic activity of the DNA-intercalated drug involves attack of the photogenerated cation to the heterocyclic bases.