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Background: Intestinal absorption of levofloxacin (LFX) is decreased by the concomitant administration of antacids due to the formation of insoluble chelate complexes with various metal cations. Methods: The following four ester prodrugs of LFX—cilexetil ester (LFX-CLX), medoxomil ester (LFX-MDX), ethoxycarbonyl 1-ethyl hemiacetal ester (LFX-EHE) and pivaloyloxymethyl ester (LFX-PVM) — were synthesized. Then, the lipophilicity, in vitro chelate formation with aluminum chloride (AlCl3), chemical and enzymatic stability, minimum inhibitory concentrations (MICs) against some bacteria, and the efficacy in preventing chelate formation of prodrugs with aluminum hydroxide (Al(OH)3) in rabbits were evaluated. Results: The synthesized ester prodrugs of LFX exhibited high purity and higher lipophilicities than LFX depending on the ester moieties. MICs of the prodrugs against S. aureus, E. coli, and P. aeruginosa were more than 10 times higher than those of LFX. Prodrugs were stable chemically but unstable enzymatically and generated LFX in biological specimens. When AlCl3 solution was mixed with LFX solution in vitro, insoluble chelate complex was formed immediately. In rabbits, co-administration of Al(OH)3 with LFX reduced the oral bioavailability of LFX by approximately 40%. In contrast, no precipitation was observed when AlCl3 solution was mixed with each prodrug solution in vitro, and co-administration of Al(OH)3 exerted no significant effect on the oral bioavailability of LFX when each prodrug was administered in rabbits. Conclusion: The ester prodrug approach of LFX could be a feasible strategy for avoiding chelate formation with aluminum ion in vivo.

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The total syntheses of the neuronal cell‐protecting carbazole alkaloids carbazomadurin A and (S)‐(+)‐carbazomadurin B were achieved. The key step of the synthesis of the polysubstituted carbazole rings included an allene‐mediated electrocyclic reaction of the 6π‐electron system that involved the indole 2,3‐bond. The cleavage of the alkoxy groups of the resulting 3‐ethoxy‐8‐isopropoxycarbazole successfully gave the 3,8‐dihydroxycarbazole, which was converted into the 3,8‐bis(OSEM)‐carbazole (SEM = 2‐trimethylsilylethoxymethyl). A Suzuki–Miyaura cross‐coupling reaction of the 3,8‐bis(OSEM)‐carbazole with the corresponding alkenyl pinacol borates afforded the 1‐alkenylcarbazoles, which were treated with tetra‐n‐butylammonium fluoride (TBAF) followed by reduction with NaBH4 to provide carbazomadurin A and (S)‐(+)‐carbazomadurin B, respectively.

Many studies have demonstrated that oxidative stress plays an important role in several ailments including neurodegenerative diseases and cerebral ischemic injury. Previously we synthesized some carbazole compounds that have anti-oxidant ability in vitro. In this present study, we found that one of these 22 carbazole compounds, compound 13 (3-ethoxy-1-hydroxy-8- methoxy-2-methylcarbazole-5-carbaldehyde), had the ability to protect neuro2a cells from hydrogen peroxide-induced cell death. It is well known that neurite loss is one of the cardinal features of neuronal injury. Our present study revealed that compound 13 had the ability to induce neurite outgrowth through the PI3K/Akt signaling pathway in neuro2a cells. These findings suggest that compound 13 might exert a neurotrophic effect and thus be a useful therapy for the treatment of brain injury.