Fluoxetine is an antidepressant classified as a selective serotonin reuptake inhibitor (SSRI). Its bioavailability is low due to its varying dissolution at different pH levels and rapid breakdown in the liver. To address these challenges, a series of five novel fluoxetine derivatives (A1–A5) were synthesized by introducing various acyloxyalkyl carbamate groups at the fluoxetine amino moiety. The structural integrity and chromatographic purity of these derivatives were confirmed through Fourier-transform infrared (FT-IR) spectroscopy, proton nuclear magnetic resonance (¹H-NMR), and carbon-13 nuclear magnetic resonance (¹³C-NMR) analyses. The enzymatic hydrolysis rates were assessed using ultraviolet-visible (UV-Vis) spectroscopy (λmax: 227 nm) in human plasma, revealing controlled-release profiles modulated by the steric bulk of the acyloxyalkyl substituents. At 120 minutes, the hydrolysis rates were as follows: A1 (99.5%), A2 (97.0%), A3 (96.9%), A4 (95.0%), and A5 (94.5%). These results highlight the potential of the acyloxyalkyl carbamate moiety to enhance drug absorption, reduce adverse effects, and improve therapeutic outcomes. The study demonstrates the feasibility of addressing fluoxetine’s pharmacokinetic limitations through prodrug design. Future research should focus on comprehensive in vivo investigations to validate the in vitro findings and evaluate these derivatives' long-term pharmacokinetics, biological efficacy, and safety.

Fluoxetine is an antidepressant classified as a selective serotonin reuptake inhibitor (SSRI). Its bioavailability is low due to its varying dissolution at different pH levels and rapid breakdown in the liver. To address these challenges, a series of five novel fluoxetine derivatives (A1–A5) were synthesized by introducing various acyloxyalkyl carbamate groups at the fluoxetine amino moiety. The structural integrity and chromatographic purity of these derivatives were confirmed through Fourier-transform infrared (FT-IR) spectroscopy, proton nuclear magnetic resonance (¹H-NMR), and carbon-13 nuclear magnetic resonance (¹³C-NMR) analyses. The enzymatic hydrolysis rates were assessed using ultraviolet-visible (UV-Vis) spectroscopy (λmax: 227 nm) in human plasma, revealing controlled-release profiles modulated by the steric bulk of the acyloxyalkyl substituents. At 120 minutes, the hydrolysis rates were as follows: A1 (99.5%), A2 (97.0%), A3 (96.9%), A4 (95.0%), and A5 (94.5%). These results highlight the potential of the acyloxyalkyl carbamate moiety to enhance drug absorption, reduce adverse effects, and improve therapeutic outcomes. The study demonstrates the feasibility of addressing fluoxetine’s pharmacokinetic limitations through prodrug design. Future research should focus on comprehensive in vivo investigations to validate the in vitro findings and evaluate these derivatives' long-term pharmacokinetics, biological efficacy, and safety.