Synthesis and Antibacterial Assessment of Novel Azithromycin Derivatives as Potential Taste-Masking Prodrugs.

<b>Background and Objective:</b> Azithromycin is a widely used macrolide antibiotic with broad-spectrum antimicrobial activity; however, its clinical acceptability is limited by poor patient compliance due to its bitter taste. Additionally, the growing threat of antimicrobial resistance necessitates the development of novel derivatives with improved therapeutic performance. This study aimed to synthesize and evaluate novel azithromycin derivatives with dual potential for taste masking and enhanced antibacterial activity. <b>Materials and Methods:</b> Five novel azithromycin derivatives were synthesized by reacting azithromycin with different functional linkers, including <i>N</i>-acetyl benzenesulfonyl chloride, <i>p</i>-nitrobenzoyl chloride, <i>p</i>-toluenesulfonyl chloride, 3,5-dinitrobenzoyl chloride and <i>p</i>-nitrobenzenesulfonyl chloride. The synthesized compounds were characterized using Fourier-Transform Infrared Spectroscopy (FT-IR), nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS). Prodrug properties were assessed through kinetic stability studies at physiological pH values (2.2, 5.5 and 7.4). Antibacterial activity was evaluated <i>in-vitro</i> using minimum inhibitory concentration (MIC) and Half-Maximal Inhibitory Concentration (IC<sub>50</sub>) assays against clinically relevant bacterial strains, including <i>Escherichia coli</i>, <i>Pseudomonas aeruginosa</i>, <i>Streptococcus pneumoniae</i> and <i>Staphylococcus aureus</i>. The bacterial strains used in this study were standard ATCC reference strains and were not derived from human or animal subjects. Therefore, ethical approval was not required. All experiments were conducted following standard microbiological laboratory practices. <b>Results:</b> All five azithromycin derivatives were successfully synthesized with satisfactory yields and confirmed structural characteristics. <strong>Compounds 2, 4 and 5</strong> demonstrated favorable prodrug behavior by undergoing pH-dependent hydrolysis and regenerating the parent drug, indicating promising taste-masking potential. Furthermore, <strong>compounds 1 and 3</strong> exhibited superior antibacterial activity against <i>Pseudomonas aeruginosa</i> compared to the parent azithromycin. <b>Conclusion:</b> The synthesized azithromycin derivatives demonstrated promising potential as next-generation therapeutic agents with improved palatability and retained or enhanced antimicrobial efficacy. These findings support their prospective application in overcoming taste-related compliance issues while addressing antimicrobial resistance challenges.