Syntheses and computational analyses of selected macrolide derivatives derived from clarithromycin A

This study presents the synthesis and experimental and computational analysis of novel macrolide derivatives obtained from clarithromycin A, with the aim of exploring their potential to address the growing problem of antimicrobial resistance. The compounds synthesized include 2?-O-acetyl-clarithromycin A, its phosphoramidite derivative, and the corresponding phosphonyl derivative. Special attention was paid to the optimization of phosphitylation conditions due to the inherent instability of phosphoramidite compounds. The purity of the phosphoramidite derivative was successfully confirmed using diffusion-ordered NMR spectroscopy (DOSY). Comprehensive conformational analyses were carried out using molecular modeling techniques, followed by molecular docking and MM-GBSA calculations with a target protein from Escherichia coli to evaluate the relative binding affinities of clarithromycin A and its derivatives. The results indicate that the phosphoramidite and phosphonyl derivatives exhibit comparable binding affinities relative to the parent antibiotic. In addition, complex mass spectrometric fragmentation patterns of the phosphorus-containing derivatives were analyzed and rationalized using the MS Fragmenter computational tool.