Anti-infective macrozones: design, biological evaluation and structure-activity relationships

Background and purpose: To discover novel compounds active against sensitive and resistant bacterial strains, a series of novel azithromycin-thiosemicarbazone conjugates, the macrozones, have been syn­the­sized and their biological activity evaluated with corresponding (quantitative) structure-activity relationship ((Q)SAR) analyses conducted. Experimental approach: A systematic variation of thiosemicarbazone side-chains and coupling at positions 4''-, 3-, and 9a of the azithromycin scaffold has resulted in a novel class of bacterial ribosome inhibitors. Key results: Compared to azithromycin, the activity of 4''-macrozones has shown the greatest improvements against efflux-resistant S. pneumoniae and S. aureus, as well as very good activity of 4'' derivatives against E. faecalis. QSAR calculations indicate that the antibacterial activity of macrozones is primarily determined by the position of the thiosemicarbazone side chain. Among the conjugated derivatives, the 4''-substituted macrozones exhibit the highest overall activity against a range of sensitive and efflux-resistant Gram-positive bacteria, as well as against Gram-negative E. coli strains, while those substituted at 9a- and 3- positions are found to be less potent. The antibacterial activity of macrozones is favourably influenced by larger fractions of their cationic and zwitterionic forms, their capacity for hydrogen bond formation, and the extension of p-electron delocalization involving the thiosemicarbazone moiety. Conclusion: The results obtained provide a sound basis for guiding further medicinal chemistry efforts toward the discovery of more potent macrolide anti-infectives, with particular emphasis on resistant bacteria that pose a serious threat to human health.