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

Area of Science:

• Medicinal Chemistry
• Bacteriology
• Drug Discovery

Background:

• Antibiotic resistance is a growing global health threat.
• Novel antibacterial agents are urgently needed to combat resistant bacterial strains.
• Azithromycin is a widely used macrolide antibiotic with limitations against resistant bacteria.

Purpose of the Study:

• To synthesize and evaluate novel azithromycin-thiosemicarbazone conjugates (macrozones) for antibacterial activity.
• To investigate the structure-activity relationships of these novel compounds.
• To identify lead compounds for developing new anti-infective therapies.

Main Methods:

• Synthesis of a series of azithromycin-thiosemicarbazone conjugates.
• Biological evaluation of synthesized compounds against sensitive and resistant bacterial strains.
• Quantitative structure-activity relationship ((Q)SAR) analyses to correlate chemical structure with antibacterial activity.

Main Results:

• The 4"-substituted macrozones demonstrated the most significant improvements in activity against efflux-resistant *S. pneumoniae* and *S. aureus*.
• Macrozones showed good activity against *E. faecalis* and Gram-negative *E. coli* strains.
• Antibacterial activity was primarily determined by the thiosemicarbazone side chain position, with 4"-substitution being optimal.

Conclusions:

• Novel azithromycin-thiosemicarbazone conjugates (macrozones) represent a promising class of antibacterial agents.
• The 4"-substituted macrozones are particularly effective against resistant Gram-positive bacteria.
• These findings provide a foundation for developing more potent macrolide anti-infectives targeting resistant bacterial infections.