New pleuromutilin derivatives with enhanced antimicrobial activity.II.Structure-activity correlations

Area of Science:

• Medicinal Chemistry
• Antimicrobial Drug Discovery

Background:

• Pleuromutilin is a natural antibiotic with antibacterial properties.
• Structural modifications are explored to enhance its efficacy and spectrum of activity.

Purpose of the Study:

• To investigate structure-activity relationships of pleuromutilin derivatives.
• To identify modifications that improve antibacterial and mycoplasma activity and solubility.

Main Methods:

• Systematic chemical modification of the pleuromutilin scaffold.
• Evaluation of antibacterial and mycoplasma activity using Minimum Inhibitory Concentration (MIC) values.
• Assessment of solubility properties of synthesized derivatives.

Main Results:

• The carbonyl group in the five-membered ring and the C11 hydroxyl group are crucial for activity.
• Hydrogenation of the vinyl group does not affect activity.
• Modification at C14 offers significant potential for optimizing activity and solubility.
• Mutilin derivatives with a free C14 hydroxyl group are inactive.
• Mutilin esters of thioglycolic acids, especially with a tertiary amino group, showed >10-fold improvement in MIC values compared to pleuromutilin.

Conclusions:

• Chemical modifications, particularly at C14, are key to developing potent pleuromutilin-based antibiotics.
• The derivative 14-deoxy-14-[(2-diethylaminoethyl) thioacetoxy]-mutilin hydrogen fumarate (tiamulin) demonstrates significant therapeutic potential.