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

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Abstract
Structural modification of the antibiotic pleuromutilin afforded several derivatives with considerably enhanced activity against bacteria and mycoplasmas, and permitted conclusions to be reached about structure-activity relationships. The carbonyl group in the 5-membered ring and the hydroxyl group at C11 seem to be essential for activity. The vinyl group can be hydrogenated without loss of activity. Chemical modification at C14 offers the most possibilities for achieving the best activity and solubility properties. Mutilin and other compounds with a free OH at C14 are inactive. Mutilin esters of substituted thioglycolic acids had distinctly superior MIC [minimal inhibitory concentration] values, especially in combination with a tertiary amino group in the side chain, the latter group of derivatives having MIC values better than pleuromutilin by a factor of more than 10. Further variation within this group led to the development of 14-deoxy-14-[(2-diethylaminoethyl) thioacetoxy]-mutilin hydrogen fumarate (81.723 hfu, tiamulin) for extensive investigation of its chemotherapeutic potential.

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