Synthesis and Antibacterial Activity of Alkylamine-Linked Pleuromutilin Derivatives

Abstract

In an effort to expand the spectrum of the antibacterial activity of pleuromutilin, a series of amine- and polyamine-linked analogues were prepared and evaluated for activities against a panel of microorganisms. Simple C-22-substituted amino esters or diamines 16, 17, 18, and 22, as well as two unusual amine-linked bis-pleuromutilin examples 20 and 23, displayed variable levels of activity towards Staphylococcus aureus ATCC 25923 and methicillin-resistant S. aureus, but with no detectable activities towards Gram-negative bacteria. Fortunately, the incorporation of a longer-chain triamine or polyamine (spermine) at C-22 did afford analogues (30, 31) that exhibited activity towards both S. aureus ATCC 25923 and Escherichia coli ATCC 25922 with MIC 6.1–13.4 µM. Spermine–pleuromutilin analogue 31 was also able to enhance the action of doxycycline towards Pseudomonas aeruginosa ATCC 27853 by eight-fold, highlighting it as a useful scaffold for the development of new antibacterial pleuromutilin analogues that exhibit a broader spectrum of activity.