Discovery of a Potent Adenine–Benzyltriazolo–Pleuromutilin Conjugate with Pronounced Antibacterial Activity against MRSA

Conjugation of pleuromutilin is an
attractive strategy for the
development of novel antibiotics and the fight against multiresistant
bacteria as the class is associated with low rates of resistance and
cross-resistance development. Herein, the preparation of 35 novel
(+)-pleuromutilin conjugates is reported. Their design was based on
a synthetically more efficient benzyl adaption of a potent lead but
still relied on the Cu­(I)-catalyzed alkyne–azide [3 + 2] cycloaddition
for conjugation onto pleuromutilin. Their antibacterial activity was
evaluated against the multiresistant Staphylococcus
aureus strain USA300 for which they displayed moderate
to excellent activity. Compound 35, bearing a para-benzyladenine substituent, proved particularly potent
against USA300 and additional strains of MRSA and displayed as importantly
no cytotoxicity in four mammalian cell lines. Structure–activity
relationship analysis revealed that the purine 6-amino is essential
for high potency, likely because of strong hydrogen bonding with the
RNA backbone of C2469, as suggested by a molecular model based on
the MM-GBSA approach.