Linker and Head-Group Exploration of Anti-MRSA Triaromatic Pleuromutilins

Based on hit 6, a triaromatic pleuromutilin
(TAP)
and potent bacterial protein synthesis inhibitor, we explored the
chemical space surrounding its pharmacophore by synthesizing 45 new
conjugates. Herein, the adenine head was exchanged for new heterocycles,
and the benzyl linker exchanged for aniline-, ether-, amide-, and
hydroxybenzyl linkages, with all of them successfully engaging the
pharmacophore, a result which was mirrored in a strict 3D pharmacophore
model. The aniline- and amide-linked conjugates moreover demonstrated
greater stability in liver microsomes, while especially conjugate 21, but also 31, 43, 45, and 55 displayed excellent potency, with MRSA activities
on par with 6 or better. Docking to the ribosome suggested
a shifted engagement with C2469 for 21 over 6, resulting in greater multivalency, while 43/45 likely coordinates Mg2+. Lastly, conjugate 21 displayed efficacy equal to commercial Fucidin LEO (5) in a mouse Staphylococcus aureus skin infection model, highlighting its potential as a topical antibiotic
lead.