Novel Terminal Bipheny-Based Diapophytoene Desaturases (CrtN) Inhibitors as Anti-MRSA/VISR/LRSA Agents with Reduced hERG Activity

CrtN has been identified as an attractive
and druggable target
for treating pigmented Staphylococcus aureus infections.
More than 100 new compounds were synthesized, which target the overwhelming
the defects of the CrtN inhibitor 1. Analogues 23a and 23b demonstrated a significant activity
against pigmented S. aureus Newman and 13 MRSA strains
(IC50 = 0.02–10.5 nM), along with lower hERG inhibition
(IC50 > 30 μM, ∼10-fold decrease in comparison
with 1). Furthermore, 23a and 23b were confirmed to reduce the staphylococcal load in the kidney and
heart in a mouse model with normal treatment deeper than pretreatment
ones, comparable even with vancomycin and linezolid. Remarkably, 23a could strongly block the pigment biosynthesis of these
nine multidrug-resistant MRSA strains, including excellent activity
against LRSA strains and VISA strains in vivo, and all of which demonstrated
that 23a has a huge potential against intractable MRSA,
VISA, and LRSA issues as a therapeutic drug.