Novel Staphyloxanthin Inhibitors with Improved Potency against Multidrug Resistant <i>Staphylococcus aureus</i>

Diapophytoene desaturase (CrtN) is a potential novel target for intervening in the biosynthesis of the virulence factor staphyloxanthin. In this study, 38 1,4-benzodioxan-derived CrtN inhibitors were designed and synthesized to overwhelm the defects of leading compound <b>4a</b>. Derivative <b>47</b> displayed superior pigment inhibitory activity, better hERG inhibitory properties and water solubility, and significantly sensitized MRSA strains to immune clearance in vitro. Notably, <b>47</b> displayed excellent efficacy against pigmented <i>S. aureus</i> Newman, Mu50 (vancomycin-intermediate MRSA, VISA), and NRS271 (linezolid-resistant MRSA, LRSA) comparable to that of linezolid and vancomycin in vivo