Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 59, Issue 7, Pages 3215-3230Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b01984
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Funding
- National Natural Science Foundation of China [21222211, 21372001, 21472207]
- Shu Guang project - Shanghai Municipal Education Commission
- Shanghai Education Development Foundation [14SG28]
- Program for New Century Excellent Talents in University [NCET-12-0853]
- Fundamental Research Funds for the Central Universities
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Blocking the staphyloxanthin biosynthesis process has emerged as a new promising antivirulence strategy. Previously, we first revealed that CrtN is a druggable target against infections caused by pigmented Staphylococcus aureus (S. aureus) and that naftifine was an effective CrtN inhibitor. Here, we identify a new type of benzofuran-derived CrtN inhibitor with submicromolar IC50 values that is based on the naftifine scaffold. The most potent analog, 5m, inhibits the pigment production of S. aureus Newman and three MRSA strains, with IC50 values of 0.38-5.45 nM, without any impact on the survival of four strains (up to 200 mu M). Notably, compound 5m (1 mu M) could significantly sensitize four strains to immune clearance and could effectively attenuate the virulence of three strains in vivo. Moreover, 5m was determined to be a weak antifungal reagent (MIC > 16 mu g/mL). Combined with good oral bioavailability (F = 42.2%) and excellent safety profiles, these data demonstrate that 5m may be a good candidate for the treatment of MRSA infections.
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