title: Discovery of Potent Benzofuran-Derived Diapophytoene Desaturase (CrtN) Inhibitors with Enhanced Oral Bioavailability for the Treatment of Methicillin-Resistant Staphylococcus aureus (MRSA) Infections.
abstract: 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 μM). Notably, compound 5m (1 μM) 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 μg/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.
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , Shanghai 200237, China.
authors.forename: Youxin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Di
authors.affiliation: Hubei Bio-pharmaceutical Industrial Technological Institute Inc. , Wuhan 430075, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Hubei Bio-pharmaceutical Industrial Technological Institute Inc. , Wuhan 430075, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xiao
authors.affiliation: Humanwell Healthcare (Group) Co. Ltd , 666 Gaoxin Road, Wuhan 430075, China.
authors.forename: Xuehai
authors.initials: X
authors.lastname: Wang
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , Shanghai 200237, China.
authors.forename: Hanwen
authors.initials: H
authors.lastname: Wei
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , Shanghai 200237, China.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , Shanghai 200237, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , Shanghai 200237, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University , Shanghai 200433, China.
authors.forename: Chunquan
authors.initials: C
authors.lastname: Sheng
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Lefu
authors.initials: L
authors.lastname: Lan
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , Shanghai 200237, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D001572:Benzofurans / Q000737:chemistry*; D001682:Biological Availability; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D014018:Tissue Distribution
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001572:Benzofurans; D004791:Enzyme Inhibitors; C091055:CrtN protein, Staphylococcus aureus; D010088:Oxidoreductases; C105430:benzofuran