Discovery of 3-acyl-2-anilino-1,4-dihydroquinolin-4-one derivatives as potential inhibitors of methicillin-resistant Staphylococcus aureus

• Published in: Bioorganic & medicinal chemistry letters 2025-04, Vol.118, p.130084, Article 130084
• Main Authors: Lee, Jun Young, Kim, Sungmin, Gim, Jihwan, Lee, Yunmi, Lee, Hyunjung, Lim, Chae Jo, Song, Hyun-Seob, Park, Hyeung-geun, Jang, Soojin, Park, Chul Min
• Format: Article
• Language: English
• Subjects: 3-Acyl-2-anilino-1,4-dihydroquinolin-4-ones; Antibacterial; Methicillin-resistant Staphylococcus aureus (MRSA); Multi-antibiotic-resistance; Quinolone
• ISSN: 0960-894X
• DOI: 10.1016/j.bmcl.2024.130084

[Display omitted] •A series of 3-acyl-2-anilino-1,4-dihycroquinolin-4-ones were designed and synthesized.•Total 20 novel derivatives were evaluated against methicillin-resistant Staphylococcus aureus.•The compounds (6b, 6k, 6m, and 6p–s) showed sub-nanomolar activity in vitro assay.•Compound 6k and 6r showed good in vivo pharmacokinetic profiles with safety as well. A series of novel 3-acyl-2-anilino-1,4-dihydroquinolin-4-one derivatives were identified as a potent inhibitor of methicillin-resistant Staphylococcus aureus. Compounds 1, 6a, 6b, 6k–6m, and 6o–6s showed potent antistaphylococcal activity (MIC50 = 0.04–4.41 µM). In addition, compounds 6k, 6m, 6r, and 6s showed ex vivo therapeutic efficacy (MIC50 = 0.57–3.0 µM) with low cytotoxicity on HepG2 cell line. Moreover, compounds 6k and 6r showed good metabolic stability, low hERG binding affinity, favorable safety, and good in vivo pharmacokinetic profiles.