QSAR of 1,4-benzoxazin-3-one antimicrobials and their drug design perspectives

Wouter J.C. de Bruijn, Jos A. Hageman, Carla Araya-Cloutier, Harry Gruppen, Jean Paul Vincken*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

7 Citations (Scopus)


Synthetic derivatives of 1,4-benzoxazin-3-ones have been shown to possess promising antimicrobial activity, whereas their natural counterparts were found lacking in this respect. In this work, quantitative structure-activity relationships (QSAR) of natural and synthetic 1,4-benzoxazin-3-ones as antimicrobials were established. Data published in literature were curated into an extensive dataset of 111 compounds. Descriptor selection was performed by a genetic algorithm. QSAR models revealed differences in requirements for activity against fungi, gram-positive and gram-negative bacteria. Shape, VolSurf, and H-bonding property descriptors were frequently picked in all models. The models obtained for gram-positive and gram-negative bacteria showed good predictive power (Q2 Ext 0.88 and 0.85, respectively). Based on the models generated, an additional set of 1,4-benzoxazin-3-ones, for which no antimicrobial activity had been determined in literature, were evaluated in silico. Additionally, newly designed lead compounds with a 1,4-benzoxazin-3-one scaffold were generated in silico by varying the positions and combinations of substituents. Two of these were predicted to be up to 5 times more active than any of the compounds in the current dataset. The 1,4-benzoxazin-3-one scaffold was concluded to possess potential for the design of new antimicrobial compounds with potent antibacterial activity, a multitarget mode of action, and possibly reduced susceptibility to gram negatives’ efflux pumps.

Original languageEnglish
Pages (from-to)6105-6114
JournalBioorganic and Medicinal Chemistry
Issue number23-24
Early online date13 Nov 2018
Publication statusPublished - 15 Dec 2018


  • 2H-1,4-benzoxazin-3(4H)-one
  • Antibacterial
  • Antifungal
  • Benzoxazinoid
  • Benzoxazinone
  • Drug design
  • QSAR
  • SAR


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