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

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Abstract

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.

LanguageEnglish
Pages 6105-6114
JournalBioorganic and Medicinal Chemistry
Volume26
Issue number23-24
Early online date13 Nov 2018
DOIs
Publication statusPublished - 15 Dec 2018

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Quantitative Structure-Activity Relationship
Drug Design
Gram-Negative Bacteria
Computer Simulation
Scaffolds
Pharmaceutical Preparations
Bacteria
Fungi
Lead compounds
Genetic algorithms
Pumps
Derivatives
Datasets

Keywords

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

Cite this

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title = "QSAR of 1,4-benzoxazin-3-one antimicrobials and their drug design perspectives",
abstract = "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.",
keywords = "2H-1,4-benzoxazin-3(4H)-one, Antibacterial, Antifungal, Benzoxazinoid, Benzoxazinone, Drug design, QSAR, SAR",
author = "{de Bruijn}, {Wouter J.C.} and Hageman, {Jos A.} and Carla Araya-Cloutier and Harry Gruppen and Vincken, {Jean Paul}",
year = "2018",
month = "12",
day = "15",
doi = "10.1016/j.bmc.2018.11.016",
language = "English",
volume = "26",
pages = "6105--6114",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
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T1 - QSAR of 1,4-benzoxazin-3-one antimicrobials and their drug design perspectives

AU - de Bruijn, Wouter J.C.

AU - Hageman, Jos A.

AU - Araya-Cloutier, Carla

AU - Gruppen, Harry

AU - Vincken, Jean Paul

PY - 2018/12/15

Y1 - 2018/12/15

N2 - 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.

AB - 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.

KW - 2H-1,4-benzoxazin-3(4H)-one

KW - Antibacterial

KW - Antifungal

KW - Benzoxazinoid

KW - Benzoxazinone

KW - Drug design

KW - QSAR

KW - SAR

U2 - 10.1016/j.bmc.2018.11.016

DO - 10.1016/j.bmc.2018.11.016

M3 - Article

VL - 26

SP - 6105

EP - 6114

JO - Bioorganic and Medicinal Chemistry

T2 - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 23-24

ER -