Design, synthesis, and molecular simulation studies of N-phenyltetrahydroquinazolinones as protoporphyrinogen IX oxidase inhibitors

Lu Liang; Shuyi Yu; Qian Li; Xia Wang; Dawei Wang; Zhen Xi

doi:10.1016/j.bmc.2021.116165

Design, synthesis, and molecular simulation studies of N-phenyltetrahydroquinazolinones as protoporphyrinogen IX oxidase inhibitors

Bioorg Med Chem. 2021 Jun 1:39:116165. doi: 10.1016/j.bmc.2021.116165. Epub 2021 Apr 21.

Authors

Lu Liang¹, Shuyi Yu¹, Qian Li¹, Xia Wang¹, Dawei Wang¹, Zhen Xi²

Affiliations

¹ State Key Laboratory of Elemento-Organic Chemistry, National Pesticide Engineering Research Center, and Department of Chemical Biology, Collaborative Innovation Center of Chemical Science and Engineering, College of Chemistry, Nankai University, Tianjin 300071, PR China.
² State Key Laboratory of Elemento-Organic Chemistry, National Pesticide Engineering Research Center, and Department of Chemical Biology, Collaborative Innovation Center of Chemical Science and Engineering, College of Chemistry, Nankai University, Tianjin 300071, PR China. Electronic address: [email protected].

PMID: 33915477
DOI: 10.1016/j.bmc.2021.116165

Abstract

Discovering new protoporphyrinogen oxidase (PPO, EC 1.3.3.4) inhibitors is a promising direction for agrochemical research. Herein, we reported the discovery and in silico structure-guided optimization of N-phenyltetrahydroquinazolinones 1 and 2 as new PPO inhibitors. Most of the obtained compounds 1 and 2 exhibited significantly enhanced Nicotiana tabacum PPO (NtPPO) inhibitory potency than that of flumioxazin. Promisingly, 1-(tert-butoxy)-1-oxopropan-2-yl 2-chloro-4-fluoro-5-(4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)benzoate, 2o, with a K_i value of 4 nM, showed ten folds more enhanced NtPPO-inhibiting potency than flumioxazin. Additionally, compounds 2b and 2i showed a broad spectrum of broadleaf weeds control at 37.5-150 g ai/ha, and selective for wheat at 150 g ai/ha in the post-emergent application. The molecular simulation studies revealed the vital basis between N-phenyltetrahydroquinazolinones and NtPPO. The present work indicated that the N-phenyltetrahydroquinazolinone motif might be a potential scaffold for herbicide discovery.

Keywords: Molecular simulation; Protoporphyrinogen oxidase; Scaffold-hopping; Structure-activity relationship; Weed control.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Drug Design*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology*
Herbicides / chemical synthesis
Herbicides / chemistry
Herbicides / pharmacology
Molecular Docking Simulation
Plant Weeds / drug effects
Protoporphyrinogen Oxidase / drug effects*
Quinazolinones / chemical synthesis
Quinazolinones / chemistry*
Quinazolinones / pharmacology*
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Herbicides
Quinazolinones
Protoporphyrinogen Oxidase