Design, Synthesis, and Biological Evaluation of Pyridazinone-Containing Derivatives As Novel Protoporphyrinogen IX Oxidase Inhibitor

Abstract

Protoporphyrinogen IX oxidase (PPO, E.C. 1.3.3.4) plays a pivotal role in chlorophyll biosynthesis in plants, making it a prime target for herbicide development. In this study, we conducted an investigation aimed at discovering PPO-inhibiting herbicides. Through this endeavor, we successfully identified a series of novel compounds based on the pyridazinone scaffold. Following structural optimization and biological assessment, compound <b>10ae</b>, known as ethyl 3-((6-fluoro-5-(6-oxo-4-(trifluoromethyl)pyridazin-1(6<i>H</i>)-yl)benzo[<i>d</i>]thiazol-2-yl)thio)propanoate, emerged as a standout performer. It exhibited robust activity against <i>Nicotiana tabacum</i> PPO (<i>Nt</i>PPO) with an inhibition constant (<i>K</i>_i) value of 0.0338 μM. Concurrently, we employed molecular simulations to obtain further insight into the binding mechanism with <i>Nt</i>PPO. Additionally, another compound, namely, ethyl 2-((6-fluoro-5-(5-methyl-6-oxo-4-(trifluoromethyl)pyridazin-1(6<i>H</i>)-yl)benzo[<i>d</i>]thiazol-2-yl)thio)propanoate (<b>10bh</b>), demonstrated broad-spectrum and highly effective herbicidal properties against all six tested weeds (<i>Leaf mustard</i>, <i>Chickweed</i>, <i>Chenopodium serotinum</i>, <i>Alopecurus aequalis</i>, <i>Poa annua</i>, and <i>Polypogon fugax</i>) at the dosage of 150 g a.i./ha through postemergence application in a greenhouse. This work identified a novel lead compound (<b>10bh</b>) that showed good activity in vitro and excellent herbicidal activity in vivo and had promising prospects as a new PPO-inhibiting herbicide lead.