Design, Synthesis, and Molecular Mechanism Studies of <i>N</i>-Phenylisoxazoline-thiadiazolo[3,4-<i>a</i>]pyridazine Hybrids as Protoporphyrinogen IX Oxidase Inhibitors
Ruibo Zhang, Shuyi Yu, Lu Liang, Ismail Ismail, Dawei Wang, Yonghong Li, Han Xu, Xin Wen, Zhen Xi
Abstract
Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) is an important target for green agrochemical discovery. Herein, a novel N-phenylisoxazoline-thiadiazolo[3,4-a]pyridazine herbicidal active scaffold was designed by the scaffold hybridization strategy. Systematic structural optimization enabled the discovery of a series of derivatives with excellent weed control at 9.375–150 g ai/ha by the post-emergent application. Some derivatives exhibited improved Nicotiana tabacum PPO (NtPPO)-inhibitory activity than fluthiacet-methyl. Of these, 2b, with Ki = 21.8 nM, displayed higher weed control than fluthiacet-methyl at the rate of 12–75 g ai/ha, and selective to maize at 75 g ai/ha. In planta, 2b was converted into a bioactive metabolite 5 (Ki = 4.6 nM), which exhibited 4.6-fold more potency than 2b in inhibiting the activity of NtPPO. Molecular dynamics simulation explained that 5 formed stronger π–π interaction with Phe392 than that of 2b. This work not only provides a promising lead compound for weed control in maize fields but is also helpful to understand the molecular mechanism and basis of the designed hybrids.