Design, Synthesis, and Molecular Mechanism Studies of N-Phenylisoxazoline-thiadiazolo[3,4-a]pyridazine Hybrids as Protoporphyrinogen IX Oxidase Inhibitors

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 K i = 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 (K i = 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.

Discovery of a Potent Thieno[2,3-d]pyrimidine-2,4-dione-Based Protoporphyrinogen IX Oxidase Inhibitor through an In Silico Structure-Guided Optimization Approach

“…In this round of tests, 20 kinds of weeds, Eclipta prostrate (EP), Polygonum Americana (PA), Aeschynomene indica (AI), Medicago sativa (MS), Alopecurus aequalis (AA), Orychophragmus violaceus (OV), DS, Chenopodium serotinum (CS), Xanthium sibiricum (XS), Commelina benghalensis (CB), Pharbitis nil (PN), Brassica juncea (BJ), Vicia gigantean (VG), Setaria faberii (SF), EC, Trifolium repens (TR), Veronica didyma (VD), Rumex acetosa (RA), Clinopodium chinense (CC), and Leptochloa panacea (LP), were selected to evaluate the herbicidal spectrum of 6g at rates ranging from 30 to 75 g ai/ha, and flumioxazin and trifludimoxazin were selected as the positive control. The test methods were based on our previous reports. − ,− Briefly, the test compounds were dissolved in dimethyl formamide (DMF) and diluted water (containing 0.1% Tween-80) before use. When the weeds reached the three-leaf stage, they were treated with the tested compounds at rates ranging from 9.375 to 150 g ai/ha, with three replications for each compound and concentration.…”

“…To evaluate whether compound 6g has the potential to develop as a herbicide or not, we tested its crop selectivity against six crops: peanut, soybean, rice, sorghum, maize, and wheat at 75 g ai/ha by the postemergence application, and flumioxazin and trifludimoxazin were selected as the positive control. The assay methods of crop safety were the same as our previous reports. ,,, The results of crop safety are shown in Table .…”

“…The MD simulations of the 1 and 6g –NtPPO systems were performed using the PMEMD module; for each system, a 30 ns simulation was performed. The binding free energy calculation and energy decomposition of each system were analyzed from the last 10 ns of the MD trajectories. ,, …”

“…The assay methods of crop safety were the same as our previous reports. 29,31,34,37 The results of crop safety are shown in Table 5.…”

In Silico Structure-Guided Optimization and Molecular Simulation Studies of 3-Phenoxy-4-(3-trifluoromethylphenyl)pyridazines as Potent Phytoene Desaturase Inhibitors

“…The parameters for the molecular dynamic (MD) simulations were prepared using the tleap program, the optimization of the 2a-Synechococcus PDS complex was performed using Sander, and the production of MD was performed using the pmemd module. The set of detailed parameters, the binding free energy calculation, and energy decomposition were the same as in the previous reports [25,30,31].…”