Lai Chen

Enhancing innovation in herbicide discovery is imperative to combat weed resistance and safeguard global food security. To develop novel herbicide targeting dihydroorotate dehydrogenase (DHODH), a series of 3-carboxy-4-pyrazole amide lead scaffold bearing ester or acid substituents were designed and synthesized. Bioassay evaluation revealed that compound II-12 achieved an 81% growth inhibition activity against Setaria viridis at 135 g ai/ha in postemergence greenhouse assays, with herbicidal efficacy comparable or higher than that of several commercial products. Moreover, II-12 exhibited favorable crop safety toward four upland crops at the same dosage. In vitro enzyme inhibition assays demonstrated that II-12 inhibited SvDHODH with a half-maximal inhibition concentration value of 8.589 μM, while surface plasmon resonance analysis revealed an apparent dissociation constant Kd of 3.83 μM. Molecular docking combined with site-directed mutagenesis displayed that II-12 binds to SvDHODH through a critical H-bond interaction with Arg189. Collectively, these results identify II-12 as a promising DHODH-targeting herbicide candidate.

This study describes a visible-light-driven photoredox/HAT cocatalytic strategy for the efficient synthesis of functionalized 3,3-difluoroallyl organogermanium compounds. Bioactivity studies indicate that representative compound 3q exhibits significant herbicidal activity against Portulaca oleracea L. with an inhibition rate of 72.6%, comparable to the commercial herbicide atrazine. Integrating continuous-flow technology enabled gram-scale synthesis. This work provides an approach to fluorinated organogermanium compounds and may facilitate the development of agrochemical agents.

The ongoing discovery of effective agrochemicals remains one of the key activities to meet crop protection needs. Computer-aided molecular design, combined with systematic bioassay screening, was employed to identify novel herbicides targeting dihydroorotate dehydrogenase (DHODH). The hydroxypyrazole scaffold previously reported was also recognized by our virtual screening system, based on which its newly designed analogues, with access selectivity affinity for Setaria viridis DHODH over human DHODH, were chosen and synthesized. In vitro enzymatic assays revealed that WF-8 and WF-19 displayed relatively high potency against SvDHODH, with IC₅₀ values of 64.97 and 91.52 μM, respectively. Preemergence herbicidal activity assessed using the Murashige and Skoog plant growth medium revealed that WF-8, WF-30, and WF-32 had remarkable inhibitory effects (>66% at 100 μg/mL) against Echinochloa crus-galli and S. viridis, comparable to niazsulfuron and atrazine controls. Postemergence foliar application tests demonstrated that WF-8 and WF-19 had more than 65% fresh weight growth inhibition activity against E. crus-galli and S. viridis at 135 g ai/ha, with performance similar to that of mesotrione and nicosulfuron. Notably, WF-8 displayed favorable crop safety toward the four tested dryland species, and molecular dynamics simulations further confirmed its binding interactions with SvDHODH. These data support the claim that WF-8 acts as a potential herbicide against DHODH.

To discover novel inhibitors of pyruvate kinase (PK) as fungicidal candidates, a series of 2-thiazol-2-yl-1,3,4-oxadiazole derivatives were designed by a prediction model with Rhizoctonia solani PK (RsPK) as a protein target and YZK-C22 as a ligand. Fungicidal screening indicated that 5b, 5g, 5h, 5j, 5l, 5p, 5q, and 5s exhibited equal or higher activity compared to YZK-C22 against Botrytis cinerea, Cercospora arachidicola, or R. solani. To our surprise, 5s showed comparable activity to flutriafol with an EC₅₀ of 0.21 μg/mL vs 0.20 μg/mL, but over 14 times more active than the lead compound YZK-C22 against R. solani with its EC₅₀ of 0.21 μg/mL vs 3.14 μg/mL (mole ratio over 17-fold). Compound 5s also displayed 2.30-fold better inhibition potency against RsPK compared with YZK-C22. Moreover, this higher potency of 5s against RsPK was also reflected in a steeper dose-response tendency in the fluorescence quenching assay and a lower dissociation constant in the microscale thermophoresis (MST) assay when compared with YZK-C22. The results in this study not only broadened the structural diversity of PK inhibitors but also supported 5s as a promising PK-based highly active fungicide lead compound, with stronger binding ability to RsPK than YZK-C22.

Transketolase (TKL; EC 2.2.1.1) is a highly promising potential target for herbicidal applications. To identify novel TKL inhibitors, we designed and synthesized a series of 3-oxopropionamide-1-methylpyrazole carboxylate analogues and assessed their herbicidal activities. Ethyl 3-((1-((2,4-dichlorophenyl)amino)-1-oxopropan-2-yl)oxy)-1-methyl-1H-pyrazole-5-carboxylate (D15) and ethyl 1-methyl-3-((1-oxo-1-((thiophen-2-ylmethyl)amino)propan-2-yl)oxy)-1H-pyrazole-5-carboxylate (D20) exhibited superior growth inhibition activities against both the root and stem of Amaranthus retroflexus (A. retroflexus) compared to nicosulfuron and mesotrione. Additionally, D15 achieved an inhibition rate of more than 90% against the roots and stems of Digitaria sanguinalis (D. sanguinalis), outperforming the four control agents at a concentration of 200 mg/L using the small cup method. In the pre-emergence herbicidal activity test, D15 effectively inhibited D. sanguinalis by more than 90% at 150 g ai/ha, surpassing the efficacy of the control, mesotrione. Conversely, in the postemergence herbicidal activity test, D20 exhibited efficient inhibition of A. retroflexus by more than 90% at 150 g ai/ha, outperforming the control agents nicosulfuron, mesotrione, and metamifop. The results of the TKL enzyme activity test showed that the IC₅₀ values of compounds D15 and D20 were 0.384 and 0.655 mg/L, respectively, which were close to those of the control agents. Furthermore, molecular docking and molecular dynamics simulation studies revealed that D15 and D20 interacted favorably with the TKL of Setaria viridis. Such findings highlight the promising potential of D15 and D20 as lead TKL inhibitors for the optimization of new herbicides.

To discover novel transketolase (TKL, EC 2.2.1.1) inhibitors with potential herbicidal applications, a series of pyrazole acyl thiourea derivatives were designed based on a previously obtained pyrazolamide acyl lead compound, employing a scaffold hopping strategy. The compounds were synthesized, their structures were characterized, and they were evaluated for herbicidal activities. The results indicate that 7a exhibited exceptional herbicidal activity against Digitaria sanguinalis and Amaranthus retroflexus at a dosage of 90 g ai/ha, using the foliar spray method in a greenhouse. This performance is comparable to that of commercial products, such as nicosulfuron and mesotrione. Moreover, 7a showed moderate growth inhibitory activity against the young root and stem of A. retroflexus at 200 mg/L in the small cup method, similar to that of nicosulfuron and mesotrione. Subsequent mode-of-action verification experiments revealed that 7a and 7e inhibited Setaria viridis TKL (SvTKL) enzyme activity, with IC₅₀ values of 0.740 and 0.474 mg/L, respectively. Furthermore, they exhibited inhibitory effects on the Brassica napus acetohydroxyacid synthase enzyme activity. Molecular docking predicted potential interactions between these (7a and 7e) and SvTKL. A greenhouse experiment demonstrated that 7a exhibited favorable crop safety at 150 g ai/ha. Therefore, 7a is a promising herbicidal candidate that is worthy of further development.

The design and synthesis of new herbicidal active compounds based on a new target are of great significance for the development of new herbicides. Transketolase (TK) plays a key role in the Calvin cycle of plant photosynthesis and has been confirmed as a potential candidate target to develop and discover new herbicides. To obtain compounds with ultraefficient targeting of TK, a series of pyrazole amide derivatives were designed and synthesized through structural optimization for lead compound 4u based on TK as the new target. The bioassay results showed that compounds 6ba and 6bj displayed a highly inhibitory effect with the root inhibition of about 90% against Digitaria sanguinalis (DS) and 80% against Amaranthus retroflexus (AR) and Setaria viridis (SV) by the small cup method, which was better than the positive control mesotrione and nicosulfuron. Furthermore, compounds 6ba and 6bj exhibited an excellent inhibitory effect with the inhibition of about 80% (against DS) and over 80% (against SV) at the dosage of 150 g of active ingredient/ha by the foliar spray method. The TK enzyme activity inhibition test showed that the inhibition effect of target compounds against TK was consistent with the results of herbicidal activities. Also, molecular docking analysis showed that compounds 6ba and 6bj went deep into the active cavity of TK, bound to TK by a strong interaction, and might act on the enzyme TK. Above of all, compounds 6ba and 6bj are promising herbicide lead compounds targeting TK. Hence, they could be developed into more efficient herbicides by further structural optimization.

2-Arylindoles are privileged structures widely present in biologically active molecules. New sustainable synthetic routes toward their synthesis are, therefore, in high demand. Herein, a mixed base-promoted benzylic C-H deprotonation of commercially available ortho-anisoles, addition of the resulting anion to benzonitriles, and S_NAr to displace the methoxy group provide indoles. A diverse array of 2-arylindoles is prepared with good yields (>30 examples, yields up to 99%) without added transition metal catalysts.

To discover novel target-based fungicidal candidates, a molecular design model was established with a three-dimensional (3D) structure of Rhizoctonia solani pyruvate kinase (RsPK) simulated with the AlphaFold 2 and YZK-C22 as a fungicidal lead. A series of novel [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives were rationally designed, synthesized, evaluated for their fungicidal performance, and validated for their mode of action. The in vitro bioassays with R. solani indicated that compounds 5g, 5o, and 5z with an EC50 value ranging from 1.01 to 1.54 mu g/mL displayed higher fungicidal activity than the positive control YZK-C22 with its EC50 of 3.14 mu g/mL. Especially, 5o exhibited high potency and a broad spectrum against Alternaria solani, Botrytis cinerea, Cercospora arachidicola, Physalospora piricola, R. solani, and Sclerotinia sclerotiorum with its EC50 value falling between 1.54 and 13.10 mu g/mL. Like all positive controls, 5g, 5o, and 5z showed excellent in vivo growth inhibition against Pseudoperonospora cubensis at 200 mu g/mL. Even though the PK enzymatic inhibition assay showed that 5o was approximately 2.6 times less active than YZK-C22 (IC50: 29.14 vs 11.15 mu g/mL, respectively), the similar fluorescence quenching patterns of RsPK by 5o and YZK-C22, and the docking results of interactions between RsPK and 5o or YZK-C22 implied that they might share the similar binding site in the RsPK active pocket. Our studies suggested that 5o could be used as a potent fungicidal lead for further optimization. The results of comparative molecular field analysis (CoMFA) provided a direction for further molecular design.