Discovery of Indole-3-acetamide Derivatives as Potent Transketolase-Inhibiting-Based Herbicidal Leads.

Transketolase (TKL; EC 2.2.1.1) has been identified as a potential new target for the development of novel herbicides. To discover natural product-based transketolase inhibitors with high herbicidal activity, some 9H-pyrido[3,4-]indoles ( targeting TKL were obtained from the biogenic library of ZINC20 using a structure-based virtual screening (SBVS) methodology. Then, a series of indole-3-acetamides - were designed by structural optimization of compounds , synthesized, and subjected to bioassay. Among them, compound exhibited the best herbicidal efficacy against () and () by both the small cup method (with an inhibition rate of over 95% at 100 mg/L) and the foliar spray method (with an inhibition rate of over 90% at 175 g (a.i.)/ha). Furthermore, compound was safe for maize, wheat, soybean, and cotton (with phytotoxicity less than 10%) at a dosage of 375 g (a.i.)/ha. Both fluorescence quenching and TKL inhibitory experiments showed that compound was a typical TKL inhibitor. A molecular docking study further verified that compound exhibited higher binding affinity with TKL, which contributed to its higher inhibitory activity on TKL. Molecular dynamics simulation was also performed to explore the dynamic stability of 7m-TKL complexes. Additionally, the DFT properties of compound further supported its superior activity against TKL. Taken together, compound could be a potential herbicide lead targeting TKL for weed control in maize, wheat, soybean, and cotton fields.