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-b]indoles (I) targeting SvTKL were obtained from the biogenic library of ZINC20 using a structure-based virtual screening (SBVS) methodology. Then, a series of indole-3-acetamides 7a-7x were designed by structural optimization of compounds I, synthesized, and subjected to bioassay. Among them, compound 7m exhibited the best herbicidal efficacy against Digitaria sanguinalis (D. sanguinalis) and Amaranthus retroflexus (A. retroflexus) 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 7m 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 SvTKL inhibitory experiments showed that compound 7m was a typical SvTKL inhibitor. A molecular docking study further verified that compound 7m exhibited higher binding affinity with SvTKL, which contributed to its higher inhibitory activity on SvTKL. Molecular dynamics simulation was also performed to explore the dynamic stability of 7m-SvTKL complexes. Additionally, the DFT properties of compound 7m further supported its superior activity against SvTKL. Taken together, compound 7m could be a potential herbicide lead targeting TKL for weed control in maize, wheat, soybean, and cotton fields.