A first-in-class dimethyl 2-acetamido terephthalate inhibitor targeting Conyza canadensis SHMT1 with a novel herbicidal mode-of-action.

[Display omitted] • The Conyza Canadensis SHMT1 (CcSHMT1) structure was firstly resolved and a typical α-class PLP-dependent enzyme. • The dimethyl 2-acetamido terephthalate containing compounds had excellent herbicidal activity through virtual screening and biological assays. • The compound 9ay (IC 50 =193.8 g a.i./ha) exhibited the highest herbicidal efficiency and had no obvious side-effect on maize. • The first-in-class Cc SHMT1 inhibitor that could be developed as a potent herbicide with a new mode-of-action. Herbicide application is a highly efficiency method of weed control that boots agricultural output and assures food security. The development of novel herbicides focuses on improved bioactivity and new modes of action. The amino acid biosynthesis was validated as a promising novel mode of action for herbicidal compounds. However, the amino acid biosynthesis enzyme remains largely unexplored for herbicidal targets. Serine hydroxymethyl transferase (SHMT) is an essential enzyme in the photorespiratory cycle. The study aims to explore Conyza canadensis SHMT1 (Cc SHMT1) as a promising target for herbicide discovery. Structure determination of Cc SHMT1 was resolved by X-ray crystallography. Virtual screening docking experiments were performed with Glide version 5.5. Novel derivatives of dimethyl 2-acetamido terephthalate were further designed, synthesized, and bioassay. The druggability of the inhibitor was evidenced by ultrastructural changes in mitochondria, in vivo and vitro enzyme activity assays, and genetics analysis. Cc SHMT1 has a typical PLP-dependent enzyme 3D structure. The dimethyl 2-acetamido terephthalate-containing compounds had herbicidal activity. Dimethyl 2-(2-(4-(2-(4-bromo-2-chlorophenoxy) acetyl)piperazin-1-yl)acetamido) terephthalate (Compound 9ay , EC 50 = 193.8 g a.i./ ha) exhibited the highest herbicidal activity on tested weed among the synthesized compounds. Compound 9ay had no obvious adverse effect on the growth of maize and honeybees. Compound 9ay was verified to target Cc SHMT1 as an herbicide candidate. A first-in-class Cc SHMT1 inhibitor that could be developed as a potent herbicide with a new mode of action and provide an avenue for discovering novel inhibitors of pyridoxal-5-phosphate-dependent enzymes. [ABSTRACT FROM AUTHOR]