Synthesis of Potential Inhibitors Targeting Dihydroorotate Dehydrogenase as Herbicide Candidates

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.

computer-aided screening; dihydroorotate dehydrogenase; herbicidal activity evaluation; hydroxypyrazolamide lead.