Discovery of New 2-[(4,6-Dimethoxy-1,3,5-triazin-2-yl)oxy]-6-(substituted phenoxy)benzoic Acids as Flexible Inhibitors of Arabidopsis thaliana Acetohydroxyacid Synthase and Its P197L Mutant.

In the search for new antiresistance acetohydroxyacid synthase (AHAS, EC 2.2.1.6) inhibitors to combat weed resistance associated with AHAS mutations, a series of 2-[(4,6-dimethoxy-1,3,5-triazin-2-yl)oxy]-6-(substituted phenoxy)benzoic acids 11-38 were designed and synthesized via the strategy of conformational flexibility analysis. Compounds 21, 22, 26, 33, 36, and 38 with high potency against both wild-type AtAHAS and its P197L mutant were identified as promising candidates with low resistance factors (RF, defined as the ratio between the ki values toward P197L mutant and wild-type AHAS) ranging from 0.73 to 6.32. Especially, compound 22 (RF = 0.73) was further identified as the most potent antiresistance AHAS inhibitor because of its significantly reduced resistance level compared with that of tribenuron-methyl (RF = 2650) and bispyribac (RF = 4.57). Furthermore, compounds 26, 33, 36, and 38 also displayed promising herbicidal activities against sensitive and resistant (P197L) Descurainia sophia at the dosage of 75-150 g of active ingredient (ai)/ha. Notably, compounds 33 and 38 still maintained over 60% herbicidal activity toward the resistant weed even at much lower dosages (37.5 g ai/ha). Therefore, the designed scaffold has the great potential to discover new candidate compounds for the control of weed resistance associated with AHAS mutation.