Fragment‐based discovery of flexible inhibitor targeting wild‐type acetohydroxyacid synthase and P197L mutant

Abstract BACKGROUND Intensifying weed resistance has challenged the use of existing acetohydroxyacid synthase (AHAS)‐inhibiting herbicides. Hence, there is currently an urgent requirement for the discovery of a new AHAS inhibitor to effectively control AHAS herbicide‐resistant weed species produced by target mutation. RESULTS To combat weed resistance caused by AHAS with P197L mutation, we built a structure library consisting of pyrimidinyl‐salicylic acid derivatives. Using the pharmacophore‐linked fragment virtual screening (PFVS) approach, hit compound 8 bearing 6‐phenoxymethyl substituent was identified as a potential AHAS inhibitor with antiresistance effect. Subsequently, derivatives of compound 8 were synthesized and evaluated for their inhibitory activities. The study of the enzyme‐based structure–activity relationship and structure−resistance relationship studies led to the discovery of a qualified candidate, 28 . This compound not only significantly inhibited the activity of wild‐type Arabidopsis thaliana ( At ) AHAS and P197L mutant, but also exhibited good antiresistance properties (RF = 0.79). Notably, compared with bispyribac at 37.5–150 g of active ingredient per hectare (g a.i. ha –1 ), compound 27 exhibited higher growth inhibition against both sensitive and resistant Descurainia sophia , CONCLUSION The title compounds have great potential to be developed as new leads to effectively control herbicide‐resistant weeds comprising AHAS with P197L mutation. Also, our study provided a positive case for discovering novel, potent and antiresistance inhibitors using a fragment‐based drug design approach.