Triazolopyrimidines as a New Herbicidal Lead for Combating Weed Resistance Associated with Acetohydroxyacid Synthase Mutation

Abstract

Acetohydroxyacid synthase (AHAS; also known as acetolactate synthase; EC 2.2.1.6, formerly EC 4.1.3.18) is the first common enzyme in the biosynthetic pathway leading to the branched-chain amino acids in plants and a wide range of microorganisms. Weed resistance to AHAS-inhibiting herbicides, increasing at an exponential rate, is becoming a global problem and leading to an urgent demand of developing novel compounds against both resistant and wild AHAS. In the present work, a series of novel 2-aroxyl-1,2,4-triazolopyrimidine derivatives (a total of 55) were designed and synthesized with the aim to discover an antiresistant lead compound. Fortunately, the screening results indicated that many of the newly synthesized compounds showed a better, even excellent, inhibition effect against both the wild-type Arabidopsis thaliana AHAS and P197L mutants. Among them, compounds 5-3 to 5-17, compounds 5-19 to 5-26, compounds 5-28 to 5-45, and compound 5-48 have the lower values of resistance factor (RF) and display a potential power to overcome resistance associated with the P197L mutation in the enzyme levels. Further greenhouse in vivo assay showed that compounds 5-15 and 5-20 displayed "moderate" to "good" herbicidal activity against both the wild type-and the resistant (P197L mutation) Descurainia sophia, even at a rate as low as 0.9375 (g of ai/ha). The above results indicated that these two compounds could be used as new leads for the future development of antiresistance herbicides.

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

“…The expression of AtAHAS (wild-type and mutant-type) was the same as our previously described method in the literature. 25,[33][34][35] In inhibition kinetic assays, the synthesized compounds were dissolved in DMSO to obtain stock solutions whose concentrations were set at 6, 60, 600, and 6000 μM. In the enzyme reaction system, the solution was diluted to a final concentration of 0.2-200 μM.…”

“…The herbicidal activities of compounds 8-28 against the tested weeds were evaluated according to the method published previously. 25,26,33,34 The results are summarized in Table 2, which was provided by the Zhejiang Research Institute of Chemical Industry (Hangzhou, China).…”

Computational design of novel inhibitors to overcome weed resistance associated with acetohydroxyacid synthase (AHAS) P197L mutant

“…There are several rational strategies to combat mutation‐induced drug resistance, for example, drug combination, targeting protein backbone, targeting highly conserved residues, dual/multiple targeting, and conformational flexibility design . In our previous work, the analysis of ligand (representative AHAS inhibitors) conformational flexibility illuminated that the rational design of conformationally flexible AHAS inhibitors was an effective way to overcome resistance . PTB series inhibitors always have low resistance against weeds among the commercialized herbicides due to the flexibility of oxygen‐bridge.…”

Review on Structures of Pesticide Targets

“…For AHAS, the complex structure of its catalyzed subunit with monsulfuron-sulfuron from Arabidopsis thaliana was successfully solved, the mechanism of monsulfuron-sulfuron is break the cofactors thiamine diphosphate of AHAS [ 55 ], and AHAS was further selected as a potent target for herbicidal discovery [ 56 ].…”