Design, Synthesis, and Herbicidal Activity of Pyrimidine–Biphenyl Hybrids as Novel Acetohydroxyacid Synthase Inhibitors

Abstract

The issue of weed resistance to acetohydroxyacid synthase (EC 2.2.1.6, AHAS) inhibitors has become one of the largest obstacles for the application of this class of herbicides. In a continuing effort to discover novel AHAS inhibitors to overcome weed resistance, a series of pyrimidine-biphenyl hybrids (4aa-bb and 5aa-ah) were designed and synthesized via a scaffold hopping strategy. Among these derivatives, compounds 4aa ( K = 0.09 μM) and 4bb ( K = 0.02 μM) displayed higher inhibitory activities against Arabidopsis thaliana AHAS than those of the controls bispyribac ( K = 0.54 μM) and flumetsulam ( K = 0.38 μM). Remarkably, compounds 4aa, 4bb, 5ah, and 5ag exhibited excellent postemergence herbicidal activity and a broad spectrum of weed control at application rates of 37.5-150 g of active ingredient (ai)/ha. Furthermore, 4aa and 4bb showed higher herbicidal activity against AHAS inhibitor-resistant Descurainia sophia, Ammannia arenaria, and the corresponding sensitive weeds than that of bispyribac at 0.94-0.235 g ai/ha. Therefore, the pyrimidine-biphenyl motif and lead compounds 4aa and 4bb have great potential for the discovery of novel AHAS inhibitors to combat AHAS-inhibiting herbicide-resistant weeds.

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

“…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).…”

“…24 Therefore, designing an antiresistance inhibitor based on the scaffold of pyrimidinyl-salicylic linked by oxygen could be considered as an effective approach that could fight weed resistance associated with AHAS/P197L mutation. 25,26 To date, fragment-based drug design (FBDD) has been regarded as an effective tool for the discovery of drugs and agrochemicals due to its high ligand efficiency (LE), high hit rate, and the diversity of fragments. 27 As an improvement, we developed a pharmacophorelinked fragment virtual screening (PFVS) approach based on the FBDD strategy, which could avoid reliance on sensitive biophysical methods and the use of large amounts of purified protein.…”

Facile one-pot three-component synthesis of 4,6-diaryl-3,4-dihydropyrimidine-2(1H)-thiones under ultrasonic irradiation

“…The produced precipitate was filtered off, washed with water, and dried. Crystallization from ethanol afforded the pure products (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). Yields: (78-95%).…”

“…Pyrimidines are among the most prominent heterocyclic compounds that exhibit a range of significant pharmacological and herbicidal activities. [1,2] They are found in many bioactive natural products as well as numerous nucleoside and non-nucleoside analogs. Pyrimidine derivatives are also important chemical scaffolds in synthetic organic chemistry.…”

Design, Synthesis and Bioactivity of New Pyrimidyl-salicylate Inhibitors

“…最近, 我们发现 在酶突变前后抑制剂分子构象柔性变化与抗性倍数高 低之间存在着一定的关联性, 并提出一种基于"构象柔 性度分析"(conformational flexibility analysis)的反抗性 分子设计策略 [8] . 基于该策略, 我们前期发展了一种通 过柔性桥链连接的嘧啶-联芳基类衍生物, 代表性化合 物 A 对野生型 AtAHAS 和 P197L 突变体均表现出良好 的酶抑制作用 [9] . 但令人遗憾的是, 虽然其对 P197L 突 变体的抗性倍数(约 19 倍)相较于 SUs、 TPs 类 AHAS 抑 制剂(＞500 倍)有大幅下降, 但仍然没有达到反抗性的 设计要求.…”