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

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 i = 0.09 μM) and 4bb (K i = 0.02 μM) displayed higher inhibitory activities against Arabidopsis thaliana AHAS than those of the controls bispyribac (K i = 0.54 μM) and flumetsulam (K i = 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.