Synthesis and Herbicidal Activity of Novel N-(7-Oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)arylsulfonamides

Triazolopyrimidine sulfonamide herbicides, a prominent class of acetohydroxyacid synthase (AHAS) inhibitors, are exceptionally effective in controlling weeds in agricultural settings. To overcome metabolic resistance caused by the 5-demethylation of pyroxsulam, we sought to replace its 5-methoxy group on the triazolopyrimidine ring with alkyl substituents. This led to the synthesis of a series of <i>N</i>-(7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)arylsulfon-amides, which displayed significant structural diversification potential, culminating in the identification of the herbicidal hit compound <b>I-20</b>. However, the suboptimal lipophilicity compromised its herbicidal efficacy. To rectify this limitation, we modified the 7-carbonyl group to a <i>tert</i>-butoxy group, resulting in the highly active compound <b>I-29</b>. This compound demonstrated herbicidal activity comparable to or exceeding that of penoxsulam against various tested weeds, establishing it as a promising new lead compound and a candidate herbicide for further investigation. Subsequent studies revealed that <b>I-29</b> exhibited a receptor binding mode and herbicidal activity profiles that closely aligned with those of penoxsulam. Moreover, its spatial structure was found to be even more conducive to inhibiting flavin adenine dinucleotide (FAD)-mediated AHAS activity. This research not only sheds light on addressing the challenge of 5-demethylation metabolic resistance in triazolopyrimidine sulfonamide herbicides but also offers new avenues for the development of AHAS-inhibiting triazolopyrimidine sulfonamide herbicides.