A New Class of Diaryl Ether Herbicides: Structure-Activity Relationship Studies Enabled by a Rapid Scaffold Hopping Approach.

We report on the development of a novel class of diaryl ether herbicides. After the discovery of a phenoxybenzoic acid with modest herbicidal activity, optimization led to several molecules with improved control of broadleaf and grass weeds. To facilitate this process, we first employed a three-step combinatorial approach, then pivoted to a one-step Ullmann-type coupling that provided faster access to new analogs. After determining that the primary target site of our benchmark diaryl ethers was acetolactate synthase (ALS), we further leveraged this copper-catalyzed methodology to conduct a scaffold hopping campaign in the hope of uncovering an additional mode of action with fewer documented cases of resistance. Our comprehensive and systematic investigation revealed that while the herbicidal activity of this area seems to be exclusively linked to ALS inhibition, our molecules represent a structurally distinct class of Group 2 herbicides. The structure-activity relationships that led us to this conclusion are described herein.

Discovery and Mode-of-Action Characterization of a New Class of Acetolactate Synthase-Inhibiting Herbicides.

Herbicides are effective tools to manage weeds and enable food production and sustainable agriculture. Corteva Agriscience R&D has recently discovered new diphenyl-ether compounds displaying excellent postemergent efficacy on important weed species along with corn safety. Here, we describe the chemistry, biology, biochemistry, and computational modeling research that led to the discovery and elucidation of the primary mode of action for these compounds. The target protein was found to be acetolactate synthase (ALS), a key enzyme in the biosynthesis of branched chain amino acids (valine, leucine, and isoleucine). While weed resistance evolution to ALS herbicides is widespread, the molecular interaction of the diphenyl-ether compounds at the active site of the ALS enzyme differs significantly from that of some commercial ALS inhibitors. The unique biochemical profile of these molecules along with their excellent herbicidal activity and corn selectivity make them a noteworthy development in the pursuit of novel, safe, and sustainable weed control solutions.

EST-SSR development from 5 Lactuca species and their use in studying genetic diversity among L. serriola biotypes.

Prickly lettuce (Lactuca serriola L.) is a problematic weed of Pacific Northwest and recently developed resistance to the auxinic herbicide 2,4-D. There are no publically available simple sequence repeat (SSR) markers to tag 2,4-D resistance genes in L. serriola. Therefore, a study was conducted to develop SSR markers from expressed sequence tags (ESTs) of 5 Lactuca species. A total of 15,970 SSRs were identified among 57,126 EST assemblies belonging to 5 Lactuca species. SSR-containing ESTs (SSR-ESTs) ranged from 6.23% to 7.87%, and SSR densities ranged from 1.28 to 2.51 kb(-1) among the ESTs of 5 Lactuca species. Trinucleotide repeats were the most abundant SSRs detected during the study. As a representative sample, 45 ESTs carrying class I SSRs (≥ 20 nucleotides) were selected for designing primers and were also searched against the dbEST entries for L. sativa and Helianthus annuus (≤ 10(-50); score ≥ 100). In silico analysis of 45 SSR-ESTs showed 82% conservation across species and 68% conservation across genera. Primer pairs synthesized for the above 45 EST-SSRs were used to study genetic diversity among a collection of 22 L. serriola biotypes. Comparison of the resultant dendrogram to that developed using phenotypic evaluation of the same subset of lines showed limited correspondence. Taken together, this study reported a collection of useful SSR markers for L. serriola, confirmed transferability of these markers within and across genera, and demonstrated their usefulness in studying genetic diversity.

Weed resistance to synthetic auxin herbicides.

Herbicides classified as synthetic auxins have been most commonly used to control broadleaf weeds in a variety of crops and in non-cropland areas since the first synthetic auxin herbicide (SAH), 2,4-D, was introduced to the market in the mid-1940s. The incidence of weed species resistant to SAHs is relatively low considering their long-term global application with 30 broadleaf, 5 grass, and 1 grass-like weed species confirmed resistant to date. An understanding of the context and mechanisms of SAH resistance evolution can inform management practices to sustain the longevity and utility of this important class of herbicides. A symposium was convened during the 2nd Global Herbicide Resistance Challenge (May 2017; Denver, CO, USA) to provide an overview of the current state of knowledge of SAH resistance mechanisms including case studies of weed species resistant to SAHs and perspectives on mitigating resistance development in SAH-tolerant crops. © 2017 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Physiological and molecular basis of acetolactate synthase-inhibiting herbicide resistance in barnyardgrass (Echinochloa crus-galli).

Barnyardgrass biotypes from Arkansas (AR1 and AR2) and Mississippi (MS1) have evolved cross-resistance to imazamox, imazethapyr, and penoxsulam. Additionally, AR1 and MS1 have evolved cross-resistance to bispyribac-sodium. Studies were conducted to determine if resistance to acetolactate synthase (ALS)-inhibiting herbicides in these biotypes is target-site or non-target-site based. Sequencing and analysis of a 1701 base pair ALS coding sequence revealed Ala122 to Val and Ala122 to Thr substitutions in AR1 and AR2, respectively. The imazamox concentrations required for 50% inhibition of ALS enzyme activity in vitro of AR1 and AR2 were 2.0 and 5.8 times, respectively, greater than the susceptible biotype. Absorption of ¹4C-bispyribac-sodium, -imazamox, and -penoxsulam was similar in all biotypes. ¹4C-Penoxsulam translocation out of the treated leaf (≤2%) was similar among all biotypes. ¹4C-Bispyribac-treated AR1 and MS1 translocated 31- 43% less radioactivity to aboveground tissue below the treated leaf compared to the susceptible biotype. ¹4C-Imazamox-treated AR1 plants translocated 39% less radioactivity above the treated leaf and aboveground tissue below the treated leaf, and MS1 translocated 54 and 18% less radioactivity to aboveground tissue above and below the treated leaf, respectively, compared to the susceptible biotype. Phosphorimaging results further corroborated the above results. This study shows that altered target site is a mechanism of resistance to imazamox in AR2 and probably in AR1. Additionally, reduced translocation, which may be a result of metabolism, could contribute to imazamox and bispyribac-sodium resistance in AR1 and MS1.

Inheritance and physiological basis for 2,4-D resistance in prickly lettuce (Lactuca serriola L.).

Experiments were conducted to determine the inheritance and physiological basis for resistance to the synthetic auxinic herbicide (2,4-dichlorophenoxy)acetic acid (2,4-D) in a prickly lettuce biotype. Inheritance of 2,4-D resistance in prickly lettuce is governed by a single codominant gene. Absorption and translocation were conducted using (14)C-2,4-D applied to 2,4-D-resistant and -susceptible biotypes. At 96 h after treatment (HAT), the resistant biotype absorbed less applied 2,4-D and retained more 2,4-D in the treated portion of the leaf compared to the susceptible biotype. The resistant biotype translocated less applied 2,4-D to leaves above the treated leaf and crown at 96 HAT compared to the susceptible biotype. No difference in the rate of metabolism of 2,4-D was observed between the two biotypes. Resistance to 2,4-D appears to originate from a reduced growth deregulatory and overstimulation response compared to the susceptible biotype, resulting in lower translocation of 2,4-D in the resistant prickly lettuce biotype.