The control of resistant grass weeds in cereal crops remains one of the most significant challenges in modern agriculture. Current agrochemical solutions to this problem are insufficient and rely on aging chemistry that sees ever‐increasing levels of resistance in the field, with new tools urgently needed. We present novel pyrrolidinyl carboxamide inhibitors of the plant‐specific enzyme acyl‐ACP thioesterase (FAT A) as an important advance in broadening the structural scope of agroscientific research in this area. Utilizing scaffold‐hopping and bioisosteric replacement strategies, we evolve fungicidal lead structures into promising herbicidal compounds with target affinity and in vivo efficacy on par with or slightly better than market compounds. A cocrystal structure of one of the most promising herbicide candidates with a model FAT A, alongside extensive SAR development, provides clear and comprehensive insight into the interaction of these compounds with their biological target and organisms of interest. Additionally, the structural motifs investigated here complement those of established FAT A inhibitors while employing efficient and robust syntheses, altogether building an excellent foundation for future development of similar scaffolds.

BACKGROUND:Owing to the economic relevance of resistance evolution against herbicides, new chemical entities addressing unprecedented molecular targets are urgently needed to develop future sustainable weed control solutions. As part of our discovery research, the new class of aminoisothiazolamides was investigated. RESULTS:Aminoisothiazolamide 3-amino-4-chloro-N-(cyclohexylmethyl)isothiazole-5-carboxamide 1a and several of its derivatives displayed potent herbicidal and fungicidal in vivo activity in initial glasshouse tests. Lysyl-tRNA synthetase 1 (KRS1) was identified as the putative target for 1a and was validated as a key contributor to the biochemical mode-of-action of aminoisothiazolamides. Thermal stability shift analysis with KRS1 from Arabidopsis thaliana (AtKRS1) revealed that 1a specifically increased the thermostability of this enzyme, proving the KRS1 enzyme as the aminoisothiazolamide target. It turned out that the inhibition of AtKRS1 and HsKRS was strongly correlated, as was the inhibition of AtKRS1 and the herbicidal activity of the aminoisothiazolamides. Hence, in vivo acute toxicity tests were initiated at a very early project stage complementing the enzyme tests. CONCLUSION:The observed toxicological effects paired with the anticipated likelihood to overcome this problem, owing to the highly conserved active sites in different species, finally resulted in the conclusion to stop the further exploration of the otherwise promising class of herbicidal aminoisothiazolamides. Thus, we opted to discard several further herbicidal lead structures before the start of in-depth investigations when sequence analyses suggested similar levels of conservation between the respective binding pockets in plants and mammalians. © 2025 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Utilizing scaffold hopping and bioisosteric replacement strategies, we explored new azetidinyl carboxamide inhibitors of the plant-specific enzyme acyl-ACP thioesterase (FAT). Amongst the investigated compounds we identified new structural motifs that showed promising target affinity coupled with good in vivo efficacy against commercially important weed species. We further studied the structure-activity relationship (SAR) of the novel azetidinyl pyrazole carboxamide scaffold which showed promise as a new type of FAT inhibiting herbicides. Accordingly, a focused synthetic approach towards azetidinyl carboxamides was explored.

The present work covers novel herbicidal lead structures that contain a 2,3-dihydro[1,3]thiazolo[4,5-b]pyridine scaffold as structural key feature carrying a substituted phenyl side chain. These new compounds show good acyl-ACP thioesterase inhibition in line with strong herbicidal activity against commercially important weeds in broadacre crops, e.g., wheat and corn. The desired substituted 2,3-dihydro[1,3]thiazolo[4,5-b]pyridines were prepared via an optimized BH3-mediated reduction involving tris(pentafluorophenyl)borane as a strong Lewis acid. Remarkably, greenhouse trials showed that some of the target compounds outlined herein display promising control of grass weed species in preemergence application, combined with a dose response window that enables partial selectivity in certain crops.

BACKGROUND:There are various methods to control weeds, that represent considerable challenges for farmers around the globe, although applying small molecular compounds is still the most effective and versatile technology to date. In the search for novel chemical entities with new modes-of-action that can control weeds displaying resistance, we have investigated two spirocyclic classes of acyl-ACP thioesterase inhibitors based on X-ray co-crystal structures and subsequent modelling studies. RESULTS:By exploiting scaffold-hopping and isostere concepts, we were able to identify new spirolactam-based lead structures showing promising activity in vivo against commercially important grass weeds in line with strong target affinity. CONCLUSION:The present work covers a series of novel herbicidal lead structures that contain a spirocyclic lactam as a structural key feature carrying ortho-substituted benzyl or heteroarylmethylene side chains. These new compounds show good acyl-ACP thioesterase inhibition in line with strong herbicidal activity. Glasshouse trials showed that the spirolactams outlined herein display promising control of grass-weed species in pre-emergence application combined with dose-response windows that enable partial selectivity in wheat and corn. Remarkably, some of the novel acyl-ACP thioesterase-inhibitors showed efficacy against resistant grass weeds such as Alopecurus myosuroides and Lolium spp. on competitive levels compared with commercial standards. © 2024 Society of Chemical Industry.

The sustainable control of weed populations, particularly resistant species, is a significant challenge in agriculture around the world. The α-aryl-keto-enol (aryl-KTE) class of acetyl-CoA carboxylase (ACCase)-inhibiting herbicides represent a possible solution for the control of resistant grasses even though achieving crop selectivity remains a challenge. Herein, we present some of our investigations into identifying the most promising structural features within the aryl-KTE class that give the highest chance of achieving soybean crop selectivity, whilst also maintaining strong and broad efficacy against problematic weed species. We further examined our results by preparing new aryl-KTE molecules which were evaluated in glasshouse screening assays for their herbicidal efficacy as well as their soybean selectivity. We consider that uniting this approach with other optimization criteria, such as toxicological and environmental safety profiles, will enable the streamlining of crop protection optimizations programmes, ultimately delivering safer and more sustainable solutions to farmers and consumers. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

BACKGROUND: The sustainable control of weed populations is a significant challenge facing farmers around the world. Although various methods for the control of weeds exist, the use of small molecule herbicides remains the most effective and versatile approach. Striving to find novel herbicides that combat resistant weeds via the targeting of plant specific modes of action (MoAs), we further investigated the bicyclic class of acyl-acyl carrier protein (ACP) thioesterase (FAT) inhibitors in an effort to find safe and efficacious lead candidates. RESULTS: Utilizing scaffold hopping and bioisosteric replacements strategies, we explored new bicyclic inhibitors of FAT. Amongst the investigated compounds we identified new structural motifs that showed promising target affinity coupled with good in vivo efficacy against commercially important weed species. We further studied the structure-activity relationship (SAR) of the novel dihydropyranopyridine structural class which showed promise as a new type of FAT inhibiting herbicides. CONCLUSION: The current work presents how scaffold hopping approaches can be implemented to successfully find novel and efficacious herbicidal structures that can be further optimized for potential use in sustainable agricultural practices. The identified dihydropyranopyridine bicyclic class of herbicides were demonstrated to have in vitro inhibitory activity against the plant specific MoA FAT as well as showing promising control of a variety of weed species, particularly grass weeds in greenhouse trials on levels competitive with commercial standards. (c) 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

BACKGROUND:Weed control is a significant challenge for farmers around the globe. Of the various methods available for combatting weeds, small molecules remain the most effective and versatile technology to date. In the search for novel chemical entities with new modes of action toward herbicide-resistant weeds, we have investigated hexahydrofuro[3,4-b]furan-based acyl-acyl carrier protein (ACP) thioesterase inhibitors inspired by X-ray co-crystal structure-based modeling studies. RESULTS:By exploiting scaffold hopping concepts and molecular modeling studies we were able to identify new hexahydrofuro[3,4-b]furan-based lead structures showing promising activity in vivo against commercially important grass weeds in line with strong target affinity. CONCLUSION:The present work covers a series of novel herbicidal lead structures that possess a hexahydrofuro[3,4-b]furan scaffold as a structural key feature, carrying ortho-substituted aryloxy side chains. Based on an optimized synthetic approach a broad structure-activity relationship (SAR) study was carried out. The new compounds emerging from our modeling-inspired structural variations show good acyl-ACP thioesterase inhibition in line with promising initial herbicidal activity. Glasshouse trials showed that the hexahydrofuro[3,4-b]furans outlined herein display good control of cold and warm season grass-weed species in pre-emergence application. Remarkably, some of the novel acyl-ACP thioesterase-inhibitors also showed promising efficacy against warm season weeds that are difficult to control. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Chemical concepts such as isosteres and scaffold hopping have proven to be powerful tools in agrochemical innovation processes. They offer opportunities to modify known molecular lead structures with the aim to improve a range of parameters, including biological efficacy and spectrum, physicochemical properties, stability, and toxicity. While recent biochemical insights into plant-specific receptors and signaling pathways trigger the discovery of the first lead structures, the disclosure of such a new chemical structure sparks a broad range of synthesis activities giving rise to diverse chemical innovation and often a considerable boost in biological activity. Herein, recent examples of isostere concepts in plant-hormone chemistry will be discussed, outlining how synthetic creativity can broaden the scope of natural product chemistry and giving rise to new opportunities in research fields such as abiotic stress tolerance and growth promotion.

BACKGROUND Whilst there are several methods to control weeds, which continuously plague farmers around the globe, the application of small molecular compounds is still the most effective technology to date. Plants can evolve to become resistant to PPO inhibitors, a class of herbicides in commercial use since the 1960s. It is therefore essential to continuously develop new herbicides based on this mode of action with enhanced intrinsic activity, an improved resistance profile and favorable physicochemical properties. Based on an Amaranthus PPO crystal structure and subsequent modelling studies, halogen-substituted pyrazoles have been investigated as isosteres of uracil-based PPO inhibitors. RESULTS By combining structural features from commercial PPO-inhibitors tiafenacil and pyraflufen-ethyl and by investigating receptor-binding properties we have identified new promising pyrazole-based lead structures showing strong activity in vitro and in vivo against economically important weeds of the Amaranthus species, e.g. Amaranthus retroflexus, and resistant Amaranthus palmeri and Amaranthus tuberculatus. CONCLUSION The present work covers a series of novel PPO inhibiting compounds that contain a pyrazole ring and a substituted thioacetic acid sidechain attached to the core phenyl group. These compounds show good receptor fit in line with excellent herbicidal activity against weeds that plague corn and rice crops with low application rates. This, in combination with promising selectivity in corn, have the potential to mitigate and affect weeds that have become resistant to some of the current market standards. Remarkably, some of the novel PPO-inhibitors outlined herein show efficacies against economically important weeds that were superior to recently commercialized and structurally related tiafenacil. This article is protected by copyright. All rights reserved.

There are several methods to control weeds, which impose particular challenges for farmers in all parts of the world, although applying small molecular compounds still remains the most efficient technology to date. However, plants can evolve to become resistant toward active ingredients which is also the case for protoporphyrinogen oxidase (PPO) inhibitors, a class of highly effective herbicides in use for more than 50 years. Hence, it is essential to continuously discover and develop new herbicidal PPO inhibitors with enhanced intrinsic activity, an improved resistance profile, enhanced crop safety, favorable physicochemical properties, and a clean toxicological profile. By modifying structural key features from known PPO inhibitors such as tiafenacil, inspired by isostere and mix&match concepts in combination with modeling investigations based on a wild-type Amaranthus crystal structure, we have found new promising lead structures showing strong activity in vitro and in vivo against several notorious dicotyledon and monocotyledon weeds with emerging resistance (e.g., Amaranthus palmeri, Amaranthus tuberculatus, Lolium rigidum, and Alopecurus myosuroides). While several phenyl uracils carrying an isoxazoline motif in their thio-linked side chain showed promising resistance-breaking potential against different Amaranthus species, introducing a thioacrylamide side chain afforded outstanding efficacy against resistant grass weeds.

The Front Cover shows one set of crop species thriving in comparison to the other – despite both enduring cold and drought conditions – as it has been treated with new compounds developed by Frackenpohl and colleagues. Notes on the Lewis acid-mediated cyclization used to synthesize these have been left on the pot of hydrangea flowers, the roots of which contain hydrangeic acid and the plant hormone lunularic acid, which inspired this work. Cover artwork by Ronald W. Brown. More information can be found in the Research Article by J. Frackenpohl et al.

New 2,3-dihydro-1-benzofuran-4-carboxylic acid derivatives have been identified as potent lead structures against drought and cold stress in crops starting from the synthetic exploration of stabilized analogs of the natural product lunularic acid. An optimized Lewis-acid mediated cyclization gave a short and efficient access to the envisaged 2,3-dihydro-1-benzofuran-4-carboxylates. Enantioselective approaches were investigated to assess the potential impact of the chiral center on in vivo activity. Whilst 2,3-dihydro-1-benzofuran-4-carboxamides and 2,3-dihydro-1-benzofuran-4-carboxylates carrying phenyl substituents with electron-withdrawing groups exhibited only low to moderate in vivo activity, the corresponding 2,3-dihydro-1-benzofuran-4-carboxylates carrying optimized electron-donating substituents in the phenyl moiety revealed strong in vivo activity, both against drought stress in several broad-acre crops, as well as against cold stress in corn. Remarkably, several 2,3-dihydro-1-benzofuran-4-carboxylates showed stronger efficacy than the internal standards used in our in vivo SAR study.

New oxotetrahydroquinolinyl- and oxindolinyl sulfonamides interacting with RCAR/(PYR/PYL) receptor proteins were identified as lead structures against drought stress in crops starting from protein docking studies of a sulfonamide lead structure, followed by in-depth SAR studies. Optimized five to six step synthetic approaches via substituted amino oxo-tetrahydro-quinolines and amino oxo-indolines as essential intermediates gave access to the envisaged oxo-tetrahydroquinolinyl and oxindolinyl sulfonamides. Whilst oxo-tetrahydroquinolinyl sulfonamides with additional carbon substituents or spiro-cycloalkyl groups exhibited only low to moderate target affinities, the corresponding spiro-oxindolinyl and oxo-tetrahydroquinolinyl sulfonamides carrying optimized N-substituents revealed strong interactions with RCAR/(PYR/PYL) receptor proteins in Arabidopsis thaliana. Remarkably, the in vitro activity observed for these new compounds was on the same level as observed for the naturally occurring plant hormone in line with strong efficacy against drought stress in-vivo (canola and wheat as broad-acre crops).

Synthetic analogues of plant hormone abscisic acid (ABA) bearing a yet unexplored head group motif were prepared based on a combination of agrochemical experience, in vivo hits and structure-based design. It could thus be explored how modifying key parts of ABA's cyclohexenone unit influenced receptor affinity and in vivo efficacy against drought stress in selected crops. Cyano-cyclopropyl groups proved to be suitable replacements of the cyclohexanone moiety leading to ABA analogues with strong activity in vitro and in vivo. Their efficient and versatile synthesis proceeded via Stille or Sonogashira couplings as the key steps. Combining novel cyano-cyclopropyl headgroups with previously identified substituents in the terpenoid side chain afforded the most promising effects against drought stress in crops, particularly canola and wheat.

Novel analogues of the plant hormone abscisic acid (ABA) were designed and prepared to explore the impact that modifications of its terpenoid side chain have on receptor affinity and in vivo efficacy against drought stress in selected crops. Their efficient and versatile synthesis proceeded via Stille or Sonogashira couplings, shortening the synthetic route significantly. In line with molecular modelling and X-ray crystallography studies novel ABA-derivatives with small alkyl, cycloalkyl or haloalkyl substituents showed strong effects in vitro and in vivo against drought stress in crops, particularly canola and wheat.

The Front Cover shows common iterative steps of modern agrochemical research in the foreground with ears of wheat plants close to being harvested in the background. Inspired by nature, that is, by plant hormone abscisic acid (ABA), novel lead structures targeting drought stress in crops such as wheat or canola have been identified. In vivo SAR studies based on greenhouse trials and chemical optimization were supported by systems biology, in vitro analyses, and X-ray crystallography. It could thus be explored how modification of the key structural features of ABA influences receptor affinity and in vivo efficacy. As a result, cyano-cyclopropyl groups proved to be suitable replacements for the cyclohexanone headgroup motif. More information can be found in the full papers by J. Frackenpohl, E. Grill et al. (ejoc.201701687 and ejoc.201701769)