Discovery and optimization of spirocyclic lactams that inhibit acyl-ACP thioesterase.

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.

A Study in Scaffold Hopping: Discovery and Optimization of Thiazolopyridines as Potent Herbicides That Inhibit Acyl-ACP Thioesterase.

In the search for new chemical entities that can control resistant weeds by addressing novel modes of action (MoAs), we were interested in further exploring a compound class that contained a 1,8-naphthyridine core. By leveraging scaffold hopping methodologies, we were able to discover the new thiazolopyridine compound class that act as potent herbicidal molecules. Further biochemical investigations allowed us to identify that the thiazolopyridines inhibit acyl-acyl carrier protein (ACP) thioesterase (FAT), with this being further confirmed via an X-ray cocrystal structure. Greenhouse trials revealed that the thiazolopyridines display excellent control of grass weed species in pre-emergence application coupled with dose response windows that enable partial selectivity in certain crops.

The Mode of Action of Adjuvants-Relevance of Physicochemical Properties for Effects on the Foliar Application, Cuticular Permeability, and Greenhouse Performance of Pinoxaden.

We comprehensively studied the complexity of the mode of action of adjuvants by uncoupling the parameters contributing to the spray process during foliar application of agrochemicals. The ethoxylated sorbitan esters Tween 20 and Tween 80 improved the efficiency of pinoxaden (PXD) in controlling grass-weed species in greenhouse experiments by aiding retention, having humectant properties, maintaining the bioavailability, and increasing the cuticular penetration of PXD. The nonethoxylated sorbitan esters Span 20 and Span 80 showed minimal effects on retention, droplet hydration, or cuticular penetration, resulting in reduced PXD effects in the greenhouse. Tris(2-ethylhexyl)phosphate (TEHP) does not contribute much to retention and spreading but strongly enhances the diffusion of PXD across isolated P. laurocerasus cuticular membranes. As TEHP was most efficient in controlling the growth of grass-weed species, we propose that the direct effect of penetration aids on cuticular permeation plays a key role in the efficiency of foliar-applied agrochemicals.

Water Sorption Isotherms of Surfactants: A Tool To Evaluate Humectancy.

Fundamental experimental data for moisture absorption of non-ionic polydisperse surfactants with differing ethylene oxide (EO) content and variable aliphatic portions were measured at relative humidities between 0 and 95% at 25 °C. Remarkable differences in moisture absorption were observed between surfactant classes but also within one series of surfactants differing in either EO content or the long-chain aliphatic fraction. Both the EO units as well as the entire molecular structure, including also the lipophilic domain, were discussed to account for the humectant activity of surfactants. Water sorption isotherms showed an exponential shape, which was argued to be associated with the formation of a "free" water domain. These humectant properties might be relevant to the behavior of a foliar-applied spray droplet of agrochemical formulation products because the uptake of active ingredients will be enhanced as a result of deferred crystal precipitation.