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.

Inspired by Nature: Isostere Concepts in Plant Hormone Chemistry.

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.

Designing New Protoporphyrinogen Oxidase-Inhibitors Carrying Potential Side Chain Isosteres to Enhance Crop Safety and Spectrum of Activity.

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.

Total Synthesis of (+)-Panacene.

The first total synthesis of the naturally occurring enantiomer of the marine bromoallene (+)-panacene is described. Central to this concise enantioselective synthesis was the use of a Noyori transfer hydrogenation for a Dynamic Kinetic Resolution (DKR) that set the desired absolute stereochemistry. A highly stereoselective Julia coupling was then used to install a Z-configured enyne, which enabled the biomimetic construction of the axially chiral bromoallene.