Synthesis and Biological Profile of Substituted Pyrrolidinyl Carboxamides for Acyl‐ACP Thioesterase Inhibition

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.