Discovery and optimization of spirocyclic lactams that inhibit acyl‐ACP thioesterase

Abstract

BACKGROUNDThere 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.RESULTSBy 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.CONCLUSIONThe 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. Greenhouse 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 species on competitive levels compared with commercial standards.This article is protected by copyright. All rights reserved.