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

Abstract

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.

Synthesis and biological profile of 2,3-dihydro[1,3]thiazolo[4,5-b]pyridines, a novel class of acyl-ACP thioesterase inhibitors

“…Likewise, 1,8-naphthyridines are easily accessed in high yield and on a multigram scale via Friedländer synthesis [18]. This was in clear contrast to the intermediate thiazolo [4,5-b]pyridines and the desired 2,3-dihydro [1,3]thiazolo [4,5-b]pyridine that we wanted to access, with approaches to prepare the thiazolo [4,5b]pyridines using the Friedländer synthesis often being met with failure or disappointingly low product yield [12]. We thus particularly emphasized on upscaling, facile workup, and a robust yield for each step.…”

“…All compounds that were prepared to explore the SAR of substituted 2,3-dihydro [1,3]thiazolo[4,5-b]pyridines, i.e., 13a-c, and 7a-c, the acylated analogues 14a-c and 16a-f, as well as selected aminoboranes 17d and 17e, were tested for target affinity in dedicated in vitro tests, as well as for herbicidal effects in vivo upon preemergence application to plants. Based on our experience with thiazolopyridine-based FAT inhibitors [12,13], five representative grass weeds (ALOMY, ECHCG, LOLRI, POAAN, and SETVI) were chosen as model plants to assess initial preemergence activity using a dose rate of 320 g/ha, whereas in vitro tests were carried out using FAT A, isolated from duckweed (Lemna paucicostata, LEMPA, Lp). As outlined in Table 2, entries 19 and 20, cinmethylin (1) and methiozolin (2) proved to be suitable commercial reference compounds.…”

“…Pleasingly, our four-step approach using a potassium O -ethyl dithiocarbonate-mediated formation of thio intermediates 11a – c (thiol–thione tautomers) with subsequent sulfur removal using iron powder in acetic acid [ 19 ] proceeded smoothly to afford thiazolopyridines 12a – c in good yield. This allowed us to circumvent the previously employed alkylation–oxidation–reduction sequences ( Scheme 2 ) [ 12 ]. Thereupon, we recognized that we could introduce two halogen atoms in the halogenation step and carry one through to the end of the synthetic route, which enabled us to introduce a methyl substituent in this position.…”

“…Further considering the rather low molecular weight (220 g/mol) and structural simplicity, compound 4 is a highly attractive initial lead structure with ample space for structural variations. By formally replacing one pyridine moiety of 1,8-naphthyridine 4 by a five-membered thiazole unit, we have identified thiazolo[4,5- b ]pyridine 5 as a strong inhibitor of acyl-ACP thioesterase, which has further been confirmed via an X-ray co-crystal structure [ 12 ]. Additionally, greenhouse trials have shown that thiazolopyridine 5 and a large number of closely related analogues display excellent control of grass weed species in preemergence applications [ 13 – 14 ].…”