De Novo Design of Potent, Insecticidal Synthetic Mimics of the Spinosyn Macrolide Natural Products

Abstract

New insect pest control agents are needed to meet the demands to feed an expanding global population, to address the desire for more environmentally-friendly insecticide tools, and to fill the loss of control options in some crop-pest complexes due to development of insecticide resistance. The spinosyns are a highly effective class of naturally occurring, fermentation derived insecticides, possessing a very favorable environmental profile. Chemically, the spinosyns are composed of a large complex macrolide tetracycle coupled to two sugars. As a means to further exploit this novel class of natural product-based insecticides, molecular modeling studies coupled with bioactivity-directed chemical modifications were used to define a less complex, synthetically accessible replacement for the spinosyn tetracycle. These studies lead to the discovery of highly insecticidal analogs, possessing a simple tri-aryl ring system as a replacement for the complex macrolide tetracycle.

Discovery of highly insecticidal synthetic spinosyn mimics – CAMD enabled de novo design simplifying a complex natural product

“…However, unlike other NPs, commercially viable synthetic mimics of the large macrolides have been unknown for agrochemicals and, as far as can be determined, pharmaceuticals. We recently reported that simplified synthetic mimics of the complex spinosyn structure are indeed possible, exhibiting laboratory efficacy near that of spinetoram . Herein we provide further elaboration on the discovery and development of synthetic spinosyn mimics, resulting in highly active, photostable analogs that demonstrate excellent in vivo efficacy in the laboratory and field.…”

“…Structures of commercial insecticides, spinosad 1 and spinetoram 4 , and a conceptual route to the discovery of the synthetic spinosyn mimics. Spinosyn mimics were synthesized as described by Crouse et al …”

“…Initial CAMD modeling of potential cores suggested that the pyridobenzimidazole (PBI) core structure (Fig. ) might be a suitable starting point as it overlaid well with the spinosyn tetracycle. Further CAMD‐based modifications to the PBI‐core included adding a 2′,3′,4′‐tri‐ O ‐methyl rhamnose sugar via an indane linker to correctly place the rhamnose in its putative binding pocket and overlay with the rhamnose moiety of the spinosyns and a N,N ‐dimethyl amine to mirror the forosamine functionality.…”

Natural products: a strategic lead generation approach in crop protection discovery

“…More recently, the NP-based discovery program at Corteva has continued to deliver new crop protection compounds, including the new fungicides fenpicoxamid 33,34 and florylpicoxamid 7 and the new insecticidal synthetic spinosyn mimics. 35,36 As noted above, a key advantage of an NP-based discovery program is the enhanced probability of finding crop protection compounds that possess new MoAs. This outcome is exemplified by both the spinosyns and new fungicidal chemistry, and it has further served to maintain interest in NP-based lead generation within CAS.…”

“…Along the way, the discovery a new family (21‐butenyl) of spinosyns and the genetic engineering of the spinosyn biosynthetic pathway to produce new spinosyn derivatives have also helped maintain interest in NPs. More recently, the NP‐based discovery program at Corteva has continued to deliver new crop protection compounds, including the new fungicides fenpicoxamid and florylpicoxamid and the new insecticidal synthetic spinosyn mimics . As noted above, a key advantage of an NP‐based discovery program is the enhanced probability of finding crop protection compounds that possess new MoAs.…”