Where Do Agrochemicals Come From?

Ensuring a safe and sustainable food production is of paramount importance to feed a growing world population. Farmers face an uphill struggle to protect their crops from insects, weeds and pathogens that compete for these foods especially in face of climate change which accentuates extreme weather events, pest pressure and promotes rapid pest shifts.[1,2]This must be achieved whilst preserving the environment and the health of future generations. The industry is responding to these challenges by actively evaluating precision agriculture technology in order to reduce overall pesticide use while developing natural product pesticides and new modalities for crop protection such as biologicals, peptides[3] and RNAi-based solutions to provide complementary solutions to synthetic chemical pesticides. Until these concepts establish their role in the marketplace, a new generation of effective, selective and safe small molecules must be designed to comply not only with current regulations but also to anticipate the rapid pace of change in the regulation of synthetic crop protection products around the globe. At the same time many known chemotypes with a specific mode of action are no longer effective against resistant pests and novel resistance breaking ones must be identified along with one acting on new biological targets. The more complex set of features, in addition to basic pest control, a modern agrochemical must meet results in a higher attrition rate in the discovery process. All these factors result in an urgent need for novel starting point. But how are new leads targeting novel targets discovered? Tounderstand the inception process of newagrochemicals,we analyzed 20 years (1998–2018 covering 218 structures) of agrochemical research focusing on public agrochemical ISO common names which are the earliest public information on development of novel agrochemicals.[4] Such a long-view enables to de-bias against recent one-off events and to focus on trends. We isolated the new chemotypes from this set and looked into the most likely origins of each these and categorized them in seven categories: 1) ‘Chemistry-Driven’ where no obvious biological hypothesis was used and chemical novelty was the goal; 2) ‘Chemistry-Driven in Known Class’, where the new chemotype was invented as part of SAR exploration project within a known chemical class; 3) ‘Hit other Mode ofAction (MoA)/indication’ where a compound made for one project is active in a different indication or mode of action than the lead series; 4) ‘Natural Product’, where an exact natural product was used; 5) ‘Natural ProductAnalog’ where post synthetic modifications were made; 6) ‘Natural Product Inspired’ where a synthetic analog of a known natural product was the starting point; 7) ‘Random Screen’ where externally purchased screening compounds were the origin. The result of this analysis is summarized in Fig. 1.