Crop protection chemistry has come a long way from its "alchemic" beginnings in the late 19th century to a high-tech science that supports the sustainable production of food, feed, and fiber for a rapidly growing population. Cutting-edge developments in the design and synthesis of agrochemicals help to tackle today's challenges of weed and pest resistance, higher regulatory safety margins, and higher cost of goods with the invention of selective, environmentally benign, low use rate, and cost-effective active ingredients.

Microtubule-targeting agents (MTAs) are some of the clinically most successful anti-cancer drugs. Unfortunately, instances of multidrug resistances to MTA have been reported, which highlights the need for developing MTAs with different mechanistic properties. One less explored class of MTAs are [1,2,4]triazolo[1,5-a]pyrimidines (TPs). These cytotoxic compounds are microtubule-stabilizing agents that inexplicably bind to vinblastine binding site on tubulin, which is typically targeted by microtubule-destabilizing agents. Here we used cellular, biochemical, and structural biology approaches to address this apparent discrepancy. Our results establish TPs as vinca-site microtubule-stabilizing agents that promote longitudinal tubulin contacts in microtubules, in contrast to classical microtubule-stabilizing agents that primarily promote lateral contacts. Additionally we observe that TPs studied here are not affected by p-glycoprotein overexpression, and suggest that TPs are promising ligands against multidrug-resistant cancer cells.

An overview is given of the significance of heterocycles in crop protection chemistry, which is enormous as more than two-thirds of all agrochemicals launched to the market within the last 20 years belong to this huge group of chemicals. This review focuses on two important aspects of heterocyclic agrochemistry: the different roles of heterocyclic scaffolds in crop protection agents and the major possibilities for their synthesis.

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Scaffold hopping, the exchange of a specific portion of a potential active ingredient with another substructure with the aim of finding isofunctional molecular structures with significantly different molecular backbones, often offers the chance in lead discovery or optimization to mitigate problems related to toxicity, intellectual property, and insufficient potency or stability. Scaffold hopping tools such as isosteric ring replacement including 1,3 nitrogen shift and cyclic imine-amide isosterism, but also ring opening and ring closure approaches, functional group isosterism, reversion of functional groups, chain shortening, chain lengthening, and scaffolds delivered by natural products, have become a permanent fixture of the innovation and optimization process in crop protection research. Their appropriate use will be explained through examples of success stories in the field of agrochemistry. Analogies to, but also differences from, the main categories of scaffold hopping in medicinal drug discovery are discussed. © 2017 Society of Chemical Industry.

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