Early twenty-first century pesticide research has focused on developing molecules that combine low use rates and that are more selective, safer, resistance-breaking and cost-effective.
[1] The sources of new molecules employ natural products, competitors, universities, chemical vendors, combinatorial chemistry libraries,[2] intermediates from projects in other indications and compound collections from pharmaceutical and animal health companies.
Developments over the past 1960–2013 period enabled reduced use rates, in the cases of the sulfonylurea herbicides (5), the piperidinylthiazole fungicides, and the emamectin insecticides and acaricides, reaching 99%, with concomitant environmental improvements.
For example, the crystal structure of a glutamate-gated chloride channel in complex with ivermectin was reported in 2011 and represents a starting point for the design of novel insecticides.
This structure led to a homology model for a related γ-aminobutyric acid (GABA)–gated chloride channel and a binding mode for the meta-diamides, another insecticide class.
A combination of in silico fragment-based design with protein ligand crystal structures yielded synthetically amenable compounds.
Because the pharmacophore of the reference ligand is well defined, a virtual library of potential herbicidal inhibitors of the enzyme anthranilate synthase was generated by keeping the core scaffold constant and attaching different linkers.
Other tools like three-dimensional (3D) shape, atom-type similarity, or 2D extended connectivity fingerprints also retrieve molecules of interest out of a database with a useful success rate.
[1] Genome-sequencing, gene knockout or antisense knockdown techniques have provided agrochemists with a method for validating potential new biochemical targets.
Examples of this procedure include the search for new herbicidal compounds of the nonmevalonate, such as the discovery of new inhibitors of 2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase (IspD, Enzyme Commission (EC) number 2.7.7.60) with the best expressing a half-maximal inhibitory concentration (IC50) of 140 nM in the greenhouse at 3 kg/ha (2.7 lb/acre).
The compounds inhibit two enzymes that inactivate the defense hormone salicylic acid (SA glucosyltransferases or SAGTs), providing enhanced disease resistance.