Pesticide research

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. Obstacles include increasing pesticide resistance and an increasingly stringent regulatory environment.^[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.^[1]

History

Along with improved agrochemicals, seeds, fertilizers, mechanization, and precision farming, improved protection of crops from weeds, insects and other threats is highly sought. 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.^[1]

The rate of new molecule introductions has declined. The costs to bring a new molecule to market have risen from U.S. $152 million in 1995 to $256 million in 2005, as the number of compounds synthesized to deliver one new market introduction rose from 52,500 in 1995 to 140,000 in 2005.^[1]

New active ingredient registrations with the US

Candidate molecules are optimized through a design-synthesis-test-analysis cycle. While compounds eventually are tested on the target organism(s). However, in vitro assays are becoming more common.[1]

Parallels with pharmaceuticals

The likelihood of finding active analogs on the basis of a screen hit from a novel scaffold can be increased by virtual screening. 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. The scores obtained from docking studies ranked these molecules. Resulting novel compounds showed a primary hit rate of 10.9%, much higher than for conventional high-throughput screening. 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. Scaffold-hopping is also efficiently achieved by virtual screening, with 2D and 3D variants providing the best results.^[1]

Genome-sequencing,

Plant activators are compounds that activate a plant's immune system in response to invasion by pathogens. They play a crucial role in crop survival. Unlike pesticides, plant activators are not pathogen specific and are not affected by drug resistance, making them ideal for use in agriculture. Wet-rice farmers across East Asia use plant activators as a sustainable means to enhance crop health.^[6][7]

The activation of plant responses is often associated with arrested growth and reductions in yield, for reasons that remain unclear. The molecular mechanisms governing plant activators are largely unknown.^[6]

Screening can distinguish compounds that independently induce immune responses from those that do so exclusively in the presence of some pathogen. Independent activators can be toxic to cells. Others enhance resistance only in the presence of pathogens. In 2012, five activators that protected against Pseudomonas bacteria by priming immune response without directly activating defense genes. The compounds inhibit two enzymes that inactivate the defense hormone salicylic acid (SA glucosyltransferases or SAGTs), providing enhanced disease resistance.^[6]

References