Chance and design in proinsecticide discovery

Abstract

Many insecticides are inactive on their target sites in the form that is sold and applied, needing first to be bioactivated. This proinsecticide strategy has often been achieved by design, through systematic derivatization of intrinsically active molecules with protecting groups that mask their toxic effects until their selective removal in target insects by metabolic enzymes generates the toxiphore. Proinsecticides can be designed to gain selectivity between target and non-target organisms, or to improve bioavailability by enhancing plant or insect uptake. In most cases, however, chance trumps design in proinsecticide discovery: most first-in-class products that we now know to be proinsecticides were only discovered a posteriori to be such, often after having been on the market for years. Knowing the active form of an insecticide is essential to mode of action identification, and early mode of action studies on novel chemotypes should take into account the possibility that the compounds might be proinsecticides. This paper reviews examples of proinsecticides in the marketplace, strategies for making proinsecticides and techniques for unmasking proinsecticides in mode of action studies. Our analysis of global agrochemical sales data shows that 34% of the dollar value of crop insecticides used in 2015 were proinsecticides. © 2016 Society of Chemical Industry.

Vectorizing agrochemicals: enhancing bioavailability via carrier‐mediated transport

“…The propesticide concept has been successfully applied in the design of agrochemicals for a long time . The catalogue of propesticides and their significance in improving biological activity and target selectivity have been comprehensively described in excellent recent reviews . Contributions of propesticides to improve bioavailability by enhancing plant or insect uptake are also acknowledged, which mainly focused on optimizing the physicochemical properties to improve water solubility and lipophilicity of the parent active ingredient .…”

“…8 The catalogue of propesticides and their significance in improving biological activity and target selectivity have been comprehensively described in excellent recent reviews. 8,21,22 Contributions of propesticides to improve bioavailability by enhancing plant or insect uptake are also acknowledged, which mainly focused on optimizing the physicochemical properties to improve water solubility and lipophilicity of the parent active ingredient. 8,23,24 However, the design of a propesticide with greater bioavailability is still challenging and there is a lack of well-established strategies to achieve this.…”

Predicting mammalian metabolism and toxicity of pesticides in silico

“…Esters of carboxylic acids are more hydrophobic than the acids themselves, so they penetrate plant cuticles more readily. This makes esterification a popular way to create pro‐pesticides, in part because the enzymes that cleave them are ubiquitous. Hence esters that are readily cleaved in plants, fungi or insects are also likely to be cleaved in the human gastrointestinal tract or liver.…”

Innovations in Agrochemical Discovery and the Role of Metabolism, Bioavailability and Formulations

“…Salgado and David (BASF) provide a unique overview of the importance of pro‐insecticides in the discovery process. The pro‐drug strategy has often been applied during lead optimization, to alleviate toxicity to non‐target organisms.…”