The novel pyridazine pyrazolecarboxamide insecticide dimpropyridaz inhibits chordotonal organ function upstream of TRPV channels.

BACKGROUND: Pyridazine pyrazolecarboxamides (PPCs) are a novel insecticide class discovered and optimized at BASF. Dimpropyridaz is the first PPC to be submitted for registration and controls many aphid species as well as whiteflies and other piercing-sucking insects. RESULTS: Dimpropyridaz and other tertiary amide PPCs are proinsecticides that are converted in vivo into secondary amide active forms by N-dealkylation. Active secondary amide metabolites of PPCs potently inhibit the function of insect chordotonal neurons. Unlike Group 9 and 29 insecticides, which hyperactivate chordotonal neurons and increase Ca2+ levels, active metabolites of PPCs silence chordotonal neurons and decrease intracellular Ca2+ levels. Whereas the effects of Group 9 and 29 insecticides require TRPV (Transient Receptor Potential Vanilloid) channels, PPCs act in a TRPV-independent fashion, without compromising cellular responses to Group 9 and 29 insecticides, placing the molecular PPC target upstream of TRPVs. CONCLUSIONS: PPCs are a new class of chordotonal organ modulator insecticide for control of piercing-sucking pests. Dimpropyridaz is a PPC proinsecticide that is activated in target insects to secondary amide forms that inhibit the firing of chordotonal organs. The inhibition occurs at a site upstream of TRPVs and is TRPV-independent, providing a novel mode of action for resistance management. © 2023 BASF Corporation. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

The potential of pro-insecticides for resistance management.

Pro-insecticides have been a significant part of the insecticide market for decades. Bioactivation of such compounds is generally an enzyme-controlled process, in which the target insect metabolizes the pro-form into an active compound. This approach has several potential advantages, including improved bio-kinetic properties and safety profiles of the pro-insecticide relative to the active form. A less common advantage of pro-insecticides is increased activity on metabolically resistant strains. Specific cases in which a pro-insecticide demonstrates negative cross-resistance (NCR) on a metabolically resistant strain due to increased bioactivation of the pro-insecticide have been noted sporadically over the past 50+ years but have not been reviewed before. The purpose of this mini-review is to catalog the cases in which a pro-insecticide demonstrated improved activity on an insect strain resistant to a second insecticide via a metabolic mechanism. Cases are relatively rare, but where it does occur the mechanism of NCR is generally recognized as being due to the increased metabolic activity of the resistant strain. These observations can provide learnings with potential application for resistance management if the correct pro-insecticide is selected for a resistant strain which is better able to bioactivate it. A better understanding of the bioactivation of pro-insecticides by resistant insects could also aid in insecticide discovery, potentially leading to improved pro-insecticide design. © 2021 Society of Chemical Industry.

Insecticide ADME for support of early-phase discovery: combining classical and modern techniques.

The two factors that determine an insecticide's potency are its binding to a target site (intrinsic activity) and the ability of its active form to reach the target site (bioavailability). Bioavailability is dictated by the compound's stability and transport kinetics, which are determined by both physical and biochemical characteristics. At BASF Global Insecticide Research, we characterize bioavailability in early research with an ADME (Absorption, Distribution, Metabolism and Excretion) approach, combining classical and modern techniques. For biochemical assessment of metabolism, we purify native insect enzymes using classical techniques, and recombinantly express individual insect enzymes that are known to be relevant in insecticide metabolism and resistance. For analytical characterization of an experimental insecticide and its metabolites, we conduct classical radiotracer translocation studies when a radiolabel is available. In discovery, where typically no radiolabel has been synthesized, we utilize modern high-resolution mass spectrometry to probe complex systems for the test compounds and its metabolites. By using these combined approaches, we can rapidly compare the ADME properties of sets of new experimental insecticides and aid in the design of structures with an improved potential to advance in the research pipeline. © 2016 Society of Chemical Industry.

Chance and design in proinsecticide discovery.

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.

Persistence of carbofuran in marine sand and water.

Marine sand and seawater samples were collected in March 2002 from Laysan Island in the Hawaiian Islands National Wildlife Refuge, where a small area was contaminated by the carbamate insecticide carbofuran. Carbofuran was still detected at microg g(-1) levels in the Laysan sand after its identification in 1998 and initial observation of the toxicity in 1988. The persistence of carbofuran in the marine sand was investigated in the dark in a 30 degrees C oven, and in distilled deionized water and seawater samples exposed to artificial 300 nm light and to direct sunlight. The laboratory study showed a half-life (t1/2) of approximately 40 days for carbofuran in the native sand and in Ottawa sand. The photolysis of carbofuran was faster in seawater than in distilled deionized water when it was exposed to 300 nm light (t1/2, 0.1 vs. 3.1 h) and to direct sunlight (t1/2, 7.5 vs. 41.6 h). The large difference between the laboratory results and the field observation of carbofuran dissipation suggests that carbofuran degradation at the remote, undisturbed marine site may be governed by its unique environmental factors.