Discovery, research and development of axalion® active insecticide: dimpropyridaz^†

Abstract

Dimpropyridaz is a novel insecticide active ingredient (a.i.) for the control of piercing and sucking pests. The discovery of dimpropyridaz included the synthesis of thousands of compound analogs which were investigated for their potential efficacy and registrability. Dimpropyridaz is the sole representative of the pyridazine pyrazolecarboxamide class, Insecticide Resistance Action Committee (IRAC) Group 36. The novel mode of action is characterized by disrupting the function of an insect's chordotonal organs in a way that is distinctly different from IRAC Groups 9 and 29. Dimpropyridaz demonstrates translaminar and systemic effects as well as high selectivity, providing both application flexibility and, when applied according to the label, beneficial organism, and environmental compatibility. Dimpropyridaz, powered formulations will be available in select markets, covering a broad range of vegetable, fruit, row crop, and ornamental production segments. Dimpropyridaz also has commercial registered name: Axalion Active. This review will focus on a broad outline of the chemical preparation, regulatory overview, and select biological performance and represents a summary of the information shared during the invited lecture at the 15th IUPAC (International Union of Pure and Applied Chemistry) International Congress of Crop Protection Chemistry held in New Delhi, India in March 2023. © 2024 BASF. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Dimpropyridaz, is a novel insecticide active ingredient for the control of piercing and sucking pests, and is the sole representative of the pyridazine pyrazolecarboxamides class, IRAC Group 36. Summary includes chemical preparation, regulatory overview, and biological performance and information shared during the 15th International Union of Pure and Applied Chemistry (IUPAC) International Congress of Crop Protection Chemistry, March 2023.

1. INTRODUCTION

With dimpropyridaz ¹ , BASF is expanding pest management with a unique insecticidal class of chemistry, pyridazine pyrazolecarboxamides (PPCs) that bring control of harmful piercing and sucking insects, including superior whitefly activity (based on BASF internal or third party trial data). ¹ , ² Dimpropyridaz has a novel mode of action, Insecticide Resistance Action Committee, (IRAC) Group 36, and is classified as chordotonal organ modulators – undefined target site. Affected insects become uncoordinated and are unable to feed or fly. With these effects, dimpropyridaz also displays quick feeding cessation leading to reduction or prevention of disease transmission without known cross‐resistance. Dimpropyridaz products will support flexibility of application timing due to its systemic properties, long‐lasting residual control, and efficacy of different life stages of targeted pests. As well as being an effective tool for insect resistance management, dimpropyridaz will also help to follow integrated pest management strategies utilizing beneficial species when applied according to label instructions.

2. HISTORY OF RESEARCH AND DEVELOPMENT OF DIMPROPYRIDAZ

BASF's first patent filing and exploration of insecticidal activity took place in 2006 via screening of compound library hits acquired by an agricultural business merger with American Cyanamid. Initial compound screening resulted in a few hundred analogs with broad but relatively weak insecticidal activity. Notably, however, aphicidal activity, namely, Myzus persicae (green peach aphid) and Aphis gossypii (cotton/melon aphid) was consistent. From 2008 through 2012, there was a significant increase in analog synthesis and characterization which resulted in more than 2500 analogs supported by structure–activity relationship (SAR) modeling, leading to increased biology and regulatory testing and the first field trials. The first synthesis of dimpropyridaz took place during this period c. 2011. ³ Early synthesis and characterization resulted in several breakthroughs such as the identification of the pyrazole moiety and a subsequent shift to the pyridazine moiety through R7 SAR. ⁴ , ⁵ , ⁶ The replacement of pyridine with pyridazine resulted in consistent whitefly activity. With the completion of SAR‐based chemistry in 2014, over 4000 pyrazolecarboxamide (PPC) analogs were generated. Overall, this resulted in improved systemicity, strong activity against aphids and whiteflies in field trials, and halogen‐free analogs. Of these analogs, dimpropyridaz was established internally as the lead, and an initial business case analysis was generated. In March of 2023, BASF lead the first public communication at the 15th IUPAC International Congress of Crop Protection Chemistry as IRAC determination was granted for Group 36. The first commercial sales followed shortly thereafter in Australia. Additional external communication has recently taken place at the 20th International Plant Protection Congress in Athens, Greece, July 2024. Further information regarding dimpropyridaz will be available in Modern Crop Protection Compounds, Fourth Edition [14]. Abridged evolution from the first insecticidal hit to dimpropyridaz is available as Fig. 1.

Figure 1.

Abridged evolution from first insecticidal hit to dimpropyridaz. ¹⁴ 1, First patent filing structure, exploration of initial chemistry class activity; 2, establishment of field testing paired with higher tier regulatory testing; 3, process development led to increased patent portfolio with replacement of pyrazole with pyridazine moiety and resulted in consistent whitefly activity; 4, excellent field activity against both whiteflies and aphid species; 5, improved systemicity and establishment of business case and lead analog; 6, dimpropyridaz.

2.1. Mode of action

The target site of dimpropyridaz clearly differs from the target sites of IRAC Groups 9 and 29. ² Dimpropyridaz uniquely limits the sensory function at an earlier step in the chordotonal organs. Chordotonal organs are specialized stretch receptors only found in insects and some crustaceans. ⁷ , ⁸ Although an overlap in target insect spectrum and intoxication symptomology occurs between the actives of IRAC Groups 9, 29, and 36, the sites of action are distinctly different. Symptomology across all groups presents as disruption of hearing, balance, gravity, acceleration, and kinesthesia senses. Insects are uncoordinated, unable to feed and eventually die. ⁹ To further explain the differences in Groups 9, 29, and 36 the vanilloid‐type transient receptor potential (TRPV) channel will be overviewed relative to each respective group. Group 9, with actives such as afidopyropen, pymetrozine, and pyrifluquinazon, directly activates TRPV channels resulting in increased firing rates in chordotonal neurons which then send false stretch signals to the insect. ¹ , ¹⁰ , ¹¹ , ¹² The Group 29 active, flonicamid, a nicotinamidase inhibitor, indirectly activates TRPV channels by upstream effects preventing degradation of the endogenous TRPV modulator nicotinamide (TFNA‐AM). ¹ , ¹³ The Group 36 active, dimpropyridaz, by contrast, indirectly inhibits chordotonal activation, effectively silencing the chordotonal neurons upstream of both Group 9 (chordotonal organ TRPV channel modulators) and Group 29 (chordotonal organ nicotinamidase inhibitors). ¹ , ¹⁰ , ¹¹ Currently, no cross‐resistance is known or expected. Illustration of positioning and interaction of chordotonal organ modulator Groups 9, 29, and 36 actives are depicted in Fig. 2.

Figure 2.

Diagrammatic representation of the effects of CO modulator insecticides Groups 9, 29, and 36; of which Groups 9 and 29 directly and indirectly activate TRPV channels, respectively, while Group 36, dimpropyridaz silences CO neurons at an upstream target site. ¹⁴

2.2. Key crops

Dimpropyridaz has uses across a variety of crops, including fruits, vegetables, soybeans, cotton, corn, cereals, beets, oilseed rape, and ornamentals. Current crop spectrum of dimpropyridaz is presented in Table 1.

Table 1.

Current crop spectrum of dimpropyridaz. ¹⁴

Crop system †	Common group/family
Trees nuts and vines	Pome fruit
	Stone fruit
	Citrus
	Grapes
Fruits and vegetables	Cucurbitaceae
	Solanaceae
	Brassicaceae
Row crops	Cotton
	Soybean
	Corn/maize
	Cereals
	Oilseed rape
	Beets
Other	Ornamentals

^† Including but not limited to, the crop species listed in the table.

2.3. Insects controlled – highlight whitefly activity (based on BASF internal or third party trial data)

Dimpropyridaz delivers control of a broad spectrum of key piercing, sucking, and rasping pests, including whiteflies, aphids, leafhoppers, psyllids, mealybugs, scales, and thrips. Dimpropyridaz can be applied both prophylactically or curatively via a range of application methods including foliar, drone, soil drench, and drip. Current insecticidal activity spectrum of dimpropyridaz is presented in Table 2. For whiteflies, dimpropyridaz exhibits life stage‐dependent control. Dimpropyridaz activity for adults is seen as population knockdown via both preventative (residual) and curative (direct) treatment. Any eggs that may be laid are affected at the crawler stage. While treated eggs will develop (i.e., no true ovicidal mortality is observed) emerging crawlers, or crawlers treated within 24 h after emergence, do not settle or attach to the leaf, and eventually desiccate and die. ⁹ Later‐stage crawlers and redeye pupae will progress through nymphal development; however, the resultant emerging adults are uncoordinated and drop off the plant shortly after eclosion. Life stage effects on eggs, nymphs and adults are presented in Fig. 3. Target label dose rates for whiteflies ranges from 96 to 120 g active ingredient (a.i.) ha⁻¹, which were determined from rate range residual efficacy screens ensuring greater than 80% control at least 8 days after treatment. Example preventative residual study results are presented in Table 3. An additional benefit of dimpropyridaz is quick feeding cessation leading to overall reduction in disease dispersion and acquisition. Secondary virus spread experiment via Instituto de Ciencias Agrarias CSIC, Spain, regarding whitefly vectored virus transmission is provided in Table 4.

Table 2.

Current insecticidal activity spectrum of dimpropyridaz ^† , ^‡ , ¹⁴

Insect pests
Scientific name	EPPO code	Species common name	Group common name	Order
Bemisia tabaci	BEMITA	Silverleaf whitefly	Whiteflies	Hemiptera
Trialeurodes vaporariorum	TRIAVA	Greenhouse whitefly
Aphis gossypii	APHIGO	Cotton/melon aphid	Aphids
Macrosiphum euphorbiae	MACSEU	Potato aphid
Myzus persicae	MYZUPE	Green peach aphid
Rhopalosiphum padi	RHOPPA	Bird cherry oat aphid
Dysaphis plantaginea	DYSAPL	Rosy apple aphid
Nasonovia ribisnigri	NASORN	Lettuce aphid
Dalbulus maidis	DALBMA	Corn leafhopper	Leafhoppers
Diaphorina citri	DIAACI	Asian citrus psyllid	Psyllids
Planococcus sp.	PLANSP	Mealybug	Mealybugs
Aonidiella aurantii	AONDAU	California red scale	Scales
Unaspis citri	UNASCI	Citrus snow scale
Frankliniella occidentalis	FRANOC	Western flower thrips	Thrips	Thysanoptera

^† Including, but not limited to, the insect species listed in the table.

^‡ Products containing dimpropyridaz, Axalion Active®, such as Efficon® and Durilon®, may not be authorized and labeled for use on all species listed in the table in all countries. Always read and follow label instructions based on the product, target species and intended crop.

Figure 3.

Dimpropyridaz whitefly life stage control: adults, eggs, second to fourth instar. Application while adults are present, or expected, controls the adult population. Application while eggs are present, or newly emerged crawlers, controls the first instar crawler population. Application during second to fourth instar nymphal development provides control at adult emergence. Based on internal BASF trial data.

Table 3.

Technical grade material rate finding, glasshouse residual study. Preventative foliar application. Adult Silverleaf whitefly and progeny population in cotton. BASF Internal Trial: 2014.

Treatment	Rate (ppm)	BEMITA Abbott's percent control			BEMITA # live F1 population
		1 DAT	4 DAT	8DAT	1 DAT	4 DAT	8 DAT
Untreated control (#live adults)	—	(149.0) c	(73.3) b	(239.3) c	1350.0 a	2100.0 a	3033.3 a
Dimpropyridaz	10	44.1 b	31.2 b	59.8 b	33.9 b	1076.7 b	1495.0 b
	100	96.9 a	98.2 a	97.5 a	2.0 b	3.3 c	11.7 c
	300	99.6 a	94.1 a	99.6 a	0.0 b	0.0 c	1.0 c

DAT, days after treatment; ppm, parts per million. Application was conducted as foliar spray, 50:50 acetone–water + 0.01%v/v/adjuvant.

Means followed by the same letter do not significantly differ, P = 0.05, Student–Newman–Keuls.

Crop: Cotton, Pima. Target Pests: BEMITA. Water volume: 300 L ha⁻¹. Single, preventative application at Crop GS:12. Three replications.

Table 4.

Secondary virus spread experiment – tomatoes/whitefly, thrid party trial data: Instituto de Ciencias Agrarias (CSIC).

Tomato/whitefly virus transmission
Treatment	Concentration (g a.i. HL−1) †	Total transmission percentage ‡ Bemisia tabaci (tomato yellow leaf curl virus)
Control	—	85.42 a
Dimpropyridaz	9.6	0.69 b
	6	1.39 b
Pymetrozine	25	76.39 a
Flupyradifurone	15	2.08 b

^† Grams of active per hectoliter (100 L).

^‡ Average response across three assays, four replications per trial.

Means followed by the same letter do not significantly differ, P = 0.05, χ ².

Application made 24 h before the start of each experiment (preventative application).

Source: Secondary virus spread experiment. Instituto de Ciencias Agrarias (CSIC).

Glasshouse conditions: temperature 25:20 ± 1 °C, photoperiod 16 h:8 h (light/dark).

2.4. Insects controlled – example: aphid activity via preventative foliar treatment based on BASF internal or third party trial data

Dimpropyridaz has inherent xylem systemicity and translaminar effects. Targeted use rates for aphids range from 24 to 60 g a.i. ha⁻¹ based on open field or glasshouse production and target aphid species. Preventive foliar treatment against green peach aphid, M. persicae, on a pepper plant via 54 g a.i. ha⁻¹ at 300 L ha⁻¹ water volume resulted in clear benefits compared with an untreated reference plant. The untreated plant suffered stunted and distorted plant growth, vigor loss, and would putatively be subjected to increased disease pressure. The dimpropyridaz‐treated plant received residual protection, as infestations of colony‐reared aphids occurred every 7 days for the duration of the testing period. A reference image of an untreated plant compared with a dimpropyridaz‐treated plant is provided as Fig. 4, 14 days after treatment (DAT), although activity has been noted to continue through roughly 21 DAT. Residual activity is dependent on application method, use rate, target crop and insect, and life stage. Third party secondary virus spread experiment via Instituto de Ciencias Agrarias CSIC regarding aphid vectored virus transmission is provided in Table 5. Internal, open field trial in winter wheat regarding aphid vectored virus transmission symptomology reduction is provided in Table 6.

Figure 4.

Image of untreated compared with dimpropyridaz, referenced within image as Axalion® Active Insecticide treated bell pepper, 14 days after treatment. Dimpropyridaz pepper plant was treated at 54 g a.i. ha⁻¹ rate, 300 L ha⁻¹ water volume. Once dried both plants were infested with Myzus persicae, from established laboratory colony. Each leaf was infested. Plants were reinfested with > 50 aphids to the crown in an interval of every 7 days.

Table 5.

Secondary virus spread experiment – physalis/aphids, third party trial data: Instituto de Ciencias Agrarias CSIC.

Physalis/aphids virus transmission
Treatment	Concentration (g a.i. HL−1) †	Total transmission percentage ‡ Myzus persicae (turnip yellows virus)
Control	—	57.75 a
Dimpropyridaz	3.6	0.0 b
	2.16	0.0 b
Pymetrozine	5	0.0 b
Flupyradifurone	12	0.0 b

^† Grams of active per hectoliter (100 L).

^‡ Average response across three assays, four replications per trial.

Means followed by the same letter do not significantly differ, P = 0.05, χ ².

Application made 24 h before the start of each experiment (preventative application).

Source: Secondary virus spread experiment. Instituto de Ciencias Agrarias (CSIC).

Glasshouse conditions: temperature 25:20 ± 1 °C, photoperiod 16 h:8 h (light/dark).

Table 6.

BASF internal open field trial, 2020: winter wheat, Rhopalosiphum padi reduction of virus transmission symptomology with dimpropyridaz.

Percentage of plot with BYDV symptoms in wheat after 39 DAT at GS:55‐59
Treatment	Rate g a.i. ha−1	Estimated plot percentage BYDV symptoms
UTC	—	67.5 a
Dimpropyridaz	26.4	18.8 c
	44	10.8 c
Lambda‐cyhalothrin	7.5	38.8 b

BYDV, barley yellow dwarf virus; DAT, days after treatment; g a.i. ha⁻¹, grams of active ingredient per hectare; UTC, untreated control.

Means followed by the same letter do not significantly differ, P = 0.05, Student–Newman–Keuls.

Crop: Winter Wheat; Variety Sandra. Target Pests: RHOPPA.

Water volume: 200 L ha⁻¹. Single application at crop GS:12‐14. Four replications.

2.5. Environmental and toxicity profile (based on internal BASF trial data)

Dimpropyridaz has low acute toxicity, except for moderate acute oral toxicity. Dimpropyridaz is not irritating to the skin or eyes and is not a skin sensitizer. The safety profile for mammals of dimpropyridaz is shown in Table 7. Dimpropyridaz has an excellent safety profile for non‐target species showing low toxicity to birds, aquatic and soil organisms, and bees. An overview of the toxicity to non‐target species is provided as Table 8. Additionally, an overview of the physiochemical properties impacting environmental profile and plant systemicity is provided as Table 9. The use of dimpropyridaz products must always be conducted according to label instructions.

Table 7.

Safety profile of dimpropyridaz: toxicity to mammals ¹⁴

Study	Species	Effect level
Oral LD50	Rat	>300 < 500 mg kg−1 BW
Dermal LD50	Rat	>2000 mg kg−1 BW
Inhalation LC50 (4 h)	Rat	>5.6 mg L−1
Skin irritation	Rabbit	Non‐irritant
Eye irritation	Rabbit	Non‐irritant
Skin sensitization	Guinea pig	Not sensitizing

LD₅₀, median lethal dose; LC₅₀, median lethal concentration; BW, body weight.

Table 8.

Safety profile of dimpropyridaz: toxicity to non‐target species ¹⁴

Study	Species	Effect level
Avian oral LD50	Northern bobwhite	1778 mg kg−1
Freshwater fish LC50 (96 h)	Rainbow trout	>30 mg L−1
Freshwater invertebrate EC50 (48 h)	Daphnia magna	>30 mg L−1
Algae ErC50	Pseudokirchneriella subcapitata	>95.3 mg L−1
Earthworm LC50	Eisenia fetida	>1000 mg kg−1
Bee oral LC50 (48 h)	Honeybee	>43.3 μg a.i. per bee
Bee contact LC50 (48 h)	Honeybee	>50.3 μg a.i. per bee

LD₅₀, median lethal dose; LC₅₀, median lethal concentration; EC₅₀, median effective concentration; ErC50 median reduction in growth rate.

Table 9.

Physicochemical properties of dimpropyridaz ¹⁴

Feature	Property
Melting point (°C)	approximately 82
Vapor pressure (Pa at 20 °C)	8.7 × 10−6
Water solubility (g L−1 at 20 °C, pH 7)	28.7
pH value (1% in water)	4.5
Partition coefficient (log P OW at 20 °C, pH 5.8)	1.1
Hydrolysis (at 25 °C, pH 4.5/pH 7)	Stable

3. CONCLUSION

Dimpropyridaz is the sole representative of a new class of chemistry, PPCs, that has received IRAC classification Group 36: Chordotonal organ modulators – undefined target site. ¹ , ² Dimpropyridaz affects the basal function of the target insect's chordotonal organs, which are responsible for movement and coordination. Residual efficacy protects for more than 2 weeks due to dimpropyridaz's systemic properties and flexible application methods. Insects stop feeding within a few hours after exposure to dimpropyridaz treatment. No cross‐resistance with other insecticides is currently known, nor expected.

CONFLICT OF INTEREST STATEMENT

The author declares no conflicts of interest.

Commercial sales of dimpropyridaz, Axalion® Active, formulated product [Efficon®] began in 2023. This material is provided for informational purposes only and not intended to promote the product's sale. Any sale of this product after registration is obtained shall be based on approved product labels, and any claims regarding product safety and efficacy shall be addressed by the label. This document, or any information provided herein does not constitute a legally binding obligation of BASF and has been prepared in good faith and is believed to be accurate as of the date of issuance. Unless expressly agreed otherwise in writing in a supply contract or other written agreement between you and BASF.

Trial summaries are based on BASF internal trial data unless otherwise noted. Such noted trials are based on third party observations under the guidance of BASF.

©2024 BASF SE. All rights reserved. [Axalion®, Durilon®, Efficon® are registered products of BASF. Axalion, Durilon, and Efficon] Dimpropyridaz and related products are not labeled for use in all countries.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.