Research & Development Story of TENEBENAL™ - Contribute to Humanity beyond the Framework of Agriculture

Chewing pests are tough enemies for farmers, causing damage on agricultural products and often show high resistance to agrochemicals.
Mitsui Chemicals Crop & Life Solutions challenged the development of a novel insecticide with an aim of exterminating chewing pests that are resistant to existing insecticides. With much efforts of researchers, we succeeded in the development of an insecticide with completely new mode of action, “TENEBENAL.”
This article introduces characteristics of “TENEBENAL” and unknown episodes in research and development.

Background of the research and development of the completely new pesticide “TENEBENAL”

TENEBENAL is an insecticide with completely new mode of action that is effective against insect pests including chewing pests, developed resistance to existing chemicals.
Why was TENEBENAL developed? What is the new mode of action?
The background of the research and development will follow.

Rage of insect pests resistant to pesticides

Many crop producers are annoyed by pesticide resistant insect pests.

Among other pesticide resistant insect pests, particularly chewing pests are serious problem. According to the data of the National Agriculture and Food Research Organization (NARO), top three pesticide resistant insect pests are diamondback moth, tobacco budworm, and tobacco cutworm that are all chewing pests. Chewing pests are the largest in the number of reported cases of pesticide resistance and represent 27% of the total reported cases.

[Source] “Proposed Guidelines for Pesticide Resistant Agricultural Insect Pest Control (March 2019)/NARO”

For example, diamondback moth is estimated to be causing damage amounting to 4 to 5 billion dollars worldwide and the damage caused by chewing pests is also devastating in Japan.

[Source] Frontiers | First Field Release of a Genetically Engineered, Self-Limiting Agricultural Pest Insect: Evaluating Its Potential for Future Crop Protection | Bioengineering and Biotechnology

In order to exterminate insect pests including chewing pests that are resistant to certain types of pesticides, it is necessary to develop a new chemical with different mode of action. It is a mission of our company to develop a pesticide to protect the agricultural products from insect pests that eat the precious harvest.

Pesticide with a completely new mode of action, “TENEBENAL”

Action of “TENEBENAL”

TENEBENAL is a nervous system inhibitor (※2) that acts on the GABA receptor (※1). It inhibits the vital neural signals of insects to cause paralysis and ultimately death.

As a nervous system inhibitor acting on the GABA receptor, phenylpyrazole insecticides have been discovered in previous, however, TENEBENAL acts on a region different from them. Accordingly, TENEBENAL is effective against insect pets that are resistant to the conventional insecticides.

This new action is recognized by “Insecticide Resistance Action Committee (IRAC)”, a worldwide organization engaged in the enlightenment activity to prevent the a insecticide resistance development. To categorize the mode of action of TENEBENAL, a new “group 30 (※3)” was established.

That means TENEBENAL’s mode of action was completely new to the world as well.

Unknown histories of the research and development of “TENEBENAL”

Do you know what this figure is? This is the time and cost generally required for the creation of a new pesticide.

Tremendous time and cost are required for a pesticide from the research and development to market launching. A new chemical is a fruit of the efforts of researchers. TENEBENAL was also developed by the long-term efforts and challenges of researchers.

Discovered the active ingredient from more than 7,000 compounds

The project started with the principal objective of exterminating chewing pests that annoy crop producers. As our goal was the discovery of world top-level activity against chewing pests, the research and development of TENEBENAL went through continuous sufferings and challenges.

The development of a new pesticide starts with selection of a “lead compound (※4)” as a basis of a new chemical. Then the lead compound will be converted by synthesis and expansion to increase the performance as a pesticide.

At first, we focused attention on a compound patented by other companies that were highly active on a wide variety of chewing pests with a chemical structure not common in general insecticides and selected it as a lead compound.

“Discovery research based on this lead compound ought to result in the development of an insecticide with new characteristics that is effective against chewing pests.” The research and development started with that belief.

The insecticides we have developed so far such as etofenprox and dinotefuran were also created by converting certain lead compounds. Our research technology is characterized by significantly converting a structure that was considered as essential for the activity in the industry at that time. It succeeded in the creation of insecticides with new characteristics that overturned the conventional wisdom and resulted in long-term use by crop producers.

In the current case of TENEBENAL too, we carried out the synthesis and evaluation by bearing in mind significantly converting the structure that had been considered as essential for the lead compound. At the beginning of the research, however, we could not obtain the expected result smoothly. Most of the significantly converted compounds lost their insecticidal activities.

Under such condition, after repeating stubborn researches, we found that there are compounds groups in which approximately 1/1000 insecticidal activity of the lead compounds remained. That being the case, we continuously studied those compound groups and challenged various conversions. As a result, we discovered that compound groups in which a certain substituent (※5) was introduced dramatically enhanced the activity against chewing pests!

On the other hand, our researchers noticed that this compound exhibited an effect against insect pests in a way completely different from the conventional lead compounds. Furthermore, our researchers found that while the lead compounds acted on the muscular system, the new compound acted on the nervous system GABA receptor of insects.

Therefore, we succeeded in differentiation from other companies' compounds. There already existed, however, a pesticide acting on the GABA receptor, phenylpyrazole insecticide, and it had been known that there were insects resistant to that chemical. Unless our developed insecticide had new characteristics that were effective against the insects resistant to that chemical, we had to discontinue the development.

With the progress of the research, it was clarified by our biological evaluation researchers that the new compound exerts an effect on insect pets resistant to phenylpyrazole insecticide. In addition, it was indicated that our new compound might have a new action mechanism against the same GABA receptor. Those findings encouraged our research teams that the direction of research is right and strongly motivated them to work forward on the drug discovery research.

After we discovered the compound group with the new functional characteristics like this, the process to develop the compound group as a “product” for practical use started. “Inventing a new compound, treating it, and evaluating it.” Invention of a new chemical is basically a repeat of this procedure. It is a very slow and mind-bogglingly steady work.

As a result of having repeated this work and study on more than 7,000 molecules, Broflanilide was finally selected as the most excellent compound and was named “TENEBENAL.”

The way to commercial production

Our research teams thus succeeded in the invention of TENEBENAL, but it was not the goal of the project.

For example, products to be sold in the market need mass production in the factory. They are synthesized in a flask at a gram scale in the laboratory, then prototyped at a kilogram scale, and finally produced at a ton scale in the commercial production facilities. The products have to also pass the strict quality inspection of course.

Our research teams organized a production recipe plan through the study on the reaction route to efficiently produce TENEBENAL, the study on the reaction conditions, and the study on the quality control method. However, a large problem occurred here. After having produced the intermediate at a kilogram scale to validate the production recipe plan, it was revealed that the produced intermediate contained many impurities. It was supposed that without taking a corrective action, this situation would result in a delay in the subsequent safety test and consequently significantly interfere with the development plan.

Our research teams faced a huge challenge but our company had accumulated knowledge on pesticide development for approximately 100 years. We succeeded in identifying the structures of the impurities by putting together the acquired experience and know-how. Then we established a purification method to eliminate the impurities in a short period of approximately 3 months. Consequently, the prototype TENEBENAL could successfully passed the quality inspection.

We manufactured the product at the production subcontractor and our own factory based on the “production recipe” established in this way. Our research teams witnessed the manufacturing site at the start of production to give technical guidance and follow up the operation, and we came to be able to mass-produce TENEBENAL with an acceptable quality at the commercial scale.

Thus, we succeeded in launching TENEBENAL in 2019 after having repeated various trials and errors and challenges.

Contribute to humanity beyond the fields and national borders

TENEBENAL that was developed by overcoming numerous hurdles in this way is expected to significantly contribute in the agricultural field. Furthermore, TENEBENAL has a potential to contribute to fields other than agriculture such as health, hygiene, and construction.

For example, TENEBENAL is effective for the extermination of household pests such as cockroaches and bedbugs. Although insecticide-resistant cockroaches and bedbugs having been reported, the new mode of action of TENEBENAL is effective for such pests resistant to the existing insecticides.

TENEBENAL can be used also for the extermination of flies and mosquitoes. Some mosquitoes transmit such diseases as malaria, yellow fever, dengue fever, and some flies transmit such diseases as African sleeping sickness and kala-azar (visceral leishmaniasis). Those insect pests are likely to become resistant to insecticides and all of them cause fatal diseases. A day will come soon when TENEBENAL will save the not-yet saved human life.

Furthermore, TENEBENAL is also effective for the extermination of termites that eat timber that comprises houses. Because TENEBENAL is highly residual and rain proof, it will contribute to the preservation and transportation of timber and the protection of buildings.

With such excellent functionality recognized, TENEBENAL is registered in various countries in the world for various applications including pesticide. An insecticide that contributes to humanity in various places and various fields. It is TENEBENAL.

  • GABA receptor: GABA means Gamma-Amino Butyric Acid and is a neurotransmitter. The GABA receptor is a protein that responds to this neurotransmitter to adjust the ion concentration inside a nerve cell.
  • Nervous system inhibitor: An insecticide that inhibits the signal transmission via the nerve.
  • group 30: 30th international category of agricultural insecticides established by IRAC.
  • Lead compound: A compound that serves as a starting point for new chemical development. A chemical based on the lead compound needs to overcome tests with such a low pass rate as one in a hundred thousand or sometimes one in a million to be commercialized.
  • Substituent: An atom or atom group that is substituted for the hydrogen atom within an organic compound.