Development of a novel herbicide, metazosulfuron

Abstract

Metazosulfuron is a novel sulfonylurea herbicide discovered and developed by Nissan Chemical Industries, Ltd., which exhibits excellent herbicidal activity against Echinochloa spp., annual and perennial weeds including sulfonylurea resistant biotypes in paddy fields at 60–120 g a.i./ha with good crop safety to rice. In addition, it has favorable toxicological, ecotoxicological and environmental profile. Metazosulfuron (trade name; Altair®) was registered and launched in Japan in 2013, and has been also introduced in Korea and China as of 2016. This paper describes a history of discovery, syntheses, herbicidal characteristics and crop safety of metazosulfuron.

Introduction

Sulfonylurea herbicides show the efficacy by inhibiting acetolactate synthase (ALS, also known as acetohydroxy acid synthase) which is a key enzyme in the biosynthesis of the branched chain amino acids in plants. They are safe to mammalian, because the ALS exist only in bacterial and plant species. They have been used for more than thirty years, and still remain an important class of herbicides in agriculture.

In Japan, sulfonylurea herbicides have been widely used in paddy fields, however, several weed species showing resistant to the herbicides have been spreading to nation-wide. Under the circumstances, we have focused on discovering a new herbicide with both rice selectivity and herbicidal activity against weeds including sulfonylurea resistant biotypes.

1. Selection of lead compound

We have developed pyrazolesulfonylurea herbicides and commercialized pyrazosulfuron-ethyl and halosulfuron-methyl (Fig. 1).

Fig. 1. Pyrazolesulfonylurea herbicides developed by Nissan Chemical Industries, Ltd.

We have re-evaluated our sulfonylurea library compounds in terms of rice selectivity and efficacy on sulfonylurea resistant weeds. As a result, we found that some pyrazole-5-sulfonylurea derivatives showed high herbicidal activity against sulfonylurea resistant biotypes, and compound 1 (Fig. 2) had good herbicidal activity and moderate rice selectivity.¹⁾ Therefore, we selected compound 1 as a lead compound and started to investigate the pyrazolesulfonylurea.

Fig. 2. The lead compound selected from the sulfonylurea library.

2. Discovery of metazosulfuron

On the hypothesis that substituents of pyrazole ring were important for herbicidal activity against sulfonylurea resistant weeds, we focused on synthesis and evaluation of sulfonylurea compounds having various substituents on pyrazole ring.

As a result, we found that compound 2 having isoxazoline moiety at 4-position of pyrazole ring had good selectivity²⁾ and compound 3 having dioxazine ring were highly effective for various weeds compared to compound 1 (Fig. 3). Further evaluation of dioxazinyl pyrazolesulfonylurea chemistry led to the discovery of metazosulfuron (Table 1).³⁾ In this optimization process, we developed new methods to synthesize the dioxazine derivatives. We obtained various dioxazine compounds using the halocyclization and the dehydration reaction (Fig. 4).⁴⁾

Fig. 3. Pyrazolesulfonylurea derivatives having heterocycle moiety at 4-position of pyrazole ring.

Table 1. Pre-emergence herbicidal activities of pyrazolesulfonylurea derivatives.

R3	Ra	Raʹ	Rb	X	Y	Z	Activitya,b)
							Ac)	Bc)	Cc)	ac)
Cl	Me	H	H	OMe	OMe	CH	5	5	5	0
Me	Me	H	H	OMe	OMe	CH	5	5	5	3
H	Me	H	H	OMe	OMe	CH	5	5	5	3
Cl	Me	Me	H	OMe	OMe	CH	5	5	5	0
Cl	H	H	Me	OMe	OMe	CH	5	5	5	0
Cl	Et	H	H	OMe	OMe	CH	4	5	5	0
Cl	Me	H	H	Me	OMe	CH	4	5	5	1
Cl	Me	H	H	Cl	OMe	CH	3	5	5	0
Cl	Me	H	H	OMe	OMe	N	0	0	0	0

^a) The dose of each compound was 64 g a.i./ha. ^b) Herbicidal activities were visually evaluated using a scale of 0 (no effect) to 5 (completely withered). ^c) A: Echinochloa oryzicola, B: Schoenoplectus juncoides, C: Monochoria vaginalis, a: Oryza sativa (transplanted).

Fig. 4. Syntheses of dioxazine derivatives.

3. Physical chemistry

• ISO name: metazosulfuron

• Chemical name (IUPAC): 1-{3-chloro-1-methyl-4-[(5RS)-5,6-dihydro-5-methyl-1,4,2- dioxazin-3-yl]pyrazol-5-ylsulfonyl}-3-(4,6-dimethoxypyrimidin-2-yl)urea

• Development code: NC-620

• CAS No.: 868680-84-6

• Molecular formula: C₁₅H₁₈ClN₇O₇S

• Molecular weight: 475.86

• Appearance: White solid, odorless

• Density: 1.49 g/cm³

• Melting point: 175.5–177.6°C

• Solubility: 33.3 mg/L (in water, 20°C)

• Vapor pressure: 7.0×10⁻⁸ Pa (25°C)

• pK_a: 3.4 (20°C)

• log P_ow: 1.87 (25°C, pH 4), −0.35 (25°C, pH 7), −0.58 (25°C, pH 9)

4. Herbicidal activity

Metazosulfuron exhibited high levels of herbicidal activity against Echinocloa oryzicola, annual and perennial weeds including Eleocharis kuroguwai, Cyperus serotinus and Schoenoplectus maritimus at 60–120 g a.i./ha. In addition, it showed excellent efficacy on sulfonylurea resistant weeds such as Schoenoplectus juncoides, Monochoria vaginalis, Monochoria korsakowii and Sagittaria trifolia (Fig. 5).^5,6)

Fig. 5. Herbicidal efficacy of metazosulfuron (100 g a.i./ha) on major paddy weeds.^a).

^a) Weed controls were visually evaluated using a scale of 0 (no effect) to 100 (completely withered). ^b) SU-R:sulfonylurea resistant. ^c) M. korsakowii:Monochoria korsakowii, L. dubia: Lindernia dubia, S. trifolia: Sagittaria trifolia, C. difformis: Cyperus difformis, C. serotinus: Cyperus serotinus, E. kuroguwai: Eleocharis kuroguwai, S. maritimus: Schoenoplectus maritimus, O. javanica: Oenanthe javanica. ^d) The growth stage or size of each weed at application are shown in parentheses.

In paddy fields in Japan, perennial Cyperaceous weeds such as E. kuroguwai, S. maritimus and S. nipponicus are known as tough weeds, because they are able to emerge from deep depth beneath soil and have a long emergence duration. Metazosulfuron inhibited the growth of these perennial weeds as shown in Fig. 6. And it showed remarkable efficacy on E. kuroguwai, S. maritimus and S. nipponicus by controlling shoot formation and tuberization strongly (Figs. 7–9).^7,8)

Fig. 6. Herbicidal activity of metazosulfuron against perennial Cyperaceous weeds.^a).

^a) Weed controls were visually evaluated using a scale of 0 (no effect) to 100 (completely withered) at 34–56 days after application. ^b) S. nipponicus: Schoenoplectus nipponicus. ^c) The shoot length of each weed at application are shown in parentheses.

Fig. 7. Pre-emergence effect of metazosulfuron on tuberization of E. kuroguwai.^a).

^a) Number of tuber was counted at 96 days after transplanting.

Fig. 8. Effect of metazosulfuron on tuberization of S. nipponicus.^a).

^a) Number of tuber was counted at 154 days after transplanting. ^b) The shoot length of S. nipponicus at application are shown in parentheses.

Fig. 9. Post-emergence effect of metazosulfuron on shoot number of S. maritimus.^a).

^a) The shoot length of S. maritimus at application was 30 cm.

5. Crop safety to rice

Summary of official field trials conducted by JAPR is shown in Fig. 10. These results indicate that the combination of metazosulfuron+daimuron (100+1000 g a.i./ha) has good rice selectivity regardless application timing.

Fig. 10. Crop safety of metazosulfuron+daimuron (100+1000 g a.i./ha) to transplanted rice (Summary of field trials by Japan Association for Advancement of Phyto-Regulators (JAPR) from 2006 to 2009).

6. Mode of action

It was confirmed that metazosulfuron inhibited plant ALS, similar to other sulfonylurea herbicides. In addition, it showed similar % of ALS inhibition to SU-R and SU-S biotypes of S. trifolia, while pyrazosulfuron-ethyl showed less % of ALS inhibition to SU-R biotype than SU-S biptype (Fig. 11).⁹⁾

Fig. 11. Percent inhibition analyses of ALS extracted from sulfonylurea susceptible (SU-S) and resistant (SU-R) biotypes of S. trifolia of metazosulfuron and pyrazosulfuron-ethyl.^a).

^a) The ALS activity was measured according to the method of Westerfield (1945) with modifications. The SU-S S. trifolia biotype from Saitama Pref. and SU-R S. trifolia biotype from Iwate Pref. were grown in the greenhouse. The accumulation of acetoin was determined from the absorbance at 530 nm and the % of ALS inhibition was calculated based on the acetoin accumulations.

7. Toxicology and ecotoxicology

Toxicity of metazosulfuron on mammalian was very low, and it showed negligible toxicity to fish, birds and beneficial insects (Table 2).

Table 2. Toxicology and ecotoxicology of metazosulfuron.

Study	Organism	Result
Acute oral	Rat	LD50 >2000 mg/kg
Acute dermal	Rat	LC50 >5.05 mg/L
Skin irritation	Rabbit	Non-irritant
Eye irritation	Rabbit	Minimal irritant
Mutagenicity	Ames tests	Negative
	Micronucleus tests	Negative
Acute toxicity	Carp	LC50 >95.1 mg/L
	Daphnia magna	EC50 >101 mg/L
Ecotoxicity	Apis mellifera	LD50 >100 µg/bee (Oral, Contact)
	Bobwhite quail	LD50 >2000 mg/kg (Oral)
	Eisenia foetida	LC50 >1000 mg/kg

Conclusion

We have re-evaluated our sulfonylurea library compounds and focused on investigating a new pyrazolesulfonylurea herbicide. Further evaluation of the pylazolesulfonylurea chemistry led to the discovery of metazosulfuron. It exhibited excellent rice selectivity and high levels of herbicidal activity against annual and perennial weeds including Echinochloa spp. in field trials and greenhouse tests. In addition, it showed excellent efficacy on sulfonylurea resistant weeds such as S. juncoides, M. vaginalis, M. korsakowii and S. trifolia, and remarkable effect against perennial Cyperaceous weeds such as E. kuroguwai, S. maritimus and S. nipponicus by controlling shoot formation and tuberization strongly.

Metazosulfuron was registered and launched in Japan in 2013 under the trade name of Altair®, and several products containing metazosulfuron are currently commercialized. Twin-star®, Gekko®, Ginga® and Comet® are one-shot herbicides and Levras® and Gepard® are late post herbicides. Metazosulfuron has been also introduced in Korea and China as of 2016.

Metazosulfuron is a unique herbicide, which was discovered and developed with ingenuities of chemists and biologists in Nissan Chemical Industries, Ltd. We continue to develop new products so that metazosulfuron will contribute further to global rice production.