Triazolopyrimidine herbicides

Baumgartner, J.R., K. Al-Khatib, and R.S. Currie (1999). Cross-reference of imazethapyr-resistant common sunflower (Helianthus annuus) to selected imidazolinone, sulfonylurea, and triazolopyrimidine herbicides. Weed Technol. 13 489 -93. 

Hall, L.M. and M.D. Devine (1990). Cross-resistance of a chlorsulfuron-resistant biotype of Stellaria media to a triazolopyrimidine herbicide. Plant Physiol., 93 962-966. 

Figure 1. Commercial triazolopyrimidine herbicides and new active analogs.

After a comprehensive extraction procedure the triazolopyrimidine herbicide me-tosulam could be determined in soil samples by LC-UV and TSP-LC-MS with excellent agreement between the methods [290]. 

The different metabolic pathway of the triazolopyrimidine herbicide diclosulam (109 1997, Spider , Dow AgroScience) [55] are guided by the substituent at the 7-position on the triazolopyrimidine ring system. The predominance of one pathway is very crop specific (Scheme 35.1). 

Florasulam (II) is a triazolopyrimidine herbicide used for selective broadleaf weed control in wheat, barley, and oats, but is included in this experiment as a positive standard because it is rapidly metabolized in the test system. Azoxystrobin (12) serves as a negative standard because it metabolizes slowly in the test system. These standards provided positive and negative controls for the system, and helped put the metabolism rates of the other compounds into perspective. 

Although the ALS inhibitor herbicides have been used for approximately 20 years, the number of resistant weed biotypes for this group now exceeds those for all other types of herbicides. Singh and Shaner (1995) and Boutsalis (2001) reported that a total of five chemical families or herbicide classes are commercially marketed as inhibitors of ALS, and that these herbicides comprise more than 50 active ingredients for selective use in many different crops. They include sulfonylureas, imidazolinones, triazolopyrimidines, sulfonylamino-carbonyl-triazolinones, and pyrimidinyl (thio)benzoates. 

ALS herbicides. Two classes of ALS-inhibiting herbicides are the sulfonylurea herbicides, discussed in Sections 2.1.2.1 and 2.2.3.1, and the imidazolinone herbicides. A third class of ALS-inhibiting herbicides is the 1,2,4-triazolo [1,5-a]pyrimidine-2-sulfonanilides. The triazolopyrimidine sulfonanilides act by disrupting the biosynthesis of branched chain amino acids in plants. Representatives of this class of herbicides include florasulam (Boxer , Nikos ) [151], initially introduced in Belgium in 1999 and used for the postemergence control of broadleaf weeds in cereals and corn, and flumetsulam (Broadstrike ) [152], used alone or in combination with other herbicides for the control of broadleaf weeds in soybean and corn. 

ALS is the first common enzyme in the biosynthetic route to valine, leucine and isoleucine. It is the site of action for the triazolopyrimidine (TP) herbicides as well as the sulfonylureas (SU) and imidazolinones (IM). These compounds act on the meristem and are slow to bring about plant death. 

Acetolactate synthase (ALS, EC 4.1.3.18) is the first common enzyme in the biosynthetic route to the branched chain amino acids, valine, leucine and isoleucine. It is the primary target site of action for at least three structurally distinct classes of herbicides, the imidazolinones (IM), sulfonylureas (SU), and triazolopyrimidines (TP) (Figure 1). SU and IM were discovered in greenhouse screening programs whereas TP was subsequently targeted as a herbicide. Numerous substitution patterns can be incorporated into the basic structure of all three classes of herbicides to provide crop selectivity as well as broad spectrum weed control. This is amply demonstrated in the seven products based on SU and four based on IM already in the market. A number of others are in various stages of development. The rapid success of ALS inhibitors as herbicidal products has attracted a world-wide research commitment. Not since the photosystem II... 

Figure 1. Three chemical families known to exhibit herbicidal activity through the inhibition of acetolactate synthase. A. sulfonylurea (sulfometuron) B. imidazolinone (imazapyr) and C. A representative triazolopyrimidine.

ALS is also inhibited by a number of compounds which are structurally unrelated to the sulfonylureas. These include two other classes of herbicides the imidazolinones (5) and the triazolopyrimidines (Hawkes, T.R. Howard, J.L. Pontin, S.E. In Herbicides and Plant Metabolism, in press). LaRossa et al. have speculated on why ALS is such an effective target for so many inhibitors (6). Blocking ALS leads to the buildup of the toxic substrate a-ketobutyrate. The elevated levels of this metabolite combined with the reduced levels of the branched chain amino acids appear to make the inhibition of ALS a particularly lethal event. 

Acetolactate synthase (ALS) is the target enzyme for three unrelated classes of herbicides, the sulfonylureas, the imidazolinones, and the triazolopyrimidines. We have cloned the genes which specify acetolactate synthase from a variety of wild type plants, as well as from plants which are resistant to these herbicides. The molecular basis of herbicide resistance in these plants has been deduced by comparing the nucleotide sequences of the cloned sensitive and resistant ALS genes. By further comparing these sequences to ALS sequences obtained from herbicide-resistant yeast mutants, two patterns have become clear. First, the ALS sequences that can be mutated to cause resistance are in domains that are conserved between plants, yeast and bacteria. Second, identical molecular substitutions in ALS can confer herbicide resistance in both yeast and plants. 

ALS has also been shown to be inhibited by two other structurally unrelated classes of herbicides, the imidazolinones (8,9) and the triazolopyrimidines (10,11). It has been shown that the toxicity of the sulfonylurea herbicides to bacteria is due, in part, to the accumulation of an ALS substrate a-ketobutyrate, which is itself toxic. It has been suggested that the dual effects of the accumulation of a toxic substrate and the inability to synthesize isoleucine, leucine and valine make ALS a particularly good target for herbicides (12). 

The properties of the herbicides that target ALS can also contribute to the emergence of resistant weeds. There are several classes of compounds which target ALS, including the sulfonylureas, the imidazolinones and the triazolopyrimidines. Within these classes are a number of herbicides that are used at rates that kill a high proportion of the weeds, thus increasing the likelihood that resistant biotypes will... 

Acetolactate synthase inhibition by imidazolinones and triazolopyrimidines, 460 sensitivity to sulfonylurea herbicides, 460 Acetolactate synthase gene activity and inheritance of resistance in tobacco, 461... 

A great number of herbicides that work through the inhibition of acetolactate synthase (ALS) have been commercialized. They belong to four chemical groups sulfonylureas (23), triazolopyrimidines (2), imidazolinones (5), and pyrimidinyloxybenzoic analogues (3). (The number of active ingredients in parentheses is taken from The Pesticide Manual.) Also in this case, potent herbicides were developed (e.g., chlorsulfuron) before the site of action was found. 

The triazolopyrimidine sulfonanilides are a class of highly active herbicides. These compounds also act by disrupting the biosynthesis of branched-chain amino acids in plants through the inhibition of AHAS. Cloransulam-methyl, diclosulam, and flor-asulam, as shown in Fig. 11.4, all introduced by Dow AgroSciences, are examples of the triazolopyrimidine sulfonanilide herbicides that contain a fluoro-substituted heterocyclic moiety. 

Table II. Herbicidal activity for substitutions in the 7- and 8-positions of the triazolopyrimidine ring.

Inhibitors of Acetolactate Synthase (ALS/AHAS) The enzyme acetolactate synthase (ALS) plays in plants an essential role in branched-chain amino acid biosynthesis. In the pathway leading to valine and leucine, ALS catalyzes the formation of 2-acetolactate from two pyruvate molecules, and in the pathway to isoleucine the formation of 2-acetohydroxybutyrate from 2-ketobutyrate and pyruvate. Due to this double function the enzyme is also called with a more general term aceto-hydroxyacid synthase. ALS is inhibited by several groups of herbicides, mainly the sulfonylureas (SUs), imidazolinones (IMIs), triazolopyrimidines (TPs), pyrimidinylthiobenzoates(PTBs) and sulfonylaminocarbonyltriazolinone (SCTs) (see Chapter 2.1, M. E. Thompson). 

The structure-activity trends for the triazolo[15-a]pyrazines have not been studied as extensively as other members of triazolopyrimidine sulfonanilides [51]. Table 2.4.10 shows the activity on broadleaf and grass species for a series of substitutions on the fused heterocyclic portion of 34. The highest levels of activity on grass and broadleaf species are observed when both 5- and 8-positions are substituted with methoxy (34, R = R = OMe). However, the herbicidal activity observed for 34 is weaker than that for the triazolo[l,5-a]pyrimidine sulfonamides. 

However, these compounds are weaker herbicides than the triazolopyrimidine sulfonamides. 

Kleschick WA, Triazolopyrimidine Sulfonanilides and Related Compounds. In Herbicides Inhibiting Branch Chain Amino Acid Biosynthesis, Stetter, J. Ed., Spinger-Verlag, Germany, 1994, Vol. 10, pp 119-143. 

The activity of the non-halogenated sulfonamide herbicide asulam (105 1965, Asulox , May Baker 1-10 kg-a.i. ha ) [196] was remarkable improved by replacing the 4-aminophenyl ring with a halogenated triazolopyrimidine moiety and/or by replacement the N-methoxycarbonyl group with a series of ortho-halogenated electron-deficient phenyl rings such as 2,6-difluoro-, 2,6-dichloro- or... 

Soil column extraction (SCE) SCE consists on a specific solvent percolation to a column packed with the sampled material (soil, sediment) containing herbicides. About 100mmoll potassium phosphate buffer adjusted to pH 8 at ambient temperature readily extracts imidazolinones, diphenyl ethers, sulfonyl ureas, aryloxyphenoxypropionic acids, and triazolopyrimidines from soil samples. The same SCE procedure was applied to 0.2-0.4% carbon-containing sediments for isolation of sulfonamides and triazines with recoveries ranging from 63% to 99%. Further cleanup (e.g., on Carbograph cartridges) or concentration (SPME) may sometimes be necessary. 

Table ni. Characterization of the Response of Susceptible (S) and Resistant (R) Kochia Biotypes to Sulfonylurea, Triazolopyrimidine sulfonanilide, and Imidazolinone Herbicides (adapted from ref. 2. and Saari, L. L. Cotterman, J. C. Primiani, M. M. 1990, Plant Phvsiol. (in press)). 

Flumetsulam is one of several in the triazolopyrimidine sulfonamide class of herbicide. This class of AHAS inhibitors is effective for broadleaf weed... 

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