The search for novel active ingredients

The ideal herbicide should:

• be highly selective to plants and non-toxic to other organisms,

• act quickly and effectively at low doses,

• rapidly degrade in the environment, and

• be cheap to produce and purchase.

This is a difficult list of criteria to fulfil and seldom are all of these properties shown in one active ingredient. However, the search to widen our herbicide portfolio continues.

High plant selectivity is achieved by targeting processes unique to plants, and the chlo-roplast is a unique organelle where these processes are located. Thus, the inhibition of photosynthesis and the biosyntheses of pigments, cofactors, amino acids and lipids is invariably lethal. Other major targets located outside the chloroplast but still unique to plants include the biosyntheses of cell wall materials, microtubules for cell division and the receptors for plant hormones (Cobb, 1992).

The number of target sites that have been exploited, however, is remarkably few, at between 15 and 20. The consequence of a limited number of target sites is that weed resistance to existing herbicides is becoming increasingly prevalent (see Chapter 12). The problem is so serious that scientists from all of the major agrochemical companies, academic institutions and national organisations have formed the Herbicide Resistance Action Committee (HRAC) to standardise herbicide classification according to mode of action and to highlight management strategies for the control of resistant weeds. An important cornerstone to the prevention of herbicide resistance is the use of herbicides with different target sites in mixtures, sequences and rotations. Scientists are becoming increasingly aware, however, of the problems of cross-resistance to herbicides of different chemical groups, and evidence is emerging that resistance due to enhanced metabolic detoxification of herbicides is becoming increasingly widespread. Thus, the combination of herbicide mixtures that exploit different target sites and are metabolised by different routes is proposed to keep resistance under control. If resistance is allowed to accumulate within our major weeds, then our current armoury of herbicides will be rendered useless in the foreseeable future, with drastic consequences to crop yields and quality.

How can this fate be averted? The scientific challenge is to discover new chemistry with novel modes of action and commercial potential as herbicides. The literature implies limited success in this regard with two target sites, namely acetolactate synthase (ALS) and protoporphyrinogen oxidase (Protox) dominating herbicide discovery in recent years. Indeed, the only novel target site to have emerged and been commercially exploited in 15 years is the enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD), EC 1.13.11.276 (see Chapter 6 for further details).

The discovery of new herbicide activity may involve three lines of approach, namely:

1 the rational design of specific inhibitors of key metabolic processes,

2 the use of known herbicides or phytotoxic natural products as lead compounds for further synthesis, or

3 the random screening of new chemicals.

To date there have been no publications to suggest that the first approach is feasible. Although we can identify target processes or enzymes that may have potential for herbicide design and discovery, we have not yet come to terms with the complexities of plant metabolism to exploit them. The literature contains many published attempts to design herbicides as enzyme inhibitors that were potent in vitro but commercially unsuccessful. Only an increased understanding of plant physiology and biochemistry will allow us to proceed beyond this theoretical phase and so turn rational design into a distinct possibility.

The second approach is essentially imitative, and is often referred to as ' analogue synthesis' or 'me-too' chemistry. It does provide new targets and standards for synthetic chemists in particular, although the search for an analogue with new activity is seldom predictable. Lead compounds may have shown biological activity either commercially or have known activity, for example as secondary metabolites, allelochemicals, or other 'natural' plant products (i.e. biorational design). Certainly, the academic and patent literature are closely scrutinised for indications of new activity.

The random screening of novel chemicals against target weeds is the approach most likely to lead to the discovery of a new class of herbicide. In this way, the agrochemical and chemical industries, sometimes in collaboration with academic institutions, employ chemists to synthesise novel molecules and biologists to screen for their activity. The outcome of the random screening process is not simply left to chance but nowadays involves a stepwise assessment of the potential of new compounds in primary, secondary, and tertiary or field screens.

The primary screen aims to establish lead structures, namely those with sufficient activity against target species at a suitably low dose to warrant further study. Since most agrochemical companies screen thousands of chemicals each year, this process is both costly and crucial (Table 2.6). Thus, if selection criteria are low, many compounds of marginal activity will be selected and screening costs may become astronomical, but if standards are too high, a potential lead may be missed. Since it is practically impossible to screen all compounds in the field, companies attempt to simulate these conditions in glasshouses or controlled environments. In this way, new chemicals are commonly applied to glasshouse-grown weeds and crops, and any growth regulatory or phytotoxic symptoms are scored visually at regular intervals. Interestingly, new compounds are routinely tested in other primary screens, for example molecules synthesised as herbicides will be tested for fungicidal or insecticidal activity. Indeed, quite surprising results have been reported from such screens with the generation of new leads (e.g. Giles, 1989).

Table 2.6 Costs for the development of an agricultural chemical (modified from Giles, 1989).

Development phase

Length(years)

Compounds tested per eventual registered product

Total costs (£ million)

First synthesis and glasshouse

1

22 500a

45

screens

Re-synthesis and first field

2

150

1

experiments

Optimisation of synthesis, large-scale

2

7.5

7

field trials and product safety

Further optimisation of synthesis, full

3

1.5

8

field development, product safety and

registration

Totals

8

1

61

a Note that Berg et al.(1999) considered this 'hit rate' to be in the region of 1 in 46,000 for 1995, as a result of increasing competition, environmental issues and toxicological considerations.

a Note that Berg et al.(1999) considered this 'hit rate' to be in the region of 1 in 46,000 for 1995, as a result of increasing competition, environmental issues and toxicological considerations.

In vitro In vivo

In vivo In vivo

In vitro In vivo

In vivo In vivo

Throughput per year

1,000,000 50,000-100,000

20,000 100

Figure 2.2 Modern herbicide screening.

Throughput per year

1,000,000 50,000-100,000

20,000 100

Amount needed

Micrograms 1-10mg

100mg Grams

Figure 2.2 Modern herbicide screening.

Most companies have now introduced high throughput technologies (HTTs) into their discovery processes (Figure 2.2). HTT refers to a range of tools and techniques to enable rapid and parallel experiments, such as herbicide screening, to increase productivity and the development of new leads. The benefits of high throughput screening can include:

1 faster discovery and optimisation of new lead compounds,

2 greater efficiency and productivity,

3 faster and improved target innovation, and

4 faster optimisation of the formulation process.

Examples in use include Lemna plants, green algae, cell suspensions from target weeds and germinating cress (Lepidum sativum L.) seeds arranged, for example, in 96 well plates. Robotics and automated assays are used to note changes in control populations. In vitro high throughput screens may reveal new classes of herbicide chemistry. Processes such as combinatorial chemistry have been developed for this purpose (e.g. see Ridley et al., 1998 for a detailed account). The modern screening process therefore starts with a large chemical library and assumes a maximum hit-rate of 0.1%, at best.

Weed spectrum

Crop selectivity

Speed of action

Formulation and > compatibility with other products

Systemicity in the plant

Crop selectivity

Dosage needed

Speed of action

Formulation and > compatibility with other products

Systemicity in the plant

Persistence in the environment

Leaching to groundwater

Animal and mammalian toxicity

Figure 2.3 Information needed to optimise herbicide development.

It is the aim of the secondary screen to optimise these initial observations by further chemistry to yield compounds with the desired characteristics for commercial potential. To be successful, a logical sequence of further study is necessary to establish whether the new structures are sufficiently active or novel to warrant further development. Thus, the characteristics shown in Figure 2.3 need to be precisely tested, with a clear list of priorities. Furthermore, biologists and chemists need to work closely if such optimisation is to be achieved.

Field Screens are used to test hypotheses formulated in laboratory and glasshouse testing, and so confirm that molecules are as active in the field as initially predicted. These screens form the basis of many decisions that may yet seal the fate of a new herbicide class. Certainly, promise must be confirmed before very expensive and thorough toxico-logical and environmental studies are pursued. Compounds showing reliable and reproducible activity in the glasshouse may prove unpredictable in the field when exposed to a wide range of environmental and climatic constraints. Thus, extensive field evaluation is needed to ensure that, for example, the compound is adequately formulated (e.g. for rainfastness, cuticule penetration, and compatibility with other pesticides) and used at the correct growth stages to give optimal weed control with minimal crop damage.

To satisfy the aforementioned criteria takes many years and the investment of huge sums of money (Table 2.6). However, as stated by Giles (1989), 'those companies which are able to optimise these processes to reduce their risks but to take advantage of opportunities arising from new types of chemistry ... have a good chance of discovering products with which to ensure their future; those that do not will have less chance of finding products and a reduced chance of survival'.

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