Acylalanines

Acylalanines constitute a chemical group of highly specific systemic fungicides for the control of oomycetes, including species of the genera Phytophthora, Downy mildew, plasmopara, Bremia e Albugo.

These compounds have excellent curative and protective activity and are widely used to control mildew, late blight and white rust in crops such as potatoes, tomatoes, grapevines, leafy vegetables, soybeans and ornamental crops.

The strategic importance of this chemical group in the global agricultural scenario is justified by its exceptional effectiveness against pathogens that historically caused significant losses in agricultural production, especially in conditions of high humidity and moderate temperature.

Development of acylalanines

The development of acylalanines represents a significant milestone in modern phytopathology. This chemical group originated in the Ciba-Geigy research laboratories during the 1970s, a period marked by the intensive search for compounds with systemic activity and greater biological specificity.

The first synthesis of metalaxyl was disclosed in patents filed by the Swiss company, using an innovative synthetic route that involved the alkylation of 2,6-xylidine with methyl 2-bromopropionate to form an alanine derivative, subsequently reacted with methoxyacetic acid chloride to produce racemic metalaxyl.

The development process followed a systematic trajectory that lasted almost a decade before actual commercialization. Between 1970 and 1975, Ciba-Geigy researchers focused their efforts on the discovery and initial synthesis phase, during which specific antifungal activity against oomycetes, a group of pathogens that until then had limited options for effective chemical control, was identified.

The subsequent period, between 1976 and 1978, was dedicated to the development of industrial-scale synthesis processes and to carrying out in-depth studies of biological efficacy, investigations that revealed the unique mechanism of action based on the selective inhibition of RNA polymerase I in oomycete cells.

The year 1979 marked a watershed in crop protection with the commercial introduction of metalaxyl, when Ciba-Geigy obtained the first registration in the United States, officially beginning the commercial era of acylalanines (some say the first occurrence was in 1977). This milestone was followed by approval by the Food and Agriculture Organization of the United Nations in 1982, an event that significantly expanded the global use of these fungicides and solidified their acceptance by the international scientific community.

The 1980s were characterized by the continuous development of new molecules within the group, culminating in the launch of benalaxyl between 1985 and 1990, representing a second generation of acylalanines that offered a similar control spectrum to metalaxyl, but with a different toxicological profile and better suitability for certain crops.

The group's technological evolution reached a new level during the 1990s, a period in which advances in asymmetric synthesis chemistry enabled the development of the homogeneous chiral version of metalaxyl, known commercially as metalaxyl-M or mefenoxam.

This innovation represented a significant refinement of the original technology, since the new molecule retained all the fungicidal activity present in the original racemic mixture, but with superior efficacy per unit of mass applied, resulting in a reduction in the necessary doses and a consequent decrease in environmental impact.

Mode of action

The mechanism of action of acylalanines is based on the selective inhibition of RNA synthesis in oomycete cells, a process that occurs through specific interference with RNA polymerase I.

This mechanism involves the binding of the fungicide to the enzyme RNA polymerase, effectively blocking the transcription of genes essential for the growth and development of the pathogen. The primary biochemical target is RNA polymerase I, an enzyme responsible for the synthesis of ribosomal RNA in oomycetes, which has specific structural characteristics that differ significantly from those found in true fungi, higher plants and animals, conferring high selectivity to the chemical group.

According to the Fungicide Resistance Action Committee classification, acylalanines belong to FRAC Group 4, with resistance code PA (Phenylamides), and are categorized as inhibitors of nucleic acid synthesis, specifically of the RNA polymerase I subgroup.

Inhibition of this enzyme results in a severe reduction in ribosome synthesis, drastically compromising cellular protein synthesis and consequently causing mycelial growth to stop, sporulation to be inhibited, spore germination to be blocked and the formation of reproductive structures to be suppressed. At effective concentrations, the pathogen completely loses its infective and reproductive capacity, characterizing the fungicidal action of the group.

Control spectrum

The spectrum of control of acylalanines covers several crops of economic importance, with emphasis on the control of late blight caused by Phytophthora infestans in potatoes and tomatoes, where doses between 0,5-2,0 L/ha and 0,5-1,5 L/ha are applied, respectively.

In viticulture, they demonstrate excellent efficacy against grapevine mildew (plasmopara viticola) at doses of 0,3-0,8 L/ha, while in leafy vegetables such as lettuce they efficiently control downy mildew caused by bremia lactucae with doses of 0,5-1,0 L/ha.

In extensive crops, the control of Peronospora manshurica in soybeans and Plasmopara halstedii in sunflower requires doses of 0,5-1,0 L/ha and 0,8-1,5 L/ha, respectively.

Safety intervals vary significantly depending on the crop and formulation used, with the Withdrawal Period ranging from 3 to 21 days, while the Re-entry Interval is typically 24 hours for open field applications and 48 hours for protected crops, and may vary depending on local legislation and specific application conditions.

Resistance management

The management of resistance to acylalanines is a critical aspect for the sustainability of the chemical group, since resistance was first documented in the 1980s, only a few years after the commercial introduction of metalaxyl.

In Brazil, the resistance of Phytophthora infestans in potatoes was reported in producing regions of the South and Southeast from the 1990s onwards, while populations of plasmopara viticola resistant strains were identified in vineyards in Serra Gaúcha and Vale do São Francisco.

Worldwide, widespread resistance has been documented in several countries, including the United States, Canada, European countries and Australia, becoming one of the main limiting factors for the continued use of these fungicides.

To delay the development of resistance, mandatory rotation with fungicides from different FRAC groups is recommended, preferably groups 11, 21, 22, 27, 28 and 40, limiting the use of acylalanines to a maximum of 30% of total applications per cycle. The implementation of pre-formulated mixtures with multisite fungicides such as copper, mancozeb e chlorothalonil, as well as the alternation between different active ingredients within the acylalanine group itself, constitute fundamental management strategies.

The high rate strategy is recommended for situations of high disease pressure and when populations with reduced sensitivity are suspected, while the reduced rate can be used preventively in low pressure conditions, always in combination with fungicides with a different mode of action.

Regarding safety and environmental impact, most acylalanine-based products have a toxicological classification of III (moderately toxic) or IV (slightly toxic), varying according to the formulation and concentration of the active ingredient. The environmental classification ranges from II (very dangerous) to III (dangerous to the environment). The persistence in the soil varies between 15-70 days of half-life, depending on the soil and climate conditions, with soils with neutral to alkaline pH presenting faster degradation, high temperatures accelerating degradation and adequate humidity favoring biodegradation.

The adsorption coefficient is between 50-162 mL/g, indicating moderate to high mobility in the soil, which gives acylalanines moderate to high leaching potential due to their high water solubility and low adsorption coefficient. Special care should be taken in sandy soils with low organic matter content, areas close to water bodies, regions with high rainfall and applications during rainy periods.

Interactions and compatibilities

The interactions and compatibilities of acylalanines are favorable with cupric fungicides, dithiocarbamates, chlorothalonil, systemic fungicides from other FRAC groups and foliar fertilizers with neutral pH.

However, they are incompatible with highly alkaline products, mineral oils and oily adjuvants in high concentrations, some organophosphate insecticides and fertilizers with high calcium content.

Phytotoxicity may occur in applications under conditions of severe water stress, overdose or repeated applications at short intervals, young crops or crops at sensitive stages, combination with incompatible adjuvants and high temperature conditions with low relative humidity.

Agronomic efficiency

The agronomic efficacy of acylalanines is influenced by several environmental and application factors. Temperatures between 15-25°C, relative humidity between 60-90%, preventive application or at the onset of symptoms and spray pH between 6,0-7,0 constitute favorable conditions for efficacy.

On the other hand, heavy rains in the first 2-4 hours after application, extreme temperatures, severe water stress in plants and application in advanced stages of the disease represent factors that limit efficacy.

The main advantages of acylalanines include excellent systemic activity with acropetal translocation, high specificity for oomycetes, curative and eradicating action, long residual period and efficacy at low application doses. Limitations include the restricted spectrum to oomycetes only, high risk of resistance development, high cost compared to multisite fungicides, potential for environmental contamination and dependence on specific climatic conditions.

Strategic positioning

The strategic positioning of acylalanines in agricultural systems varies according to the crop and regional conditions.

In soybeans, preventive use at the V4-V6 stage is recommended for controlling downy mildew, especially in regions with a history of the disease and favorable climatic conditions.

In corn, preventive application in hybrids susceptible to mildew is a priority in regions with continuous cultivation and humid climates.

For cotton, control of downy mildew in seedlings and young plants requires emphasis on preventive applications during the first 60 days of cultivation.

In sugarcane, use is limited to controlling mildew in nurseries and seedlings, focusing on protecting propagation material.

In coffee growing, preventive application to control mildew is especially important in mountainous regions with high humidity and frequent cloudiness.

In wheat, preventive control of downy mildew is essential in irrigated cultivation regions and conditions of high relative humidity.

For vegetables, intensive use in protected crops and open fields requires emphasis on preventive and rotational programs to avoid resistance.

In fruit growing, strategic application in grapevines, citrus and temperate climate fruits should focus on protection during critical periods of development.

The strategic positioning of acylalanines should always consider integrated disease management, including genetic resistance, cultural practices, climate monitoring and careful rotation with fungicides with different modes of action, aiming at long-term sustainability and effectiveness in the control of oomycetes.