*4.1.1 Compounds acting via chitin metabolism*

• N-amino-maleimide

N-amino-maleimide derivatives containing a hydrazone group are imides mimicking the synthesis of linderone and methyllinderone which were isolated from *Lindera erythrocarpa* M. Makino. They are fungicides that inhibit chitin synthase B-1,3-glucan synthase, leading to an alteration of the cell walls of fungi. A hemisynthetic method is described as follows: various aryl-substituted unsaturated ketones were synthesized and reacted with N-amino-maleimide under reflux of dry ethanol with a catalytic amount of *p*-toluenesulfonic acid to produce a variety of N-amino-maleimide derivatives containing a hydrazone group (**Figure 21**) [83].

**Figure 20.** *Fungal cell wall components [82].*

**Figure 21.** *Synthesis of N-amino-maleimide derivatives containing a hydrazone group.*

#### **4.2 Cell membrane**

In any living being, the cell membrane ensures the smooth-running of the exchanges between the cytoplasm and the extracellular matrix. It is composed of a lipid bilayer containing proteins, glycoprotein, glycolipids and sterols. The latter are important component of the cell membrane, they regulate its fluidity and the enzymes in it (like the chitin synthases) [84].

#### *4.2.1 Compounds acting via the cell membrane*

• Spiroxamine

Spiroxamine is a synthetic fungicide mimic of the class of natural or synthetic morpholines such as fenpropidin, tridemorph, fenpropimorph etc. It inhibits both delta-14 reductase and delta-7–delta-8 isomerase, which leads to the formation of carbocation sterols, and strongly affects hyphae and mycelium development [85]. One method of synthesis of this molecule is as follows, tert-butyl cyclohexanone is first reacted with 3-chloro-1,2-propanediol. Formation of the ketal under acidic conditions leads to 8-tert butyl-1,4-dioxanspiro[4,5]decan-2-ylmethyl chloride, which is reacted with ethyl propylamine to form spiroxamine following nucleophilic substitution (**Figure 22**) [86].

• Prochloraz

Nitrogen compounds such as prochloraz (imidazole), fenarimol (pyrimidine), epoxyconazole, fluzilazole, and tebuconazole (triazole) are synthetic fungicides that act on essential fungal functions. They are inhibitors of the α-methylation of sterols [84]. Prochloraz for example is a fungicide of the imidazole family which can be obtained in several steps. Initially 2,4,6-trichlorophenol is alkylated with 1,2-dibromomethane in a Williamson ether synthesis. The following reaction with propylamine provides a secondary amine which is reacted with phosgene. This acid chloride of a carbamic acid is finally reacted with imidazole to give prochloraz (**Figure 23**) [87].

**Figure 22.** *Spiroxamine synthesis.* *DOI: http://dx.doi.org/10.5772/intechopen.105158 Biomimetic and Hemisynthetic Pesticides*

#### **4.3 Cytoskeleton**

The cytoskeleton and membrane systems of eukaryotic cells play key roles in the intracellular transport of vesicles, organelles, and macromolecules. The actin cytoskeleton is mainly composed of globular actin (G-actin), which is monomeric actin able to self-assemble into filamentous actin (F-actin) [88]. The actin cytoskeleton is subjected to alterations and organizations to promote cellular dynamic and particle transport within and between cells. Eukaryotic cells polymerize actin filaments to provide mechanical integrity and motility force for a wide range of cellular mechanisms [89]. Microtubules are the main components of the cytoskeleton and the spindle apparatus (the cytoskeletal structure separating the sister chromatids during cell division). They are formed through α−/β-tubulin heterodimers assembling into cylindric filaments (**Figure 24**). The plus-ends of these filaments grow pointing towards the plasma membrane into protrusions, while their minus ends are anchored at microtubule-organizing centers (MTOCs) such as the centrosome. This polarity allows selective directional long-range cargo transport at the cell periphery [88]. Any substance able to impair with the formation or functioning of those microtubules blocks cell division in general and hyphae in fungi [84].

#### *4.3.1 Compounds acting via the cytoskeleton*

• Carbendazim

Carbendazim is a biomimetic benzimidazole that inhibits microtubule assembly and therefore blocks cell division in fungi. This effect appears to be related to their β-tubulin

#### **Figure 24.**

*Microtubules formation: A. Tubulin dimerization; B. Tubulin dimers polymerization; C. Protofilament association; D. Formed microtubule [90].*

**Figure 25.** *Carbendazim synthesis.*

binding, the main component of microtubulins. Carbendazim binds to β-tubulin and prevents tubulin formation [84]. A simple way to synthesize this molecule was realized by the condensation of orthophenylene diamine with an ester of aminonitrile in the presence of ammonia according to the figure below (**Figure 25**) [91].

Carbendazim is a widely used broad-spectrum fungicide that inhibits mitotic microtubule formation and cell division. The use of proteomics approaches, suggest that carbendazim is an environmental risk factor that likely weakens honeybees (*Apis mellifera*) colonies, partially due to reduced expression of major royal jelly proteins, which may be potential causes of colony collapse disorder [92].

• Ethylicin

Biomimetic organosulfur compounds have received considerable attention in recent years. Among various organosulfur compounds have shown a broad spectrum of biological activity such as fungicidal activity [93, 94]. They can block the normal metabolism of microorganisms by sulfenylation of the thiol groups of enzymes [95, 96]. Ethylicin is therefore a biomimetic organosulfur fungicide with a broad spectrum for plants. It can inhibit the growth of *Pseudomonas syringae* pv. *actinidiae* and prevent cancer in the plant stem [97, 98]. It is a bionic organosulfur pesticide (S-ethyl ethanethiosulfonate) that mimics the natural allicin obtained from garlic (*Allium sativum* L.). It was first prepared and studied in the laboratory during the synthetic research of allicin and its homologs in 1958 and developed as a broad spectrum biomimetic fungicide in China [99]. Because of the widespread application *DOI: http://dx.doi.org/10.5772/intechopen.105158 Biomimetic and Hemisynthetic Pesticides*

**Figure 26.** *Ethylicin synthesis.*

of thiosulfonates, considerable effort has been made to develop synthetic methods for these compounds. Therefore, one of the synthesis methods used is the reduction of sulfonyl chlorides (**Figure 26**) [100].

### **5. Pesticides targeting digestive system**

All insects have a complete digestive system in the form of a tube-like enclosure. Named the alimentary canal and running lengthwise through the body from mouth to anus, it consists of three regions: the foregut or stomodaeum, the midgut or mesenteron, and the hindgut or proctodaeum (**Figure 21**). An insect's mouth, located centrally at the base of the mouthparts, is a sphincter that marks the "front" of the foregut. Then goes the pharynx, from which food passes into the esophagus, a simple tube that connects the pharynx to the crop, a food-storage organ where food remains until it can be processed through the remaining sections of the alimentary canal. In some insects, the crop opens posteriorly into the proventriculus, which grinds and pulverizes food particles before they reach the stomodeal valve, a sphincter regulating the flow of food from the stomodeum to the mesenteron. The midgut begins just past the stomodeal valve. Near its anterior end, finger-like projections (usually from 2 to 10) diverge from the walls of the midgut. Gastric caecae provide extra surface area for secretion of enzymes or absorption of water (and other substances) from the alimentary canal. The rest of the midgut is called the ventriculus — it is the primary site for enzymatic digestion of food and absorption of nutrients. Digestive cells lining the walls of the ventriculus have microscopic projections (microvilli) that increase surface area for nutrient absorption. The posterior end of the midgut is marked by another sphincter muscle, the pyloric valve. It serves as a point of origin for dozens to hundreds of Malpighian tubules. These long, spaghetti-like structures extend throughout most of the abdominal cavity where they serve as excretory organs, removing nitrogenous wastes from the hemolymph (analog of blood in arthropods). The rest of the hindgut plays a major role in homeostasis by regulating the absorption of water and salts from waste products in the alimentary canal (**Figure 27**) [101].

#### **5.1 Compounds acting** *via* **the digestive system**

• Triterpenic derivatives

Balanced nutritional intake is essential to ensure that insects undergo adequate larval development and metamorphosis. Terpenes are a class of hydrocarbons,

#### **Figure 27.**

*Generalized insect digestive system illustrating the three main regions at different stages of development [102] (JH = juvenile hormone).*

produced by many plants. The aim is to optimize insecticidal triterpene derivatives by biomimetic oxidation with hydrogen peroxide and iodosobenzenes catalyzed by porphyrin complexes. Therefore, the hemisynthesis of the derivatives were made from 31-norlanosterol an insecticide isolated from the latex of *Euphorbia officinarum* L. and were subjected to oxidation with hydrogen peroxide (H2O2) and iodosobenzene (PhIO) catalyzed by porphyrin complexes following a biomimetic strategy. Main transformations were epoxidation of double bonds and hydroxylations of non-activated C-H groups as shown in **Figure 12** [103]. These compounds caused a decreased digestive enzyme secretion and histolysis of intestinal tissues and led to indigestion, nutritional deficiency and decreased body weight of larvae. This prevented the larvae from reaching a critical weight and a normal population [103]. Similarly, work carried out on the development of *Chlosyne lacinia* caterpillars fed on *Heliantheae* leaves showed that the main discriminating metabolites of these leaves, diterpenes, caused a delay in the complete development of the caterpillars to the adult phase and that the latter showed a higher rate of diapause (**Figure 28**) [104].

*DOI: http://dx.doi.org/10.5772/intechopen.105158 Biomimetic and Hemisynthetic Pesticides*

**Figure 28.** *Triterpenic derivatives synthesis.*

## **6. Electron transport chain**

Mitochondria regulate critical cellular processes, from energy production to apoptosis; within these organelles, sugars and long chain fatty acids are broken down, ADP is recycled back into ATP, steroids and lipids are synthesized, ancient DNA is replicated, transcribed and proteins are translated, along with numerous other reactions that are essential for human life [105]. Characteristic properties of all insect mitochondria are their low stability, their exceptionally high respiratory and phosphorylative activity with their physiological substrates, their relatively poor rate of oxidation of Krebs-cycle intermediates and the low P:0 ratios accompanying these slow oxidations. The phosphorylating respiratory chain of insect mitochondria strongly resembles that of mammalian mitochondria [106]. The electron transport chain is a mitochondrial pathway in which electrons move across a redox span of 1.1 V from NAD/NADH to O2/H2O. Three complexes are involved in this chain, namely, complex I, complex III, and complex IV. Some compounds like succinate, which have more positive redox potential than NAD/NADH, can transfer electrons via a different complex—complex II (**Figure 29**) [107].

#### **6.1 Compounds acting** *via* **electron transport chain**

• Cyazofamid

Cyazofamid is a cyanoimidazole fungicide particularly effective on *Oomycota*. This molecule, inspired in natural imidazoles, inhibits ATP production in cells by

**Figure 29.** *Electron transport chain [108].*

inhibiting the complex III of the respiratory chain of the mitochondria [84]. It is a synthetic fungicide whose synthesis is described as follows; an acetophenone derivative was treated with aqueous glyoxal and hydroxylamine to form an oxime substituted imidazole ring system. This intermediate was treated with thionyl chloride and disulfide dichloride to convert the oxime to a cyano group chlorinating the imidazole in the position near the phenyl ring. Finally, treatment with dimethylsulfamoyl chloride gave cyazofamide (**Figure 30**).
