• Avermectins

The avermectins are hemisynthetic pesticides acting on glutamate-gated chloride channels (GluCls) and gamma-amino butyric acid (GABA) receptors, and then causes neuromuscular paralysis that eventually leads to death [52]. Several derivates can be synthetized starting from avermectins. For example, the hydrogenation of avermectin

**Figure 10.** *Dihydroavermectin A1 synthesis.*

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

A1 with Wilkinson's catalyst ((PH3P)3RhCl) [53] yields to the dihydroavermectin A1 (**Figure 10**).

#### • Emamectin

Emamectin (**Figure 11**) is another hemisynthetic pesticide targeting the same receptors (GABA and GluCls) that the avermectins. The emamectin causes neuromuscular paralysis that eventually leads to death [23]. Emamectin activates chloride channels by stimulating high-affinity GABA receptors and GluCls channels, which increases membrane permeability to Cl− and disrupts nerve signals in arthropods. This results in hyperpolarization and removal of signal transduction in the insect nervous system, which reduces neurotransmission [54]. The insect larva stops feeding after exposure and becomes irreversibly paralyzed which leads to death within 3 or 4 days [55].

#### **2.5 Octopaminergic (OA) system**

Octopamine is a neurohormone (released in the hemolymph for lipid mobilizing during flight and long-lasting motor behaviors), a neuromodulator and a neurotransmitter present in relatively high concentrations in every invertebrate tissue [56]. Octopamine binds to a specific G protein-coupled membrane receptor. The binding of octopamine to these receptors leads to the activation of the enzyme adenylyl cyclase. It transforms ATP to cAMP and causes an increase in the cAMP level, which is a signaling molecule, activating the protein kinase A (PKA). The G protein also activates phospholipase C (**Figure 12**). It leads to the release of calcium from deposits in the endoplasmic reticulum and to the elevation of its intracellular level as well as to the activation of the calcium-dependent protein kinase C (PKC). Protein kinases phosphorylate several enzymes and receptors leading to the modulation of their activity. This phosphorylation produces important changes in cell functions [57].

**Figure 11.** *Structure of emamectin.*

#### *2.5.1 Compounds acting via the Octopaminergic (OA) System*

• Phenylpropanoids

Hemisynthetic phenylpropanoids derivatives can interfere with the octopaminergic system. Their binding to the octopamine receptor causes its blockage which leads to decreased cAMP levels within cells, thus resulting in antifeedant and larvicidal effect [58]. For example, the dillapiole, a phenylpropanoid isolated from the essential oil of leaves of *Piper aduncum* L. and several hemisynthetic derivatives present an activity against *Aedes aegypti* L. being several derivates more actives than the dillapiole [59]. Following a similar approach, Sinha's team designed a hemisynthetic method to obtain cinnamic esters from the oxidation of cinnamaldehydes (**Figure 13**).

Eugenol is a phenylpropanoid and a major constituent of clove oil (*Syzygium aromaticum* L.) with many applications in the pharmaceutical, food, agricultural and cosmetic industries [60]. Eugenol can mimic octopamine by increasing intracellular calcium levels in cloned brain cells of *Periplaneta americana* L. and *Drosophila melanogaster* Meigen [61].

#### **2.6 Nicotinic acetylcholine receptors (nAChRs)**

Nicotinic acetylcholine receptors (nAChRs) are ion channels that mediate fast neurotransmission in the central and peripheral nervous systems. nAChRs are

#### **Figure 12.**

*Effects of OA on different tissues of invertebrates. Sense organs (italic); central systems (underlined) modulated by OA [56].*

**Figure 13.** *Hemisynthesis of phenylpropanoids derivatives.*

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

formed by the assembly of 5 transmembrane subunits (**Figure 9**) among 17 different nAChR subunits. nAChRs regulate the flow of mainly sodium, potassium and calcium ions across the cell membrane (**Figure 14**) [62].

#### *2.6.1 Compounds acting via nicotinic acetylcholine receptors*

• Flupyradifurone

Flupyradifurones are a class of synthetic butenolide insecticides, mimic of natural neonicotinoids, active against various pests and suckers with an excellent safety profile. It acts reversibly as an agonist on the nicotinic acetylcholine receptors of insects. It binds to the nAChR blocking it. Flupyradifurone is a

#### **Figure 14.**

*Structure of the nicotinic acetylcholine receptors. (a). The threading pattern of receptor subunits through the membrane. (b). A schematic representation of the quaternary structure, showing the arrangement of the subunits in the muscle-type receptor, the location of the two acetylcholine (ACh)-binding sites (between an α- and a γ-subunit, and an α- and a δ-subunit), and the axial cation-conducting channel. (c). A cross-section through the 4.6-Å structure of the receptor [63].*

novel butenolide insecticide that is also systemic and a nicotinic acetylcholine receptor (nAChR) agonist. Tosi and Nieh [64] provide the first demonstration of adverse synergistic effects on honeybee survival and behavior (*Apis mellifera* L.) (poor coordination, hyperactivity, apathy). Two different pathways for the synthesis of flupyradifurone are presented in **Figure 15**. Starting from tetronic acid, one approach consists in two consecutive reactions. Where the tetronic acid reacts firstly with a difluoroethane-1-amine and secondly with 2-Chloro-5- (chloromethyl)pyridine (Method A, **Figure 15**). And the other approach, where the tetronic acid reacts with difluoroethane-1-amine derivative in the presence of 4-toluenesulfonic acid in a "one pot" approach (Method B, **Figure 15**) to yield flupyradifurone [65].

• Triflumezopyrim

Triflumezopyrim is biomimetic mesoionic insecticide, containing domains characteristics of natural betaines that have shown excellent control of sucking insects. Mesoionic insecticides bind to the orthosteric site of the nACHR and act primarily by inhibition of the binding site. A method for the synthesis of these pyrimidones is described as follows: 2-aminopyridine reacted with pyrimidine-5-carbadehyde to form imine, the imine was exposed to reductive amination conditions to generate amine which reacts with malonic chloride to form triflumezopyrim (**Figure 16**) [66].

**Figure 15.** *Flupyradifurone synthesis.*

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

**Figure 16.**

*Triflumezopyrim synthesis.*

## **3. Pesticides targeting endocrine system**

Complementary to the nervous system, the endocrine system ensures the functioning of the organism thanks to the production and the transport of various hormones trough the body. There are types of endocrine glands: neurosecretory cells within the central nervous system whose secretions act on effector organs or on other endocrine glands and specialized endocrine glands, *corpora cardiaca*, *corpora allata*, and the prothoracic glands [67].

#### **3.1 Apoptosis**

Apoptosis is a programmed cellular death occurring under regulated conditions. At the end of the process, the cell divides in many apoptotic bodies that will be phagocyted. Caspases (cysteine aspartate-specific proteinases) are a family of cysteine proteases that serve as both the initiators and the executioners of apoptosis. They are crucial mediators of apoptosis, and their activation is carefully controlled

by a death program. An unbalance in this program can lead to deleterious apoptosis [68]. Caspases are frequently considered synonymous with apoptotic cell death [69], but the review of Accorsi, 2015 [70] prove that these proteases may exert their activities in non-apoptotic functions (developmentally regulated autophagy during insect metamorphosis, neuroblast self-renewal and the immune response).

#### *3.1.1 Compounds acting via apoptosis*

• Phenylpropanoids

Several amino-alcohols biomimetic derivates of the phenylpropanoid eugenol are insecticides that act against *Spodoptera frugiperda* Smith and increase the activity of caspases leading to apoptosis [71]. The amino-alcohols are derivatives obtained by a hemisynthetic reaction of eugenol. In this reaction eugenol was converted to the corresponding epoxide with *m*-chloroperoxybenzoic acid (*m*-CPBA) in dichloromethane and then reacted with a series of nucleophilic amines to give the corresponding β-amino alcohols (**Figure 17**) [71].

#### **3.2 Ecdysteroids**

Steroid hormones play indispensable roles in modulating a broad range of biological processes in nearly all multicellular organisms. Once produced, steroid hormones are circulated in hemolymph and are easily transported to target cells to act as ligands for the nuclear receptor family of transcription factors. In insects, the major steroid hormones are ecdysteroids, also known as molting hormones (**Figure 18**). They play essential roles in coordinating developmental transitions, such as larval molting and metamorphosis (**Figure 13**) [73].

**Figure 17.** *Hemisynthesis of eugenol alcohols.*

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

#### **Figure 18.**

*The developmental stages and ecdysteroid titers in D. melanogaster [72].*

The different metamorphoses undergone by insects to pass from one stage to another (larval stage to metamorphosis) are called molts (ecdysis). Molting takes place under the control of steroid hormone (ecdysone) responsible for molting [74] and the juvenile hormone (JH), responsible for inhibiting the steroid hormone to maintain the insect in its larval state and thus avoid premature ecdysis [75]. Activation and release of ecdysone into the hemolymph are controlled by the prothoracic hormone (PPTH), produced by the *corpora cardiaca*, and the insect insulin.

#### *3.2.1 Compounds acting via ecdysteroids*

• Azadirachtin-A derivatives

Tetrahydroazadirachtin, alongside with other azadirachtin-A analogues like 22,23-dihydroazadirachtin; 3-tigloylazadirachtol; 11-methoxydihydroazadirachtin and 22,23-bromoethoxydihydroazadirachtin are hemisynthetic pesticides disrupting the endocrine system. By blocking the release of neurosecretory peptides which regulate synthesis of ecdysteroids and juvenile hormone they provoke molt disruption leading to death [76].

Azadirachtin causes a slowdown in the synthesis and release of prothoracicotropic hormone (PPTH), which affects the functioning of the nucleus of secretory neurons and endocrine glands and the insect can no longer molt. Azadirachtin also modifies the production and stop of the growth functions [77].

Azadirachtin is a synthetic insecticide that belongs to the triterpenoid class of limonoids. One method of synthesis of azadirachtin starts with the selective acetylation in C3 of the triol to give the acetate derivate which by a series of reactions gives the triglate intermediate. Cleavage of the benzyl ether from the triglate intermediate occurred to provide lactol. Then the conversion of methyl acetal into phenyl sulfide during a treatment with thiophenol and catalytic PPTS (pyridinium toluene-Psulfonic acid) in toluene followed by an oxidation with dimethyldioxirane (DMDO) followed by a pyrolysis to obtain azadirachtin (**Figure 19**) [78].

**Figure 19.**

*Azadirachtin synthesis.*

## **4. Pesticides targeting cellular structure**

#### **4.1 Chitin metabolism**

Chitin is one of the most important natural biopolymers. It is mainly produced by fungi, arthropods, and nematodes. In insects, it supports the cuticles of tissues like the epidermis or the trachea. As for bones in the vertebrates, chitin is constantly synthesized and degraded. This balance is strictly controlled by the production of chitin synthases and chitinolytic enzymes to ensure a correct growth [79]. Chitin is widely distributed in the fungal kingdom since nearly all fungi have significant amounts of chitin in their cell wall (**Figure 14**). Cell wall architecture is well documented and it was described several decades ago that inhibition of chitin synthesis produces cell death [80]. Regarding the importance of chitin in growth and development of insects and in fungi cell wall, its synthesis is an interesting target for a pesticide. Chitin plays a key role in the insect's water system. It controls water homeostasis. The loss of this impermeable layer leads to transpiration which is fatal for the insect (**Figure 20**) [81].
