**Natural Alkamides: Pharmacology, Chemistry and Distribution**

María Yolanda Rios

*Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Col. Chamilpa, Cuernavaca, Morelos, México* 

#### **1. Introduction**

106 Drug Discovery Research in Pharmacognosy

[14] Ruiying Fang,Zhongyao Shi.Observing ten kinds of traditional Chinese medicine on the

cells.[J] Modern pharmaceutical application : 1995, 12 (1): 5-7.

function of resistance to toxic liver in using original generation to cultivate liver

Alkamides are a broad and expanding group of bioactive natural compounds found in at least 33 plant families. Despite the relatively simple molecular architecture of alkamides (fig. 1), these natural products show broad structural variability and an important range of biological activities, such as immunomodulatory, antimicrobial, antiviral, larvicidal, insecticidal, diuretic, pungent, analgesic, cannabimimetic and antioxidant activities. Additionally, alkamides are involved in the potentiation of antibiotics and the inhibition of prostaglandin biosynthesis, RNA synthesis and the arachidonic acid metabolism, among others.

Many plant species containing alkamides have been used in traditional medicine by different civilizations around the world. Many of the plants containing these natural products have been used in the treatment of toothaches and sore throats (Rios-Chavez et al., 2003). These compounds are present in different organs of the plant, such as roots (*Heliopsis longipes*, *Echinaceae purpurea*, *Achillea wilhelmsii*, A*cmella oppositifolia*, *Asiasarum heterotropoide, Cissampelos glaberrima*, etc.), leaves and stems (*Aristolochia gehrtii*, *Phyllanthus fraternus*, *Amaranthus hypochondriacus*, *Achyranthes ferruginea*, etc.), the pericarpium (*Zanthoxylum piperitum* and *Piper spp*.), the placenta of *Capsicum spp*., the fruits of *Piper longum*, the flowers of *Spilanthes acmella*, the seeds of the *Piper* species and tubers of *Lepidium meyenii*. It is believed that alkamides act as plant growth regulators, promoting or inhibiting the growth and formation of roots in a dose-dependent manner and showing a positive effect in plant biomass production (Campos-Cuevas, et al., 2008).

Structurally, natural alkamides commonly have an aliphatic, cyclic or aromatic amine residue, and a C8 to C18 saturated or unsaturated chain (including double or triple bonds, or both) acid, which can also be aromatic. The nature of the acid (carbon chain lengths, unsaturation level, stereochemistry, etc.) and the amine residues are characteristic of each family and genus of plants such that these characteristics serve as chemotaxonomic criteria (fig. 1). Because the nitrogen atom of alkamides is not part of a heterocyclic ring, these compounds are classified as protoalkaloids or pseudoalkaloids.

Alkamides represent a class of lipidic compounds structurally related to animal endocannabinoids. Notably, based on the structural similarity of these compounds to

Natural Alkamides: Pharmacology, Chemistry and Distribution 109

Plants belonging to the Asteraceae, Convolvulaceae, Euphorbiaceae, Menispermaceae and Rutaceae families specialize in the biosynthesis of alkamides with both amine and acid aliphatic residues. Chemical analysis of these species revealed that aliphatic alkamides are the major and most characteristic components of several Asteraceae plants based on the number of isolated compounds from each plant and the yield obtained for each alkamide. In contrast, Convolvulaceae, Euphorbiaceae, Menispermaceae and Rutaceae families produce alkamides along with other types of natural products, resulting in alkamides being the

The Asteraceae family is characterized by the accumulation of aliphatic alkamides. *Aaronsohnia*, *Achilea*, *Acmella*, *Anacyclus*, *Artemisia*, *Echinaceae*, *Heliopsis*, *Spilanthes*, *Salmea*, *Sanvitalia* and *Wedelia* are genera that belong to this alkamide-producing family. These genera share the biogenetic capacity to combine C8 to C18 (with exception of C17) olefinic and acetylenic acid residues with the more widespread *N*-isobutyl, *N*-2-methylbutyl, *N*phenethyl and cyclic amines [piperidinyl (piperidide), 2,3-dehydro-piperidinyl (piperideide), pyrrolidinyl and pyrrolidyl]. However, other minor amides including *N*-4 methylbutyl, *N*-tyramidyl and *O*-methyl-tyramidyl residues have also been found (fig. 3).

**O**

**R2**

*N***-isobutyl** *N***-2-methylbutyl** *N***-4-methylbutyl**

**<sup>H</sup> <sup>N</sup>**

*N***-phenethyl** *N***-tyramidyl** *N***-(***O***-methyl-tyramidyl)**

**H**

**N H**

**pyrrolidyl pyrrolidinyl**

**OCH3**

**OH**

**R1 N**

**N**

**H**

**piperidinyl (piperidide)**

Fig. 3. Amine residues (R2) of aliphatic alkamides from the Asteraceae family.

**N N N N**

**2. Aliphatic alkamides** 

minor components.

**2.1 Alkamides from the Asteraceae family** 

**N H**

**<sup>H</sup> <sup>N</sup>**

**2,3-dehydro-piperidinyl (piperideide)**

**N**

anandamide (*N*-arachidonoylethanolamine), an endogenous cannabinoid cerebral neurotransmitter, alkamides are highly active in the central nervous system (CNS, fig. 2).

Fig. 1. Characteristic alkamides from different plant genera.

Fig. 2. Anandamide (*N*-arachidonoylethanolamine) structure.

In general, when alkamide-producing plants are chewed, a pungent taste is released causing itching and salivation. Chloroform is the best solvent for the extraction of alkamides, though both methanol and ethanol have also been used. Pure alkamides are sensitive to oxidation and polymerization of double and triple bonds occur during the drying, handling and storage of these compounds. Notably, alkamides are promising chemical and pharmacological entities that are useful therapeutics for the treatment of several important illnesses. This chapter describes the distribution of alkamides, the chemical aspects used to distinguish these important natural products and the pharmacological properties of the plants from which these compounds are isolated.

## **2. Aliphatic alkamides**

108 Drug Discovery Research in Pharmacognosy

anandamide (*N*-arachidonoylethanolamine), an endogenous cannabinoid cerebral neurotransmitter, alkamides are highly active in the central nervous system (CNS, fig. 2).

O

H3C

HO

OH

OCH3

In general, when alkamide-producing plants are chewed, a pungent taste is released causing itching and salivation. Chloroform is the best solvent for the extraction of alkamides, though both methanol and ethanol have also been used. Pure alkamides are sensitive to oxidation and polymerization of double and triple bonds occur during the drying, handling and storage of these compounds. Notably, alkamides are promising chemical and pharmacological entities that are useful therapeutics for the treatment of several important illnesses. This chapter describes the distribution of alkamides, the chemical aspects used to distinguish these important natural products and the pharmacological properties of the

O

OH

O N

*Piper*

O

N H

*Amaranthus*

O

CH3 *Gly cosmis*

O

N H OH

S N

O

O

*Achillea*

*Echinaceae*

O

*Capsicum*

N H

Fig. 1. Characteristic alkamides from different plant genera.

Fig. 2. Anandamide (*N*-arachidonoylethanolamine) structure.

plants from which these compounds are isolated.

N

N H Plants belonging to the Asteraceae, Convolvulaceae, Euphorbiaceae, Menispermaceae and Rutaceae families specialize in the biosynthesis of alkamides with both amine and acid aliphatic residues. Chemical analysis of these species revealed that aliphatic alkamides are the major and most characteristic components of several Asteraceae plants based on the number of isolated compounds from each plant and the yield obtained for each alkamide. In contrast, Convolvulaceae, Euphorbiaceae, Menispermaceae and Rutaceae families produce alkamides along with other types of natural products, resulting in alkamides being the minor components.

#### **2.1 Alkamides from the Asteraceae family**

The Asteraceae family is characterized by the accumulation of aliphatic alkamides. *Aaronsohnia*, *Achilea*, *Acmella*, *Anacyclus*, *Artemisia*, *Echinaceae*, *Heliopsis*, *Spilanthes*, *Salmea*, *Sanvitalia* and *Wedelia* are genera that belong to this alkamide-producing family. These genera share the biogenetic capacity to combine C8 to C18 (with exception of C17) olefinic and acetylenic acid residues with the more widespread *N*-isobutyl, *N*-2-methylbutyl, *N*phenethyl and cyclic amines [piperidinyl (piperidide), 2,3-dehydro-piperidinyl (piperideide), pyrrolidinyl and pyrrolidyl]. However, other minor amides including *N*-4 methylbutyl, *N*-tyramidyl and *O*-methyl-tyramidyl residues have also been found (fig. 3).

Fig. 3. Amine residues (R2) of aliphatic alkamides from the Asteraceae family.

Natural Alkamides: Pharmacology, Chemistry and Distribution 111

Currently, the most commonly found alkamides in the Asteraceae family include a C10, C11 and C12 long chain residue acids, which represent approximately 72% of aliphatic alkamides isolated from this family. The second most important group of these natural products includes C14 and C18 long chain residue acids, constituting approximately 13% of Asteraceae alkamides. Most phytochemical and pharmacological studies have been conducted with *Achillea*, *Acmella*, *Sphilantes*, *Echinaceae* and *Heliopsis* genera, which will be discussed in subsequent sections.

## **2.1.1** *Achillea* **genus**

The occurrence of alkamides with cyclic amide moieties is confined to the Anthemideae tribe, being *Achillea* species especially rich in both pyrrolidides and piperidides and their corresponding dehydroderivatives. Apart from the more widespread isobutylamides, this genus is characterized by the frequent occurrence of saturated and unsaturated 5- and 6-ring amides (Greger et al., 1987a, 1987b). The accumulation of amides with characteristic olefinic and acetylenic patterns is characteristic of this genus. These amides are mainly accumulated in the subterranean parts of these plants (table 1).

#### **2.1.2** *Acmella* **genus**

A name frequently used in folk medicine for species containing alkamides is "the tooth herb". These plants exhibit analgesic properties and are frequently used as odontologic agents. For example, *Acmella decumbens* roots have a pungent taste and when chewed a numbing sensation is felt on the tongue. *Acmella radicans* is another species also used for the treatment of toothache (Rios-Chavez et al., 2003).

Alkamides from the *Acmella* genus consist of an *N*-isobutyl, *N*-2-methylbutyl or *N*-phenethyl amine and C8 to C12 acid residues. Of the seven *Acmella* species that have been chemically analyzed, four species have been observed to produce affinin (spilanthol, *N*-isobutyl-2*E*,6*Z*,8*E*-decatrienamide, **70**), an alkamide with established analgesic properties (Rios et al., 2007). Several affinin analogues are present in extracts from these *Acmella* species (see table 1), which probably contribute to the analgesic sensation induced by these plants.

#### **2.1.3** *Spilanthes* **genus**

For years *Spilanthes acmella* has been used as traditional folk medicine to treat toothaches, stammering, and stomatitis. Previous studies have demonstrated the diuretic, antibacterial, and anti-inflammatory activities of *Spilanthes acmella*. Spilanthol (**70**), the main alkamide isolated from this plant, exhibits antiseptic activity. Additionally, spilanthol (**70**) is involved in immune stimulation and the attenuation of the inflammatory responses in murine RAW 264.7 macrophages (Wu et al., 2008).

#### **2.1.4** *Echinaceae* **genus**

*Echinacea* is a native herb from North America and Europe that is used as an immunostimulant. Extracts from the *Echinacea* species are widely used due to the strong belief that the components of the extract stimulate the immune system and help to prevent infections, colds, respiratory infections and influenza. However, the clinical efficacy of this


Currently, the most commonly found alkamides in the Asteraceae family include a C10, C11 and C12 long chain residue acids, which represent approximately 72% of aliphatic alkamides isolated from this family. The second most important group of these natural products includes C14 and C18 long chain residue acids, constituting approximately 13% of Asteraceae alkamides. Most phytochemical and pharmacological studies have been conducted with *Achillea*, *Acmella*, *Sphilantes*, *Echinaceae* and *Heliopsis* genera, which will be

The occurrence of alkamides with cyclic amide moieties is confined to the Anthemideae tribe, being *Achillea* species especially rich in both pyrrolidides and piperidides and their corresponding dehydroderivatives. Apart from the more widespread isobutylamides, this genus is characterized by the frequent occurrence of saturated and unsaturated 5- and 6-ring amides (Greger et al., 1987a, 1987b). The accumulation of amides with characteristic olefinic and acetylenic patterns is characteristic of this genus. These amides are mainly accumulated

A name frequently used in folk medicine for species containing alkamides is "the tooth herb". These plants exhibit analgesic properties and are frequently used as odontologic agents. For example, *Acmella decumbens* roots have a pungent taste and when chewed a numbing sensation is felt on the tongue. *Acmella radicans* is another species also used for the

Alkamides from the *Acmella* genus consist of an *N*-isobutyl, *N*-2-methylbutyl or *N*-phenethyl amine and C8 to C12 acid residues. Of the seven *Acmella* species that have been chemically analyzed, four species have been observed to produce affinin (spilanthol, *N*-isobutyl-2*E*,6*Z*,8*E*-decatrienamide, **70**), an alkamide with established analgesic properties (Rios et al., 2007). Several affinin analogues are present in extracts from these *Acmella* species (see table

For years *Spilanthes acmella* has been used as traditional folk medicine to treat toothaches, stammering, and stomatitis. Previous studies have demonstrated the diuretic, antibacterial, and anti-inflammatory activities of *Spilanthes acmella*. Spilanthol (**70**), the main alkamide isolated from this plant, exhibits antiseptic activity. Additionally, spilanthol (**70**) is involved in immune stimulation and the attenuation of the inflammatory responses in murine RAW

*Echinacea* is a native herb from North America and Europe that is used as an immunostimulant. Extracts from the *Echinacea* species are widely used due to the strong belief that the components of the extract stimulate the immune system and help to prevent infections, colds, respiratory infections and influenza. However, the clinical efficacy of this

1), which probably contribute to the analgesic sensation induced by these plants.

discussed in subsequent sections.

in the subterranean parts of these plants (table 1).

treatment of toothache (Rios-Chavez et al., 2003).

**2.1.1** *Achillea* **genus** 

**2.1.2** *Acmella* **genus** 

**2.1.3** *Spilanthes* **genus** 

**2.1.4** *Echinaceae* **genus** 

264.7 macrophages (Wu et al., 2008).




#### 114 Drug Discovery Research in Pharmacognosy Natural Alkamides: Pharmacology, Chemistry and Distribution 115





Table 1. Alkamides from the Asteraceae family.

Natural Alkamides: Pharmacology, Chemistry and Distribution 119

agent has not been proven. *E. angustifolia*, *E. pallida* and *E. purpurea* are three species of *Echinacea* that are used in commercial preparations with reported alkamide profiles. These species contain complex mixtures of alkamides that are good chemotaxonomic characters (table 1). The major alkamides in *E. purpurea* roots are the C12-2,4-diene and C12-2,4-dienediyne type, while the C11 diene-diynes were highest in vegetative stems (Binns et al., 2002). *E. angustifolia* roots are characterized by the presence of di-, tri- and tetraenes in coexistence with mono- and diynes, all of them with variable insaturation degree at the C2, C4, C9 or C10 position. In *E. pallida*, the major compounds are polienes (also di-, tri- and tetraenes)

Lipophilic alkamides from *Echinacea* show immunostimulatory activity and have been used for the treatment of cold, flu, respiratory infections and inflammations, making a considerable contribution to the activities attributed to *Echinaceae* plants (Bauer, 1989a, 1989b, 1990, 1991). Studies on the mechanisms of action of the immunomodulatory activity of *Echinacea* have indicated that alkylamides can act as cannabinomimetics. Endogenous ligands for cannabinoid receptors such as anandamide (fig. 2), an animal alkamide that shares structural similarity with the *Echinacea* alkylamides, can bind to CB2 cannabinoid receptors (LaLone et al., 2010). The cannabinoid receptors CB1 and CB2 have been implicated in the modulation of the CNS and the inflammatory response. CB1 receptors are present in neurons from the central and peripheral nervous system and are concentrated in

the brain. CB2 receptors are mainly present in immune cells, such as macrophages.

opiodergic, serotoninergic and GABAergic systems (Déciga-Campos et al., 2010).

Convolvulaceae, Euphorbiaceae, Menispermaceae and Rutaceae are other plant families that produce aliphatic alkamides. *N*-isobutyl, 2'-hydroxy-*N*-isobutyl, NH2 and pyrrolidinyl amine residues have been identified in the structures of alkamides isolated from these plants

**2.2 Aliphatic alkamides from other plant families** 

*Heliopsis longipes* is a Mexican plant that was broadly used by the Náhuatl civilization as flavoring in food preparation. The stems of this climber are used in traditional medicine as a condiment, buccal anesthetic, analgesic in pain toothache, antiparasitic, anti-inflammatory and antiulcerative agent and to prepare homemade insecticides that, similar to pyrethrins, are toxic and exhibit paralyzing effects. Chewing of a little piece of the *Heliopsis longipes* stem results in intense salivation and a local analgesic effect (Molina et al., 1996). An ethanolic extract of this plant exhibited antinociceptive effects on acute thermal and chemical inflammation induced nociception in mice with a mechanism partly linked to the lipoxygenase and/or cyclooxygenase systems (Cariño-Cortés et al., 2010). This extract exhibited synergistic interactions with diclofenac in the Hargreaves model of thermal hyperalgesia (Acosta-Madrid et al., 2009). Various unsaturated aliphatic alkamides have also been identified and characterized from the roots of this plant (table 1), such as affinin (**70**), its most abundant and bioactive alkamide. The analgesic activity of affinin was determined by measuring the release of GABA in mice brain slices (Rios et al., 2007). Furthermore, dosedependent antinociceptive effects have been observed to be a result of the activation of

and diynes (C2 or C2 and C4 unsaturated)

**2.1.5** *Heliopsis* **genus** 

(table 2).

agent has not been proven. *E. angustifolia*, *E. pallida* and *E. purpurea* are three species of *Echinacea* that are used in commercial preparations with reported alkamide profiles. These species contain complex mixtures of alkamides that are good chemotaxonomic characters (table 1). The major alkamides in *E. purpurea* roots are the C12-2,4-diene and C12-2,4-dienediyne type, while the C11 diene-diynes were highest in vegetative stems (Binns et al., 2002). *E. angustifolia* roots are characterized by the presence of di-, tri- and tetraenes in coexistence with mono- and diynes, all of them with variable insaturation degree at the C2, C4, C9 or C10 position. In *E. pallida*, the major compounds are polienes (also di-, tri- and tetraenes) and diynes (C2 or C2 and C4 unsaturated)

Lipophilic alkamides from *Echinacea* show immunostimulatory activity and have been used for the treatment of cold, flu, respiratory infections and inflammations, making a considerable contribution to the activities attributed to *Echinaceae* plants (Bauer, 1989a, 1989b, 1990, 1991). Studies on the mechanisms of action of the immunomodulatory activity of *Echinacea* have indicated that alkylamides can act as cannabinomimetics. Endogenous ligands for cannabinoid receptors such as anandamide (fig. 2), an animal alkamide that shares structural similarity with the *Echinacea* alkylamides, can bind to CB2 cannabinoid receptors (LaLone et al., 2010). The cannabinoid receptors CB1 and CB2 have been implicated in the modulation of the CNS and the inflammatory response. CB1 receptors are present in neurons from the central and peripheral nervous system and are concentrated in the brain. CB2 receptors are mainly present in immune cells, such as macrophages.

#### **2.1.5** *Heliopsis* **genus**

118 Drug Discovery Research in Pharmacognosy

Table 1. Alkamides from the Asteraceae family.

*Heliopsis longipes* is a Mexican plant that was broadly used by the Náhuatl civilization as flavoring in food preparation. The stems of this climber are used in traditional medicine as a condiment, buccal anesthetic, analgesic in pain toothache, antiparasitic, anti-inflammatory and antiulcerative agent and to prepare homemade insecticides that, similar to pyrethrins, are toxic and exhibit paralyzing effects. Chewing of a little piece of the *Heliopsis longipes* stem results in intense salivation and a local analgesic effect (Molina et al., 1996). An ethanolic extract of this plant exhibited antinociceptive effects on acute thermal and chemical inflammation induced nociception in mice with a mechanism partly linked to the lipoxygenase and/or cyclooxygenase systems (Cariño-Cortés et al., 2010). This extract exhibited synergistic interactions with diclofenac in the Hargreaves model of thermal hyperalgesia (Acosta-Madrid et al., 2009). Various unsaturated aliphatic alkamides have also been identified and characterized from the roots of this plant (table 1), such as affinin (**70**), its most abundant and bioactive alkamide. The analgesic activity of affinin was determined by measuring the release of GABA in mice brain slices (Rios et al., 2007). Furthermore, dosedependent antinociceptive effects have been observed to be a result of the activation of opiodergic, serotoninergic and GABAergic systems (Déciga-Campos et al., 2010).

#### **2.2 Aliphatic alkamides from other plant families**

Convolvulaceae, Euphorbiaceae, Menispermaceae and Rutaceae are other plant families that produce aliphatic alkamides. *N*-isobutyl, 2'-hydroxy-*N*-isobutyl, NH2 and pyrrolidinyl amine residues have been identified in the structures of alkamides isolated from these plants (table 2).


Table 2. Aliphatic alkamides from Convolvulaceae, Euphorbiaceae, Menispermaceae and

Rutaceae plant families.


Table 2. Aliphatic alkamides from Convolvulaceae, Euphorbiaceae, Menispermaceae and Rutaceae plant families.

Natural Alkamides: Pharmacology, Chemistry and Distribution 123

*Capsicum* (also known as "chile" or "chilli") are species used as vegetables, condiments, and for an important number of medicinal preparations*.* The fruits of *Capsicum* have been utilized in food preparation, for medicinal applications to tone body muscles after workouts, hot infusions for toothache and muscle pain and aerosols such as *Capsicum* extracts that are used as personal protection. This species are the source of highly pungent capsacinoids that induce a hot or burning sensation. Capsaicinoids are the major chemical constituents from the following five domesticated species of *Capsicum* (peppers) genus: *C. annuum* L., *C. baccatum* L., *C. chinense* Jacq., *C. frutescens* L. and *C. pubescens*. All of these species have *N*vanillylamides (all contain a 4-hydroxy-3-methoxybenzyl amine group) of C8 to C18 fatty

> **N H**

**O**

**R1**

caprylic acid vanillylamide nonivamide nordihydrocapsaicin norcapsaicin decylic acid vanillylamide dihydrocapsaicin capsaicin homocapsaicin-I homocapsaicin-II homodihydrocapsaicin-I homodihydrocapsaicin-II *N*-vanillyl-hexadecanamide (palvanil) *N*-vanillyl-octadecanamide (stevanil) *N*-vanillyl-9*E*-octadecenamide (olvanil) *N*-vanillyl-9*E*,12*E*-octadecadienamide (livanil)

Table 3. Capsaicinoids from *Capsicum annuum.* 

**OH**

**R1**

**(including C=O)** 

> C8 C9 C9 C9 C10 C10 C10 C11 C11 C11 C11 C16 C18 C18 C18

**Reference long chain**

**Chain** 

linear linear 7-CH3 5*E*; 7-CH3 linear 8-CH3 6*E*; 8-CH3 6*E*; 9-CH3 6*E*; 8-CH3 9-CH3 8-CH3 linear linear 9*E*  9*E*,12*E*

(Kozukue et al., 2005) (Kobata et al., 2010)

**OCH3**

**3.1 The alkamides from Solanaceae family: Capsaicinoids** 

acids (table 3).

**Alka-**

**mide Name** 

#### **2.2.1 Convolvulaceae alkamides**

Convolvulaceae alkamides are also known as alkaloids MQ. These alkamides are characterized by linear or branched saturated acid residues. All Convolvulaceae alkamides have a pyrrolidinyl residue as the amine group and have been isolated from the *Ipomoea* and *Merremia* genera (compounds **130**-**136**).

## **2.2.2 Euphorbiaceae alkamides**

*Phyllanthus fraternus* is used by traditional healers and tribes in the northern region of India as a folklore remedy for the treatment of malaria and various liver diseases. An aqueous extract of this plant exhibited antioxidant activity, preventing the oxidation of proteins and lipids. Additionally, aqueous extracts of *Phyllanthus fraternus* protect against allyl alcoholinduced oxidative stress in liver mitochondria (Sailaja & Setty, 2006). Two aliphatic alkamides C4 isomers , *E*,*E*-2,4-octadienamide (**137**) and *E*,*Z*-2,4-decadienamide (**138**), have been isolated from this plant. Both isomers lack an alkyl residue at the amine group, which is typically joined to an acid residue (Sittie et al., 1998). Instead, these compounds possess an α,β,γ,δ-unsaturated conjugated amide, a feature believed to enhance antiplasmodial activity. Notably, *in vitro* assays of these two isomers demonstrated that these compounds possess moderate antiplasmodial activity.

#### **2.2.3 Menispermaceae alkamides**

The roots of some species of the *Cissampelos* genus exhibit significant activity against mechanical, chemical and arthritic pain, increasing the pain threshold and dictating the medicinal value of the plants of this genus. For example, *C. glaberrimma* is a plant whose bioactivity is a reflection of its alkamide content (alkamides **139**-**142**, Rosario et al., 1996).

#### **2.2.4 Rutaceae alkamides**

The fruits of *Zanthoxylum integrifoliolum* possess a pungent taste. Chemical analysis enabled the isolation and identification of nine isobutylamides (**143**-**151**). These amides have a 2*E*,4*E*dienamide moiety, including an oxo, diene, tetraene or pentaene acidic fragment (table 2). However, no activity has been reported for these molecules.

Amides have also been isolated from the *Glycosmis* genus (Rutaceae); however, those isolated from this genus are sulfur-containing amides, a rare group of secondary metabolites that have an aromatic amine residue. *Glycosmis* alkamides will be discussed in section 3.3 (*vide infra*).

## **3. Aromatic alkamides**

Alkamides isolated from Solanaceae, Piperaceae, Brassicaceae and Rutaceae plant families either have one aromatic ring at the amine residue, at the acid residue or both. Capsaicinoids, amides from *Lepidium meyenii*, and sulfur derivatives from the *Glycosmis* genus are alkamides with one aromatic ring at the amine residue. Piperine and its analogs are amides with one aromatic residue at the acid fragment. Alkamides that have an aromatic ring at the amine and acid residues are distributed among a large group of plants.

Convolvulaceae alkamides are also known as alkaloids MQ. These alkamides are characterized by linear or branched saturated acid residues. All Convolvulaceae alkamides have a pyrrolidinyl residue as the amine group and have been isolated from the *Ipomoea* and

*Phyllanthus fraternus* is used by traditional healers and tribes in the northern region of India as a folklore remedy for the treatment of malaria and various liver diseases. An aqueous extract of this plant exhibited antioxidant activity, preventing the oxidation of proteins and lipids. Additionally, aqueous extracts of *Phyllanthus fraternus* protect against allyl alcoholinduced oxidative stress in liver mitochondria (Sailaja & Setty, 2006). Two aliphatic alkamides C4 isomers , *E*,*E*-2,4-octadienamide (**137**) and *E*,*Z*-2,4-decadienamide (**138**), have been isolated from this plant. Both isomers lack an alkyl residue at the amine group, which is typically joined to an acid residue (Sittie et al., 1998). Instead, these compounds possess an α,β,γ,δ-unsaturated conjugated amide, a feature believed to enhance antiplasmodial activity. Notably, *in vitro* assays of these two isomers demonstrated that these compounds possess

The roots of some species of the *Cissampelos* genus exhibit significant activity against mechanical, chemical and arthritic pain, increasing the pain threshold and dictating the medicinal value of the plants of this genus. For example, *C. glaberrimma* is a plant whose bioactivity is a reflection of its alkamide content (alkamides **139**-**142**, Rosario et al., 1996).

The fruits of *Zanthoxylum integrifoliolum* possess a pungent taste. Chemical analysis enabled the isolation and identification of nine isobutylamides (**143**-**151**). These amides have a 2*E*,4*E*dienamide moiety, including an oxo, diene, tetraene or pentaene acidic fragment (table 2).

Amides have also been isolated from the *Glycosmis* genus (Rutaceae); however, those isolated from this genus are sulfur-containing amides, a rare group of secondary metabolites that have an aromatic amine residue. *Glycosmis* alkamides will be discussed in section 3.3

Alkamides isolated from Solanaceae, Piperaceae, Brassicaceae and Rutaceae plant families either have one aromatic ring at the amine residue, at the acid residue or both. Capsaicinoids, amides from *Lepidium meyenii*, and sulfur derivatives from the *Glycosmis* genus are alkamides with one aromatic ring at the amine residue. Piperine and its analogs are amides with one aromatic residue at the acid fragment. Alkamides that have an aromatic

ring at the amine and acid residues are distributed among a large group of plants.

However, no activity has been reported for these molecules.

**2.2.1 Convolvulaceae alkamides** 

*Merremia* genera (compounds **130**-**136**).

**2.2.2 Euphorbiaceae alkamides** 

moderate antiplasmodial activity.

**2.2.3 Menispermaceae alkamides** 

**2.2.4 Rutaceae alkamides** 

**3. Aromatic alkamides** 

(*vide infra*).

#### **3.1 The alkamides from Solanaceae family: Capsaicinoids**

*Capsicum* (also known as "chile" or "chilli") are species used as vegetables, condiments, and for an important number of medicinal preparations*.* The fruits of *Capsicum* have been utilized in food preparation, for medicinal applications to tone body muscles after workouts, hot infusions for toothache and muscle pain and aerosols such as *Capsicum* extracts that are used as personal protection. This species are the source of highly pungent capsacinoids that induce a hot or burning sensation. Capsaicinoids are the major chemical constituents from the following five domesticated species of *Capsicum* (peppers) genus: *C. annuum* L., *C. baccatum* L., *C. chinense* Jacq., *C. frutescens* L. and *C. pubescens*. All of these species have *N*vanillylamides (all contain a 4-hydroxy-3-methoxybenzyl amine group) of C8 to C18 fatty acids (table 3).


Table 3. Capsaicinoids from *Capsicum annuum.* 

Natural Alkamides: Pharmacology, Chemistry and Distribution 125

Table 4. Alkamides from *Lepidium meyenii.* 

Some capsaicinoids exhibit strong pungent sensory properties when consumed as part of the diet. Additionally, capsaicinoids possess a variety of biological properties that may affect human health (Kozuke et al., 2010), such as antiviral, antibacterial, antifungal, insecticidal, antioxidative, anti-inflammatory and anticancer activities. Furthermore, capsaicinoids influence neuronal structures that contain substances that are associated with pain transmission and neurogenic inflammation. As a result, these compounds are used as topical analgesics for treating pain. The aforementioned properties are the basis for the use of capsaicinoids to prevent or reduce chronic and age-related pain (Kozuke et al., 2005). Capsaicin (**158**) and dihydrocapsaicin (**157**) are notable among natural capsaicinoids because they constitute approximately 90% of the total capsaicinoids in many varieties of peppers. The burning sensation caused by capsaicin is induced by the direct activation of a nonselective cation channel-transient receptor potential, vanilloid 1 (TRPV1), located at the end of sensory nerves. Several physiological activities caused by capsaicin are related to the activation of the TRPV1 receptor. Meghvansi and coworkers have written a review of capsaicinoids in which their ethnopharmacological applications are discussed (Meghvansi et al., 2010). Long acyl chain capsaicinoids exhibiting similar activities to capsaicin, such as anti-inflammatory, antinociceptive and enhanced adrenaline secretion, have been recently reported. The advantages of these compounds are the lack of irritancy or pungency due to the lower accessibility of TRPV1 in the tongue due to higher lipophilicity compared to capsaicin (Kobata et al., 2010).

#### **3.2 The alkamides from** *Lepidium meyenii* **(Brassicaceae)**

The roots from of *L. meyenii* are used to enhance fertility and sexual behavior in men and women. Additionally, *L. meyenii* roots serve as a traditional remedy for menopausal symptoms, the regulation of hormone secretion, immunostimulation, memory improvement, as an antidepressant or anticancer agent, and to prevent anemia. Phytochemical analysis of the roots of this plant led to the identification of *m*methoxybenzyl and *N*-benzyl amine residues and macamides, linear C16, C18 or C24 alkamides with one or two double bonds and possible oxidation of C5, C9 or C13 (table 4).

#### **3.3 The alkamides from** *Glycosmis* **(Rutaceae)**

Sulfur-containing amides (phenethyl/styrylamine-derived amides) form a rare group of secondary metabolites in the Rutaceae family. These amides are only present in the leaves of plants that belong to the *Glycosmis* genus. Sulfur-containing amides represent a typical chemical profile of this genus. The acid moieties of these alkamides are probably derived from cysteine, which can be oxidized to sulfones and sulfoxides or shortened by β-oxidation (as in ritigalin). With the exception of simple methylamides, the amine residues are characterized by the presence of phenethyl or styryl groups (derived from phenylalanine) that can be linked to different prenyloxy (dambullins) or geranyloxy groups in *para* position (gerambullins). More recently, a group of similar (methylsulfonyl)propenoic acid amides has been detected in which dopamine is linked to various oxidized geranyl chains (sakerines). Some of these alkamides exhibit pronounced antifungal and/or insecticidal activity (Greger & Zechner, 1996) (table 5).


Table 4. Alkamides from *Lepidium meyenii.* 

Some capsaicinoids exhibit strong pungent sensory properties when consumed as part of the diet. Additionally, capsaicinoids possess a variety of biological properties that may affect human health (Kozuke et al., 2010), such as antiviral, antibacterial, antifungal, insecticidal, antioxidative, anti-inflammatory and anticancer activities. Furthermore, capsaicinoids influence neuronal structures that contain substances that are associated with pain transmission and neurogenic inflammation. As a result, these compounds are used as topical analgesics for treating pain. The aforementioned properties are the basis for the use of capsaicinoids to prevent or reduce chronic and age-related pain (Kozuke et al., 2005). Capsaicin (**158**) and dihydrocapsaicin (**157**) are notable among natural capsaicinoids because they constitute approximately 90% of the total capsaicinoids in many varieties of peppers. The burning sensation caused by capsaicin is induced by the direct activation of a nonselective cation channel-transient receptor potential, vanilloid 1 (TRPV1), located at the end of sensory nerves. Several physiological activities caused by capsaicin are related to the activation of the TRPV1 receptor. Meghvansi and coworkers have written a review of capsaicinoids in which their ethnopharmacological applications are discussed (Meghvansi et al., 2010). Long acyl chain capsaicinoids exhibiting similar activities to capsaicin, such as anti-inflammatory, antinociceptive and enhanced adrenaline secretion, have been recently reported. The advantages of these compounds are the lack of irritancy or pungency due to the lower accessibility of TRPV1 in the tongue due to higher lipophilicity compared to

The roots from of *L. meyenii* are used to enhance fertility and sexual behavior in men and women. Additionally, *L. meyenii* roots serve as a traditional remedy for menopausal symptoms, the regulation of hormone secretion, immunostimulation, memory improvement, as an antidepressant or anticancer agent, and to prevent anemia. Phytochemical analysis of the roots of this plant led to the identification of *m*methoxybenzyl and *N*-benzyl amine residues and macamides, linear C16, C18 or C24 alkamides with one or two double bonds and possible oxidation of C5, C9 or C13 (table 4).

Sulfur-containing amides (phenethyl/styrylamine-derived amides) form a rare group of secondary metabolites in the Rutaceae family. These amides are only present in the leaves of plants that belong to the *Glycosmis* genus. Sulfur-containing amides represent a typical chemical profile of this genus. The acid moieties of these alkamides are probably derived from cysteine, which can be oxidized to sulfones and sulfoxides or shortened by β-oxidation (as in ritigalin). With the exception of simple methylamides, the amine residues are characterized by the presence of phenethyl or styryl groups (derived from phenylalanine) that can be linked to different prenyloxy (dambullins) or geranyloxy groups in *para* position (gerambullins). More recently, a group of similar (methylsulfonyl)propenoic acid amides has been detected in which dopamine is linked to various oxidized geranyl chains (sakerines). Some of these alkamides exhibit pronounced antifungal and/or insecticidal

capsaicin (Kobata et al., 2010).

**3.2 The alkamides from** *Lepidium meyenii* **(Brassicaceae)** 

**3.3 The alkamides from** *Glycosmis* **(Rutaceae)** 

activity (Greger & Zechner, 1996) (table 5).


Table 5. Sulfur-containing alkamides from the *Glycosmis* species.


Table 5. Sulfur-containing alkamides from the *Glycosmis* species.

Natural Alkamides: Pharmacology, Chemistry and Distribution 129

*corcovadensis*. Alkamides isolated from the *Ottonia* genus contain 1-oxo-5-(3',4' methylenedioxyphenyl)-2*E*,4*E*-pentadien-1-yl and 1-oxo-6-(*p*-methoxyphenyl)-2*E*,4*E*hexadien-1-yl residues as acidic fragments with *N*-isobutyl or *N*-3-acetoxy-isobutyl

> N O

chabamide (**212**) chabamide F (**213**) chabamide G (**214**)

chabamide H (**208**) chabamide I (**209**) chabamide J (**210**) chabamide K (**211**)

N O

N

O N

pipercyclobutanamide A (**215**) nigramide R (**216**) pipercyclobutanamide C (**217**)

The *Piper* species have been used in traditional medicine for thousands of years in China, India and Mexico, among other countries, for the treatment of several diseases and ailments. For example, *P. longum* is used for treatment of gonorrhea, menstrual and chronic intestinal pain, tuberculosis, sleeping problems, respiratory infections such as coughs, bronchitis and asthma, malarial fever, diarrhea, jaundice and arthritis. The beneficial effects of this species include analgesic and diuretic activities, relaxation of muscle tension, and the alleviation of

N H

O O

> O N

O O

> O O

N O

> O O

> > O N

O N

N H

O

N H O

O

O HN

fragments as the amide residues (Antunes et al., 2001; Costa & Mors, 1981, table 6).

NH O

> N O

O O

O O

O

O O

> N O

Fig. 5. Dimeric [4+2] alkamides from *Piper chaba.* 

O O

Fig. 6. Dimeric [2+2] alkamides from *Piper nigrum.*

<sup>O</sup> <sup>O</sup>

N O

O O

O O

> O O

<sup>O</sup> <sup>N</sup>

NH O

> O O

> > O N

O N

O O

O

O

anxiety.

O O

#### **3.4 The Piperaceae family. Piperine and its analogs**

Alkamides from the Piperaceae family are produced by plants that are classified as being in either the *Piper*, *Ottonia* or *Peperomia* genera. These alkamides are characterized by the presence of *N*-isobutyl, *N*-3-acetoxy-isobutyl, piperidinyl (piperidide), 5,6-dihydro-2(1*H*)pyridinone and pyrrolidinyl groups as amine residues, with *N*-isobutyl and piperidinyl being the most commonly found. The presence of carboxylic acid fragment is also characteristic of the alkamides isolated from plants that belong to the Piperaceae family. These fragments include the 3',4'-methylenedioxyphenyl as the most common terminal group. However, *p*-methoxyphenyl, 3',4',5'-trimethoxyphenyl and 4'-hydroxy-3' methoxyphenyl groups can also be joined to a chain of 2, 4, 5, 6, 8, 9, 10, 11, 12 or 14 carbons, with one, two or three unsaturations at the even-numbered carbons (with the exception of C12, fig. 4).

Fig. 4. The most common alkyl and amide residues of alkamides from the Piperaceae family.

Dimeric alkamides have been found in *P. chaba* and *P. nigrum*. *P. chaba* dimers are [4+2] adducts obtained from the combination of piperlonguminine and piperine [chabamide H (**208**) and I (**209**)], two molecules of pellitorine [chabamide J (**210**), and K (**211**)], two molecules of piperine [chabamide (**212**)], or two molecules of piperamine [chabamide F (**213**) and G (**214**)] (fig. 5). Notably, these dimeric alkamides exhibited potent cytotoxic activity against the COLO-205 cell line (Rao et al., 2011).

In contrast, *P. nigrum* dimers constituting [2+2] adducts are the combination of either two molecules of piperine [pipercyclobutanamide A (**215**) and nigramide R (**216**)] or from the piperine analogue piperrolein A [pipercyclobutanamide C (**217**)] (Rao et al, 2011; Subehan et al., 2006) (fig. 6).

The compounds produced by the Piperaceae family are pharmacologically very important, as several species of these plants are being used in folkloric medicine in different parts of the world. For example, the roots of plants from the *Ottonia* genus have a piquant taste and cause intense salivation when are in contact with the mouth. These roots exhibit local anesthetic and hallucinogenic effects and are used in the treatment of toothaches and sore throats. The toothache-relieving reputation of plants that belong to this genus led to the isolation of piperovatine (**222**), a buccal local anesthesic isobutyl amide isolated from *O.* 

Alkamides from the Piperaceae family are produced by plants that are classified as being in either the *Piper*, *Ottonia* or *Peperomia* genera. These alkamides are characterized by the presence of *N*-isobutyl, *N*-3-acetoxy-isobutyl, piperidinyl (piperidide), 5,6-dihydro-2(1*H*)pyridinone and pyrrolidinyl groups as amine residues, with *N*-isobutyl and piperidinyl being the most commonly found. The presence of carboxylic acid fragment is also characteristic of the alkamides isolated from plants that belong to the Piperaceae family. These fragments include the 3',4'-methylenedioxyphenyl as the most common terminal group. However, *p*-methoxyphenyl, 3',4',5'-trimethoxyphenyl and 4'-hydroxy-3' methoxyphenyl groups can also be joined to a chain of 2, 4, 5, 6, 8, 9, 10, 11, 12 or 14 carbons, with one, two or three unsaturations at the even-numbered carbons (with the exception of

Fig. 4. The most common alkyl and amide residues of alkamides from the Piperaceae family.

Dimeric alkamides have been found in *P. chaba* and *P. nigrum*. *P. chaba* dimers are [4+2] adducts obtained from the combination of piperlonguminine and piperine [chabamide H (**208**) and I (**209**)], two molecules of pellitorine [chabamide J (**210**), and K (**211**)], two molecules of piperine [chabamide (**212**)], or two molecules of piperamine [chabamide F (**213**) and G (**214**)] (fig. 5). Notably, these dimeric alkamides exhibited potent cytotoxic activity

In contrast, *P. nigrum* dimers constituting [2+2] adducts are the combination of either two molecules of piperine [pipercyclobutanamide A (**215**) and nigramide R (**216**)] or from the piperine analogue piperrolein A [pipercyclobutanamide C (**217**)] (Rao et al, 2011; Subehan et

The compounds produced by the Piperaceae family are pharmacologically very important, as several species of these plants are being used in folkloric medicine in different parts of the world. For example, the roots of plants from the *Ottonia* genus have a piquant taste and cause intense salivation when are in contact with the mouth. These roots exhibit local anesthetic and hallucinogenic effects and are used in the treatment of toothaches and sore throats. The toothache-relieving reputation of plants that belong to this genus led to the isolation of piperovatine (**222**), a buccal local anesthesic isobutyl amide isolated from *O.* 

N H

piperidinyl (piperidide)

<sup>N</sup> <sup>N</sup>

N H OAc

O

5,6-dihydro-2(1H)pyridinone

*N*-isobutyl *N*-*3*-acetoxy-isobutyl

Amine group

N

pyrrolidinyl

**3.4 The Piperaceae family. Piperine and its analogs** 

unsaturated chain

R1=R2=OCH2O 3',4'-methylenedioxyphenyl (MDP) R1=R3=H; R2=OCH3 *p*-methoxyphenyl (*p*-MP) R1=R2=R3=OCH3 3',4',5'-trimethoxyphenyl (TMP) R1=OCH3; R2=OH; R3=H 4´-hydroxy-3´-methoxyphenyl (HMP)

against the COLO-205 cell line (Rao et al., 2011).

Alkyl group

C12, fig. 4).

R3

al., 2006) (fig. 6).

R2

R1

*corcovadensis*. Alkamides isolated from the *Ottonia* genus contain 1-oxo-5-(3',4' methylenedioxyphenyl)-2*E*,4*E*-pentadien-1-yl and 1-oxo-6-(*p*-methoxyphenyl)-2*E*,4*E*hexadien-1-yl residues as acidic fragments with *N*-isobutyl or *N*-3-acetoxy-isobutyl fragments as the amide residues (Antunes et al., 2001; Costa & Mors, 1981, table 6).

Fig. 5. Dimeric [4+2] alkamides from *Piper chaba.* 

Fig. 6. Dimeric [2+2] alkamides from *Piper nigrum.*

The *Piper* species have been used in traditional medicine for thousands of years in China, India and Mexico, among other countries, for the treatment of several diseases and ailments. For example, *P. longum* is used for treatment of gonorrhea, menstrual and chronic intestinal pain, tuberculosis, sleeping problems, respiratory infections such as coughs, bronchitis and asthma, malarial fever, diarrhea, jaundice and arthritis. The beneficial effects of this species include analgesic and diuretic activities, relaxation of muscle tension, and the alleviation of anxiety.


Table 6. Alkamides from the Piperaceae family. MDP=3',4'-methylenedioxyphenyl; p-MP=*p*methoxyphenyl; TMP= 3',4',5'-trimethoxyphenyl; HMP=4´-hydroxy-3´-methoxyphenyl.


Table 6. Alkamides from the Piperaceae family. MDP=3',4'-methylenedioxyphenyl; p-MP=*p*methoxyphenyl; TMP= 3',4',5'-trimethoxyphenyl; HMP=4´-hydroxy-3´-methoxyphenyl.

Natural Alkamides: Pharmacology, Chemistry and Distribution 133

N H

**Alkamide Name R1 R2 R3 R4 R5 R6** *p*-coumaroyltyramine H OH H H H OH caffeoyltyramine OH OH H H H OH feruloyltyramine OCH3 OH H H H OH dihydro-feruloyltyramine OCH3 OH H H H OH sinapoyltyramine OCH3 OH OCH3 H H OH feruloylmethoxytyramine OCH3 OH H H OCH3 OH terrestriamide OCH3 OH H =O H OH feruloyldopamine OCH3 OH H H OH OH coumaroyldopamine H OH H H OH OH feruloyl-4-*O*-methyldopamine OCH3 OH H H OH OCH3 feruloyl-3-*O*-methyldopamine OCH3 OH H H OCH3 OH *p*-coumaroyl-3-*O*-methyldopamine H OH H H OCH3 OH

R4

R6

R5

ethylcaffeic amide OH OH H H H OH

*<sup>p</sup>*-hydroxycinnamamide H OH H H H OH

R1

R2

**277** *N*-*cis*-feruloyloctopamine OCH3 OH H OH H OH **278** coumaroyloctopamine H OH H OH H OH

**280** 3-methoxyaegeline H H H OH OCH3 OCH3 **281** 3-methoxy-7-acetylaegeline H H H OAc OCH3 OCH3 **282** 3-methoxy-7-cinnamoylaegeline H H H Ocinnamoyl OCH3 OCH3

> N H

**Alk Name** Δ **R1 R2** *N*-[2-(3,4-dihydroxyphenyl)ethyl]-3,4-dihydroxybenzamide --- OH OH alatamide [*N*-(*E*)-(*p*-methoxystyryl)-benzamide] 2*E* OCH3 H dihydroalatamide [*N*-benzoyltyramine methyl ether] **---** OCH3 H

Despite the broad distribution of alkamides with both fragments, including aromatic residues among a wide variety of plant families, the presence of feruloyltyramine (**266**) is exceptionally important because it is a common compound found in the majority of alkamide-producing plants. The *Z*- and *E*-stereoisomers of feruloyltyramine have been isolated and are two of the most frequently characterized alkamides. The second most important alkamide is *p*-coumaroyltyramine (**264**), which is isolated also in both

O

O

R3

R2

**<sup>276</sup>**2-(4'-hydroxyphenyl)

**<sup>279</sup>**β-(*p*-hydroxy-phenylethyl)

Table 7. Cinnamoylphenethylamides isolated from diverse plants.

HO

Table 8. Benzylphenethylamides isolated from diverse plants.

stereoisomeric forms, the *E*-stereoisomer being the most common (table 9).

HO

R1

In contrast, *P. hispidum* and *P. tuberculatum* exhibit antifungal activity and produce amides with the *cis* geometry in their side chains, a structural feature quite rare in nature (table 6, Navickiene et al., 2000).

Pipernonaline (**238**) is an alkamide possessing mosquito larvicidal activity that has been isolated from *P. longum* (Huang et al., 2010), whereas some piperamides, such as (*Z*) piplartine (**244**), (*E*)-piplartine (**231**), 8,9-dihydropiplartine (**245**) and pellitorine (**228**), isolated from P. *tuberculatum* seeds have been shown to inhibit the proliferation of *Trypanosoma cruzi* parasites. These alkamides are considered to be templates for the design of novel and potent hit compounds for the treatment of Chagas' disease (Cotinguiba et al., 2009).

Piperine (*E,E* isomer of 1-piperolypiperidine, **224**) is the major component in the fruits of several species of *Piper*, particularly *P. longum* and *P. nigrum*. This compound showed diverse biological activities such as antioxidant, anti-inflammatory, analgesic, antiplatelet aggregation, antihyperlipidemic, antihypertensive, cytoprotective, antitumor, antimicrobial, hepatoprotective and antidepressant activities. The structure of piperine resembles that of Capsaicin (158, table 3), the pungent component in the majority of the chilli peppers species. Similar to capsaicin, piperine also serves as a natural agonist of the vanilloid receptor (TRPV1 channel), which is involved in the neurotransmission of thermal and nociceptive stimuli.

Piplartine (5,6-dihydro-1-[(2*E*)-1-oxo3-(3',4',5'-trimethoxyphenyl)-2-propen-1-yl]-2(1*H*) pyridinone, **244**, table 6) is another important alkamide isolated from the *Piper* species. This compound exhibits antifungal properties and has demonstrated antiplatelet aggregation, anxiolytic, antidepressant and antitumor activities in murine models. This naturally occurring alkamide is also a cytotoxic agent against cultured tumor cells, exhibiting promising anticancer properties. However, piplartine also shows mutagenic activity in yeast and cultured mammalian cells, inducing *in vitro* and *in vivo* chromosomal damage, potentially due to DNA breaks (Bezerra et al., 2009). The alkamides isolated from plants that belong to the Piper family are shown in table 6.

#### **4. Other family plants - Alkamides with both fragments including aromatic residues**

The cinnamoylbenzylamide tribulusimide (**263**, fig. 7) and several cinnamoylphenethylamides (table 7) and benzylphenethylamides (table 8) are the condensation products of cinnamic acid and benzylamine derivatives, cinnamic acid and phenethylamine and benzylic acid and phenethylamine, respectively. These alkamides have been isolated from a broad variety of plants that belong to at least 28 families. A selection of these alkamides are shown in table 9.

Fig. 7. Cinnamoylbenzylamide.

In contrast, *P. hispidum* and *P. tuberculatum* exhibit antifungal activity and produce amides with the *cis* geometry in their side chains, a structural feature quite rare in nature (table 6,

Pipernonaline (**238**) is an alkamide possessing mosquito larvicidal activity that has been isolated from *P. longum* (Huang et al., 2010), whereas some piperamides, such as (*Z*) piplartine (**244**), (*E*)-piplartine (**231**), 8,9-dihydropiplartine (**245**) and pellitorine (**228**), isolated from P. *tuberculatum* seeds have been shown to inhibit the proliferation of *Trypanosoma cruzi* parasites. These alkamides are considered to be templates for the design of novel and potent hit compounds for the treatment of Chagas' disease (Cotinguiba et al.,

Piperine (*E,E* isomer of 1-piperolypiperidine, **224**) is the major component in the fruits of several species of *Piper*, particularly *P. longum* and *P. nigrum*. This compound showed diverse biological activities such as antioxidant, anti-inflammatory, analgesic, antiplatelet aggregation, antihyperlipidemic, antihypertensive, cytoprotective, antitumor, antimicrobial, hepatoprotective and antidepressant activities. The structure of piperine resembles that of Capsaicin (158, table 3), the pungent component in the majority of the chilli peppers species. Similar to capsaicin, piperine also serves as a natural agonist of the vanilloid receptor (TRPV1 channel), which is involved in the neurotransmission of thermal and nociceptive stimuli.

Piplartine (5,6-dihydro-1-[(2*E*)-1-oxo3-(3',4',5'-trimethoxyphenyl)-2-propen-1-yl]-2(1*H*) pyridinone, **244**, table 6) is another important alkamide isolated from the *Piper* species. This compound exhibits antifungal properties and has demonstrated antiplatelet aggregation, anxiolytic, antidepressant and antitumor activities in murine models. This naturally occurring alkamide is also a cytotoxic agent against cultured tumor cells, exhibiting promising anticancer properties. However, piplartine also shows mutagenic activity in yeast and cultured mammalian cells, inducing *in vitro* and *in vivo* chromosomal damage, potentially due to DNA breaks (Bezerra et al., 2009). The alkamides isolated from plants that

**4. Other family plants - Alkamides with both fragments including aromatic** 

The cinnamoylbenzylamide tribulusimide (**263**, fig. 7) and several cinnamoylphenethylamides (table 7) and benzylphenethylamides (table 8) are the condensation products of cinnamic acid and benzylamine derivatives, cinnamic acid and phenethylamine and benzylic acid and phenethylamine, respectively. These alkamides have been isolated from a broad variety of plants that belong to at least 28 families. A selection of these alkamides are shown in table 9.

> N H

O

OH

O

tribulusimide (**263**)

Navickiene et al., 2000).

belong to the Piper family are shown in table 6.

HO

Fig. 7. Cinnamoylbenzylamide.

2009).

**residues** 


Table 7. Cinnamoylphenethylamides isolated from diverse plants.


Table 8. Benzylphenethylamides isolated from diverse plants.

Despite the broad distribution of alkamides with both fragments, including aromatic residues among a wide variety of plant families, the presence of feruloyltyramine (**266**) is exceptionally important because it is a common compound found in the majority of alkamide-producing plants. The *Z*- and *E*-stereoisomers of feruloyltyramine have been isolated and are two of the most frequently characterized alkamides. The second most important alkamide is *p*-coumaroyltyramine (**264**), which is isolated also in both stereoisomeric forms, the *E*-stereoisomer being the most common (table 9).

Natural Alkamides: Pharmacology, Chemistry and Distribution 135

These alkamides have been associated with diverse biological activities, such as the potentiation of antibiotics, inhibition of prostaglandin biosynthesis, antioxidant activity and more. Furthermore, cinnamoylphenethylamines have been suggested to have an impact on

Some dimeric alkamides have been isolated from *Cannabis sativa* (Cannabinaceae,

cannabisin A (**288**) Grossamine (**289**)

Alkamides are natural products distributed among several medicinal plants that are a part of at least 33 families. These plants are used for a variety of medicinal purposes in many places throughout the world. Chemical and pharmacological research of these plants have established that alkamides contribute to the notable bioactivity of these plants. Asteraceae, Solanaceae, Rutaceae and Piperaceae are plant families that specialize in the biosynthesis of these natural products. Importantly, alkamides are chemical markers for plants in each

Alkamides with both acid and amine aliphatic residues are characteristic compounds produced by the Asteraceae family, especially from the *Achillea*, *Acmella*, *Spilanthes*, *Echinaceae* and *Heliopsis* genera. Alkamides with one aromatic residue can be classified in the following two groups: (1) alkamides with an aromatic residue at the amine core and (2) alkamides with an aromatic residue at the acid. The first group has been isolated from the Solanaceae family, specifically from the *Capsicum* genus for which those alkamides are named "capsaicinoids". Other alkamides that belong to this group have been isolated from the *Lepidium* (Brassicaceae) and *Glycosmis* (Rutaceae) genera. *Glycosmis* alkamides are rare and have characteristic sulfur-containing structures. The second group corresponds to piperine and its analogs. These compounds are characteristic of the *Piper* genus (Piperaceae). Furthermore, the alkamides with both acid and amine aromatic residues are widely distributed among at least 28 plant families. Feruloyltyramine and *p*-coumaroyltyramine are

the most commonly isolated alkamides that belong to this group of compounds.

Pure alkamides and plants that produce alkamides have a pungent and/or irritating taste as well as analgesic and anesthetic effects. Many alkamides are used to treat dental, muscular

O

OCH3 <sup>N</sup>

O

H N

H

<sup>O</sup> HO

HO

OCH3

OH

human health if present in the diet (Pedersen et al., 2010).

OH

OH

Sakakibara et al., 1991) (fig. 8).

HO

HO

H N

N H

O

O

OH

Fig. 8. Dimeric alkamides from *Cannabis sativa.*

OH

**5. Conclusion** 

family and genus.


Table 9. Distribution of alkamides including both acid and amide residues.

These alkamides have been associated with diverse biological activities, such as the potentiation of antibiotics, inhibition of prostaglandin biosynthesis, antioxidant activity and more. Furthermore, cinnamoylphenethylamines have been suggested to have an impact on human health if present in the diet (Pedersen et al., 2010).

Some dimeric alkamides have been isolated from *Cannabis sativa* (Cannabinaceae, Sakakibara et al., 1991) (fig. 8).

Fig. 8. Dimeric alkamides from *Cannabis sativa.*

## **5. Conclusion**

134 Drug Discovery Research in Pharmacognosy

**Family Species Alkamide Reference**  Alliaceae *Allium fistulosum* **264** (Nishioka et al., 1997) Amaranthaceae *Amaranthus hypochondriacus* **264, 265, 266, 268, 271, 273** (Pedersen et al., 2010) *mantegazzianus* **264, 265, 266, 268, 271, 273**

Anacardiaceae *Mangifera indica* **<sup>276</sup>**(Ghosal & Chakrabarti,

*gigantea trans-***264,** *trans***-266,** *cis-*

Cannabidaceae *Cannabis sativa* **264,** *trans***-265,** *trans***-266** (Sakakibara et al, 1991) Chenopodiaceae *Chenopodium album trans***-273,** *cis-***275** (Horio et al., 1993) Concolvulaceae *Ipomoea aquatica cis***-266,** *trans***-266** (Tseng et al., 1992)

Flacourtiaceae *Casearia membranacea cis***-266,** *trans***-266** (Chang et al., 2003) Fumariaceae *Dactylicapnos torulosa trans***-266** (Rucker et al., 1994)

Lauraceae *Actinodaphne longifolia trans***-266,** *trans***-273** (Tanaka et al., 1989) Leguminosae *Mucuna birdwoodiana trans***-266** (Goda et al., 1987) Magnoliaceae *Michelia alba cis***-266,** *trans***-266** (Chen et al., 2008) Malvaceae *Hibiscus taiwanensis cis***-266,** *trans***-266** (Wu et al., 2005) Menispermaceae *Sinomenium acutum* **266** (Otsuka et al., 1993) Nyctagenaceae *Mirabilis jalapa trans***-273** (Michalet et al., 2007) Papaveraceae *Hypecoum imberbe trans***-266** (Hussain et al., 1982) *parviflorum trans***-266** 

Plumbaginaceae *Ceratostigma willmottianum trans-***265,** *trans***-266** (Yue et al., 1997) Polygonaceae *Eskemukerjea megacarpum trans***-266** (Miyaichi et al., 2006) Portulacaceae *Portulaca oleracea trans***-266** (Mizutani et al., 1998)

Zygophyllaceae *Tribulus terrestris* **24,** *trans-***265, 271, 263** (Lv et al., 2008)

Annonaceae *Annona cherimola* **264,** *cis***-265,** *cis***-266, 267,** 

*gehrtii* 

Euphobiaceae *Antidesma membranaceum trans***-266,** *cis***-277,** 

Piperaceae *Peperomia duclouxii* **268,** *trans***-274,** 

*khasianum* 

Table 9. Distribution of alkamides including both acid and amide residues.

Aristolochiaceae *Aristolochia*

Hernandiaceae *Sparattanthelium* 

Rutaceae

Solanaceae *Solanum* 

*Achyranthes ferruginea trans***-273** (Alam et al, 2003)

*cis***-264,** *trans-***264,** *cis***-266,**  *trans***-266,** *cis-***275,**  *trans-***275** 

**275, 276,** *cis***-277** 

*tupiniquinorum trans-***264,** *trans***-266** (Pereira et al., 2007)

*Evodia belahe* **279** (Pedersen et al. , 2010) *Pleiospermium alatum* **284, 285** (Chatterjee et al., 1975) *Zanthoxylum syncarpum* **280, 281, 282** (Ross et al., 2005)

> *cis***-264,** *trans-***264,** *cis***-266,**  *trans***-266,** *cis***-277,** *trans***-277,** *cis***-278,** *trans***-278**

*citrullifolium trans***-266** (Turnock et al., 2001) *Cestrum lanatum trans***-266** 

*lycopersicum* **264, 266, 272, 273** (Zacares et al., 2007)

1988)

(Navickiene & Lopes, 2001)

(Holzbach & Lopes, 2010)

(Muhlenbeck et al., 1996)

*cis***-269,** *trans***-269** (Chen et al., 1998)

*trans***-277** (Buske et al., 1997)

*trans***-271, 283** (Li et al., 2007)

Alkamides are natural products distributed among several medicinal plants that are a part of at least 33 families. These plants are used for a variety of medicinal purposes in many places throughout the world. Chemical and pharmacological research of these plants have established that alkamides contribute to the notable bioactivity of these plants. Asteraceae, Solanaceae, Rutaceae and Piperaceae are plant families that specialize in the biosynthesis of these natural products. Importantly, alkamides are chemical markers for plants in each family and genus.

Alkamides with both acid and amine aliphatic residues are characteristic compounds produced by the Asteraceae family, especially from the *Achillea*, *Acmella*, *Spilanthes*, *Echinaceae* and *Heliopsis* genera. Alkamides with one aromatic residue can be classified in the following two groups: (1) alkamides with an aromatic residue at the amine core and (2) alkamides with an aromatic residue at the acid. The first group has been isolated from the Solanaceae family, specifically from the *Capsicum* genus for which those alkamides are named "capsaicinoids". Other alkamides that belong to this group have been isolated from the *Lepidium* (Brassicaceae) and *Glycosmis* (Rutaceae) genera. *Glycosmis* alkamides are rare and have characteristic sulfur-containing structures. The second group corresponds to piperine and its analogs. These compounds are characteristic of the *Piper* genus (Piperaceae). Furthermore, the alkamides with both acid and amine aromatic residues are widely distributed among at least 28 plant families. Feruloyltyramine and *p*-coumaroyltyramine are the most commonly isolated alkamides that belong to this group of compounds.

Pure alkamides and plants that produce alkamides have a pungent and/or irritating taste as well as analgesic and anesthetic effects. Many alkamides are used to treat dental, muscular

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#### **6. Acknowledgments**

To CONACyT (Grant number 79584-Q). I am grateful to Enrique Salazar Leyva for technical assistance. I apologize to all colleagues whose studies were not cited due to space limitations.

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**7** 

*Canada* 

*University of Saskatchewan* 

**A Comparison Between Lignans from** 

**Creosote Bush and Flaxseed and Their Potential** 

The popularity in natural product use we witness today arose from a growing public skepticism about taking "pharmaceutical chemicals" to treat illness. Such skepticism was supplanted by a public perception that "medications" from natural sources are safer to use and have similar efficacies as their pharmaceutical equivalents. The diverse assortment of natural products on the shelves of pharmacies, health food stores, and grocery stores attest to this enhanced public demand, but has compelled regulatory agencies to question the adequacy of the safety and efficacy data associated with the use of these products (Natural Health Products Directorate 2007). In the current regulatory environment, full realization of the wellness and therapeutic value of these natural products can only come about with more

This is particularly true of natural products that contain lignans as the principal bioactive component. Interest in lignans continues to grow due to an increased awareness of their putative health benefits. One such product, Chaparral, contains lignans extracted from creosote bush. Creosote bush had centuries of traditional use by aboriginal peoples of the Southwestern United States as an effective natural medicine and was marketed as an extract of the plant in capsule form based on this historical medicinal value (Clark & Reed 1992). While traditional creosote bush use appears to be quite safe, chronic use of Chaparral led to reports of toxicity (Clark & Reed 1992; Gordon et al., 1995; Batchelor et al., 1995; Grant et al., 1998). Nordihydroguaiaretic acid (NDGA) is the major lignan in creosote bush, which is believed to be responsible for both the efficacious and toxic properties of Chaparral (Grice et al., 1968; Moore 1989; Arteaga et al., 2005; Lambert et al., 2004). Wagner and Lewis 1980 previously reported that NDGA undergoes oxidation to "activated NDGA" (Wagner & Lewis 1980). Billinsky et al. 2008 suggest this "activated NDGA" is the result of an autoxidation process to a stable dibenzocyclooctadiene product of NDGA (Billinsky & Krol 2008). Whether this dibenzocyclooctadiene is present in traditional creosote bush products

The recent popularity of lignans from flaxseed, which are currently marketed as concentrated extracts of the principal plant lignan, secoisolariciresinol diglucoside (SDG), in

**1. Introduction** 

rigorous assessments of their safety and efficacy.

or is formed *in vivo* is not known.

**to Inhibit Cytochrome P450 Enzyme Activity** 

Jennifer Billinsky, Katherine Maloney, Ed Krol and Jane Alcorn *Drug Design and Discovery Research Group, College of Pharmacy and Nutrition,* 

*Systematics and Ecology*, Vol.29, No.2, (February 2001), pp. 209–211, doi:10.1016/S0305-1978(00)00030-2

