Natural Bioactive Cinnamoyltyramine Alkylamides and Co-Metabolites

Natural products are a vital source for agriculture, medicine, cosmetic and other fields. Among them alkylamides are a broad and expanding group found in at least 33 plant families. Frequently, they possess a simple carbon skeleton architecture but show broad structural variability and important properties such as immunomodulatory, antimicrobial, antiviral, larvicidal, insecticidal and antioxidant properties, amongst others. Despite to these several and promising biological activities, up to today, only two reviews have been published on natural alkylamides. One focuses on their potential pharmacology application and their distribution in the plant kingdom and the other one on the bioactive alkylamides specifically found in Annona spp. The present review is focused on the plant bioactive cinnamoyltyramine alkylamides, which are subject of several works reported in the literature. Furthermore, the co-metabolites isolated from the same natural sources and their biological activities are also reported.


Introduction
Alkylamides are a broad and expanding group of bioactive natural compounds grouped at least in 33 plant families as Aristolochiaceae, Asteraceae, Brassicaceae, Convolvulaceae, Euphorbiaceae, Menispermaceae, Piperaceae, Poaceae, Rutaceae and Solanaceae [1]. Many of these species were used in folk medicine for the broad spectra of biological activities as immunomodulatory, antimicrobial, antiviral, larvicidal, insecticidal, diuretic, analgesic, cannabimimetic and antioxidant activities. They are also involved in the antibiotic's potentiation, the prostaglandin biosynthesis inhibition, RNA synthesis and the arachidonic acid metabolism. Alkylamides possess a broad range of pharmacological effects [2] and thus their potential application in the pharmaceutical, cosmetic and food industries could be planned. Alkylamides are found in different organs of the plants such as roots, leaves, stems, fruits, flowers, seeds and tubers. Alkylamides were also formulated as plant growth regulators, which affect the growth, roots development and inducing of plant biomass production [3]. Natural alkylamides are constituted by an aliphatic, cyclic or aromatic amine residue (R1), and a C8 to C18 saturated or unsaturated chain acid, which can also be aromatic (R2). The structural formula representing all the alkylamides is reported in Figure 1. The nature of the acid and the amine residues are characteristic of each plant family and species. They are also classified as protoalkaloid or pseudoalkaloid compounds and The nature of the acid and the amine residues are characteristic of each plant family and species. They are also classified as protoalkaloid or pseudoalkaloid compounds and represent a group of lipidic compounds structurally related to animal endocannabinoids and are strongly active metabolites in the central nervous system. Some previous reviews reported the chemistry and the biological activity of alkylamides, and although they cover a broad range of literature, they are organized differently. One was organized accordingly to the family of the plant source [4], and another one reported the chemistry and the detailed description of their biological activities [5].
The present review is focused on the cinnamoyltyramine subgroup of the alkylamides, reporting their biosynthesis, chemical structures, biological activities, hemisynthetic derivatives and structure activity studies. Furthermore, the co-metabolites isolated from the same natural sources and their biological activity are also described.

Biosynthesis of N-trans-Cinnamoyltyramine
The biosynthesis of N-trans-cinnamoyltyramine (1) in plants could occur in several steps. The biosynthetic pathway starts from trans-cinnamic acid and tyramine, which were, respectively, generated from phenylalanine (L-Phe), as were the other cinnamic acids (i.e., p-coumaric, caffeic, ferulic, 5-hydroxyferulic and sinapic acids) and tyrosine (Tyr), as reported in Scheme 1. Both aromatic amino acids (Phe and Tyr) were synthesized from prefenic acid, which was, in turn, generate from shikimic acid according to the shikimate pathway [6,7] reported in Scheme 2.
In particular, Phe was converted by phenylalanine ammonia-lyase into cinnamic acid according to [7,8], and tyramine was synthesized by decarboxylation of tyrosine as reported in Scheme 1 [7,9]. As reported in Scheme 3, cinnamic acid was converted by COA ligase into the corresponding activate form [10]. The final step provides the conjugation of cinnamoylCoA and tyramine catalyzed by the tyramine n-hydroxycinnamoyl transferase (THT): this enzyme is not specific to cinnamoylCoA and tyramine, but also catalyzes Scheme 1. Biosynthesis of cynnamic acids and tyramine from phenylalanine and tyrosine, respectively.
Both aromatic amino acids (Phe and Tyr) were synthesized from prefenic acid, which was, in turn, generate from shikimic acid according to the shikimate pathway [6,7] reported in Scheme 2.
In particular, Phe was converted by phenylalanine ammonia-lyase into cinnamic acid according to [7,8], and tyramine was synthesized by decarboxylation of tyrosine as reported in Scheme 1 [7,9]. As reported in Scheme 3, cinnamic acid was converted by COA ligase into the corresponding activate form [10]. The final step provides the conjugation of cinnamoylCoA and tyramine catalyzed by the tyramine n-hydroxycinnamoyl transferase (THT): this enzyme is not specific to cinnamoylCoA and tyramine, but also catalyzes the conjugation of tyramine with the other CoA-activated cinnamic acids cited above [11,12].
activities. Their promising practical applications are also described. Furthermore, chemical and biological aspects of the co-metabolites isolated from the same sources are described.
N-cis-feruloyltyramine (NCFT) and grossamide (2 and 3, Figure 2), two previously undescribed phenolic amides, were isolated from the roots of bell pepper (Capsicum annuum var. grossum, Solanaceae) together with p-aminobenzaldehyde and other alkylamides as N-trans-p-coumaroyltyramine (NTCT, also called prapazine), N-trans-feruloyltyramine (NTFT), N-trans-p-coumaroyloctopamine (NTCO) and N-trans-feruloyloctopamine (NTFO) (4-7, Figure 2) [13,14]. These latter compounds were previously isolated from the roots of eggplant (Solanum melongena L., Solanacee) [15]. The structure of grossamide was confirmed by its synthesis starting from N-trans-feruloyltyramine by an oxidative radical coupling. It is classified into a group of lignin accordingly McCredie et al. (1969) [16], who suggested to include in the lignin group all low molecular weight natural compounds that were generated from the oxidative coupling of p-hydroxyphenylpropene [13]. Very few studies have been reported on oxidative coupling products possessing amide groups. Among them there are hordatines A, B and M (8-10, Figure 2) found as antifungal factors in barley (Hordeum vulgare, Graminacee) [17]. Hordatin M is a mixture of glucosides of hordatins A and B. Hordatins belong to polyammide, whose biosynthesis Very few studies have been reported on oxidative coupling products possessing amide groups. Among them there are hordatines A, B and M (8-10, Figure 2) found as antifungal factors in barley (Hordeum vulgare, Graminacee) [17]. Hordatin M is a mixture of glucosides of hordatins A and B. Hordatins belong to polyammide, whose biosynthesis started from p-hydrocynnamic acid CoA and agamatine obtained from decarboxylation of arginine. Then agmatinecoumaroyl transerase (ACT) catalyzes agamatine conjugates from coumaroylor feruloyl-CoA to give the corresponding p-hydrocinnamoylagamantine amide. The latter generate the dimeric hordatines by peroxidase oxidation [18]. Hordatines showed significant antifungal activities [19,20] and are biosynthesized as pro-defense compounds in barley seedlings or are accumulated in plants after a pathogen attack [21,22].
NTCT and N-cis-p-cumaroyltyramine (NCCT, 11, Figure 2), lunularic acid (12, Figure 2) and p-coumaric acid were isolated from bulbs of Allium chinense (Amaryllidaceae), which is used in Chinese folk medicine [23]. They are well known as inhibitors of prostaglandin (PG) and thromboxane synthetases. Rhapontigenin, piceatannol, rhaponticin and piceatannol glucoside (13-16, Figure 2) are stilbene derivatives structurally related to lunularic acid and obatined from rhubarb (Rheum rhabarbarum, Polygonaceae) [24]. They were tested among other analogues to evaluate their effect on prostaglandin synthetase, using platelet-rich plasma (PRP) obtained from blood collected from the main leg artery of a male albino rabbit. Rhapontigenin showed the most potent inhibition on PG-ase and strongly inhibited platelet aggregation induced by arachidonic acid and collagen. Platelet aggregation was demonstrated in in vivo studies. The balance between thromboxane (TX) A 2 and prostaglandin (PG) I 2 (prostacyclin) plays a very important role in the regulation of blood flow. In fact, an excessive platelet aggregation is responsible to co-cause thrombosis and arteriosclerosis. Consequently, the inhibitory effect against PG or TX biosynthesis showed by the stilbene metabolites isolated from A. chinese could have an important therapeutic potential [23].
NTFT was successively isolated together with new alkaloids, papracinine and paprazine, and six already known ones, fumaritine N-oxide, parfumine, lastourvilline, fumariflorine and N-methyl corydaldine from the aerial parts of Fumaria indica (Papaveraceae), which is diffused in Europe, Central Asia and Africa. However, no activity was reported [25]. In the same year, but from the bark ethanolic extract of Asimina triloba L. (Annonaceae), NTCT and NTFT were isolated by a bio-guided fractionation testing brine shrimp lethality, together with a previously undescribed cytotoxic compound named acetogenin, and some known compounds such as asimicin, bullatacin, bullatacinone and (+)-syringaresinol. A. triloba L., an Annonaceae, commonly known as the pawpaw tree, which is native to the United States and spread in Europe, has been prized for its delicious, custard-like fruit. Trilobacin is a diastereomer of asimicin and both compounds showed potent and selective cytotoxicities in the NCI human tumor cell line screen [26].
NTCT was isolated from the stem bark extracts of Isolona maitlandii (Annonaceae), together with hexalobine-type, aporphinoids, amides and sterols. The leaf extract contained only hexalobines including ent-hexalobine C and five previously undescribed hexalobines. Any biological activity was reported [27].
NTCT and NCCT were isolated also from Aristolochia mollissima belong to Aristolochiaceae. Aristolochia is a genus constituted by ca. 400 species that are widely distributed from the tropics to temperate regions. The roots and fruits of A. mollissima are used in Chinese folk medicine as analgesic, anticancer, antimalarial and anti-inflammatory agents, and also for the treatment of stomachache, abdominal pain and rheumatism. New sesquiterpenes, named mandolins S, R, U (17-19, Figure 2), W and X (20 and 21, Figure 3), together with 38 already known compounds belonging to different groups of natural compounds, were isolated from this plant [28].
NCFT, NTCT and NTFT were again isolated together with NCCT (11) and the already known lariciresinol, 13-hydroxycapsidiol, lubiminol and drummondol from red pepper (Capsicum annuum) (Solanaceae). However, the main metabolite isolated from C. annnum was capsaicin, a compound known to be responsible of pungent activity, and the plant was studied for its components, dietary effects and analgesic antioxidant activity [29,30]. Furthermore, 10 previously undescribed co-metabolites (eight bicyclic and two spiranic sesquiterpenes) were isolated from the same plant and named canusesnol A-J (22-31, Figure 3). The sesquiterpenes and the known compounds showed scant cytotoxic and anti-HIV activity [31].
NTFT and NTCT were isolated together with an azanthracene alkaloid, characterized as 1-aza-9,10-dimethoxy-4-methyl-2-oxo-1,2-dihydroanthracene and named kalasinamide, from the stems of Polyalthia suberosa (Annonaceae), which is a shrubby tree spread between southeast Asia and south China [32]. From the organic extract of its stems and leaves collected in China, a triterpene was previously isolated, named suberosol, with anti- HIV activity [33]. Successively, from the same plant together with NTFT and NTCT, two undescribed 2-substituted furans, 1-(2-furyl)pentacosa-16,18-diyne and 23-(2-furyl)tricosa-5,7-diynoic acid [34], were also isolated. As NTCT was isolated in limited amount not sufficient to investigate its biological activity, its synthesis was realized in one step starting from coumaric acid and tyramine with a final yield about of 55%. It showed suppression of growth of human tumor cells, such as U937 and Jurkat cells, which appeared associated with an increased percentage of cells in the S phase of the cell cycle progression. Furthermore, NTCT was able to inhibit the protein tyrosine kinases including epidermal growth factor receptor (EGFR) [35].
Biomolecules 2021, 11, x FOR PEER REVIEW 6 of 42 (22-31, Figure 3). The sesquiterpenes and the known compounds showed scant cytotoxic and anti-HIV activity [31]. NTFT and NTCT were isolated together with an azanthracene alkaloid, characterized as 1-aza-9,10-dimethoxy-4-methyl-2-oxo-1,2-dihydroanthracene and named kalasinamide, from the stems of Polyalthia suberosa (Annonaceae), which is a shrubby tree spread between southeast Asia and south China [32]. From the organic extract of its stems and leaves collected in China, a triterpene was previously isolated, named suberosol, with anti-HIV activity [33]. Successively, from the same plant together with NTFT and NTCT, two undescribed 2-substituted furans, 1-(2-furyl)pentacosa-16,18-diyne and 23-(2-furyl)tricosa-5,7-diynoic acid [34], were also isolated. As NTCT was isolated in limited amount not sufficient to investigate its biological activity, its synthesis was realized in one step starting from coumaric acid and tyramine with a final yield about of 55%. It showed suppression of growth of human tumor cells, such as U937 and Jurkat cells, which appeared associated with an increased percentage of cells in the S phase of the cell cycle progression. Furthermore, NTCT was able to inhibit the protein tyrosine kinases including epidermal growth factor receptor (EGFR) [35]. NTCT was isolated from twigs of Celtis chinensis, which was used in folk medicine in Korea, Japan and China to treat lumbago, irregular menstruation and gastric diseases [36]. Furthermore, NTCT inhibited acetylcholinesterase (ACHE), a well-known enzyme that plays an important role in Alzheimers disease [37].
The same four alkymides, NCFT, NTCT, NTFT and NCCT, were again isolated together with other already known compounds, belonging to different classes of naturally occurring compounds, from the root and stem of Aristolochia elegans [38]. A. elegans belong to the genus Aristolochia (Aristolochiaceae), and the alcoholic extracts of some species were investigated for their uterus contraction stimulating [39], antimitotic and antiviral properties [40]. A. elegans also produced previously undescribed compounds characterized as two aristolactams, aristolactam E and aristolactam-AIIIa-6-O-β-D-glucoside (32 and 33, Figure 3), three benzoyl benzyltetrahydroisoquinoline ether N-oxide alkaloids, aristoquinolines A-C (34-36, Figure 3), as well as a biphenyl ether, aristogin F (37, Figure 3). All the metabolites were tested to evaluate their potential antioxidative and antityrosinase properties, but neither the four alkylamines or the new metabolites showed activity [38].
NTCT, NCCT and NTFT were isolated together with six previously undescribed lignans (53-58, Figure 5), and 11 other types of known compounds from Peperomia duclouxii (Piperaceae), which is a plant used in folk medicine as an anticancer agent in mainland China. When these compounds were tested in cytotoxic and MDR (multidrug resistance) reversal cell activity assays, only compound 55 inhibited the growth of VA-13 and HepG2 cancer cells, with IC 50 values of 5.3 and 13.2 µg/mL, respetively. Compound 55 also showed potent effects on calcein accumulation in MDR 2780AD cells than verapamil, which was used as a positive control. Compound 58 exhibited anti-inflammatory activity using an ICAM-1 assay (induction of the intercellular adhesion molecule-1) and stimulated IL-1α (Interleukin 1 alpha) and TNF-α (tumor necrosis factor alpha) with IC 50 values of 107 and 13.4 µM, respectively, and without cytotoxicity against A549 cells [44].
Biomolecules 2021, 11, x FOR PEER REVIEW 9 of 42 palmatrubin and jatrorrhizine. All the compounds were assayed for antileishmanial activity against Leishmania donovani testing the effects of promastigotes and intracellular amastigotes, and only compound 63 exhibited the highest in vitro antileishmanial activity, whereas compounds 62, palmatine and palmatrubin showed moderate activity. The other compounds were found to be inactive [54]. Piper sarmentosum and Piper nigrum (Piperaceae) are well known for their therapeutic effects and content of alkaloid and amides [55]. P. nigrum has showed CNS (central nervous system) stimulant, analgesic, antipyretic and antifeedant activities [56], while the P. sarmentosum leaves were used to treat malaria, coughs and colds, as well as toothache, and NTCT was isolated together with cannabisin G and (±)-lyoniresinol from the organic extract of the root bark of Berberis vulgaris L. (Berberidaceae). Different parts of this species were used for the treatment of diarrhea, gallbladder and liver dysfunctions, leishmaniasis, malaria, stomach problems and urinary tract diseases [45]. Cannabisin G and (±)-lyoniresinol, using a hydroxyl radical scavenging assay, exhibited antioxidant activity, while cannabisin G showed cytoprotective activity in cultured MCF-7 cells [46].
Biomolecules 2021, 11, x FOR PEER REVIEW 11 of 42  NTCT and NCCT, 1,7-bis(4-hydroxyphenyl)heptane-3,5-diol and 6-hydroxy-2,4,7trimethoxyphenanthrene were isolated from the fresh tuberous rhizomes of Chinese yam (Dioscorea opposita Thunb.) (Dioscoreaceae) [64]. This plant has a noteworthy interest in agriculture, food and pharmaceutical fields [65,66]. NTCT, NTCT and the hepatanediol derivative were isolated for the first time from D. opposita. The inhibitory activities of crude extracts as well as those of purified constituents were evaluated against yeast αglucosidase to search for the active principles for treatment of diabetes. NTCT, the heptanediol and the phenanthrene derivative showed a significant activity with IC50 = 0.40, NTCT and NCCT, 1,7-bis(4-hydroxyphenyl)heptane-3,5-diol and 6-hydroxy-2,4,7trimethoxyphenanthrene were isolated from the fresh tuberous rhizomes of Chinese yam (Dioscorea opposita Thunb.) (Dioscoreaceae) [64]. This plant has a noteworthy interest in agriculture, food and pharmaceutical fields [65,66]. NTCT, NTCT and the hepatanediol derivative were isolated for the first time from D. opposita. The inhibitory activities of crude extracts as well as those of purified constituents were evaluated against yeast α-glucosidase to search for the active principles for treatment of diabetes. NTCT, the heptanediol and the phenanthrene derivative showed a significant activity with IC 50 = 0.40, 0.38 and 0.77 µM, respectively, while NCCT was inactive suggesting that the stereochemistry of the double bond of this alkylamide is a structural feature important for the activity [64].
NTCT, NCCT and NTFT were isolated together with ferul aldehyde, 6,7-dimethoxycoumarin and ficusal from the organic extract of Solanum melongena L. (Solanaceae) root [76]. The roots of this plant, called "Qie gen" in China, were used in folk Chinese medicine for the treatment of toothache, chilblains and beriberi. Other studies showed that the extracts of S. melongena had anti-inflammatory, analgesic and antiatherosclerosis activities [77,78]. Only the three alkylamides NTCT, NCCT and NTFT inhibited α-glucosidase with IC 50 values of 500.6, 5.3 and 46.3 µM, respectively, and they were not competitive inhibitors. Thus, the plant could be proposed for pharmacological application [76].
NTCT, NTFT and NTCAT were isolated as the main component from the organic extract of Polygonum hyrcanicum (Polygonaceae) aerial parts, which showed high activity against Trypanosoma brucei rhodesiense (IC 50 = 3.7 µg/mL). This protozoan parasite induces sleeping sickness, also known as human African trypanosomiasis (HAT). HAT infects more than 50,000 people each year and about 60 million people are at risk of trypanosomiasis [79]. The three alkylamides, NTCT, NTFT and NTCAT, showed activity with C50s ranging from 2.2 to 13.3 µM [80]. P. hyrcanicum is an endemic plant growing in northern areas of Iran and is known as Gheq-buqun in the Turkmen Sahra region, where its decoction has been used for the treatment of liver problems, anemia, hemorrhoids and kidney stones [81]. From the same organic extract, some other known and lesser active compounds were also isolated as cannabisin B, tyrosol, p-coumaric and ferulic acids, and NCFT and N-trans-3,4-dimethoxycinnamoyldopamine (90, Figure 7). This data again showed that E stereoisomer is more active than the Z one (NCFT). However, it is important to remember that cinnamoylphenethyl amides rapidly isomerize when exposed to UV light and therefore NCFT could be an artifact formed during the isolation procedure [82].
NTFT was isolated together with two bis-alkaloids, flavifloramides A and B (104 and 105, Figure 8), and paprazine from the aerial part of Piper flaviflorum [92]. This plant belongs to the Piper genus, which is well known as a rich source of a variety of alkaloids, having interesting pharmacological activities, such as anti-inflammatory, antino-ciceptive, anticancer and antidepressant properties [92][93][94].
N-trans-Cinnamoyltyramine (1, Scheme 3) and NTCT were isolated together with two sesquiterpenes, named aristoyunnolins I and J (106 and 107, Figure 8), and six other known compounds from the roots of Aristolochia yunnanensis (syn. Aristolochia griffithii) (Aristolochiaceae) [95]. This plant is endemic to Yunnan Province of China, known as "Nan Mu Xiang", and is used in Chinese medicine for the treatment of trichomoniasis, gastrointestinal diseases and rheumatic pain [94]. All the compounds were evaluated against P-388 and A-549 cell lines, and among them costunolide (108, Figure 8) exhibited moderate activity [95].
NTCT, NTFT, NTCAT, dihydro-NTCAT and three neolignanamides and two lignanamides were isolated from the root bark of Lycium chinense Miller, Lycii Radicis Cortex (Solanacee). This plant was used in traditional Chinese medicine to treat different inflammation symptoms and diabetes mellitus [96]. The results of biological assays showed that akylamides, as main components of L. chinese, were responsible for NF-κB inhibition. The SAR study also suggests that the NF-κB inhibitory activity of NTCAT could be due to its Michael acceptor-type structure (α,β-unsaturated carbonyl group) [97].
NTFT, NTCAT and NTCT were isolated from the leaves Miliusa cuneata (Annonaceae) organic extract together with five oxoprotoberberine alkaloids, named miliusacunines A-E (140-144, Figure 10). The twig extract of the same plant allowed researchers to identify five known metabolites as 5-hydroxy-3,7-dimethoxy-3 ,4 -methylenedioxyflavone, pachypodol, 4 -hydroxy-3,5,7,3 -tetramethoxyflavone, (+)-miliusol and (+)-syringaresinol [114]. This plant as well as others belonging to the same genus are distributed from the Indian subcontinent to Indochina, the Malaysia Peninsula and the southeast Asian islands, to New Guinea and northern Australia. Some species are used in traditional medicine as a tonic and aphrodisiac and for gastropathy. All the compounds were assayed for cytotoxic activity against KB and Vero cancer cell lines and for antimalarial activity against the Plasmodium falciparum. Miliusacunine A (138) showed in vitro antimalarial activity against the TM4 strain, with an IC 50 value of 19.3 ±3.4 µM, while miliusacunine B (139) exhibited strong activity against the K1 strain, with an IC 50 value of 10.8 ± 4.1 µM. No compound showed cytotoxic activity [114].
NCFT, NTCAT and NTCT were isolated together with 11 new octahydroxylated C 21 steroids, named with lyciumsterols A-K (152-162, Figure 11), and 13 already known compounds from the root bark of Lycium chinense, a plant used in Chines folk medicine as described above. Lyciumsterols B, C and G (153, 154, and 157) showed protective effects on pancreatic islet cells but were dose dependent, while lyciumsterols G-I and K, (158-160 and 162) exhibited autophagy activation [118].
NTCT, NTFT, five rearranged clerodane diterpenoids, named 4-epi-baenzigeride A, its 4-O-D-glucoside, 4,12-di-epi-baenzigeride A, tinobaenzins A and B (183, 187, 184-1864, Figure 13), along with four known compounds were isolated from Tinospora baenzigeri (Menispermacae) stem organic extract [143]. This plant is widely diffused in Asia, Africa, Australia and the Pacific [143][144][145] and in Thailand its decotion is used in traditional medicine for antipyretic and antimalarial treatment as well as its root extract. The other already known compounds were identified as baenzigeroside B, (+)-lariciresinol, caruilignan D and the aglycone of breyniaionoside D. Only the last two compounds and NTCT showed hepatoprotective activity against N-acetyl-p-aminophenol (APAP)-induced HepG2 cell damage at 10 µM with 17.0%, 19.2% and 39.0% inhibition, respectively [143].   Figure 13), together with 13 known compounds, were isolated from the twig and leaf extracts of Goniothalamus cheliensis (Annonaceae) [150]. This large tree is distributed throughout the world, but it is present essentially in southeast Asia [151] and is used in folk medicine to treat fever, scabies, edema, rheumatism, tympanites and typhoid fever [151,152]. The other already known compounds were identified as 3-methyl-1H-benz  NTCT, NCCT, NTFT, NCFT and some of their derivatives as well as that of NCAT were identified in fruits, leaves and root barks of Lycium barbarum (Solanaceae) by UPLC-Q-Orbitrap-MS/MS [146]. They are widely used in traditional Chinese prescriptions and patent medicines [147][148][149]. The other 131 known compounds were identified using the same method and among them, 98, 28 and 35 constituents were detected in L. barbarum fruits, leaves and root barks, respectively. Dicaffeoylspermidine/sperminidine derivatives were the most detected compounds (74/131) while six saponins and 5,6-dihydrosolasonine were reported for the first time in this plant. The root bark extract possessed the strongest antioxidative and cytotoxic activity [146].

Conclusions
The sources and biological activities of both E-and Z-diastereomers of p-coumaroyl-, caffeoyl-, feruloyl-, 5-hydroxyferuloyl-serotonine-, sinapoyl-and tryptamine-tyramine alkylamides and other related alkylamides described in the text are summarized in Table  1, while those of the co-metabolites isolated from the same sources are reported in Table  2. Among the alkylamides, NTCT is that produced by several plants belonging to different species followed by NTFT and NCFT. Some promising activities were also reported for them suggesting their potential use in different fields. However, further studies are needed to determine their mode of actions as well as suitable formulations should be prepared for their practical applications.  NTFT, NTCAT, NTCT and two previously undescribed phenolic imidates, named fistuloimidates A and B (205 and 206, Figure 15), were isolated together with persicoimidate, N-coumaroyltyrosine, isorhamnetin-3-O-galactopyranoside and 1-O-(4-hydroxybenzoyl)β-D-glucopyranose from the extract of the previously described A. fistulosum [164].  [164].