Compilation of Secondary Metabolites from Bidens pilosa L

Bidens pilosa L. is a cosmopolitan annual herb, known for its traditional use in treating various diseases and thus much studied for the biological activity of its extracts, fractions and isolated compounds. Polyacetylenes and flavonoids, typical metabolite classes in the Bidens genus, predominate in the phytochemistry of B. pilosa. These classes of compounds have great taxonomic significance. In the Asteraceae family, the acetylene moiety is widely distributed in the Heliantheae tribe and some representatives, such as 1-phenylhepta-1,3,5-triyne, are noted for their biological activity and strong long-wave UV radiation absorbance. The flavonoids, specifically aurones and chalcones, have been reported as good sub-tribal level markers. Natural products from several other classes have also been isolated from different parts of B. pilosa. This review summarizes the available information on the 198 natural products isolated to date from B. pilosa.


Introduction
The genus Bidens (Asteraceae: Heliantheae) comprises about 240 species with cosmopolitan distribution [1]. Many of these species have been investigated chemically to contribute to the classification of Asteraceae [2][3][4]. Interesting relationships within the Heliantheae, as well as its relationship with other tribes have been proposed on the basis of various types of compounds found in the tribe, especially acetylenes, sesquiterpene lactones and flavonoids [4,5]. The interest in these classes of compounds also has gone beyond chemotaxonomy. The biological activities, including antiparasitic, antifungal and antioxidant properties, of the predominant components in the tribe Heliantheae have been widely reported, and the investigation of these species for the discovery of new active compounds has expanded [6][7][8][9][10][11][12].
Bidens pilosa L. (Figure 1) stands out among the species of the genus due to the large number of natural products characterized in it and the biological activities reported for its extracts, fractions and compounds. Therefore, in continuation of our research on bioactive molecules from the various species of the different families cited , we offer this compilation of the chemical constituents of B. pilosa.

Bidens pilosa L.
B. pilosa is an annual, erect and ruderal herb originating from South America and now found in almost all tropical and subtropical region countries [44][45][46]. It grows to a height of up to 1.5 m, branching from the base and its yellow flowers have 5-15 mm diameter [44,46]. It is a cosmopolitan herb, considered invasive of annual and perennial crops and widely distributed in disturbed areas and along roadsides in tropical and subtropical climates [46]. Nevertheless, this plant is commonly used in the traditional medicine. In Martinique, the decoction of the whole plant is used for its anti-inflammatory and hypoglycemic effects [47]. Aqueous preparations of the leaves are used by Zulu people for the treatment of dysentery, diarrhea and colic [48]. B. pilosa has been popularly used in China as a herbal tea ingredient or in traditional medicine for treating various disorders, such as diabetes, inflammation, enteritis, bacillary dysentery and pharyngitis [49]. In Brazil, it is widely used as a folk medicine by indigenous people to treat a variety of illnesses including pain, fever, angina, diabetes, edema, infections and inflammation [50,51]. In addition, in the Amazon and regions in the South of Brazil, hydroalcoholic solutions of B. pilosa roots are also regarded as useful in the treatment of malaria [52] and even tumors [53].
There have been a few reviews of B. pilosa [6,51,92,93], however the phytochemical data have not included all classes of metabolites. To date almost 198 compounds have been described from this species. These secondary metabolites are listed in Table 1, where they were grouped based on the classification adopted by a standard reference work, the Dictionary of Natural Products [94].
The order begins with the structurally most simple metabolites, derived from aliphatic natural produts (branched, unbranched, saturated or unsaturated hydrocarbons), and among these, the acetylenes are highlighted. Next the derivatives of simple aromatic hydrocarbons and the phenylpropanoids, in which a C3 substituent is attached to the aromatic unit (C6), form a biosynthetically distinct group of aromatic metabolites. The flavonoids, also considered a large group of metabolites in B. pilosa are subdivided into aurones, chalcones, flavanones, flavones and flavonols. The terpenoids group is divided according to the number of carbons, starting in sesquiterpenes and continuing with diterpenes, sterols, triterpenes and finally tetraterpenes. Finally, porphyrins, nitrogen and sulphur-containing natural products, one disaccharide and miscellaneous compounds are arranged.

Acetylene compounds
The acetylenes are one class of aliphatic hydrocarbons that has a taxonomically interesting distribution pattern in higher plant families; they occur regularly in only five families, namely the Campanulaceae, Asteraceae, Araliaceae, Pittosporaceae and Umbelliferae [95]. Within the Asteraceae family, these compounds are widely distributed in the Heliantheae tribe [2,4]. The genus Bidens is known to produce compounds of this class [5]. They occur in all parts of the plant, often accumulating in roots [96].
The principal representative of the C 13 -polyacetylenes is 1-phenylhepta-1,3,5-triyne (64). This C 13phenylacetylene is abundant in B. pilosa and is present in leaves, stems and roots of the species [5,73,96,97]. The compound is biologically active and several studies have reported that it strongly absorbs long-wave UV radiation, and the activity is altered upon exposure to light (photo activation) [98].
The occurrence of C 17 -acetylenes is rare in the genus, being limited to the Hawaiian species of Bidens [4], while one compound (35) was related to B. pilosa grown in China [2,99]. Also, three C 14acetylenes 39,44,46, with one (46) being common in species of genus Coreopsis, and another (44), a new compound, were reported first in B. pilosa [4,51,100].
Another group of polyacetylenes isolated from B. pilosa are the polyacetylene glucosides (PAGs), which are glycosides of polyacetylenes in which a sugar moiety (glycose or rhamnose) is joined to a polyacetylene through an -O-glucosidic linkage. Of even more restricted distribution, these have been reported for only two families, Asteraceae and Campanulaceae. So far 22 PAGs are known, however most of them have been isolated from Bidens species [101].
Phenylthiophenes, classified as C 13 -acetylene and related compounds [4], are related to only occur in Coreopsis and in Hawaiian Bidens [4,103], however a phenylthiophene 67 and its glycosylate 68 were reported for B. pilosa growing in China [100].

Flavonoids
Flavonoids are the class of compound of higher occurrence in the species and are described as chemotaxonomic markers at lower hierarchical levels of the Asteraceae [104]. According to the Bidens genus, the flavonoid profile of B. pilosa is a complex one that includes aurones, chalcones, flavanones, flavones and flavonols with a wide variety of O-methylation patterns and glycosylations [105], totaling 58 different compounds isolated to date (Table 1).
Anthochlors (aurones and chalcones) are found in a number of plant families, including the Asteraceae. However research indicates that, despite some variations, anthochlors are good markers for the taxonomic subtribe Coreopsidinae (Heliantheae tribe), thus representing the only case in the family Asteraceae in which a certain type of flavonoid is taxonomically diagnostic at the sub tribal level [106].

Other compound classes
Several other compound classes have been isolated from different parts of B. pilosa and are listed in Table 1. Among these, aliphatic hydrocarbon derivatives and simple aromatic hydrocarbons have been reported, although these constituents are rather ubiquitous in plants. Long chain saturated unbranched hydrocarbons between C 21 and C 33 (1-13) have been isolated of B. pilosa [44,91]. Of the saturated unbranched alcohols, the compound 2-butoxyethanol (14) is the only ether-ethanol, while for the unbranched aliphatic carboxylic acid and ester group, three compounds have ether-ester functions (32)(33)(34). The simple aromatic hydrocarbons and simple phenylpropanoid compounds form two small groups of natural products in B. pilosa. In the first, vanillic (80), salicylic (78) and protocatechuic (79) acids and their derivatives are predominant [87], while the phenylpropanoids are represented by coumaric (82), ferulic (84) and caffeic (85) acid. In this group, one new disubstituted acetylacetone (86) was described for B. pilosa growing in India [90].
Of the mevalonate pathway, several sesquiterpenes (160-167), sterols (171-177) and triterpenes (178-183) have been isolated of leaves from B. pilosa [44,51,86]. The sesquiterpenes reported were characterized by GC-MS [46]. These are divided into mono-and bicyclic, commonly found in leaf extracts from Asteraceae. In the diterpenes, acyclic phytane diterpenoids have been reported; among them phytyl heptanoate (170) is an unusual compound that has an aliphatic chain of seven carbon atoms linked to the terminal acid portion [84].
Only two representatives of the class of nitrogen-containing natural products, one being the nucleoside thymidine (194) are reported [122]. One thyophene (195) was reported from B. pilosa [99]. One disaccharide (196) was isolated from an entire B. pilosa. Also, two miscellaneous representatives were reported, a quinone linked to an aliphatic chain (197) [85] and one compound of unidentified structure (198) [59].
The content of essential oil from flowers, leaves and stems of B. pilosa has been analyzed by GC-MS in China, Japan, USA, Cameroon, Nigeria and Iran [66,[115][116][117][118][119][120]136]. In this review, the series of components identified as being commonly found in plants containing essential oils and present mostly in very small quantities are not listed. It is then just a brief comment about the main and unusual constituents. In the species a series of mono-and sesquiterpenes have been detected [66,116,[117][118][119]. The major constituents are the sesquiterpenes germacrene-D and β-caryophyllene. Polyacetylenes (36,59,60,64), including 1-phenylhepta-1,3,5-tryin (64) have been identified in root oil and aerial parts [117,119]. A chromone, known as precocene I, isolated from oil of the leaves from B. pilosa also was reported [116].