The genus Haplopappus: botany, phytochemistry, traditional uses, and pharmacological properties

Abstract

Background

The genus Haplopappus Cass. [Asteraceae] comprises a large number of species distributed mainly in Chile and with various traditional medicinal uses.

Purpose

The present review addresses the botany, traditional uses, chemistry, biological and pharmacological activities of the genus, aiming to further potentiate the associated research and applications.

Study design and Methods

Literature data on the chemistry and bioactivity of the genus Haplopappus were mainly retrieved from digital databases such as SciFinder^®, PubMed^®, and Google Scholar^®, as well as from the scientific journal publishers’ platforms linked with these databases.

Results and discussion

Although the majority of the botanical taxa of the genus Haplopappus has been understudied, available information is promising regarding its phytochemistry and bioactivity. A total of more than 400 compounds are present in different Haplopappus species, mostly terpenoids and phenolic compounds. Scientific literature supports various health promoting effects of Haplopappus extracts and isolated compounds, principally their effect against human pathogenic bacteria and their high antioxidant capacity. The existing limitations highlighted hereby are mainly associated to the lack of modern investigation regarding a wider number of Haplopappus species and chemical compounds, as well as to the absence of in vivo bioactivity results and clinical trials.

Conclusion

Scientific literature supports the ethnopharmacological, phytochemical and bioactive potential of the genus Haplopappus, however the aforementioned limitations need to be addressed in order to further promote and broaden both scientific research and future applications and uses.

1 Introduction

Haplopappus Cass. (Asteraceae (Compositae) - Astereae - Machaerantherinae), is a strictly endemic botanical genus of southern South America, distributed in Chile, with some species also present in Argentina (Klingenberg, 2007). The vernacular name ‘bailahuén’ (‘baylahuén’ or ‘vaila-huen’) has been mainly attributed to the species Haplopappus baylahuen Remy, although the other species of the genus are commonly referred to using the same name (Vogel et al., 2007).

The different species of the genus Haplopappus, although used without differentiation in terms of botanical taxa, are of high ethnopharmacological importance and form part of the longstanding traditional medicines of the Andean peoples. In Chile, where the genus is mainly distributed, its species have been widely used in all territory, from the Aymara communities in the north to Mapuche communities in the south, and in big cities by different social groups (Hoffmann et al., 1992). Bailahuén is used at the prevention and/or treatment of various human and animal pathologies, mainly -but not exclusively-associated to gastrointestinal ailments and wound healing (Muñoz et al., 1981; de Mösbach, 1992; Hoffmann et al., 1992). Alongside its traditional use, H. baylahuen is also included in the German Homeopathic Pharmacopeia as a herbal medicine against fatigue and low blood pressure, although its use is considered limited (Arzneibuch, 2006; Vogel et al., 2007).

Regarding its commercialization, it is reported that its production in Chile is exclusively based on the collection of plant material in the wild, which, in most cases, is realized by non-trained individuals (Vogel et al., 2007). Furthermore, in the same study it is highlighted that the 80% of bailahuén commercial samples correspond to Haplopappus multifolius, probably due to the fact that this species is distributed in the Metropolitan Region of Santiago, where the companies that commercialize the plant material at a national and international level are also located. The over-exploitation of H. multifolius, along with inadequate collection practices, have led to the species being recently included in The IUCN Red List of Threatened Species as Near Threatened (Plummer, 2022).

In this context, despite its high botanical diversity and the rich ethnopharmacological background of the genus Haplopappus, both scientific investigation and commercial use is often limited to a few botanical taxa, while in many cases the traditional knowledge associated with the genus is not taken into consideration, thus hindering unravelling the full phytochemical and bioactive potential of the genus.

Thus, the present article aims to present a comprehensive review of the current state of knowledge regarding the botany, traditional uses, chemistry, biological and pharmacological activities of the genus Haplopappus in an attempt to underline its phytochemical uniqueness, elucidate its bioactive potential, and highlight future research opportunities.

2 Methods

Literature data on the chemistry and bioactivity of the genus Haplopappus were mainly retrieved from digital databases such as SciFinder^®, PubMed^®, and Google Scholar^®, as well as from the scientific journal publishers’ platforms linked with these databases. The search strategy included the scientific name of the genus, excluding the species presently classified in other genera, i.e., Ericameria Nutt., Grindelia Willd., Gundlachia A.Gray, Isocoma Nutt., Notopappus L. Klingberg (Klingenberg, 2007; POWO, 2024). All publications in peer-reviewed journals until May 2024 were considered. The chemical compounds present in the raw materials were classified according to their pathway and superclass (Supplementary Table S1; Figures 1–11) using the NPClassifier tool (Kim et al., 2021).

FIGURE 1.

Chemical structures of miscellaneous compounds identified from Haplopappus species.

FIGURE 11.

Chemical structures of cinnamic acid derivatives identified from Haplopappus species.

FIGURE 2.

(A) Chemical structures of acyclic monoterpenes identified from Haplopappus species. (B) Chemical structures of monocyclic monoterpenes identified from Haplopappus species. (C) Chemical structures of aromatic monocyclic monoterpenes identified from Haplopappus species. (D) Chemical structures of bicyclic monoterpenes identified from Haplopappus species. (E) Chemical structures of tricyclic monoterpenes identified from Haplopappus species.,

FIGURE 3.

(A) Chemical structures of acyclic sesquiterpenes identified from Haplopappus species. (B) Chemical structures of monocyclic sesquiterpenes identified from Haplopappus species. (C) Chemical structures of bicyclic sesquiterpenes identified from Haplopappus species. (D) Chemical structures of tricyclic sesquiterpenes identified from Haplopappus species.,

FIGURE 4.

(A) Chemical structures of diterpenes labdane-type1 identified from Haplopappus species. (B) Chemical structures of diterpenes labdane-type2 identified from Haplopappus species. (C) Chemical structures of diterpenes labdane-type3 identified from Haplopappus species. (D) Chemical structures of diterpenes friedolabdane-type identified from Haplopappus species. (E) Chemical structures of diterpenes clerodane-type identified from Haplopappus species. (F) Chemical structures of miscellaneous diterpenes identified from Haplopappus species., ,

FIGURE 5.

Chemical structures of triterpenes and triterpenoids identified from Haplopappus species.

FIGURE 6.

Chemical structures of meroterpenes identified from Haplopappus species.

FIGURE 7.

Chemical structures of steroids identified from Haplopappus species.

FIGURE 8.

Chemical structures and substitution patterns of flavonoids identified from Haplopappus species.

FIGURE 9.

Chemical structures and substitution patterns of coumarins identified from Haplopappus species.

FIGURE 10.

Chemical structures of benzoic acid derivatives identified from Haplopappus species.

3 Botany and distribution

The genus Haplopappus Cass. (Asteraceae - Astereae - Machaerantherinae) is a strictly endemic genus of South America and its species are mainly distributed in Chile and, to a lesser extent, Argentina (Klingenberg, 2007; Rodriguez et al., 2018; Zuloaga et al., 2019; García et al., 2024).

According to the latest taxonomic studies of the genus and after the separation of numerous, mainly North American, species that formed the genus Notopappus L. Klingenberg, the genus Haplopappus consists of 70 specific and intraspecific taxa (Table 1) and is subdivided into three subgenera (Haplopappus subgen. Haplopappus, H. subgen. Grindelioidae Klingenberg, and H. subgen. Baylahuen Klingenberg) and five sections: Haplopappus sect. Haplopappus, H. sect. Gymnocoma Nuttall, H. sect. Grindelioidae Klingenberg, H. sect. Chromochaeta Candolle, and H. sect. Leiachaenium Candolle (Klingenberg, 2007; Garcia et al., 2018; García et al., 2024). Haplopappus taxonomy is mainly based on morphological traits, due to the limited phylogenetic data available up to date (García et al., 2024). In general, Haplopappus species are shrubs or subshrubs, with aerial parts that bear glandular trichomes, usually yellow florets, and numerous pappus bristles (Klingenberg, 2007; García et al., 2024).

TABLE 1.

Scientific names and distribution of reported Haplopappus species (Klingenberg, 2007; Garcia et al., 2018; García et al., 2024).

No.	Haplopappus species	Synonyms	Distribution a
1	H. angustifolius (DC.) Reiche subsp. angustifolius	Aster atenes Kuntze, Aster sternbergii Kuntze, H. durus Reiche, Pyrrocoma angustifolia DC., Pyrrocoma rigida Phil	Chile (Atacama, Coquimbo)
2	H. angustifolius (DC.) Reiche subsp. saxatilis (Remy) Klingenb	Aster saxatilis (Remy) Kuntze, Haplodiscus sphacelatus Phil., H. saxatilis (Remy) Reiche, H. sphacelatus (Phil.) Reiche, Pyrrocoma saxatilis Remy	Chile (Coquimbo, Metropolitan of Santiago, Maule)
3	H. anthylloides Meyen & Walp	Aster anthylloides (Meyen & Walp.) Kuntze, Aster radicans (Remy) Kuntze, H. radicans Remy	Chile (Valparaíso, Libertador Bernardo O’Higgins, Maule, Metropolitan of Santiago) Argentina (Mendoza)
4	H. arbutoides Remy	Aster arbutoides (Remy) Kuntze, H. obovatus Phil., H. baccharidifolius Phil., H. zanartui (Phil.) Reiche	Chile (Coquimbo, Valparaíso, Libertador Bernardo O’Higgins, Maule, Ñuble, Biobío, Araucanía)
5	H. baylahuen Remy subsp. baylahuen	Aster baylahuen (Remy) Kuntze, H. domeykoi Phil., H. lastarrianus Remy, H. medicinalis Phil	Chile (Atacama, Coquimbo) Argentina (San Juan)
6	H. baylahuen Remy subsp. fluehmannii (Phil.) Klingenb	H. fluehmannii Phil	Chile (Atacama)
7	H. bezanillanus (Remy) Reiche	Aster bezanillanus (Remy) Kuntze, Pyrrocoma bezanillana Remy	Chile (Coquimbo)
8	H. boelckei Tortosa & A. Bartoli	-	Argentina (Mendoza)
9	H. bustillosianus Remy	Aster bustillosianus (Remy) Kuntze, Aster patagoniensis Kuntze, H. australis Phil., H. glutinosus f. patagonicus (Phil.) Cabrera, H. patagonicus Phil., H. subandinus Phil	Chile (Maule, Ñuble, Biobío, Araucanía, Los Lagos) Argentina
10	H. cerberoanus (Remy) Reiche subsp. cerberoanus	Aster cerberoanus (Remy) Kuntze, Pyrrocoma cerberoana Remy	Chile (Atacama, Coquimbo) Peru
11	H. cerberoanus (Remy) Reiche subsp. elquianus Klingenb	-	Chile (Coquimbo)
12	H. chrysanthemifolius (Less.) DC.	Andromachia alternifolia Kuntze, Diplopappus chrysanthemifolius Less., Grindelia glutinosa Bertero, H. berteroi DC., H. leucanthemifolius Phil	Chile (Coquimbo, Valparaíso, Libertador Bernardo O’Higgins, Maule, Ñuble, Biobío, Metropolitan of Santiago)
13	H. coquimbensis (Hook. & Arn.) Klingenb	Aster hirtellus (Phil.) Kuntze, Diplopappus coquimbensis Hook. & Am, Haplodiscus elatus Phil., H. acanthodon Phil. Reiche, H. elatus (Phil.) Reiche, H. hirtellus Phil., (Phil.) H. hirtellus Phil. var. hirsutus, H. limarensis Phil., H. vidalii Phil	Chile (Atacama, Coquimbo, Valparaíso, Libertador Bernardo O’Higgins)
14	H. colliguayensis M.A.Villalobos, V.Morales & Nic.García	-	Chile (Valparaíso)
15	H. decurrens Remy	Aster remyanus Kuntze	Chile (Coquimbo, Valparaíso, Libertador Bernardo O’Higgins, Metropolitan of Santiago)
16	H. deserticola Phil	H. involucratus Phil., H. rengifoanus Phil	Chile (Antofagasta, Atacama, Coquimbo)
17	H. diplopappus Remy subsp. diplopappus	Aster diplopappus (Remy) Kuntze, Diplopappus spinulosus Hook. & Arn., H. heterophysus Phil., H. pallidus Phil H. peteroanus Phil., H. reticulatus Phil	Chile (Valparaíso, Libertador Bernardo O’Higgins, Maule, Metropolitan of Santiago)
18	H. diplopappus Remy subsp. villosus (Phil.) L. Klingenberg	Aster villiger Kuntze, Diplopappus spinulosus Hook. & Arn., H. diplopappus Remy var. struthionum (Speg.) Cabrera, H. villosus Phil	Chile (Valparaíso, Libertador Bernardo O’Higgins, Maule, Metropolitan of Santiago) Argentina (Chubut, Mendoza, Santa Cruz)
19	H. donianus (Hook. & Arn.) Sch.Bip. ex Reiche	Diplopappus donianus Hook. & Arn., Haplodiscus exserens Phil., Haplodiscus tenuifolius Phil., H. canescens var. exserens (Phil.) Reiche	Chile (Valparaíso, Libertador Bernardo O’Higgins, Maule, Biobío)
20	H. foliosus (Hook. & Arn.) Hook. & Arn. subsp. foliosus	Aster foliosus (DC.) Kuntze, Aster polyphyllus (Phil.) Kuntze, Diplopappus foliosus Hook. & Arn., Haplodiscus densifolius Phil., Haplodiscus polyphyllus Phil., H. foliosus DC., H. phyllophorus Reiche	Chile (Coquimbo, Valparaíso, Libertador Bernardo O’Higgins, Maule, Metropolitan of Santiago)
21	H. foliosus (Hook. & Arn.) Hook. & Arn. subsp. meyenii (Walp.) L. Klingenberg	Aster meyenii (Walp.) Kuntze, H. meyenii Walp	Chile (Coquimbo)
22	H. glabratus Phil	Aster glabratus (Phil.) Kuntze, H. arbutoides Remy var. glabratus (Phil.) Reiche	Chile (Valparaíso, Libertador Bernardo O’Higgins, Maule, Metropolitan of Santiago) Argentina (Chubut, Neuquén, Río Negro, Santa Cruz)
23	H. glutinosus Cass	Aster senebierifolius Kuntze, Diplopappus coronopifolius Less., H. coronopifolius DC.	Chile (Valparaíso, Libertador Bernardo O’Higgins, Maule, Biobío, Araucania, Los Ríos, Los Lagos, Aisén) Argentina
24	H. grindelioides (Less.) DC.	Aster grindelioides (Less.) Kuntze, Aster marginalis (Phil.) Kuntze, Aster reversus Kuntze, Diplopappus grindelioides Less., H. corniculatus Phil., H. heterocomus Phil., H. marginalis Phil., H. reflexus Phil	Chile (Libertador Bernardo O’Higgins, Maule, Ñuble, Biobío, Araucania, Magallanes, Metropolitan of Santiago) Argentina (Chubut, Mendoza, Neuquén, Río Negro, Santa Cruz)
25	H. humilis (Phil.) Reiche	Haplodiscus humilis Phil	Chile (Libertador Bernardo O’Higgins, Maule, Ñuble, Biobío, Metropolitan of Santiago)
26	H. integerrimus (Hook. & Arn.) H.M. Hall	Diplopappus integerrimus Hook. & Arn., Grindelia acerosa Bertero, H. acerosus Phil., H. pulchellus var. elongaus Remy, Steriphe acerosa Phil	Chile (Coquimbo, Valparaíso, Libertador Bernardo O’Higgins, Maule, Biobío, Metropolitan of Santiago)
27	H. kingii (Phil.) Reiche	Haplodiscus kingii Phil	Chile (Atacama)
28	H. linifolius (Phil.) Reiche	Aster linodes (Phil.) Kuntze, Pyrrocoma linifolia Phil	Chile (Atacama, Coquimbo)
29	H. litoralis Phil	-	Chile (Coquimbo, Valparaíso)
30	H. macrocephalus (Poepp. Ex Less.) DC.	Aster macrocephalus (Poepp. ex Less.) Kuntze, Aster spinuliger Kuntze, Diplopappus macrocephalus Poepp. ex Less., H. caespitosus Nutt., H. scaposus Remy, H. serrulatus Reiche, H. spinulosus Phil	Chile (Valparaíso, Libertador Bernardo O’Higgins, Maule, Ñuble Biobío, Araucania, Metropolitan of Santiago)
31	H. maulinus Klingenb	-	Chile (Maule, Biobío)
32	H. mendocinus Tortosa & A. Bartoli	-	Argentina (La Pampa, Mendoza)
33	H. mieresii P. Medina & Nic. García	-	Chile (Coquimbo)
34	H. mucronatus (Hook. & Arn.) Hook	Aplopappus macraenus Gray, Aster ilicifolius (Remy) Kuntze, Aster macraenus (Remy) Kuntze, Baccharis hookeriana DC., Baccharis mucronata Hook. & Arn., Diplopappus mucronatus Hook. & Arn., H. axilliflorus Phil., H. fonckii Phil., H. hookerianus DC., H. ilicifolius Remy, H. ilicifolius var. platylepis (Phil.) Reiche, H. platylepis Phil., H. macraenus (Remy) Reiche, Pyrrocoma macraena Remy	Chile (Atacama, Coquimbo, Valparaíso)
35	H. multifolius Reiche subsp. baccharidiformis Klingenb	-	Chile (Metropolitan of Santiago)
36	H. multifolius Reiche subsp. multifolius	Aster multifolius (Reiche) Kuntze, Diplopappus foliolosus Hook. & Arn., Diplopappus ilicifolius Hook. & Arn., H. rotundifolius H.M. Hall, Pyrrocoma foliosa Phil	Chile (Coquimbo, Valparaíso, Metropolitan of Santiago)
37	H. multifolius Reiche subsp. ovalifolius Klingenb	-	Chile (Valparaíso, Metropolitan of Santiago)
38	H. nahuelbutae Klingenb	-	Chile (Biobío, Araucania)
39	H. ochagavianus Phil	Aster ochayaviensis Kuntze, H. reicheanus H.M. Hall, H. tiltilensis Phil., H. vernicosus Reiche	Chile (Coquimbo, Valparaíso, Metropolitan of Santiago)
40	H. paucidentatus Phil	Aster glutinosus (Less.) Kuntze, Aster oligodontus Kuntze, Diplopappus glutinosus Less., H. glutinosus (Less.) DC., H. glutinosus f. spathulata Cabrera., H. prostratus Phil	Chile (Maule, Ñuble Biobío, Araucania, Los Lagos)
41	H. parvifolius (DC.) Gay	Aster parvifolius (DC.) Kuntze, Pyrrocoma parvifolia DC.	Chile (Atacama, Coquimbo)
42	H. pulchellus DC.	Aster valparaisanus Kuntze	Chile (Coquimbo, Valparaíso, Libertador Bernardo O’Higgins, Maule, Metropolitan of Santiago)
43	H. philippii (Kuntze) H.M. Hall	Aster philippii Kuntze, H. breviradiatus Reiche, H. paniculatus Phil	Chile (Atacama, Coquimbo, Valparaíso)
44	H. pinea (Phil.) Reiche	Aster pineus (Phil.) Kuntze, Pyrrocoma pinea Phil	Chile (Coquimbo, Valparaíso)
45	H. pinnatifidus Nutt	Aster andinus Kuntze, Aster setiger (Phil.) Kuntze, Diplopappus setiger Hook. & Arn., H. setigerus (Phil.) Meigen, Pyrrocoma nuttalli Remy, Pyrrocoma setigera Phil	Chile (Coquimbo, Valparaíso, Libertador Bernardo O’Higgins, Maule, Metropolitan of Santiago)
46	H. poeppigianus (Hook. & Arn.) A. Gray	Aster griseus Kuntze, Diplopappus poeppigianus Hook. & Arn., Grindelia canescens Bertero, Haplodiscus polycladus Phil., H. argenteus Steud., H. canescens (Phil.) Reiche, Pyrrocoma canescens Phil	Chile (Valparaíso, Libertador Bernardo O’Higgins, Metropolitan of Santiago)
47	H. punctatus (Willd.) Hall	Aster adalbertii Kuntze, Aster pedunculosus (Remy) Kuntze, Conyza punctata Willd., Diplopappus chamissonis Less., H. chamissonis (Less.) DC., H. corymbosus (Phil.) Reiche, H. pedunculosus Remy, H. rosmarinifolius Reiche, Steriphe corymbosa Phil	Chile (Maule, Biobío)
48	H. pusillus Klingenb	Aster cuneifolius (Nutt.) Kuntze, Diplopappus bellidifolius Hook. & Arn., H. cuneifolius Nutt., H. nanus Phil	Chile (Coquimbo, Valparaíso, Metropolitan of Santiago)
49	H. racemiger Klingenb	-	Chile (Atacama, Coquimbo)
50	H. reicheanus H.M. Hall	-	Chile (Coquimbo, Valparaíso, Metropolitan of Santiago)
51	H. remyanus Wedd	Aster remyanus (Wedd.) Kuntze, Haplodiscus latifolius Phil., Haplodiscus vernicosus Phil., Haplodiscus vernicosus var. geissei Phil., H. latifolius (Phil.) Reiche, H. prinophyllus Phil., Pyrrocoma ilicifolia Remy	Chile (Atacama, Coquimbo, Valparaíso, Libertador Bernardo O’Higgins, Metropolitan of Santiago)
52	H. rengifoanus Remy	Aster rengifoanus Kuntze, Haplodiscus pachyphyllus Phil., Pyrrocoma densifolia Phil	Chile (Antofagasta, Atacama, Coquimbo, Libertador Bernardo O’Higgins)
53	H. retinervius (Kuntze) Klingenb	Aster retinervius Kuntze, Haplodiscus ischnos Phil., Haplodiscus landbecki Phil., Pyrrhocoma reticulata Phil., H. ischnos (Phil.) Reiche, H. reticulatus (Phil.) Reiche	Chile (Coquimbo, Valparaíso)
54	H. rigidus Phil	Aster atacamensis Kuntze	Chile (Antofagasta, Atacama, Coquimbo) Argentina (Catamarca, Salta) Bolivia (Potosí)
55	H. rosulatus H.M. Hall	-	Chile (Antofagasta, Atacama, Coquimbo)
56	H. schumannii (Kuntze) G.K. Br. & W.D. Clark	Aster schumannii Kuntze, H. armerioides Phil., H. poeppigianus (Hook. & Arn.) A. Gray var. radiatus A. Gray, H. sericeus Phil., Steriphe navarroi Phil	Chile (Valparaíso, Metropolitan of Santiago)
57	H. scrobiculatus (Nees) DC.	Aster cuneifolius (Nutt.) Kuntze, Aster densifolius (Remy) Kuntze, Diplopappus cuneatus Hook. & Arn., Diplopappus scrobiculatus Nees, H. densifolius Remy, Perezia spathulata Phil	Chile (Coquimbo, Valparaíso, Libertador Bernardo O’Higgins, Maule, Ñuble, Biobío, Araucania, Metropolitan of Santiago) Argentina (Mendoza, San Juan)
58	H. setulosus Klingenb	-	Chile (Maule, Ñuble)
59	H. stelliger Remy	Aster denticulatus (Phil.) Kuntze, Aster stelliger (Remy) Kuntze, H. denticulatus (Phil.) Reiche, Pyrrocoma denticulata Phil	Chile (Coquimbo)
60	H. stolpii Phil	-	Chile (Maule, Ñuble, Biobío, Araucania, Metropolitan of Santiago)
61	H. taeda Reiche	Haplodiscus peteroanus Phil., Haplodiscus graveolens Phil., H. graveolens (Phil.) Reiche	Chile (Valparaíso, Libertador Bernardo O’Higgins, Maule, Metropolitan of Santiago)
62	H. teillieri A.Cádiz-Véliz, V.Morales & Nic.García	-	Chile (Coquimbo, Valparaíso)
63	H. uncinatus Phil	Aster uncinatus (Phil.) Kuntze, Diplopappus canescens Hook. & Arn., H. candolei Phil., H. uncinatus Phil. var. candolei (Phil.) Reiche	Chile (Coquimbo, Valparaíso, Libertador Bernardo O’Higgins, Maule, Metropolitan of Santiago)
64	H. undulatus Klingenb	-	Chile (Coquimbo, Valparaíso, Metropolitan of Santiago)
65	H. valparadisiacus Klingenb	Diplopappus inuloides Hook. & Arn., H. berteroi var. lanceolatus DC., H. formosus Phil	Chile (Coquimbo, Valparaíso, Libertador Bernardo O’Higgins, Metropolitan of Santiago)
66	H. velutinus Remy subsp. illinitus (Phil.) Klingenb	H. glutinosus var. illinitus (Phil.) Reiche, H. illinitus Phil	Chile (Libertador Bernardo O’Higgins, Maule)
67	H. velutinus Remy subsp. longipes (Phil.) Klingenb	Aster longipes (Phil.) Kuntze, Pyrrocoma longipes Phil	Chile (Libertador Bernardo O’Higgins, Maule)
68	H. velutinus Remy subsp. velutinus	Aster gayanus Kuntze, Aster scopiformis Kuntze, Diplopappus glutinosus Hook. & Arn., Haplodiscus fallax Phil., Haplodiscus longiscapus Phil., H. fallax (Phil.) Reiche, H. stenophyllus Phil., H. virgatus Phil., Pyrrocoma scaposa Phil	Chile (Coquimbo, Valparaíso, Libertador Bernardo O’Higgins, Maule, Metropolitan of Santiago) Argentina (Mendoza)
69	H. vicuniensis Klingenb	-	Chile (Coquimbo)
70	H. villanuevae Phil	-	Chile (Antofagasta, Atacama)

^a (Rodriguez et al., 2018; Zuloaga et al., 2019; POWO, 2024).

4 Phytochemistry

Available scientific literature provides relevant information on the phytochemistry of the genus Haplopappus. However, it must be mentioned that this information refers to only 28 species and subspecies of a total of 70 taxa (Table 1), thus highlighting the largely understudied potential of the genus Haplopappus and stressing the need to further investigate its phytochemistry. Moreover, of these 28 taxa for which scientific evidence is available, for the 24 there are less than 35 compounds reported per taxa, whereas the remaining four species are associated to a higher -yet still rather diverse-number of reported compounds, i.e., H. foliosus (n = 146), H. velutinus (n = 59), H. chrysanthemifolius (n = 52), H. bustillosianus (n = 40).

Regarding the type of metabolites reported in Haplopappus species, more than 400 different molecules have been detected in various plant parts of the studied taxa. However, the number of reported compounds per chemical group is highly diverse, to an extent that it raises the question of whether this variability can be solely attributed to differences at a plant metabolic level or it can also be associated with a focus of scientific research towards certain groups of metabolites, e.g., terpenoids and phenolics. Indeed, products of the terpenoid metabolic pathway are by far the most abundant group of molecules reported in the genus Haplopappus, including more than 200 compounds, i.e. 54 monoterpenoids (abbreviated as Mon in compound codification used in the present review), 60 sesquiterpenoids (Sqt), 107 diterpenoids (Dit), five triterpenoids (Tri), one meroterpenoid (Mer) and two steroids (Str). The second most abundant group of reported compounds includes flavonoids (Flv; flavonols, n = 46; flavones, n = 20; flavanones, n = 8; flavanonols, n = 11) and other products of the metabolic pathway of shikimic acid, i.e., coumarins (Cum, n = 16), benzoic (Ben, n = 3) and cinnamic (Cin, n = 12) acid derivatives. Other compounds reported in the genus Haplopappus include alkanes (Ala, n = 29), alkenes (Ale, n = 4), alkynes (Aly, n = 1), alcohols (Alc, n = 5), ethers (Eth, n = 1), aromatic hydrocarbons and derivatives (Arh, n = 10), aldehydes (Ald, n = 8), ketones (Ket, n = 7), esters (Est, n = 8), furanones (Fur, n = 1), lactones (Ltn, n = 2) and lactams (Ltm, n = 1).

The aforementioned compounds as classified per chemical group are detailed in Figures 1–11 and Tables 2–4, and Supplementary Table S1, while their distribution among the studied Haplopappus taxa is presented as follows.

TABLE 2.

Substitution pattern of flavonols and flavones reported in species of the genus Haplopappus.

No.	Compound	R3	R5	R6	R7	R8	R3'	R4'	R5'
Flavonols
Flv1	quercetin	OH	OH	H	OH	H	OH	OH	H
Flv2	quercetin 3-methyl ether	OMe	OH	H	OH	H	OH	OH	H
Flv3	tamarixetin (quercetin 4′-methyl ether)	OH	OH	H	OH	H	OH	OMe	H
Flv4	rhamnazin (quercetin 7,3′-dimethyl ether)	OH	OH	H	OMe	H	OMe	OH	H
Flv5	quercetin 3,3′-dimethyl ether	OMe	OH	H	OH	H	OMe	OH	H
Flv6	quercetin 3,7-dimethyl ether	OMe	OH	H	OMe	H	OH	OH	H
Flv7	ayanin	OMe	OH	H	OMe	H	OH	OMe	H
Flv8	retusin (5-hydroxy-3,7,3′,4′-tetramethoxyflavone)	OMe	OH	H	OMe	H	OMe	OMe	H
Flv9	3-O-acetyl-7-methylquercetin	OAc	OH	H	OMe	H	OH	OH	H
Flv10	isoquercitrin (quercetin-3-β-D-glucoside)	O-Glu	OH	H	OH	H	OH	OH	H
Flv11	hyperoside (quercetin-3-β-D-galactoside)	O-Gal	OH	H	OH	H	OH	OH	H
Flv12	quercetagetin 3-methyl ether	OMe	OH	OH	OH	H	OH	OH	H
Flv13	quercetagetin 3,7-dimethyl ether	OMe	OH	OH	OMe	H	OH	OH	H
Flv14	centaureidin	OMe	OH	OMe	OH	H	OH	OMe	H
Flv15	betuletol (3,5,7-trihydroxy-6,4′-dimethoxyflavone)	OH	OH	OMe	OH	H	H	OMe	H
Flv16	eupatolitin	OH	OH	OMe	OMe	H	OH	OH	H
Flv17	rhamnetin	OH	OH	H	OMe	H	OH	OH	H
Flv18	isorhamnetin	OH	OH	H	OH	H	OMe	OH	H
Flv19	isorhamnetin-3-β-D-glucoside	O-Glu	OH	H	OH	H	OMe	OH	H
Flv20	isorhamnetin-3-β-D-galactoside	O-Gal	OH	H	OH	H	OMe	OH	H
Flv21	kaempferol	OH	OH	H	OH	H	H	OH	H
Flv22	astragalin (kaempferol 3-β-D-glucoside)	O-Glu	OH	H	OH	H	H	OH	H
Flv23	isokaempferide (kaempferol 3-methyl ether)	OMe	OH	H	OH	H	H	OH	H
Flv24	kaempferol 3-methyl ether 7-β-D-glucoside	OMe	OH	H	O-Glu	H	H	OH	H
Flv25	rhamnocitrin (kaempferol 7-methyl ether)	OH	OH	H	OMe	H	H	OH	H
Flv26	ermanin (kaempferol 3,4′-dimethyl ether)	OMe	OH	H	OH	H	H	OMe	H
Flv27	kaempferol 7,4′-dimethyl ether	OH	OH	H	OMe	H	H	OMe	H
Flv28	kumatakenin (kaempferol 3,7-dimethyl ether)	OMe	OH	H	OMe	H	H	OH	H
Flv29	kaempferol 3,7,4′-trimethyl ether	OMe	OH	H	OMe	H	H	OMe	H
Flv30	3-O-acetyl-7,4′-dimethylkaempferol	OAc	OH	H	OMe	H	H	OMe	H
Flv31	haplopappin	OMe	OH	H	OH		H	OMe	H
Flv32	haplopappin A	OH	OH	H	OMe		H	OMe	H
Flv33	myricetin	OH	OH	H	OH	H	OH	OH	OH
Flv34	myricetin 3′,4′-dimethyl ether	OH	OH	H	OH	H	OMe	OMe	OH
Flv35	myricetin 3,3′,4′-trimethyl ether	OMe	OH	H	OH	H	OMe	OMe	OH
Flv36	myricetin 3,7,4′-trimethyl ether	OMe	OH	H	OMe	H	OH	OMe	OH
Flv37	3,8-dimethylherbacetin (5,7,4′-trihydroxy-3,8-dimethoxyflavone)	OMe	OH	H	OH	OMe	H	OH	H
Flv38	3,8,4′-trimethylherbacetin (5,7-dihydroxy-3,8,4′-trimethoxyflavone)	OMe	OH	H	OH	OMe	H	OMe	H
Flv39	5,7,4′-trihydroxy-3,8,3′-trimethoxyflavone	OMe	OH	H	OH	OMe	OMe	OH	H
Flv40	3,5-dihydroxy-3′,4′,6,7-tetramethoxyflavone	OH	OH	OMe	OMe	H	OMe	OMe	H
Flv41	santin	OMe	OH	OMe	OH	H	H	OMe	H
Flv42	eupatorin	H	OH	OMe	OMe	H	OH	OMe	H
Flv43	jaceidin	OMe	OH	OMe	OH	H	OMe	OH	H
Flv44	jaceidin 7-methyl ether	OMe	OH	OMe	OMe	H	OMe	OH	H
Flv45	penduletin	OMe	OH	OMe	OMe	H	H	OH	H
Flv46	pachypodol	OMe	OH	H	OMe	H	OMe	OH	H
Flavones
Flv47	apigenin	H	OH	H	OH	H	H	OH	H
Flv48	3,6-dimethoxyapigenin	OMe	OH	OMe	OH	H	H	OH	H
Flv49	vicenin-2	H	OH	C-Glu	OH	C-Glu	H	OH	H
Flv50	vitexin	H	OH	H	OH	C-Glu	H	OH	H
Flv51	isovitexin	H	OH	C-Glu	OH	H	H	OH	H
Flv52	isoschaftoside	H	OH	C-Ara	OH	C-Glu	H	OH	H
Flv53	luteolin	H	OH	H	OH	H	OH	OH	H
Flv54	luteolin 5-glucoside	H	O-Glu	H	OH	H	OH	OH	H
Flv55	luteolin 7-glucoside	H	OH	H	O-Glu	H	OH	OH	H
Flv56	chrysoeriol	H	OH	H	OH	H	OMe	OH	H
Flv57	velutin (luteolin 7, 3′-dimethyl ether)	H	OH	H	OMe	H	OMe	OH	H
Flv58	diosmetin	H	OH	H	OH	H	OH	OMe	H
Flv59	eupafolin (6-methoxyluteolin)	H	OH	OMe	OH	H	OH	OH	H
Flv60	6-methoxyluteolin 4′-methyl ether	H	OH	OMe	OH	H	OH	OMe	H
Flv61	cirsiliol (6-methoxyluteolin 7-methyl ether)	H	OH	OMe	OMe	H	OH	OH	H
Flv62	hispidulin (scutellarein 6-methyl ether)	H	OH	OMe	OH	H	H	OH	H
Flv63	pectolinaringenin	H	OH	OMe	OH	H	H	OMe	H
Flv64	scutellarein 6-β-D-glucoside	H	OH	O-Glu	OH	H	H	OH	H
Flv65	3′,4′-dihydroxyflavone 5-glucoside	H	O-Glu	H	H	H	OH	OH	H
Flv66	verbenacoside	H	O-Glu	H	H	H	H	OH	H

TABLE 4.

Substitution pattern of coumarins reported in species of the genus Haplopappus.

No.	Compound	R6	R7
Cum1	esculetin	OH	H
Cum2	esculin	Glu	H
Cum3	prenyletin	OH
Cum4	haplopinol	OH
Cum5	6-deoxyhaplopinol	H
Cum6	6-hydroxy-7-(5′-hydroxy-3′,7′-dimethylocta-2′,6′-dien)-oxycoumarin	OH
Cum7	6-hydroxy-7-(7′-hydroxy-3′,7′-dimethylocta-2′,5′-dien)-oxycoumarin	OH
Cum8	6-hydroxy-7-[(E,E)-3′,7′-dimethyl-2′,4′,7′-octatrienyloxy] coumarin	OH
Cum9	scopoletin	OMe	H
Cum10	7-O-prenylscopoletin	OMe
Cum11	7-O-geranylscopoletin	OMe
Cum12	scoparone	OMe	Me
Cum13	hernianin	H	Me
Cum14	umbelliferone	H	H
Cum15	O-prenylumbelliferone	H

TABLE 3.

Substitution pattern of flavanones and flavanonols reported in species of the genus Haplopappus.

No.	Compound	R3	R5	R6	R7	R8	R3'	R4'	R5'
Flavanones
Flv67	sakuranetin (5,4′-dihydroxy-7-methoxyflavonone)	H	OH	H	OMe	H	H	OH	H
Flv68	sakuranetin 4′-methyl ether	H	OH	H	OMe	H	H	OMe	H
Flv69	persicogenin	H	OH	H	OMe	H	OH	OMe	H
Flv70	sternbin	H	OH	H	OMe	H	OH	OH	H
Flv71	eriodictyol	H	OH	H	OH	H	OH	OH	H
Flv72	eriodictyol 7,3′-dimethyl ether	H	OH	H	OMe	H	OMe	OH	H
Flv73	eriodictyol 7,3′,4′-trimethyl ether	H	OH	H	OMe	H	OMe	OMe	H
Flv74	pinostrobin	H	OH	H	OMe	H	H	H	H
Flavanonols
Flv75	7,4′-dimethylaromadendrin	OH	OH	H	OMe	H	H	OMe	H
Flv76	7-O-methylaromadenrin	OH	OH	H	OMe	H	H	OH	H
Flv77	3-O-acetyl-7-O-aromadendrin	OAc	OH	H	OMe	H	H	OH	H
Flv78	padmatin	OH	OH	H	OMe	H	OH	OH	H
Flv79	3-O-acetylpadmatin	OAc	OH	H	OMe	H	OH	OH	H
Flv80	blumeatin B	OH	OH	H	OMe	H	OH	OMe	H
Flv81	7,3′-di-O-methyltaxifolin	OH	OH	H	OMe	H	OMe	OH	H
Flv82	dihydromyricetin	OH	OH	H	OH	H	OH	OH	OH
Flv83	alpinone 3-acetate	OAc	OH	H	OMe	H	H	H	H

4.1 H. angustifolius (DC.) Reiche

Information on the chemical composition of H. angustifolius is limited to reports of the presence of hentriacontane (Ala22), hexacosanol (Alc1), the diterpenes haplopappic acid (Dit96) and its methylester (Dit97) and the triterpenes friedelin (Tri1) and epi-friedelinol (Tri3) in the aerial parts of the plant (Silva and Sammes, 1973).

4.2 H. anthylloides Meyen & Walp

The ketone 4-hydroxyacetophenone (Ket2) is the only compound identified in the aerial parts of H. antylloides (Zdero et al., 1990).

4.3 H. arbutoides Remy

The majority of the compounds identified in the aerial parts and/or resin of H. arbutoides belong to the diterpenoids group, i.e. 15-oxo-labda-8(17),14E-diene-18-oic acid (Dit32), 15-oxo-labda-8(17),14Z-diene-18-oic acid (Dit33), labda-8(17),13E-dien-15,18-dioic acid 15-methyl ester (Dit34), 15-hydroxylabd-8(17)-en-18-oic acid (Dit35), labd-13(E)-ene-8α,15-diol (Dit62), 13R-labdane-8,15-diol (Dit63), 8α-hydroxy-ent-labd-13(14)Z-en-15-al (Dit64), 8α-hydroxylabdan-15-al (Dit65), epi-manoyl oxide (Dit68), 8,13-epoxy-14-labdeb-3-ol (Dit74), 8,13-epoxy-labdan-15-al (Dit75), 15-oxocleroda-3,13E-dien-18-oic acid (Dit91), and 15-oxocleroda-3,13Z-dien-18-oic acid (Dit92) (Zdero et al., 1991a; Rossomando et al., 1995). Additionally, the aerial parts are reported to contain 4-hydroxyacetophenone (Ket2), the sesquiterpene 1β-hydroxy-β-cyperone (Sqt44) and the flavonols santin (Flv41) and penduletin (Flv45) (Zdero et al., 1991a; Rossomando et al., 1995).

4.4 H. baylahuen Remy

The essential oil of the leaves of H. baylahuen is reported to contain eicosane (Ala11), benzene (Arh1), azulene (Arh2), naphthalene (Arh4), and the sesquiterpenes bergamotol (Sqt8) and α-cadinol (Sqt24) (Becerra et al., 2010). Phenolic compounds detected in this species include quercetin (Flv1), quercetin 3-methyl ether (Flv2), rhamnetin (Flv17), isorhamnetin (Flv18), kaempferol (Flv21), rhamnocitrin (Flv25), velutin (Flv57), sakuranetin (Flv67), persicogenin (Flv69), sternbin (Flv70), 7,4′-dimethylaromadendrin (Flv75), 7-O-methylaromadenrin (Flv76), 7,3′-di-O-methyltaxifolin (Flv81), dihydromyricetin (Flv82), prenyletin (Cum3), and 3,5-dicaffeoylquinic acid (Cin12) (Schwenker et al., 1967; Hörhammer et al., 1973; Nuñez-Alarcon et al., 1993; Vera et al., 2001; Schmeda-Hirschmann et al., 2015).

4.5 H. bezanillanus (Remy) Reiche

The compounds detected in the aerial parts of H. bezanillanus are the diterpenoid labd-13(E)-ene-8α,15-diol (Dit62), the steroid β-sitosterol (Str2) and the flavonol jaceidin 7-methyl ether (Flv44) (Maldonado et al., 1993).

4.6 H. bustillosianus Remy

The aerial parts of H. bustillosianus contain the alkenes C₁₁H₂₄ – C₁₄H₃₀ (Ala2 – Ala5), C₁₆H₃₄ – C₃₃H₆₈ (Ala7 – Ala24), along with 3-hydroxyacetophenone (Ket1) and the flavonoids santin (Flv41) and 3,6-dimethoxyapigenin (Flv48) (Urzúa et al., 2007a). Their phenolic profile includes α-linalool (Mon4), α-pinene (Mon37), β-pinene (Mon38), α-bisabolol (Sqt4), humulene (Sqt5), α-cadinene (Sqt18), γ-cadinene (Sqt20), δ-cadinene (Sqt21), (−)-isocaryophyllene (Sqt30), α-cubebene (Sqt48), β-cubebene (Sqt49), α-copaene (Sqt58), populifolic acid (Dit89) and its methyl ester (Dit90), and thunbergol (Dit102) (Urzúa et al., 2007a).

4.7 H. chrysanthemifolius (Less.) DC

The phytochemistry of H. chrysanthemifolius has been thoroughly investigated and various chemical groups of compounds have been identified in this species. Among them, in the flower heads there are present the alkanes C₁₀H₂₂ – C₁₉H₄₀ (Ala1 – Ala10), C₂₁H₄₄ – C₃₃H₆₈ (Ala12 – Ala24), 2-methyldecalin (Ala25), 2,4,6-trimethyloctane (Ala26), 2,6-dimethylundecane (Ala27), 4,6-dimethylundecane (Ala28), and 2,10-dimethylundecane Ala29) (Urzúa et al., 2007a). Furthermore, the terpenoid profile of the species includes β-myrcene (Mon3), limonene (Mon8), α-pinene (Mon37), β-pinene (Mon38), humulene (Sqt5), δ-cadinene (Sqt21), (−)-isocaryophyllene (Sqt30), β-bulgarene (Sqt31), γ-bulgarene (Sqt32), (−)-amorpha-4,11-diene (Sqt33), α-cubebene (Sqt48), β-cubebene (Sqt49), (−)-calarene (Sqt50), 1,3,4,5,6,7-hexahydro-2,5,5-trimethyl-2H-2,4a-ethanonaphthalene (Sqt51), α-copaene (Sqt58), 6α-hydroxy-ent-labd-8(17)-en-15-oic acid (Dit1), 3β-acetoxy-ent-labd-8(17)-en-15-oic acid (Dit2), and 18α-acetoxylabd-8(17)-en-15-oic acid (Dit3) (Faini et al., 1999; Urzua et al., 2007b). Regarding the phenolic compounds of H. chrysanthemifolius, it is reported the presence of quercetin (Flv1), tamarixetin (Flv3), ayanin (Flv7), myricetin 3,7,4′-trimethyl ether (Flv36), luteolin (Flv53), and diosmetin (Flv58) (Faini et al., 1999; Urzua et al., 2007b; Urzúa et al., 2012).

4.8 H. coquimbensis (Hook. & Arn.) Klingenb

The aerial parts of H. coquimbensis (syn. H. hirtellus Phil. (Klingenberg, 2007)) contain the terpenoids 7,13-labdadien-15,18-dioic acid 15-methyl ester (Dit44) and epi-friedelin (Tri2), as well as stigmasterol (Str1) (Maldonado et al., 1993). Regarding its flavonoid profile, the following compounds were detected in its aerial parts: kaempferol 7,4′-dimethyl ether (Flv27), kaempferol 3,7,4′-trimethyl ether (Flv29), pachypodol (Flv46), sakuranetin 4′-methyl ether (Flv68), eriodictyol 7,3′-dimethyl ether (Flv72), 7,4′-dimethylaromadendrin (Flv75), and 7,3′-di-O-methyltaxifolin (Flv81) (Maldonado et al., 1993).

4.9 H. deserticola Phil

In the aerial parts of H. deserticola there were detected the diterpenoids methyl-ent-4-epi-agath-18-oate (Dit17), dimethyl-ent-4-epi-agathoate (Dit18), copaiferolic acid (Dit19), copaiferolic acid 15-methyl ester (Dit20), methyl haplodesertoate (Dit26), 8α-hydroxyanticopalic acid (Dit60), 8α-hydroxyanticopalic acid methyl ester (Dit61), ent-19-hydroxy-cis-cleroda-3,13(E)-dien-15-oic acid (Dit98), and 18-acetoxy-cis-cleroda-3,13(E)-dien-15-oic acid (Dit99), along with the sesquiterpenoid germacrene D (Sqt7) (Zdero et al., 1990; Urzúa Moll et al., 1997; Tojo et al., 1999).

Regarding its phenolic composition, the aerial parts of this species are reported to contain the flavonoids quercetin (Flv1), quercetin 3-methyl ether (Flv2), isokaempferide (Flv23), 3,8-dimethylherbacetin (Flv37), 3,8,4′-trimethylherbacetin (Flv38), and 5,7,4′-trihydroxy-3,8,3′-trimethoxyflavone (Flv39); the coumarins 7-O-prenylscopoletin (Cum10), 7-O-geranylscopoletin (Cum11), O-prenylumbelliferone (Cum15) and the dimeric umbelliferone 3,3-dimethylallyl ether (Cum16), as well as the cinnamic acid derivatives chlorogenic acid (Cin10), 3,4-dicaffeoylquinic acid (Cin11), and 3,5-dicaffeoylquinic acid (Cin12) (Zdero et al., 1990; Tojo et al., 1999; Schmeda-Hirschmann et al., 2015).

4.10 H. diplopappus Remy

The resinous exudate of H. diplopappus is reported to contain the diterpenoid ent-manool (Dit9) and its 13-O-β-xylopyranoside (Dit8) (Urzua et al., 1995a).

4.11 H. foliosus (Hook. & Arn.) Hook. & Arn

H. foliosus is the species for which the greatest number of compounds has been reported. Among them, there are the alkanes C₁₂H₂₆ (Ala3), C₁₄H₃₀ (Ala5), C₁₆H₃₄ (Ala7), C₁₈H₃₈ (Ala9), and C₂₃H₄₈ – C₃₃H₆₈ (Ala14 – Ala24) (Silva and Sammes, 1973; Urzúa et al., 2000; Urzúa, 2004). Furthermore, the aerial parts of this species contain 11-tricosene (Ale1), hexacosanol (Alc1), ethylresorcinol (Alc2), diisopropyl ether (Eth1), α-asarone (Arh3), 1,2,3,4,5,6,7,8-octahydro-1-methylphenantrene (Arh5), eugenol (Arh6), styrene (Arh7), safrol (Arh8), elemicin (Arh9), dihydrobenzofuran (Arh10), benzaldehyde (Ald1), 2,3-dichloro-2-methylpropanal (Ald2), trans-2-hexenal (Ald3), nonanal (Ald4), decanal (Ald5), 3-ethylbenzaldehyde (Ald6), 4-vinylbenzaldehyde (Ald7), 3-hydroxyacetophenone (Ket1), 3-ethylacetophenone (Ket3), 4-ethylacetophenone (Ket4), dihydro-α-ionone (Ket6), 4,4-dimethyl-2-allylcyclohexanone (Ket7), (Z)-3-hexenyl acetate (Est8), tetrahydroactinidiolide (Ltn2), 4-phenyl-2-azetidinone (Ltm1), and stigmasterol (Str1) (Silva and Sammes, 1973; Urzúa et al., 2000; 2010; Urzúa, 2004; Villagra et al., 2021).

The terpenoid fraction of H. foliosus has been thoroughly studied and more than 70 compounds have been reported. Among them, there are the monoterpenoids cis-α-ocimene (Mon1), β-ocimene (Mon2), β-myrcene (Mon3), limonene (Mon8), α-terpinene (Mon9), γ-terpinene (Mon10), terpinen-4-ol (Mon11), terpinolene (Mon16), isoterpinolene (Mon17), α-terpineol (Mon18), p-menth-2-en-4-ol (Mon19), trans-p-menth-2-en-1-ol (Mon21), cis-p-menth-2-en-1-ol (Mon22), α-phellandrene (Mon25), m-cymene (Mon27), p-cymene (Mon28), p-cymen-8-ol (Mon29), o-cumenol (Mon30), 3-carene (Mon31), thujane (Mon32), α-thujene (Mon33), cis-(+/−)-4-thujanol (Mon34), 4-thujanol (Mon35), α-thujone (Mon36), α-pinene (Mon37), β-pinene (Mon38), pinocarveol (Mon39), borneol (Mon42), bornyl acetate (Mon43), camphor (Mon44), camphene (Mon45), fenchol (Mon46), 1,5-dimethyl-6-methylenespiro[2.4]heptane (Mon48), sabinene (Mon49), 5-(acetyloxy)-4,6,6-trimethyl-endobiciclo[2.2.1]heptan-2-one (Mon50), ascaridole (Mon52), and tricyclene (Mon54) (Urzúa et al., 2000; 2010; Urzúa, 2004; Villagra et al., 2021). The equally diverse sesquiterpenoid fraction includes germacrene D (Sqt7), (1α,7β,10β)-11-hydroxy-4-guaien-3-one (Sqt9), (1β,7β,10β)-1,11-dihydroxy-4-guaien-3-one (Sqt10), (1α,6α,7β,10β)-6,11-dihydroxy-4-guaien-3-one (Sqt11), α-selinene (Sqt13), γ-selinene (Sqt14), 5-eudesmen-11-ol (Sqt15), γ-eudesmol (Sqt16), cadalene (Sqt17), α-cadinene (Sqt18), β-cadinene (Sqt19), γ-cadinene (Sqt20), δ-cadinene (Sqt21), guaiol (Sqt22), 1(10),11-eremophiladiene (Sqt23), α-cadinol (Sqt24), ionene (Sqt25), 6-(1,1-dimethylethyl)-2,3-dihydro-1,1-dimethyl-3-methylene-1H-indene (Sqt26), δ-ambrinol (Sqt27), decahydro-3a,8-dimethyl-5-(1-methylethenyl)azulene (Sqt28), 1,2,3,4,5,6,7,8-octahydro-1,4-dimethyl-7-(1-methylethylidene)azulene (Sqt29), β-guaiene (Sqt36), (−)-caryophyllene (Sqt38), epi-bicyclosesquiphellandrene (Sqt39), α-muurolene (Sqt40), γ-muurolene (Sqt41), agarospirol (Sqt42), aromadendrene (Sqt47), α-cubebene (Sqt48), β-cubebene (Sqt49), spathulenol (Sqt52), β-bourbonene (Sqt55), α-copaene (Sqt58), β-copaene (Sqt59), and β-ylangene (Sqt60) (Labbé et al., 1998; Urzúa et al., 2000; 2010; Urzúa, 2004; Villagra et al., 2021). Much less diverse are the reported di- and triterpenoid profiles of the species, which include 2α-hydroxy-cis-clero-3,13(Z),8(17)-trien-15-oic acid (Dit87), 2α-acetoxy-cis-clero-3,13(Z),8(17)-trien-15-oic acid (Dit88), haplopappic acid (Dit96), friedelin (Tri1), and epi-friedelinol (Tri3) (Silva and Sammes, 1973; Urzúa et al., 2003).

The flavonoid profile of H. foliosus has also been thoroughly investigated and reported to include quercetin 3-methyl ether (Flv2), rhamnazin (Flv4), isoquercitrin (Flv10), hyperoside (Flv11), beturetol (Flv15), eupatolin (Flv16), isorhamnetin (Flv18), isorhamnetin 3-β-D-glucoside (Flv19), kaempferol (Flv21), astragalin (Flv22), isokaempferide (Flv23), kaempferol 3-methyl ether 7-β-D-glucoside (Flv24), ermanin (Flv26), kumatakenin (Flv28), haplopappin (Flv31), and haplopappin A (Flv32) (Ulubelen et al., 1982; Tschesche et al., 1985; Urzúa, 2004).

Furthermore, the following coumarins were detected in H. foliosus: esculetin (Cum1), prenyletin (Cum3), scopoletin (Cum9), and scoparone (Cum12) (Ulubelen et al., 1982; Urzúa, 2004), along with the benzoic and cinnamic acid derivatives methyl salicylate (Ben3), trans-cinnamic acid (Cin1), cis-cinnamic acid (Cin2), isobutyl-(E)-cinnamate (Cin3), pentyl-(E)-cinnamate (Cin4), benzyl-(E)-cinnamate (Cin5), and 2-phenylethyl-(E)-cinnamate (Cin6) (Urzúa et al., 2000; Urzúa, 2004; Villagra et al., 2021).

4.12 H. glutinosus Cass

The aerial parts of H. glutinosus are reported to contain 4-hydroxyacetophenone (Ket2), β-farnesene (Sqt2), germacrene D (Sqt7), 6,18-dihydroxy-ent-labd-7,13E-dien-15-oic acid (Dit41), 4-hydroxybenzoic acid (Ben1), syringic acid (Ben2), trans-cinnamic acid (Cin1), caffeic acid (Cin9), and chlorogenic acid (Cin10) (Jakupovic et al., 1986; Marambio and Silva, 1996). Furthermore, the flavonoid profile of the species includes isokaempferide (Flv23), ermanin (Flv26), santin (Flv41), jaceidin (Flv43), apigenin (Flv47), 3,6-dimethoxyapigenin (Flv48), luteolin 5- (Flv54) and 7- (Flv55) glucosides, hispidulin (Flv62), pectolinaringenin (Flv63), 3′,4′-dihydroxyflavone 5-glucoside (Flv65), and verbenacoside (Flv66) (Marambio and Silva, 1996; Valant-Vetschera and Wollenweber, 2007).

4.13 H. integerrimus (Hook. & Arn.) H.M. Hall

Scientific literature only contains information on the flavonoid profile of the leaves of H. integerrimus var. punctatus (Willd.) G.K.Br. & W.D.Clark, according to which the following compounds were detected: quercetin (Flv1), quercetin 3-methyl ether (Flv2), rhamnazin (Flv4), quercetin 3,3′-dimethyl ether (Flv5), quercetin 3,7-dimethyl ether (Flv6), isoquercitrin (Flv10), isorhamnetin (Flv18), myricetin 3′,4′dimethyl ether (Flv34), and myricetin 3,3′,4′-trimethyl ether (Flv35) (Ayanoglu et al., 1981).

4.14 H. litoralis Phil

The resin of H. litoralis is reported to contain the diterpenoids 18α-acetoxylabd-8(17)-en-15-oic acid (Dit3),18-hydroxylabd-8(17)-en-15-oic acid (Dit14), (+)-copalic acid (Dit16), and (−)-eperuic acid (Dit21) (Urzúa et al., 2004b). Moreover, the flavonols ayanin (Flv7) and retusin (Flv8) were identified in the resinous exudate of this species (Urzúa et al., 2012).

4.15 H. multifolius Reiche

The terpenoids 2,9-epoxy-p-menth-6-en-8-ol (Mon51), 9-cis-p-coumaroyloxy-α-terpineol (Sqt12), 18-hydroxylabda-7,13(E)-dien-15-oic acid (Dit39), and 18-hydroxylabda-7,13(Z)-dien-15-oic acid (Dit42) are present in the aerial parts of H. multifolius (Maatooq et al., 2002). However, the phenolic composition of this species has been more thoroughly investigated and the following compounds have been identified: quercetin (Flv1), quercetin 3-methyl ether (Flv2), isorhamnetin (Flv18), persicogenin (Flv69), sternbin (Flv70), 3-O-acetylpadmatin (Flv79), blumeatin B (Flv80), esculetin (Cum1), esculin (Cum2), prenyletin (Cum3), haplopinol (Cum4), 6-deoxyhaplopinol (Cum5), 6-hydroxy-7-(5′-hydroxy-3′,7′-dimethylocta-2′,6′-dien)-oxycoumarin (Cum6), 6-hydroxy-7-(7′-hydroxy-3′,7′-dimethylocta-2′,5′-dien)-oxycoumarin (Cum7), 6-hydroxy-7-[(E,E)-3′,7′-dimethyl-2′,4′,7′-octatrienyloxy] coumarin (Cum8), hernianin (Cum13), umbelliferone (Cum14), O-prenylumbelliferone (Cum15), and 3,5-dicaffeoylquinic acid (Cin12) (Chiang et al., 1982; Nuñez-Alarcón and Quiñones, 1995; Urzúa et al., 1995b; Maatooq et al., 2002; Torres et al., 2004; 2006; 2013; Schmeda-Hirschmann et al., 2015).

4.16 H. parvifolius (DC.) Gay

The group of compounds identified in the aerial parts of H. parvifolius includes mainly diterpenoids, as well as the sesquiterpenoids 2,8-dimethyl-2′-vinyl-5-[4-methyl-pent-3-enyl]-chromane (Sqt43) and aphanamol I (Sqt46) (Zdero et al., 1991b). The diterpenoids detected in this species are 13-hydroxylabda-6,8,14-triene (Dit27), 13-hydroxylabda-6,8(17),14-triene (Dit28), 9α,13-epoxy-labda-6,8(17),14-triene (Dit29), 6β-acetoxy-13-hydroxylabda-8,14-dien-7-one (Dit30), 6β-acetoxy-7β,13-dihydroxylabda-8,14-diene (Dit31), 6β-acetoxy-13-hydroxylabda-7,14-diene (Dit47), 13-hydroxy-6α-butyryloxylabda-7,14-diene (Dit48), 13-hydroxylabda-7,14-diene-6-one (Dit49), 9α,13-dihydroxylabda-7,14-dien-6-one (Dit50), 6α,13-dihydroxylabda-7,14-dien-17-al (Dit51), isomanool (Dit52), 6α-hydroxy-9α,13-epoxy-labda-7,14-diene (Dit53), 6α-acetoxy-9α,13-epoxy-labda-7,14-diene (Dit54), 6α-butyryloxy-9α,13-epoxy-labda-7,14-diene (Dit55), 5α-hydroxy-9α,13-epoxy-labda-7,14-diene-6-one (Dit56), 6α-acetoxy-9α,13-epoxy-labda-7,14-dien-17-al (Dit57), 6-oxo-14,15-nor-labda-7-ene (Dit58), 8α,13-dihydroxylabda-6,14-diene (Dit66), 8α,13-dihydroxylabda-5,14-dien-7-one (Dit67), epi-manoyl oxide (Dit68), 6,7-dehydro-13-epi-manoyl oxide (Dit69), 6,7-dehydro-8,13-bis-epi-manoyl oxide (Dit70), 13,17-epoxy-labda-5,7,14-triene (Dit71), 9α,13-epoxy-5α,8α-dihydroxylabda-6,14-diene (Dit72), 5α-hydroxy-7,8-epoxy-7,8-seco-6,7-dehydro-13-epi-manoyl oxide (Dit73), haploparvone (Dit103), 5α-hydroxyhaploparvone (Dit104), haploparviolide (Dit105), 1,1,5,6-tetramethyl-4-[3-hydroxy-3-methyl-pent-(4)-enyl]-tetralin (Dit106), and 1,1,5-trimethyl-6-(3-hydroxy-3-methyl-pent-4-enyl)-tetralin (Dit107) (Zdero et al., 1991b).

4.17 H. poeppigianus (Hook. & Arn.) A. Gray

The aerial parts of H. poeppigianus (syn. H. canescens (Phil.) Reiche (Klingenberg, 2007)) contain the flavonoid compounds centaureidin (Flv14), myricetin (Flv33), chrysoeriol (Flv56), diosmetin (Flv58), hispidulin (Flv62), and scutellarein 6-β-D-glucoside (Flv64) (Oksuz et al., 1981).

4.18 H. paucidentatus Phil

The aerial parts of H. paucidentatus contain 4-hydroxyacetophenone (Ket2) and the terpenoids germacrene D (Sqt7), caryophyllene oxide (Sqt34), 8-oxo-β-cyperone (Sqt45), 18-hydroxy-friedolabd-5-en-15-oic acid (Dit78), 18-hydroxy-cis-cleroda-3-en-15-oic acid (10βH, 16ξ, 19β, 17β, 20α form) (Dit83), 19-hydroxy-cis-cleroda-3-en-15-oic acid (10βH, 16ξ, 19β, 17β, 20α form) (Dit85), 18-hydroxy-cis-cleroda-3,13(E)-dien-15-oic acid (Dit93), and 18-acetoxy-cis-cleroda-3,13(E)-dien-15-oic acid (Dit99) (Jakupovic et al., 1986).

4.19 H. pulchellus DC

Regarding the compounds identified in the aerial parts of H. pulchellus, those include the diterpenoids 7α-hydroxylabd-8(17)-en-15,18-dioic acid (Dit4), labd-7-en-15,18-dioic acid (Dit36), 18-acetoxy-friedolabd-5-en-15-oic acid (Dit76), 18-acetoxy-friedolabd-5-en-7-one-15-oic acid (Dit77), 18-hydroxy-friedolabd-5-en-15-oic acid (Dit78), 18-hydroxy-7-oxo-friedolabd-5-en-15-oic acid (Dit79), friedolabd-5-en-15,18-dioic acid (Dit80), and 15-hydroxy-friedolabd-5-en-18-oic acid (Dit81) (Zdero et al., 1991a).

4.20 H. remyanus Wedd

The esters benzenepropanoic acid, 2-methyl-6-methylene-2,7-octadienyl ester (Est3), (±)-1-acetoxy-2-(p-tolyl)-2-propanol (Est4), 2-hydroxy-2-(4-methylphenyl)propyl benzenepropanoate (Est5), 2-hydroxy-2-(4-methyl-3-cyclohexen-1-yl)propyl benzenepropanoate (Est6), and 2-hydroxy-2-(4-methyl-3-cyclohexen-1-yl)propyl 3-phenyl-2-propenoate (Est7) have been detected in the aerial parts of H. remyanus (Zdero et al., 1991a). Regarding its terpenoid profile, the species contains uroterpenol (Mon12), 9-benzoyloxy-(1-formyl)-α-terpineol (Mon13), 9-benzoyloxy-α-terpineol (Mon14), 7-hydroxy-9-benzoyloxy-α-terpineol (Mon15), 8-hydroxy-9-acetoxy-β-phellandrene (Mon26), 18-hydroxylabda-7,13(E)-dien-15-oic acid (Dit39), 18-acetoxy-labda-7,13(E)-dien-15-oic acid (Dit40), and 18-dihydrocinnamoyloxy-labda-7,13E-dien-l5-oic acid (Dit46) (Zdero et al., 1991a; Faini et al., 2011). Morever, the following flavonoid compounds are present in H. remyanus: quercetin (Flv1), 3-O-acetyl-7-methylquercetin (Flv9), kaempferol 7,4′-dimethyl ether (Flv27), kaempferol 3,7,4′-trimethyl ether (Flv29), 3-O-acetyl-7,4′-dimethylkaempferol (Flv30), sakuranetin 4′-methyl ether (Flv68), eriodictyol (Flv71), pinostrobin (Flv74), 7,4′-dimethylaromadendrin (Flv75) and alpinone 3-acetate (Flv83) (Zdero et al., 1991a; Faini et al., 2011).

4.21 H. rengifoanus Remy

The aerial parts and/or leaves of H. rengifoanus are reported to contain the sesquiterpenoid liguloxide (Sqt57) and the flavonoids quercetagetin 3-methyl ether (Flv12), quercetagetin 3,7-dimethyl ether (Flv13), isorhamnetin (Flv18), isorhamnetin 3-β-D-glucoside (Flv19), isorhamnetin 3-β-D-galactoside (Flv20), apigenin (Flv47), luteolin (Flv53), and scutellarein 6-β-D-glucoside (Flv64) (Ulubelen et al., 1981; Zdero et al., 1991a).

4.22 H. rigidus Phil

The diterpenoids rigiduside (Dit6), 18-acetoxy-cis-clerode 3,13(Z)-dien-15 oic acid (Dit82), rigidusol (Dit100), and deacetylrigidusol (Dit101) are present in the aerial parts of H. rigidus (Morales et al., 2000a; 2000b; 2003). Furthermore, the flavonoids quercetin 3-methyl ether (Flv2), beturetol (Flv15), kaempferol (Flv21), isokaempferide (Flv23), sakuranetin (Flv67) and sternbin (Flv70) were detected in the aerial parts (Morales et al., 2000a; 2003; 2009; Schmeda-Hirschmann et al., 2015), along with 3,5-dicaffeoylquinic acid (Cin12) (Schmeda-Hirschmann et al., 2015).

4.23 H. schumannii (Kuntze) G.K. Br. & W.D. Clark

The alkanes C₂₃H₄₈ – C₃₁H₆₄ (Ala14 – Ala22) and C₃₃H₆₈ (Ala14) have been identified in the aerial parts of H. schumannii, along with 1-octadecyne (Aly1), dihydro-α-ionone (Ket6), and the lactone tetrahydroactinidiolide (Ltn2) (Urzúa et al., 2004a). The terpenoid profile of this species includes the sesquiterpenoids β-cadinene (Sqt19), β-bourbonene (Sqt55), and globulol (Sqt56), as well as the diterpenoids manool (Dit7), (−)-eperuic acid (Dit21), epi-manool (Dit25), 8α-hydroxylabdan-15-oic acid (Dit59), and 2-oxoclerod-3-en-15-oic acid (Dit86) (Urzúa et al., 1997; 2004a). Moreover, the flavonoids quercetin (Flv1), isoquercitrin (Flv10), vicenin-2 (Flv49), vitexin (Flv50), and isovitexin (Flv51) are present in the leaves of H. schumannii (Ates et al., 1982).

4.24 H. scrobiculatus (Nees) DC

The presence of the terpenoids α-farnesene (Sqt1), 18-hydroxymanool (Dit15), and 2-oxokolavenic acid (Dit94) has been reported in the case of the aerial parts and resinous exudates of H. scrobicultus (Rossomando et al., 1995; Urzúa et al., 2004b). However, the largest group of compounds in this species is that of phenolics, namely, quercetin (Flv1), isoquercitrin (Flv10), isorhamnetin (Flv18), isorhamnetin 3-β-D-glucoside (Flv19), rhamnocitrin (Flv25), santin (Flv41), eupatorin (Flv42), penduletin (Flv45), vicenin-2 (Flv49), vitexin (Flv50), isovitexin (Flv51), isoschaftoside (Flv52), eupafolin (Flv59), 6-methoxyluteolin 4′-methyl ether (Flv60), cirsiliol (Flv61), and esculetin (Cum1) (Ates et al., 1982; Rossomando et al., 1995; Urzúa et al., 2012).

4.25 H. taeda Reiche

The terpenoid profile of H. taeda includes taedol (Mon41), 18-hydroxylabda-7,13(E)-dien-15-oic acid (Dit39), 7,13-labdadien-15,18-dioic acid (Dit43), cleroda-3,13 (E)-dien-15,18-diol (Dit95), and 18-acetoxy-cis-cleroda-3,13(E)-dien-15-oic acid (Dit99) (Marambio and Silva, 1989; Torres et al., 2005; Faini et al., 2007; 2008). However, scientific literature provides more information on the phenolic composition of this species, with the following compounds being reported: quercetin (Flv1), quercetin 3-methyl ether (Flv2), quercetin 3,7-dimethyl ether (Flv6), kaempferol (Flv21), sakuranetin (Flv67), sternbin (Flv70), eriodictyol 7,3′-dimethyl ether (Flv72), eriodictyol 7,3′,4′-trimethyl ether (Flv73), 3-O-acetyl-7-O-aromadendrin (Flv77), padmatin (Flv78), 3-O-acetylpadmatin (Flv79), 9-trans-p-coumaroyloxy-α-terpineol (Cin7), 7-trans-p-coumaroyloxy-taedol (Cin8), chlorogenic acid (Cin10), 3,4-dicaffeoylquinic acid (Cin11), and 3,5-dicaffeoylquinic acid (Cin12) (Marambio and Silva, 1989; Faini et al., 2007; 2008; Schmeda-Hirschmann et al., 2015).

4.26 H. uncinatus Phil

The alkanes C₂₃H₄₈ – C₃₁H₆₄ (Ala14 – Ala22) and C₃₃H₆₈ (Ala14) have been identified in the resinous exudates and/or aerial parts of H. uncinatus (Urzúa et al., 2000; 2004a; 2006), along with 2,7-dimethyl-5-(1-methylethenyl)-1,8-nonadiene (Ale3) and 3,5-dihydroxy-3′,4′,6,7-tetramethoxyflavone (Flv40) (Urzúa et al., 2004a; 2006). Regarding its terpenoid profile, the species is reported to synthesize 3,3,7,7-tetramethyl-5-(2-methyl-1-propenyl)-tricyclo[4.1.0.0(2,4)]heptane (Mon53), the sesquiterpenoids cadalene (Sqt17), aromadendrene (Sqt47), α-cubebene (Sqt48), β-cubebene (Sqt49), spathulenol (Sqt52), cedryl acetate (Sqt53), β-bourbonene (Sqt55), globulol (Sqt56), α-copaene (Sqt58), as well as the clerodane diterpenoid 18-acetoxy-cis-cleroda-3-en-15-oic acid (10βH, 16ξ, 19β, 17β, 20α form) (Dit84) (Urzúa et al., 2000; 2004a; 2006).

4.27 H. velutinus Remy; H. velutinus Remy subsp. illinitus (Phil.) Klingenb

Several compounds are reported to be present in both H. velutinus and the subspecies H. velutinus subsp. illinitus. These are the alkanes C₂₃H₄₈ – C₃₁H₆₄ (Ala14 – Ala22) and C₃₃H₆₈ (Ala14), 5,5-dimethyl-2(5H)-furanone (Fur1), β-myrcene (Mon3), limonene (Mon8), α-pinene (Mon37), β-pinene (Mon38), labd-7-en-15,18-dioic acid-18α-methylester (Dit37), β-sitosterol (Str2), and quercetin (Flv1) (Latorre et al., 1990; Marambio and Silva, 1996; Faini et al., 2002; Urzúa et al., 2004a; Echeverría et al., 2019).

In contrast, compounds solely identified in H. velutinus include 3-ethyl-1,4-hexadiene (Ale2), 2-nonyn-1-ol (Alc3), 2-pentadecen-1-ol (Al4), n-dodecenyl-1-ol (Alc5), vanillin (Ald8), picein (Ket5), lavender lactone (Ltn1), linalyl anthranilate (Mon5), davanone (Mon6), davana ether (Mon7), 1,2:8,9-diepoxy-p-menthane (Mon19), cis-p-menth-2-en-1-ol (Mon22), trans-pulegone oxide (Mon23), α-campholenal (Mon24), m-cymene (Mon27), α-thujene (Mon33), pinocarveol (Mon39), trans-2-pinanol (Mon40), cis-verbenol (Mon47), α-sinensal (Sqt3), humulene epoxide II (Sqt6), caryophyllene oxide (Sqt34), α-guaiene (Sqt35), (−)-oplopanone (Sqt37), spathulenol (Sqt52), patchouli alcohol (Sqt54), dehydropinipholic acid 19-methyl ester (Dit11), 4α-hydroxy-18-norlabd-8(17)-en-15-oic acid (Dit12), 4β-hydroxy-19-norlabd-8(17)-en-15-oic acid (Dit13), 18-hydroxylabd-8(17)-en-15-oic acid (Dit14), 7,13-(E)-labdadien-15,18-dioic-acid-18-methyl ester (Dit45), friedelin (Tri1), epi-friedelinol (Tri3), taraxerol (Tri4), erythrodiol (Tri5), stigmasterol (Str1), isoquercitrin (Flv10), isokaempferide (Flv23), kumatakenin (Flv28), luteolin (Flv53), and scopoletin (Cum9) (Urzúa and Mendoza, 1989; Urzúa et al., 1991; Urzúa et al., 1995a; 2004a; Urzua and Mendoza, 1993; Marambio and Silva, 1996; Echeverría et al., 2019).

The group of compounds identified solely in the subspecies H. velutinus subsp. illinitus consists of 3,3,5,5-tetramethylcyclopentene (Ale4), methyl octanoate (Est1), 5-methyl-octanoic acid methyl ester (Est2), β-cadinene (Sqt19), procerin (Mer1), as well as the diterpenoids 7α-hydroxylabd-8(17)-en-15,18-dioic acid-15-methylester (Dit5), pinifolic acid 15-methyl ester (Dit22), pinifolic acid 18-methyl ester (Dit23), pinifolic acid dimethyl ester (Dit24), labd-7-en-15,18-dioic acid (Dit36), labd-7-en-15,18-dioic acid-15-methylester (Dit38), and 7-oxo-labd-8(9)-en-15,18-dioic acid-15-methylester (Dit10), (Faini et al., 2002; Urzúa et al., 2004a).

5 Traditional uses and evidence-based pharmacological activities related to human health

5.1 Traditional uses

The plants of the genus Haplopappus are of high medicinal value and form essential part of the traditional medicines of the Andean region (Chile, Argentina), where the genus presents high endemicity. Haplopappus species and their preparations have traditionally been associated with numerous health benefits, associated with multiple aspects of the human health and also with veterinary applications (Table 5).

TABLE 5.

Traditional uses of Haplopappus species.

Species	Plant part(s) – preparation(s)	Traditional use(s)	References
Haplopappus spp.	whole plant (alone or combined with Satureja parvifolia or Lycopodium Saururus); aerial parts; leaf/aerial parts infusion (with or without milk); stem juice; resin (applied externally or ingested)	antidiarrheic; antiseptic; antispasmodic; antitussive; aphrodisiac; cholagogue; choleretic; cicatrizant (in particular, to treat horses); digestive; disinfectant; emmenagogue; hepatic; stimulant; sudorific; against altitude sickness, abdominal colic, dysentery, chronic dyspepsia, colds, flu and urinary diseases	Alonso, 2005; de Mösbach (1992), Hoffmann et al. (1992), Mellado Campos (1996), Ministerio de Salud (2010), Montes and Wilkomirsky (1987), Ratera and Ratera (1980), Schrickel and Bittner (2001)
H. baylahuen	whole plant; aerial parts; leaf/aerial parts infusion; leaf decoction; stem juice; taken with milk	aphrodisiac; antidiarrheic; antirheumatic; antiseptic; antispasmodic; antitussive; antiviral, astringent; carminative; cholagogue; choleretic; cicatrizant (in particular, to treat horses and other animals); digestive; disinfectant; emmenagogue; expectorant; hepatic; stimulant; stomachic; against altitude sickness, chronic hemorrhagic intestinal inflammation, colds, flu, flatulent dyspepsia, dysentery, gastritis, male and female hormonal disorders, pneumonia, pains provoked by air currents, genital, renal and urinary disorders	Cárdenas (1998), Del Vitto et al. (2010), Espinoza (1897), Gómez-Parra and Siarez Flores (1995), Hoffmann et al. (1992), Houghton and Manby (1985), Laval (1957), Madaleno and Delatorre-Herrera (2013), Ministerio de Salud (2010), Montes and Wilkomirsky (1987), Mostny et al. (1954), Munizaga (1963), Munizaga and Gunkel (1958), Muñoz S. et al. (1981), Murillo (1861), 1889; Remington and Woods (1918), Serracino et al. (1974), Steinmetz (1954), Vogel et al. (2005b)
H. multifolius	whole plant; leaf infusion	antidiarrheic; antiseptic; digestive; emmenagogue; hepatic; stomachic; against dysentery and urinary disorders	Muñoz S. et al. (1981), Vogel et al. (2005b)
H. remyanus	whole plant; leaf infusion	antidiarrheic; antiseptic; antispasmodic; digestive; emmenagogue; hepatic; stomachic; against dysentery and urinary disorders	Montes and Wilkomirsky (1987), Muñoz S. et al. (1981), Vogel et al. (2005b)
H. rigidus	whole plant; aerial parts infusion; taken with milk; decoction with fruits of Opuntia camachoi Espinosa	antirheumatic; antitussive; aphrodisiac; diuretic; febrifuge; hepatic; laxative; stomachic; against colds, flu, pains provoked by air currents, pneumonia, renal colic, cardiac pain, gastrointestinal, ovary and urinary disorders; against veterinary ailments	Aldunate et al. (1981), Gómez et al. (1997), Hoffmann et al. (1992), Mellado Campos (1996), Monterrey (1996), Montes and Wilkomirsky (1987), Muñoz S. et al. (1981), Ratera and Ratera (1980), Villagrán et al. (2003), 1998; Wickens (1993)
H. taeda	whole plant; resinous leaves; leaf infusion	antidiarrheic; antiseptic; digestive; emmenagogue; hepatic; stomachic; against dysentery, intestinal and urinary disorders	Faini et al. (2007), Vogel et al. (2005b)

The main health benefits traditionally attributed to different preparations of Haplopappus plants are associated with pathologies of the human alimentary tract and metabolism. Various species and preparations have widespread use as digestives, antidiarrheic, remedies against dyspepsia, dysentery and gastrointestinal ailments, in general.

Moreover, there are reported several traditional uses associated with the human genitourinary system, with Haplopappus preparations being considered as aphrodisiacs, emmenagogues, diuretic and as remedies against urinary and renal disorders and colics or even against male and female hormonal disorders.

Other traditional uses are associated with health benefits for the human respiratory (antitussives, expectorants, cold remedies) and nervous (stimulant, antispasmodic) system, as well as with their role as disinfectants.

Finally, it is well-documented in traditional Andean medicines the use of Haplopappus preparations as cicatrizants with veterinary applications, especially to treat horses’ wounds.

It has to be mentioned that H. baylahuen Remy is recognized by the Chilean health authorities as a traditional herbal medicine against liver diseases, abdominal colics, chronic dyspepsia, kidney stones, flus and colds, as well as an aphrodisiac and wound disinfectant (Ministerio de Salud, 2010). Meanwhile, pharmaceutical products that include bailahuén, e.g., the formulations ‘Ulcenat’ and ‘Ubenat’ (Grüne Leben) and ‘Bailahuen extracto fluido’ (Knop Laboratorios S.A.) are commercialized in Chile as treatments against digestive disorders. However, there are no internationally or nationally established norms and/or protocols regarding quality, standardization, safety, and adulteration control of bailahuén preparations and commercial products.

5.2 Evidence-based pharmacological activity related to the human health

Scientific literature provides evidence related to various human health-promoting effects of extracts and isolated compounds of Haplopappus species (Table 6), with their inhibitory effect against human pathogens of bacterial origin being the most thoroughly investigated.

TABLE 6.

Biological activity attributed to the species of the genus Haplopappus.

Biological activity	Plant species	Plant part(s)	Type of extract and/or isolated compound	Outcome	References
Antibacterial	H. anthylloides	resin	extract (CH2Cl2)	In vitro growth inhibition of Bacillus anthracis, B. pumilis, B. subtilis, Escherichia coli, Micrococcus flavus, M. luteus, Proteus vulgaris, Pseudomonas aeruginosa, Staphylococcus aureus, S. epidermidis	Urzúa et al. (1995b)
	H. baylahuen	aerial parts	decoction, extracts (EtOH, EtOAc)	In vitro growth inhibition of Acremonium falciforme, Bacillus subtilis, Staphylococcus aureus	Lazo, (1990)
		leaves	extract (H2O/EtOH)	Bactericide activity against Salmonella enteritidis and inhibition of its ability to form biofilm, express adrA/hilA genes and adhere to Caco-2 cells	Elgueta et al. (2021)
	H. chrysanthemifolius	resin	extract (MeOH)	In vitro growth inhibition of Bacillus cereus, B. subtilis, Enterococcus faecalis, Listeria monocytogens, Micrococcus luteus, Staphylococcus aureus	Urzúa et al., 2004a, 2012
	H. deserticola	resin	18-acetoxy-cis-cleroda-3,13(E)-dien-15-oic acid (Dit99)	Bactericidal effect against Streptococcus mutans	Urzúa Moll et al. (1997)
	H. diplopappus subsp. diplopappus	resin	extract (CH2Cl2)	In vitro growth inhibition of Bacillus anthracis, B. pumilis, B. subtilis Bordetella bronchiseptica, Micrococcus flavus, M. luteus, Proteus vulgaris, Pseudomonas aeruginosa, Staphylococcus aureus, S. epidermidis	Urzúa et al. (1995b)
			13-O-β-xylopyranosyl-ent-manool (Dit8)		Urzúa et al. (1995a)
	H. foliosus	resin	extracts (MeOH, CH2Cl2)	In vitro growth inhibition of Bacillus anthracis, B.cereus, B. coagulans, B. pumilis, B. subtilis, Micrococcus luteus, Proteus vulgaris, Staphylococcus aureus, S. epidermidis	Urzúa et al., 1995b, 2003; Urzúa and Mendoza, 2001
			2α-hydroxy-cis-clero-3,13(Z),8(17)-trien-15-oic acid (Dit87); 2α-acetoxy-cis-clero-3,13(Z),8(17)-trien-15-oic acid (Dit88)	In vitro growth inhibition of Bacillus cereus, B. coagulans, B. subtilis, Micrococcus luteus, Staphylococcus aureus	Urzúa et al. (2003)
	H. litoralis	resin	extract (MeOH)	In vitro growth inhibition of Bacillus cereus, B. subtilis, Enterococcus faecalis, Listeria monocytogens, Micrococcus luteus, Staphylococcus aureus	Urzúa et al., 2004, 2012
	H. multifolius	aerial parts	esculetin (Cum1)	In vitro growth inhibition and bactericide effect against Escherichia coli, Sarcina lutea, Staphylococcus aureus	Chiang et al. (1982)
			prenyletin (Cum3)	In vitro growth inhibition and bactericide effect against Sarcina lutea, Staphylococcus aureus
			haplopinol (Cum4)	In vitro growth inhibition and bactericide effect against Escherichia coli, Staphylococcus aureus
		aerial parts	extracts (EtOH), infusion	In vitro growth inhibition of Bacillus cereus, B. subtilis, Staphylococcus aureus, S. epidermidis, S. pyogenes	Padilla et al. (2021)
		resin	extract (CH2Cl2)	In vitro growth inhibition of Bacillus anthracis, B. pumilis, B. subtilis, Bordetella bronchiseptica, Micrococcus flavus Proteus vulgaris, Pseudomonas aeruginosa, Staphylococcus aureus	Urzúa et al. (1995b)
	H. rigidus	aerial parts	extracts (EtOH/H2O, CHCl3, EtOAc)	In vitro growth inhibition of Bacillus cereus, B. subtilis, Corynobacterium minutissimum, Enterococcus faecalis, Listeria monocytogenes, Staphylococcus aureus, S. lugdunesis	Morales et al., 2003; Ortiz et al., 2019
	H. schumannii	resin	extract (CH2Cl2)	In vitro growth inhibition of Bacillus anthracis, B. pumilis, B. subtilis, Bordetella bronchiseptica, Escherichia coli, Micrococcus flavus, M. luteus, Proteus vulgaris, Staphylococcus aureus, S. epidermidis	Urzúa et al. (1995b)
	H. scrobiculatus	resin	extracts (MeOH, CH2Cl2)	In vitro growth inhibition of Bacillus anthracis, B. cereus, B. pumilis, B. subtilis, Enterococcus faecalis, Escherichia coli, Listeria monocytogens, Micrococcus flavus, M. luteus, Proteus vulgaris, Staphylococcus aureus, S. epidermidis	Urzúa et al., 1995b; Urzúa et al., 2004, 2012
	H. taeda	aerial parts	extracts (EtOH), infusion	In vitro growth inhibition of Bacillus cereus, B. subtilis, Staphylococcus agalactiae, S. aureus, S.epidermidis, S. pyogenes	Padilla et al. (2021)
	H. uncinatus	resin	extract (MeOH)	In vitro growth inhibition of Bacillus cereus, B. coagulans, B. subtilis, Micrococcus luteus, Staphylococcus aureus	Urzúa and Mendoza, (2001)
			extract (CH2Cl2)	In vitro growth inhibition of Bacillus anthracis, B. pumilis, B. subtilis, Bordetella bronchiseptica, Escherichia coli, Micrococcus flavus, M. luteus, Proteus vulgaris, Staphylococcus aureus, S. epidermidis	Urzúa et al. (1995b)
		aerial parts	resin	In vitro growth inhibition of Bacillus cereus, B. subtilis, Micrococcus luteus	Urzúa et al. (2006)
			18-acetoxy-cis-cleroda-3-en-15-oic acid (10βH, 16ξ, 19β, 17β, 20α form) (Dit84)
	H. velutinus	resin	extract (CH2Cl2)	In vitro growth inhibition of Bacillus anthracis, B. pumilis, B. subtilis, Bordetella bronchiseptica, Proteus vulgaris, Micrococcus flavus, M. luteus, Staphylococcus aureus, S. epidermidis	Urzúa et al. (1995b)
	H. velutinus subsp. illinitus	resin	extract (CH2Cl2)	In vitro growth inhibition of Bacillus anthracis, B. pumilis, B. subtilis, Bordetella bronchiseptica, Micrococcus flavus, Pseudomonas aeruginosa, Staphylococcus aureus	Urzúa et al. (1995b)
Antidysenteric	H. baylahuen	resin	extract suspended in milk, cream or almond emulsion	Symptomatic treatment of dysentery in humans	Fingland, (1903)
Anti-inflammatory	H. baylahuen	aerial parts	aqueous extract	Inhibition of carrageenan-induced edema in rats	Adzet and Gene, (1991)
	H. multifolius	leaves	esculetin (Cum1); esculin (Cum2); prenyletin (Cum3); 6-hydroxy-7-(5′-hydroxy-3′,7′-dimethylocta-2′,6′-dien)-oxycoumarin (Cum6); 6-hydroxy-7-(7′-hydroxy-3′,7′-dimethylocta-2′,5′-dien)-oxycoumarin (Cum7); umbelliferone (Cum14); O-prenylumbelliferone (Cum15)	In vitro inhibition of soybean 15-lipoxygenase (15-sLOX)	Torres et al. (2013)
	H. remyanus	resin	extract	Inhibition of arachidonic acid-induced ear edema in mice	Faini et al. (2011)
	H. taeda	-	extract (EtOH); taedol (Mon41); 18-acetoxy-cis-cleroda-3,13(E)-dien-15-oic acid (Dit99); sakuranetin (Flv67)	Inhibition of arachidonic acid-induced ear edema in mice	Faini et al. (2008)
Antioxidant	H. baylahuen	commercial product (herbal tea)	infusion	Antioxidant capacity in vitro (ORAC, TEAC-ABTS, HClO quenching and ONOO−quenching assays)	Speisky et al., 2006; Alarcón et al., 2008
		aerial parts	infusion, extract (MeOH)	Antioxidant capacity in vitro (DPPH assay)	Schmeda-Hirschmann et al. (2015)
		leaves	infusion, extract (MeOH, H2O/EtOH, EtOH), resin	Antioxidant capacity in vitro (DPPH assay)	Vogel et al., 2005a; Méttola et al., 2018; Elgueta et al., 2021
	H. deserticola	aerial parts	infusion, extract (MeOH)	Antioxidant capacity in vitro (DPPH assay)	Schmeda-Hirschmann et al. (2015)
	H. multifolius	aerial parts	infusion, extract (MeOH)	Antioxidant capacity in vitro (DPPH assay)	Schmeda-Hirschmann et al. (2015)
		aerial parts	quercetin (Flv1); isorhamnetin (Flv18); prenyletin (Cum3); haplopinol (Cum4); 6-hydroxy-7-(5′-hydroxy-3′,7′-dimethylocta-2′,6′-dien)-oxycoumarin (Cum6); 6-hydroxy-7-(7′-hydroxy-3′,7′-dimethylocta-2′,5′-dien)-oxycoumarin (Cum7); 6-hydroxy-7-[(E,E)-3′,7′-dimethyl-2′,4′,7′-octatrienyloxy] coumarin (Cum8)	Antioxidant capacity in vitro (DPPH assay)	Torres et al. (2006)
		leaves	infusion, extract (MeOH), resin	Antioxidant capacity in vitro (DPPH assay)	Vogel et al. (2005a)
	H. remyanus	leaves	infusion, extract (MeOH), resin	Antioxidant capacity in vitro (DPPH assay)	Vogel et al. (2005b)
	H. rigidus	aerial parts	sternbin (Flv70)	Antioxidant capacity in vitro (TEAC – ABTS, DPPH assay)	Morales et al. (2009)
		aerial parts	infusion, extract (MeOH)	Antioxidant capacity in vitro (DPPH assay)	Schmeda-Hirschmann et al. (2015)
	H. taeda	resin, aerial parts	9-trans-p-coumaroyloxy-α-terpineol (Cin7); 7-trans-p-coumaroyloxy-taedol (Cin8)	Antioxidant capacity in vitro (DPPH assay)	Faini et al. (2007)
		aerial parts	infusion; extract (MeOH)	Antioxidant capacity in vitro (DPPH assay)	Schmeda-Hirschmann et al. (2015)
		leaves	infusion, extract (MeOH), resin	Antioxidant capacity in vitro (DPPH assay)	Vogel et al. (2005b)
Antitumoral	H. remyanus	resin	extract (CH2Cl2)	Cytotoxic effect against T-lymphoblastic leukemia cell line (CCRF-CEM)	Faini et al. (2011)
	H. rigidus	aerial parts	rigidusol (Dit100)	Cytotoxic effect against human breast adenocarcinoma cell line (MCF-7)	Morales et al., 2000a; Vogel et al., 2005a
			sternbin (Flv70)	Cytotoxic effect against human breast adenocarcinoma (MCF-7), human lung carcinoma (A-549) and human colon adenocarcinoma (HT–29) cell lines	Morales et al. (2009)
Diuretic	H. baylahuen	leaves	extract (EtOH)	Diuretic effect on Wistar rats	Méttola et al. (2018)
Hepatoprotective	H. baylahuen	aerial parts	infusion; 7-O-methylaromadenrin (Flv76)	Decrease of glutamic pyruvic transaminase (GTP) levels in serum of rats under CCl4-induced liver injury	Nuñez-Alarcon et al. (1993)
			infusion	Reduction of serum bilirubin concentration, bromosulfophthalein and alanine aminotransferase activity in dogs under CCl4-induced liver injury	Martin et al. (1988)
Inhibitory of lipid peroxidation	H. baylahuen	leaves	infusion; extracts (MeOH, EtOH)	Inhibition of lipid peroxidation in vitro and in erythrocyte membranes	Vogel et al., 2005; Méttola et al., 2018
	H. multifolius	leaves	infusion; extract (MeOH)	Inhibition of lipid peroxidation in erythrocyte membranes	Vogel et al. (2005a)
	H. remyanus	leaves	infusion; extract (MeOH)	Inhibition of lipid peroxidation in erythrocyte membranes	Vogel et al. (2005a)
	H. rigidus	aerial parts	sternbin (Flv70)	Inhibition of iron/ascorbate-induced lipid peroxidation in rat cells	Morales et al. (2009)
	H. taeda	leaves	infusion; extract (MeOH)	Inhibition of lipid peroxidation in erythrocyte membranes	Vogel et al. (2005a)
Muscle relaxant	H. rigidus	aerial parts	extracts (H2O, MeOH, CH2Cl2)	Relaxation of L-phenylephrine precontracted corpus cavernosum smooth muscles of Guinea pigs	Hnatyszyn et al. (2003)
Inhibition of GLUT1 transporter	H. baylahuen	leaves	rhamnetin (Flv17)	Inhibition of GLUT1 transporter in human myeloid HL-60 cells, in transfected Chinese hamster ovary cells overexpressing GLUT1, and in normal human erythrocytes; inhibition of binding of cytochalasin B to GLUT1 in erythrocyte ghosts	Vera et al. (2001)
			isorhamnetin (Flv18)

5.2.1 H. anthylloides meyen & walp

Although the bioactivity of the species H. anthylloides has not been extensively studied, it is reported that dichloromethane extracts of its resinous exudates present antibacterial effects, inhibiting the in vitro growth of several human pathogenic bacteria (Urzúa et al., 1995a).

5.2.2 H. baylahuen remy

Haplopappus baylahuen is the species with the highest number of bioactivity studies. Extracts and decoctions of its aerial parts are reported to have antibacterial and bactericide effects against Staphylococcus aureus, Bacillus subtilis, Acremonium falciforme (Lazo, 1990) and Salmonella enteritidis (Elgueta et al., 2021). Moreover, emulsions of its resin have been successfully used to treat the symptoms of dysentery in affected individuals (Fingland, 1903), while extracts of the aerial parts of H. baylahuen have shown anti-inflammatory (Adzet and Gene, 1991), diuretic (Méttola et al., 2018) and hepatoprotective (Nuñez-Alarcon et al., 1993) effects in rat models and hepatoprotective activity in dog models (Martin et al., 1988). The hepatoprotective effect in rats under CCl₄-induced liver injury has also been confirmed in the case of 7-O-methylaromadenrin (Flv76) isolated from the aerial parts of the plant (Nuñez-Alarcon et al., 1993). Moreover, rhamnetin (Flv17) and isorhamnetin (Flv18) isolated from the leaves of H. baylahuen have been found to inhibit in a dose-dependent manner the glucose transporter GLUT1 in human cell lines and in vivo in hamsters (Vera et al., 2001). Finally, extracts of the aerial parts of this species have demonstrated significant antioxidant capacity as measured by various in vitro assays (Vogel et al., 2005a; Speisky et al., 2006; Alarcón et al., 2008; Schmeda-Hirschmann et al., 2015; Méttola et al., 2018; Elgueta et al., 2021), while also inhibiting lipid peroxidation in vitro and in erythrocyte membranes (Vogel et al., 2005a; Méttola et al., 2018).

5.2.3 H. chrysanthemifolius (Less.) DC

In the case of H. chrysanthemifolius, scientific evidence supports the antibacterial effect of the methanolic extracts of its resinous exudates, as this has been demonstrated through the in vitro growth inhibition of several Gram-positive human pathogenic bacterial strains (Urzúa et al., 2004b; 2012).

5.2.4 H. deserticola Phil

The diterpene 18-acetoxy-cis-cleroda-3,13(E)-dien-15-oic acid (Dit99) isolated from the resin of H. deserticola presented a bactericidal effect against Streptococcus mutans (Urzúa Moll et al., 1997), while the in vitro antioxidant capacity of the infusion and methanolic extract of the plant’s aerial parts has also been documented (Schmeda-Hirschmann et al., 2015).

5.2.5 H. diplopappus Remy subsp. diplopappus

The resin of H. diplopappus subsp. diplopappus, as well as the isolated diterpenoid 13-O-β-xylopyranosyl-ent-manool (Dit8) present antibacterial effect against various Gram-positive and Gram-negative human pathogenic bacteria (Urzúa et al., 1995a).

5.2.6 H. foliosus (Hook. & Arn.) Hook. & Arn

Scientific evidence supports the antibacterial effect of the resinous exudate of H. foliosus against several Gram-positive and Gram-negative human pathogenic bacteria (Urzúa et al., 1995a; 2003; Urzúa and Mendoza, 2001). Similar bioactivity has been attributed to the diterpenes 2α-hydroxy-cis-clero-3,13(Z),8(17)-trien-15-oic acid (Dit87) and 2α-acetoxy-cis-clero-3,13(Z),8(17)-trien-15-oic acid (Dit88) which were isolated from the resin of H. foliosus (Urzúa et al., 2003).

5.2.7 H. litoralis Phil

In the case of H. litoralis, it has been reported that its resinous exudate inhibits the in vitro growth of Bacillus cereus, B. subtilis, Enterococcus faecalis, Listeria monocytogens, Micrococcus luteus, S. aureus (Urzúa et al., 2004b; 2012).

5.2.8 H. multifolius reiche

Scientific literature provides evidence that support the antibacterial effect of H. multifolius resin and aerial parts extracts against a wide spectrum of Gram-positive and Gram-negative human pathogenic bacteria (Urzúa et al., 1995a; Padilla et al., 2021). Moreover, similar antibacterial activity has been documented for the coumarins esculetin (Cum1), prenyletin (Cum3) and haplopinol (Cum4) isolated from the aerial parts of this species (Chiang et al., 1982). Regarding the in vitro antioxidant capacity of H. multifolius, this has been demonstrated in the case of extracts, aerial parts infusions and resin (Vogel et al., 2005a; Schmeda-Hirschmann et al., 2015), as well as for the isolated compounds quercetin (Flv1), isorhamnetin (Flv18), prenyletin (Cum3), haplopinol (Cum4), 6-hydroxy-7-(5′-hydroxy-3′,7′-dimethylocta-2′,6′-dien)-oxycoumarin (Cum6), 6-hydroxy-7-(7′-hydroxy-3′,7′-dimethylocta-2′,5′-dien)-oxycoumarin (Cum7) and 6-hydroxy-7-[(E,E)-3′,7′-dimethyl-2′,4′,7′-octatrienyloxy] coumarin (Cum8) (Torres et al., 2006). Furthermore, the isolated compounds esculetin (Cum1), esculin (Cum2), prenyletin (Cum3), 6-hydroxy-7-(5′-hydroxy-3′,7′-dimethylocta-2′,6′-dien)-oxycoumarin (Cum6), 6-hydroxy-7-(7′-hydroxy-3′,7′-dimethylocta-2′,5′-dien)-oxycoumarin (Cum7), umbelliferone (Cum14) and O-prenylumbelliferone (Cum15) have demonstrated an anti-inflammatory effect associated to the in vitro inhibition of soybean 15-lipoxygenase (Torres et al., 2013). Finally, methanolic extracts and infusions of H. multifolius leaves inhibited the lipid peroxidation in erythrocyte membranes (Vogel et al., 2005a).

5.2.9 H. remyanus wedd

Infusions, methanolic extracts and resin from the leaves of H. remyanus demonstrated a significant antioxidant capacity in vitro, while also inhibiting lipid peroxidation in erythrocyte membranes (Vogel et al., 2005a). Furthermore, the resinous exudates of the plant exhibited an anti-inflammatory effect in mice (Faini et al., 2011) and a cytotoxic effect against T-lymphoblastic leukemia cell line (CCRF-CEM) (Faini et al., 2011).

5.2.10 H. rigidus Phil

Extracts of the aerial parts of H. rigidus have effectively inhibited the in vitro growth of several Gram-positive bacterial strains (Morales et al., 2003; Ortiz et al., 2019), presented a significant in vitro antioxidant capacity (Schmeda-Hirschmann et al., 2015) and also acted as muscle relaxants in Guinea pig models (Hnatyszyn et al., 2003). The isolated flavanone sternbin (Flv70) presented high in vitro antioxidant capacity, lipid peroxidation inhibitory effects in rat cells and also antitumoral effect against the human breast adenocarcinoma (MCF-7), human lung carcinoma (A-549) and human colon adenocarcinoma (HT–29) cell lines (Morales et al., 2009). The isolated diterpene rigidusol (Dit100) also had a cytotoxic effect on human breast adenocarcinoma cells line (MCF-7) (Morales et al., 2000b).

5.2.11 H. schumannii (Kuntze) G.K. Br. & W.D. Clark

The resinous exudates of H. schumannii inhibited the in vitro growth of several Gram-positive bacterial human pathogens (Urzúa et al., 1995a).

5.2.12 H. scrobiculatus (Nees) DC

Similarly, the only known bioactivity regarding the resin of H. scrobiculatus is that of the in vitro antibacterial effect against several Gram-positive bacteria (Urzúa et al., 1995a; 2004b; 2012).

5.2.13 H. taeda reiche

Ethanolic extracts and infusions of aerial parts of H. taeda successfully inhibited the in vitro growth of several Bacillus and Staphylococcus bacterial strains (Padilla et al., 2021). Regarding the in vitro antioxidant capacity of the species, this has been shown to be significant in the case of aerial parts infusions, extracts and resinous exudates (Vogel et al., 2005a; Schmeda-Hirschmann et al., 2015), as well as for the isolated compounds 9-trans-p-coumaroyloxy-α-terpineol (Cin7) and 7-trans-p-coumaroyloxy-taedol (Cin8) (Faini et al., 2007). Moreover, leaf infusions and methanolic extracts of H. taeda inhibited lipid peroxidation in erythrocyte membranes (Vogel et al., 2005a). Ethanolic extracts, as well as the isolated compounds taedol (Mon41), 18-acetoxy-cis-cleroda-3,13(E)-dien-15-oic acid (Dit99), and sakuranetin (Flv67) exhibited an anti-inflammatory effect against arachidonic acid-induced ear edema in mice (Faini et al., 2008).

5.2.14 H. uncinatus Phil

Extracts of the aerial parts and resinous exudates of H. uncinatus, as well as the isolated diterpenoid 18-acetoxy-cis-cleroda-3-en-15-oic acid (10βH, 16ξ, 19β, 17β, 20α form) (Dit84) have been reported to inhibit in vitro the growth of various Gram-positive human pathogenic bacteria (Urzúa et al., 1995a; 2006; Urzúa and Mendoza, 2001).

5.2.15 H. velutinus remy, H. velutinus Remy subsp. illinitus (Phil.) Klingenb

Dichloromethane extracts of the resinous exudates of H. velutinus and its subspecies H. velutinus subsp. illinitus inhibited in vitro the growth of various Gram-positive and Gram-negative human pathogenic bacteria (Urzúa et al., 1995a).

6 Non-human health related bioactivity and toxicity

Among the pharmacological activities attributed to Haplopappus species and not related to the human health, the most studied is the antimicrobial effect against plant pathogens. The essential oil of the leaves of H. baylahuen inhibited the in vitro growth of the fungi Aspergillus nigra and Fusarium oxysporum (Becerra et al., 2010). Moreover, the diterpenoid 7,13-(E)-labdadien-15,18-dioic acid 18-methyl ester (Dit45) was isolated from the resinous exudate of Haplopappus velutinus and inhibiting in vitro the mycelial growth of Botrytis cinerea (Echeverría et al., 2019). In the case of the phytopathogenic bacterium Clavibacter michiganensis subsp. michiganensis, its in vitro growth was inhibited by the resin (Urzúa and Mendoza, 2001) and the isolated diterpene 18-acetoxy-cis-cleroda-3-en-15-oic acid (10βH, 16ξ, 19β, 17β, 20α form) (Dit84) (Urzúa et al., 2006) from H. uncinatus, as well as by the methanolic extract of the resin of H. foliosus (Urzúa and Mendoza, 2001).

The essential oil of H. foliosus also exhibited insecticide effects against house flies (Musca domestica) (Urzúa et al., 2010), while hydroethanolic and chloroform extracts of H. rigidus presented biotoxic activity against Artemia salina (Morales et al., 2003).

7 Concluding remarks and future perspectives

The available scientific literature on the genus Haplopappus can be said to support, although partially, its widespread and longstanding use as a medicinal plant. However, the results of the present review highlight several limitations that need to be addressed.

Firstly, phytochemical and bioactivity research of the genus Haplopappus is largely concentrated in the 1990s and 2000s, with almost 80% of the investigation having been performed before 2010. Therefore, a revival of scientific interest and the application of modern, more advanced and diverse analytical and biological techniques can further elucidate the composition and bioactivity of Haplopappus plant species, thus broadening the existing knowledge and promoting its potential uses.

Furthermore, phytochemical and pharmacological evidence is available only for the 40% and 23%, respectively, of the botanical taxa of the genus Haplopappus, while for many of the studied taxa, the available information is rather limited. Similarly, terpenoids and phenolics correspond to approximately 70% of the compounds reported in Haplopappus spp., suggesting that scientific investigation up to date has possibly understudied other chemical groups. It is, therefore, suggested to extend the focus of scientific research to more, if not all, Haplopappus species and groups of chemical compounds, thus permitting to fully explore its promising chemical and biological prospects.

Based on the available bioactivity and pharmacological evidence, Haplopappus species can be considered as a valuable plant resource for health-promoting applications. However, the majority of the investigation provides evidence associated to the in vitro antibacterial and antioxidant activity of the genus Haplopappus. In contrast, there is a lack of scientific evidence to support or refute various traditional uses, while, at the same time, the limited number of in vivo studies and/or clinical trials hinders its wider human health-promoting application and secure use.

In this context, the information presented in the present review supports the ethnopharmacological, phytochemical and bioactive potential of the genus Haplopappus, while addressing the aforementioned limitations could further promote and broaden both scientific research and future applications and uses.

Funding Statement

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. We gratefully acknowledge support from Comisión Nacional de Investigación Científica y Tecnológica—CONICYT PAI/ACADEMIA No. 79160109 and from Dirección de Investigación Científica y Tecnológica—DICYT USACH 022341EM_Ayudante.

Author contributions

CM: Writing–review and editing, Writing–original draft, Methodology, Investigation, Formal Analysis, Data curation, Conceptualization. JE: Writing–review and editing, Writing–original draft, Supervision, Project administration, Methodology, Investigation, Formal Analysis, Data curation, Conceptualization.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2024.1490243/full#supplementary-material