Introduction

The genus Pulicaria Gaertn. (family: Asteraceae) belongs to the tribe Inuleae, which comprises 82 accepted species of shrubs, shrublets, and herbs (Coutinho and Dinis 2009; POWO 2024). These Pulicaria species are native to Africa, temperate Eurasia to the Indian Subcontinent (Salleh et al. 2021; POWO 2024). Traditionally, Pulicaria species have a long history of use as a tonic, herbal tea, galactagogues, anti-epileptics, carminative, and insect repellent (Mirghani et al. 2020; Zekry et al. 2021). Recent pharmacological investigations on Pulicaria species showed various medicinal properties, such as antimicrobial, anticancer, antioxidant, anti-inflammatory, and antipyretic (Maggio et al. 2015). Among these, anticancer activity is commonly reported in most Pulicaria species (Alamdary and Baharfar 2023). These Pulicaria species are essential oil-bearing plants. The phytochemicals reported in these Pulicaria species include polyphenols, terpenes, diterpenes, sesquiterpenes, triterpenes, caryophyllenes, and steroids (Alamdary and Baharfar 2023). However, flavonoids and sesquiterpenoids are the major class of phytochemicals within the genus Pulicaria (Liu et al. 2010).

Basically, Pulicaria is a taxonomically problematic genus (Coutinho and Dinis 2009). Taxonomic ambiguities have also been reported in the Pulicaria species occurring in Qatar, primarily because of their morphological resemblance. In Qatar, Pulicaria species such as Pulicaria crispa (Forssk.) Oliv. (Synonym: Pulicaria undulata subsp. undulata), Pulicaria undulata (L.) C.A.Mey., Pulicaria sicula (L.) Moris, and Pulicaria gnaphalodes (Vent.) were reported earlier (Abdel-Bari 2012). However, P. crispa has merged into P. undulata and is considered a single species (Hind and Boulos 2002). The local taxonomists believe that there are two distinct species or perhaps subspecies of P. undulata in Qatar, but this has not yet been proven scientifically (Abdel-Bari 2012). Here, it is noteworthy that P. undulata subsp. undulata is an accepted subspecies (POWO 2024). P. undulata is widely spread across Qatar and is locally called Jithjath/Yethyas (Abdel-Bari 2012). P. gnaphalodes, locally known as Nufaij, is more commonly found in northeast and central Qatar. However, P. sicula (local name: Shay Al Jabal) is a rarely occurring species in Qatar (Abdel-Bari 2012; Norton et al. 2009). Figure 1 shows the images of the three main species of Pulicaria that occur in Qatar.

Fig. 1
figure 1

A Pulicaria undulata C.A.Mey B Pulicaria gnaphalodes (Vent.) Boiss. and C) Pulicaria sicula (L.) Moris [Photos: M. Alsafran, D. Kasote]

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Besides medicinal uses, these Pulicaria species have considerable significance in the local food chain of Qatar, including Arabian/Persian region countries. Hence, to understand the phytochemical uniqueness and therapeutic significance of each of these species, including species differentiation at the subspecies level, a comparative review of literature about these species based on their traditional knowledge, phytochemistry, and health benefits is critical. Thus, this article aims to comparatively review the available literature about botany, traditional uses, phytochemistry, and biological and pharmacological activities of these species, and provide insight into their phytochemical uniqueness and future potential utilization. We believe that this review will help to understand the phytochemical diversity among these species, including the therapeutic or nutraceutical value of each of these species.

Research methodology

The available information on the three species and one subspecies of Pulicaria was retrieved using electronic databases such as Scopus, and PubMed. Books and monographs published in English were used to collect information. The search was conducted from publications from all years until Dec. 2023 by the combination of the search terms and Boolean operators; ‘Pulicaria’ OR ‘traditional uses’ OR ‘ethnopharmacology’ AND ‘essential oil’ OR ‘flavonoids’ OR ‘biological and pharmacological activity’. The Plant List and Royal Botanical Garden, Kew databases were used to authenticate the botanical names of plants (POWO 2024). The information about the occurrence and distribution of species in Qatar was obtained from the Digital Flora of Qatar (https://www.floraofqatar.com/).

Botanical description

P. undulata is a perennial aromatic low compact suffrutescent herb with numerous basal branches that form a circular compact growth. Flowers in small yellow capitula on long peduncles (Abdel-Bari 2012). P. sicula is a yellow flowered woolly aromatic herb with numerous upright branches ending in sweet-scented capitula much larger than in other Pulicaria species (Abdel-Bari 2012). P. gnaphalodes is an aromatic perennial plant producing a cluster of strongly branched stems from a thick rootstock. Flowers yellow, small, in capitula carried on slender peduncles (Abdel-Bari 2012).

Traditional uses in Qatar and the arabian/persian region

In Qatar, all these Pulicaria species are traditionally used as herbal tea (Abdel-Bari 2012). However, several other medicinal properties have been reported for these species in the Arabian/Persian region countries (Table 1). The significance of each of these species in traditional uses appears to be linked with their widespread distribution in the region. P. undulata is a widespread species in Saudi Arabia, Egypt, Sudan, Qatar, and Yemen. It is locally known as “Gethgath” in Saudi Arabia and Egypt, and in Yemen, its local name is “Koaa, ensif. Mashmoom” (Al-Haj et al. 2019; Abd-ELGawad et al. 2021; Foudah et al. 2015). Due to the inconsistent use of names, the reported traditional uses of P. crispa and P. undulata are almost identical (Foudah et al. 2015; Abd-ELGawad et al. 2021). There is little known information about the traditional use of P. sicula due to its limited and rare occurrence in the region. In the Persian region, P. gnaphalodes widely distributed species and is reported as a medicinal plant, locally known as “Kakkosh-Biabani” (Hassanabadi et al. 2023).

Table 1 Traditional uses of Pulicaria species
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Phytochemistry

Volatile organic compounds (VOCs)

Being aromatic plants, the chemical composition of essential oils of these species has been extensively studied. In general, aerial parts of these species were mostly used for the extraction of essential oils. However, in some studies, essential oils were also extracted from Flowers and leaves (Al-Qudah et al. 2022; Abd-ELGawad et al. 2021; Maggio et al. 2015). Hydro-distillation (HD) is the preferred method for the extraction of essential oils from these species. Along with this, solid phase micro-extraction (SPME) is also used to extract the essential oils from the Flowers and leaves (Al-Qudah et al. 2022). Extraction methods were found to have a considerable impact on the composition and amounts of volatile organic compounds (VOCs) extracted in essential oils (Al-Qudah et al. 2022). In almost all reported studies, gas chromatography-mass spectrometry (GC–MS) is used for qualitative and quantitative estimation of VOCs in essential oils of these species.

P. crispa is a synonym of P. undulata subsp. undulata. However, almost all information about this subspecies is found in the literature with the older name ‘P. crispa’, though this is not currently an ‘accepted' name. Herein, we have reviewed literature about P. crispa and P. undulata to differentiate them at the subspecies level based on reported phytochemistry and bioactivities. VOCs of essential oils mainly include compounds from two groups: terpene hydrocarbans and oxygenated compounds (Tongnuanchan and Benjakul, 2014). So far, over 300 VOCs have been reported in the essential oils of these Pulicaria species (Table 2). Approximately 147, 176, 64, and 54 VOCs have been reported in P. crispa, P. undulata, P. sicula, and P. gnaphalodes, respectively. Of these, nearly 83, 110, 37, and 22 VOCs were exclusively reported in the essential oils of P. crispa, P. undulata, P. sicula, and P. gnaphalodes, respectively. On the contrary, around 64 VOCs are reported in two or more species (Table 2). Oxygenated monoterpenes and sesqueiterpenes are the dominant VOCs in the essential oils of these species, followed by sesquiterpene and monoterpene hydrocarbans, respectively (Table 2).

Table 2 Distribution of the volatile compounds in the Qatari Pulicaria species
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Essential oils from aerial parts, Flowers, and leaves of P. crispa have been extracted and chemically characterized using GC–MS. Hydro-distillation of P. crispa aerial parts, Flowers, and leaves yielded yellow-colored oils (Al-Qudah et al. 2022; Mohamed et al. 2020). Available literature suggested that essential oils extracted from different parts of P. crispa are dominated by oxygenated hydrocarbans (sesquiterpenes and monoterpenes). P. crispa can be distinguished from other Pulicaria species based on the presence of sesquiterpenes of the xanthane nucleus, which is not common in the genus (Liu et al. 2010). The main reported constituents in the essential oil from aerial parts of P. crispa were 1,4-ditert butylbenzene (22.81%), caryophyllene (13.19%), carvone (11.80%), and neryl(s)-2-methylbutanoate (10.33%) (Mohamed et al. 2020). Chrysanthenone, p-cymene-8-ol, 7-epi-α-eudesmol, and 2,6-dimethyl phenol were the major VOCs in the essential oils of P. crispa leaves and Flowers (Al-Qudah et al. 2022). The essential oil extracted from aerial parts of the Saudi P. crispa was rich in β-caryophyllene oxide (33.97%) and modephene (23.34%) (AlMotwaa and Al-Otaibi 2022). However, it has been found that essential oils obtained from the different parts of P. crispa showed considerable quantitative and qualitative differences (Al-Qudah et al. 2022). Similar variations in the composition of essential oils of P. crispa have been seen in plants collected from different locations (Yusufoglu et al. 2021). Moreover, the essential oil extracted from P. crispa leaves and Flowers using an HD method had a higher amount of phenolic compounds than SPME, this highlights the impact of the extraction procedure as well (Al-Qudah et al. 2022). Similarly, the essential oil obtained from aerial parts of Iranian P. crispa was characteristically rich in τ-cadinol (53.5%) and β-caryophyllene (10.8%) (Yusufoglu et al. 2021). Taken together, eleven VOCs (1,4-ditert butylbenzene, β-caryophyllene, carvone, neryl(s)-2-methylbutanoate, Chrysanthenone, p-cymene-8-ol, 7-epi-α-eudesmol, 2,6-dimethyl phenol, β-caryophyllene oxide, modephene, τ -cadinol) have been reported to be present in the high amount in the different essential oils of P. crispa (Fig. 2). Of this, carvone, eryl(s)-2-methylbutanoate, p-cymene-8-ol,7-epi-α-eudesmol, 2,6-dimethyl phenol, and modephene are solely reported in essential oils of P. crispa so far that can be marker compounds for characterization P. crispa essential oils.

Fig. 2
figure 2

A Major and distinguishable volatile organic compounds (VOCs) in the essential oil of P. cripa. B Exclusively reported phenolic acids, flavonoids, and other polyphenols in the P. cripa

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The yellow-colored essential oil was obtained from aerial parts and leaves of P. undulata, with a yield of 0.5–2.1% (Ali et al. 2012; Issa et al. 2020a, b). Carvotanacetone (< 90%) was the major VOC in the essential oils of Egyptian and Yemeni P. undulata leaves and aerial parts followed by 2,5-dimethoxy-p-cymene (Ali et al. 2012; Issa et al. 2020a, b).

However, the essential oil of Algerian P. undulata also had carvotanacetone (14.8%) as a main compound, followed by δ-cadinene (8.2%), α-cadinol (4.7%), epi-α-cadinol (3.4%), and thujanol (4.6%). The observed low level of carvotanacetone compared to the literature was attributed to the different climates, seasons, geographic locations, and harvesting periods of the plants (Boumaraf et al. 2016). However, carvotanacetone was not reported as the main compound in the essential oil obtained from aerial parts of Iranian P. undulata. The main components identified in this oil were 4-terpineole (20.12%), 1S-cis-calamenene (13.37%), junipene (8.66%), α-terpinene (4.02%), cis-sabinene hydrate (8.29%), γ-terpinene (7.00%), and linalool (5.60%) (Ravandeh et al. 2011).

Similarly, essential oils of Saudi and Egyptian ecospecies of P. undulata had major VOCs: pinene, isoshyobunone, 6-epi-shyobunol, α-pinene, α-terpinolene, pathulenol, hexahydrofarnesyl acetone, α-bisabolol, and τ -cadinol. Substantial variations (both quantity and quality) have been seen in essential oils obtained from these species, which was attributed to the difference in the environmental and climatic conditions (Abd-ELGawad et al. 2021). Among these, some of these VOCs (2,5-dimethoxy-p-cymene, epi-α-cadinol, thujanol, 1S-cis-calamenene, junipene, isoshyobunone, 6-epi-shyobunol, spathulenol, hexahydrofarnesyl acetone, α-bisabolol) are solely reported in P. undulata essential oils so far and that can be chemical markers for its characterization (Fig. 3).

Fig. 3
figure 3

Major and distinguishable volatile organic compounds in the essential oil of P. undulata

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The VOCs composition of the Italian P. sicula essential oil showed a peculiar profile containing around 37 compounds. Among these, borneol was the main compound identified in the P. sicula essential oil (Maggio et al. 2015). The structure of borneol is shown in Fig. 4.

Fig. 4
figure 4

Structures of borneol (a major volatile organic compound in the essential oil of P. sicula) and exclusively reported flavonols in P. sicula

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The essential oils obtained from Iranian P. gnaphalodes have around 22 distinguishable VOCs (Table 2). α-pinene (32.2%) and 1–8-cineole (10.9–22.9%) were the major components in this essential oil (Gandomi et al. 2015; Batoli et al. 2017). However, these two compounds are also reported in the other Pulicaria species. In other studies, besides these two, amorpha-4,9-dien-2-ol, calamenene-10-one, longifolol, ar-curcumen-15-al, trans-calamenen-10-ol, curcumenol, and cedr-8(15)-en-9-α-ol were also reported as major and distinguishable VOCs (Batoli et al. 2017; Gandomi et al. 2015; Hassanabadi et al. 2022). Of these nine compounds, α-pinene and 1–8-cineole are reported other species as well. Hence, the remaining VOCs can be used as maker compounds for the characterization of P. gnaphalodes essential oils (Fig. 5).

Fig. 5
figure 5

A Major and distinguishable volatile organic compounds (VOCs) reported in the essential oil of P. gnaphalodes. B Exclusively reported phenolic acids and flavonoids in the P. gnaphalodes

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Flavonoids and phenolic compounds

In these Pulicaria species, flavonoids and sesquiterpenes are the most studied classes of compounds. So far, nearly or over 45 different flavonoids have been identified in these species (Table 3). Besides this, 9 phenolic acids and other polyphenols are also reported in these species (Table 3).

Table 3 Flavonoids, phenolic and non-essential oil fractions terpene compounds reported in the Qatari Pulicaria species
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In P. crispa, most of the flavonoids and phenolic compounds have been identified in methanolic extracts of its aerial parts, including Flowers and leaves (Foudah et al. 2015; El-Sabagh et al. 2021; Rizk et al. 1993; Thinina et al. 2020). Around, 29 different flavonoids, phenolic acids, and other polyphenols have been identified in P. crispa. Of these, 14 are flavonoids, followed by 8 phenolic acids and 7 other polyphenols (Table 3). Among these reported compounds, 20 flavonoids, phenolic acids, and other polyphenols are only reported in the P. crispa (Table 3, Fig. 2). Both flavonoid aglycones and flavonoid glycosides have been reported in P. crispa (El-Sabagh et al. 2021; Thinina et al. 2020). Along with phenolic acids,

p-hydroxybenzoic acid, and hydroxycinnamoylquinic acid conjugates such as cafffeoyl-, and p-coumaroyl quinic acids were also reported in the methanolic extract of P. crispa aerial parts (El-Sabagh et al. 2021). Other reported polyphenols in the methanolic extracts of P. crispa aerial parts include tannins, such as ellagic acid and proanthocyanidin dimer (Thinina et al. 2020).

Flavonoids are reported compounds in the different parts of P. undulata (whole plant, aerial parts, Flowers, and leaves). Out of 23 reported compounds, 19 are flavonoids. Among these 19 reported flavonoids, 12 are exclusively identified in the P. undulata. So far, several flavonoids and their glycosides have been isolated from the aqueous methanolic extract of P. undulata (70–95%) (Elhady et al. 2021; Hussien et al. 2016; Hussein et al. 2017; Bishay et al. 1982). Caffeic acid phenethyl ester and caffeic anhydride are the two polyphenolic compounds solely reported in P. undulata so far (Abdel Bar et al. 2020; Mohammed et al. 2021). The structures of characteristic flavonoids and polyphenolic compounds exclusively reported in P. undulata are shown in Fig. 6.

Fig. 6
figure 6

Structures of characteristic flavonoids and polyphenolic compounds reported in P. undulata

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It has been reported that the occurrence of 6-oxygenation of flavonols is a common feature of P. sicula (Wollenweber et al. 2005). Among 11 reported flavonoids in aerial parts of P. sicula, 10 were quercetagetin derivatives (Wollenweber et al. 2005). Except, quercetagetin 3,6,7,3',4'-pentamethyl ether, all are solely reported in the P. sicula that can be used as chemical marker compounds for the characterization of this plant species (Table 3, Fig. 4).

So far, 2 phenolic acids and 10 flavonoids have been isolated from the aerial parts of the P. gnaphalodes (Table 3). Of these, p-anisic acid (phenolic acid) and 5 flavonoids are exclusively reported in the P. gnaphalodes (Fig. 5).

Non-essential oil fractions sesquiterpenes, diterpenes and triterpenes

Besides essential oil fractions, sesquiterpenes, diterpenes, and triterpenes compounds are isolated from these Pulicaria species. Sesquiterpenes are the main reported compounds in the P. crispa. Most of these sesquiterpenes were isolated from the methanolic extracts of P. crispa aerial parts (El-Sabagh et al. 2021; Stavri et al. 2008a, 2008b; Dendougui et al. 2000; Abdel-Mogib et al. 1990; Bohlmann et al. 1979). So far, 18 sesquiterpenes have been isolated and characterized from aerial parts of P. crispa. Of these, 17 sesquiterpenes are exclusively reported in the P. crispa (Table 3). Among the 5 reported diterpenes, salvicinolide, salvicinolin, and hardwickiic acid were solely isolated diterpenes from the methanolic extracts of P. crispa aerial parts.

It has been found that P. undulata is rich in sesquiterpene lactones. So far, around 23 sesquiterpenes have been isolated from the whole plant or aerial part of P. undulata (Table 3). Interestingly, all are exclusively reported in the P. undulata so far (Table 3). Sesquiterpene lactone, 2α-hydroxyalantolactone was one of the major metabolites isolated from the P. undulata (Hegazy et al. 2021). Besides this, 5 ditepenes and 4 triterpenes have been isolated from P. undulata. Among these, grandifloric acid-15-β-glucoside (diterpenoid), ent-16β,17-dihydroxy-kauran-19-oic acid (diterpenoid), pulicaroside-B (diterpenoid), 13-dihydro-4H-xanthalongin 4-O-β-D-glucopyranoside (triterpenoid), 23hydroxytormenticacid (triterpenoid), and 8-epi-ivalbin (triterpenoid) were exclusively isolated from the P. undulata (Abdel Bar et al. 2020; Hussien et al. 2016; Hussein et al. 2017; Hegazy et al. 2015; Rasool et al. 2008, 2013; Elhady et al. 2021; Rustaiyan et al. 1991).

Sesquiterpene lactones such as neryl isobutyrate, thymol derivatives, xanthanolides, and guaianolides were isolated from the Qatari P. sicula aerial part (Zdero et al. 1988). Clerodane-type diterpenoid such as salvin, salvinin, casticin, and 7-oxo-15,16-epoxy-trans-cleroda-3,13(14)-dien-19,6-olide have been isolated from the aerial parts of Uzbek P. gnaphalodes (Komilov et al. 2019; Eshbakova et al. 2018). Sesquiterpenes such as anabsinthin, isointermedeol, and gnapholide were characteristically isolated from the chloroform extract of Pakistani P. gnaphalodes (Ali et al. 2002, 1999; Sarg 1975).

Other compounds

Besides the above class of compounds, organic acids (quinic acid and malic acid) and fatty acids have also been identified in the methanolic extracts of P. crispa aerial parts (El-Sabagh et al. 2021). Xanthoxyline (methyl ketone) and stigmasterol (phytosterols) were isolated from the 95% methanolic extract of aerial parts of P. undulata (Elhady et al. 2021). Stigmasterol and β-sitosterol have been isolated from the aerial part of the Pakistani P. gnaphalodes (Ali et al. 1999; Sarg 1975).

Biological and pharmacological activities

Antimicrobial activity

Controlling microbial infectious diseases is becoming a major public health concern worldwide, mainly due to the emergence of antibiotic resistance and biofilm-forming microbes, including the limited availability of antibiotics (Kasote et al. 2023). Considering this, these days, extensive research has been undertaken about developing new antibiotics, including exploring new antimicrobials from plants and other natural products. Thus far, these Pulicaria species have been extensively investigated for their antimicrobial activity (Table 4). Among these, P. crispa and P. undulata are the most studied in the context of their antimicrobial activity, followed by P. gnaphalodes and P. sicula.

Table 4 Biological and pharmacological activities of Qatari Pulicaria species
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Essential oils, alcoholic extracts, and their fractions of P. crispa whole plant or aerial parts are reported to exhibit antimicrobial activity. The essential oil obtained from P. crispa was found to have an antibacterial effect against Gram-positive bacteria such as Staphylococcus aureus and methicillin-resistant S. aureus (MRSA), but not against Gram-negative bacteria (AlMotwaa and Al-Otaibi 2022). In another study, essential oil and methanol extract of P. crispa displayed similar and broad-spectrum antibacterial activity, particularly against Gram-positive bacteria such as S. aureus. Significant antifungal activities were observed in essential oil than in methanolic extract (Mohamed et al. 2020). The ethanol and hexane extracts of aerial parts of P. crispa were found to be effective against only Gram-positive bacteria (MIC-1–8 mg/ml) and yeast, Candida albicans (MIC-1 mg/ml) (Abdelah Bogdadi, 2007). Similarly, different extracts (methanol, chloroform, diethyl ether, acetone, and water) of whole P. crispa plants were studied for antibacterial activity against Gram-positive and -negative bacteria. All the studied extracts showed activity only against S. aureus. However, methanol extract was the most potent among these (Ejaz et al. 2023). In another study, methanol extract of P. crispa aerial parts and its fractions (hexane, dichloromethane, ethyl acetate, and water) were investigated against Gram-positive and -negative bacterial isolates and found that the hexane fraction (HF) was the most potent against the studied bacteria, which not only inhibited bacterial growth (minimum inhibitory concentration (MIC)-15.6–125 μg/ml) but also killed the bacteria (minimum bactericidal concentration (MBC)-31.25–250 μg/ml). Based on the observed MBC/MIC ratio, HF had a bactericidal effect against all tested bacteria. The bactericidal effect of HF was linked with its ability to reduce the expression levels of penicillin-binding protein (PBP2A) and DNA gyrase B enzymes in S. aureus and Pseudomonas aeruginosa, respectively. This observed anti-PBP2A and anti-DNA gyrase B effects of the HF were attributed to its main phytoconstituents such as β-sitosterol, phytol, stigmasterol, and lupeol. Moreover, HF also showed a dose-dependent inhibition of biofilm formation. At a concentration of 250 µg/ml, HF significantly reduced biofilm formation in Proteus mirabilis, S. aureus (ATCC 25923), Acinetobacter baumannii (ATCC 19606), and P. aeruginosa by 63.33%, 75.21%, 81.85%, and 85.52%, respectively. Similarly, HF fraction (250 µg/ml) was effective in inducing biofilm detachment in all the above-tested bacterial strains (Abo-Elghiet et al. 2023). The antibacterial and antifungal activities of methanol extract of P. crispa aerial parts and its fractions (n-hexane, chloroform, ethyl acetate, and n-butanol) were also investigated in another study. It was found that ethyl acetate fraction (EAF) exhibited the strongest antibacterial effect against Klebsiella pneumonia, S. aureus (animal pathogenic isolate), and S. aureus ATCC 29213, with MIC, 5 mg/ml. This activity was even stronger than the reference standard used, ciprofloxacin. The EAF also exhibited the strongest antifungal effect against C. albicans (animal pathogenic isolate), C. albicans ATCC 60193, and C. tropicalis ATCC 66029, with MIC values of 5 mg/ml and 25 mg/ml, respectively (AlZain et al. 2023). Besides this, polyphenolic extract of P. crispa Flowersy tops, containing quercetin as a major component, was reported to prevent the formation of biofilms in K. pneumoniae and inhibit 80% of planktonic forms. The observed MIC of this extract was in the range of 0.21–3.40 mg gallic acid equivalent (GAE) (Thinina et al. 2020).

Likewise, essential oils, different extracts, and their isolates of P. undulata are studied for antibacterial activity, including anti-quorum-sensing activity. Essential oil and the methanolic extract of P. undulata inhibited the growth of various tested Gram-positive and -negative bacteria, including fungi (Mohamed et al. 2020). The essential oil obtained from P. undulata (L.) C. A. Mey. and P. jaubertii E. Gamal-Eldin (syn. Pulicaria orientalis Jaub. & Spach) leaves showed strong bactericidal activity against S. aureus and MRSA, as well as C. albicans with MBC in the range 3.12–6.25 μl/ml (Ali et al. 2012). However, it has been found that the methanolic extract had a significantly higher inhibitory effect on the fungal skin pathogens than the essential oil. These tested strains of dermatophytes were more susceptible to methanolic extract than the opportunistic pathogenic strains of Candida and Aspergillus. Furthermore, the methanolic extract exhibited higher inhibitory activity against the fungi: Microsporum boulardii IFM 56403, Trichophyton mentagrophytes AUMC 11661, Microsporum canis AUMC 11663, and C. albicans AUMC 9142 than the essential oil (Mohammed et al. 2020). Interestingly, a fungicidal effect was only observed for methanolic extract, but not for essential oil (Helal et al. 2019). In general, like P. crispa, the alcoholic extract of P. undulata was also found to be most effective against Gram-positive bacteria (Elbalola and Abbas 2023). The ethanol extract (95%) of P. undulata demonstrated antimicrobial activity only against the Gram-positive bacteria but not against the tested Gram-negative bacteria, or fungi. The observed MICs and MBCs values were 49–1560 μg/ml and 49–3125 μg/ml against the tested Gram-positive bacteria, respectively (Mohammed et al. 2021). In another study, among the different solvent extracts studied, chloroform extract of P. undulata aerial parts showed potent activity against Gram-positive bacteria (MIC/MBC: 50–120 μg/ml) (Alshehri and Ghobashy, 2020). It has been reported that the phenolic compounds of P. undulata exhibited remarkable antimicrobial and anti-quorum-sensing activities compared to terpenoid compounds, such as sesquiterpenoids and terpenoids (Abdel Bar et al. 2020). The quorum-sensing potential of methylene chloride (CH2Cl2) and ethyl acetate extracts, including isolates of P. undulata aerial parts were investigated along with their antibacterial and antifungal activities (Abdel Bar et al. 2020). Phenolic compounds viz., caffeic acid, quercetin, and axillarin exhibited strong antibacterial activity against S. aureus. However, only axillarin showed pronounced antifungal activity against C. albicans. The flavonoids such as axillarin, and quercetin exhibited remarkable quorum-sensing (QS) inhibition (4.5 and 4.0 mm, respectively) comparable to that of the standard compound, catechin (QS 4.8 mm). The predominance of these aglycones in the CH2Cl2 extract may account for its higher activity (QS 3.5 mm) compared to the ethyl acetate extract (Abdel Bar et al. 2020).

So far, P. sicula has been the least investigated species for its biological and pharmacological activities, compared to the other Pulicaria species. There is only one study, in which ethanol extract of P. sicula was found to be weakly active against Gram-positive bacteria such as Bacillus subtilis, MRSA, and S. aureus (Nath et al. 2021).

Essential oils and alcoholic extracts of P. gnaphalodes were also investigated for their antimicrobial potential like other species. The essential oil obtained for the aerial parts of P. gnaphalodes showed a maximum zone of inhibition against C. albicans (23 ± 1.2 mm), which was higher compared to standard, fluconazol (18.0 ± 0.3 mm) (Kazemi et al. 2013). Similarly, the essential oil of P. gnaphalodes was found to be effective against Candida zeylanoides strains (Shokri 2014). In another study, the essential oil of P. gnaphalodes whole plant was found to be more potent against food-borne pathogens bacteria and fungi studied, followed by aqueous and alcoholic extracts (Gandomi et al. 2015). The ethanolic and methanolic extracts of the P. gnaphalodes stem were also found to be effective against the S. aureus and B. subtilis (MICs: 2.8 ± 0.3 and 2.9 ± 0.3 μg/ml, respectively) (Naqvi et al. 2020).

Anticancer activity

Cancer is one of the leading causes of death worldwide, and its global burden is constantly growing. Considering limited therapeutic options, there is a need to undertake extensive research in exploring the utility of different alternative and complementary medicines in the treatment of various cancers. Several studies in the literature confirm the utility of Pulicaria species as a promising anticancer agent for the treatment of several types of cancers, including, liver, breast, lung, and colon. So far, anticancer activities have been reported in the essential oils, extracts, fractions, and their isolates of P. crispa, P. undulata, and P. gnaphalodes (Table 4).

The essential oil obtained from P. crispa aerial parts showed promising cytotoxic activity against several types of cancers including liver, breast, and colon. Following 24 h of incubation, the essential oil of P. crispa showed a cytotoxic effect on liver cancerous, HepG2 cells (AlMotwaa and Al-Otaibi, 2022). The essential oil extracted from the leaves and Flowers of P. crispa also showed cytotoxic effects on MDA-MB-231 (breast cancer) and HL-60 (human leukemia) cell lines, with IC50 ranging from 103 to 355 μg/ml (Al-Qudah et al. 2022). These observed cytotoxic activities were attributed to the monoterpenes, sesquiterpenes, and phenolic compounds of essential oil (Al-Qudah et al. 2022). Besides this, ethanol extract (70%) of P. crispa aerial parts also showed cytotoxic activity (IC50: 180 µg/ml) on MDA-MB-231 cell lines, and this observed activity was linked with its membrane destruction potential, more precisely to the loss of cell integrity, shrinkage of cytoplasm, and cell detachment (Barnawi and Ali, 2019). Similarly, cytotoxicity on leukemia CCRF-CEM cell line has been reported to the 80% methanol extract of P. crispa aerial parts (IC50: 1.81 μg/ml). This treatment induced cell cycle arrest in the G0/G1 phase, and also induced apoptosis in CCRF-CEM cells with the alteration of the mitochondrial membrane potential (Kuete et al. 2013). In another study, ethyl acetate fraction of methanol extract P. crispa aerial parts showed potent anticancer activity against breast (MCF-7) and lung (A549) cancer cells, with IC50 values of 229.23 and 251.09 µg/ml, respectively (AlZain et al. 2023).

So far, P. undulata has been more extensively studied for its anticancer properties than P. crispa. Potent cytotoxic activity has been reported in the essential oils, extracts, and fractions, including isolated compounds of P. undulata, against different cancerous cell lines. The essential oil of P. undulata aerial parts exhibited promising cytotoxic activity against human malignant melanoma (A375, IC50-18.53 μg/ml), glioblastoma multiform tumor (T98G, IC50-40.64 μg/ml), and human colorectal carcinoma (HCT116, IC50: 22.23 μg/ml) cell lines (Mustafa et al. 2020). Similarly, the essential oil obtained from the P. undulata leafy stems also showed anti-proliferative activity (IC50: 9.6–18.6 μg/ml) towards human breast carcinoma (MCF7) and human colon adenocarcinoma (HT29 and HCT116) cell lines (Mohammed et al. 2020). The reported cytotoxicity of the P. undulata leaves essential oil against MCF-7 breast tumor cells was attributed to the presence of carvotanacetone (Ali et al. 2012). Besides this, the ethanol extract (95%) of P. undulata demonstrated concentration-dependent cytotoxicity in K562 (human leukemia), MCF-7, and PANC-1 (human pancreatic) cancerous cell lines. This treatment inhibited growth and induced late apoptosis in MCF-7 cell lines (Mohammed et al. 2021). Likewise, methanol extract of P. undulata aerial part induced apoptosis in HepG2 cells by overexpression of miR-34 that regulates p53/B-cell lymphoma-2/caspases signaling pathway (IC50-27.7 mg/ml) (Emam et al. 2019). In another study, methanol extract (95%) of P. undulata and six isolated compounds such as xanthosine (2-hydroxy-4, 6-dimethoxyacetophenone), stigmasterol, oleanolic acid, salvigenin (5-hydroxy-4’,6,7-trimethoxyflavone), rhamnetin (5,3’,4’-trihydroxy-7 methoxyflavonol) and dihydroquercetin 4 methyl ether were investigated for in vitro and in vivo antiproliferative activity against MCF-7, and Ehrlich’s ascites carcinoma (EAC) cell lines, respectively. Extract and isolates showed remarkable in vitro antitumor activity against an MCF-7 (IC50-18–28 μg/ml) and displayed promising in vivo cytotoxic effects against EAC (at 50 and 200 μg/ml of isolates and extracts). This observed antiangiogenic activity was associated with their vascular endothelial growth factor (VEGF) signaling inhibitory potential. In a molecular docking simulation study, alvigenin, rhamnetin, dihydroquercetin-4′-methyl ether, and xanthoxyline showed binding affinity towards VEGFR-2 (Elhady et al. 2021). The sesquiterpenoids, 2α-hydroxyalantolactone isolated from P. undulata showed potent cytotoxicity towards the muti drug-sensitive and -resistant cell lines (IC50-5.91–49.22 μM), and also inhibited human tumor cell growth through DNA damage, G2/M cell cycle arrest, and apoptosis. This compound bypasses resistance of multidrug-resistant cancer cells with either overexpression of ABC transporters (P-glycoprotein, BCRP/ABCG2, ABCB5) or deregulated tumor suppressors and oncogenes (TP53, EGFR) (Hegazy et al. 2021). Likewise, eupatolitin isolated from the P. undulata aerial part showed considerable cytotoxicity against MCF-7 and Hep G2 cells, with IC50 27.6 and 23.5 µg/ml, respectively (Hussien et al. 2016). In a comparative study, among different extracts (chloroform, ethyl acetate, and methanol extracts) of P. undulata, chloroform extract showed promising anticancer potential on three types of human carcinoma (HEPG-2, MCF-7, and HCT-116) cell lines (Alshehri and Ghobashy, 2020). The CH2Cl2:methanol (1:1) extract of P. undulata aerial parts also exhibited promising cytotoxic activity against CCRF-CEM leukemia cell lines (IC50: 5.72–6.04 μg/ml) by inducing apoptosis and cell cycle arrest in the G2/M (Hegazy et al. 2019).

Thus far, P. gnaphalodes has little been investigated for anticancer potential, compared to P. crispa and P. undulata. There is one study that investigated the cytotoxicity of ethyl acetate fraction and its isolated compounds (luteolin and quercetin) of methanol extract of P. gnaphalodes aerial part on MCF-7 and DU-145 (human prostate) cancerous cell lines (Pourhossein Alamdary et al. 2023). Interestingly, in this study, the observed IC50 values for methanol extract and all fractions were much lower than corresponding pure compounds (Pourhossein Alamdary et al. 2023).

Antioxidant activity

Antioxidant activity has been reported in the essential oil and non-essential oil extracts of these Pulicaria species in various assays, mainly in vitro assays (Table 4). Essential oil extracted from the leaves and Flowers of P. crispa showed good antioxidant activity in in vitro assays. However, the most promising antioxidant activity was found in the ABTS assay for both these essential oils (Al-Qudah et al. 2022). In general, the ABTS assay represents the antioxidant potential of hydrophilic and lipophilic compounds, whereas, the DPPH assay represents the antioxidant activity of more lipophilic compounds. This indicates that the ABTS assay estimates better the antioxidant capacity compared to DPPH (Kasote et al. 2019). The radical scavenging potential of different P. crispa extracts (methanol, ethanol, and ethyl acetate) have been investigated in both DPPH and ABTS assays, and the observed results were different in these two assays. Methanol extract of P. crispa aerial parts, including its fractions (n-hexane, chloroform, ethyl acetate, and n-butanol) showed radical scavenging activity in the ABTS assay, and the highest activity was reported in the chloroform fraction (IC50: 333.78 µg/ml) (AlZain et al. 2023). In another study, ethyl acetate extract of P. crispa showed the most effective anti-oxidant activity in the DPPH test (Feriel et al. 2021). The methanolic extract of P. crispa aerial parts was found to be rich in flavonoids (172 mg rutin equivalent/g dry wt.) and showed moderate activity in both DPPH (IC50 0.5123 ± 0.02 mg/ml) and ABTS (IC50 0.733 ± 0.08 mg/ml) assays (El-Sabagh et al. 2021). Besides radical scavenging activity, the potential of P. crispa extract in preventing DNA damage as an antioxidant has also been shown in the 8-hydroxy-2'-deoxyguanosine (8-OHdG) assay conducted on cultured human lymphocytes. This study showed that treatment with P. crispa extract (100 μg/ml) significantly decreased (36%) the level of 8-OHdG (Daradka et al. 2018). Similarly, the in vivo antioxidant activity of methanol extract of P. crispa aerial parts was also investigated in rats against chloropromazine (CPZ) induced oxidative stress. Administration of methanol extract of P. crispa (20 mg/kg) in rats following CPZ intoxication significantly decreased the elevated levels of malondialdehyde (MDA) by 46% compared to animals treated with CPZ only (El-Sabagh et al. 2021).

Ethanol extract (95%) of P. undulata aerial parts exhibited ferric-reducing and free-radicals scavenging activities in FRAP and DPPH assays, respectively. Observed activities were attributed to the presence of well-known antioxidant phenolics and flavonoids (e.g., trans-ferulic acid, chlorogenic acid, caffeic acid, quercetin, luteolin, rutin, and kaempferol 3-O-rutinoside) (Mohammed et al. 2021).

In the available literature, P. undulata essential oils and extracts are mainly reported to have radical scavenging activity. The essential oil obtained from P. undulata aerial parts had remarkable radical scavenging activity in the ABTS assay, which was comparable to that reported for Trolox (Mustafa et al. 2020). Similarly, essential oil of P. undulata leafy stems had considerable radical scavenging (20.92 ± 0.05DPPH and 62.36 ± 0.25ABTS mg trolox equivalents (TEs)/g) activities in DPPH and ABTS assays (Mohammed et al. 2020). It has been found that the methanolic extract of P. undulata exhibited greater DPPH radical scavenging and total antioxidant activities than those of the petroleum ether extract containing oil (Helal et al. 2019). The isolated compounds from the methanolic extract of P. undulata were also investigated for DPPH radical scavenging activity, and the observed activity was in the order of 7,2′,3′,4′ penta hydroxyl isoflavone-4′-O-β-glucopyranoside > quercetin > quercetin 3-O-galactoside > caffeic acid > quercetin 3,7-O-dimethyl ether > kaempferol. Most of these isolates showed more activity than that of crude methanolic extract. Similarly, in the anti-tert-butyl hydroperoxide (anti-TBHP) assay conducted using murine hepatoma Hepa1c1c7 cell line, it was found that TBHP toxicity was completely inhibited by quercetin 3,7-O-dimethyl ether (EC50 = 33.6 ± 1.7 μM). Interestingly, other tested compounds were not able to protect Hepa1c1c7 cells (Hussein et al. 2017). Similarly, the isolated compound, 6-methoxykaempferol from P. undulata aerial parts also had potent radical scavenging activity (IC50 2.3 µg/ml) in the DPPH assay (Hussien et al. 2016). In another study, isolated compounds (6-methoxy-kaempferol 3-O-β-D-glucopyranoside, 6-methoxykaempferol, and axillarin) from ethyl acetate soluble fraction of the whole plant of P. undulata were also found to have promising superoxide anion scavenging activity (75–92%), at their 100 µM studied concentration (Ahmad et al. 2006).

The essential obtained from the aerial parts of P. gnaphalodes had the strongest free radical scavenging activity in the DPPH assay, which was higher than that of trolox. Also, this essential oil showed a high percentage inhibition in β-carotene bleaching test (Kazemi et al. 2013). In another study, the reported DPPH radical scavenging activity to the essential oil of P. gnaphalodes (aerial part) was in the range of 37.1–70.7% (Hassanabadi et al. 2022) Hassanabadi et al. 2022). Like essential oil, ethyl acetate fraction of the methanolic extract of P. gnaphalodes aerial part also exhibited a promising radical scavenging activity (IC50- 10.64 ± 1.45 μg/ml) in the DPPH assay (Pourhossein Alamdary et al. 2023).

Anti-inflammatory activity

Anti-inflammatory properties are mainly reported in the P. crispa and P. undulata extracts. The methanol extract (80%) of P. crispa aerial parts exhibited ani-inflammatory properties by significantly suppressing the edematous response for up to 3 h in carrageenan-induced paw edema in albino rats at higher doses of 500 mg/kg, p.o. (Soliman et al. 2022). In another study anti-inflammatory property of CH2Cl2:methanol (1:1) extract of P. crispa aerial parts was linked with its COX-1 and COX-2 inhibitory potential, as these enzymes are generally involved in prostaglandin biosynthesis (Shahat et al. 2020).

In carrageenan-induced paw edema in mice model, the oral administration of the chloroform fraction of ethanolic extract of P. undulata (whole plant) at two doses (150 and 300 mg/kg) significantly inhibited inflammatory response in a dose-related manner. Similarly, the isolated pure compounds (+)-asteriscunolide A and methyl pulicaroate showed moderate anti-denaturation activity in albumin denaturation inhibitory assay, and among this, asteriscunolide A was the most effective compound (44.44% inhibition at 10 μM concentration) (Boumaraf et al. 2017). In albumin denaturation inhibitory assay, inhibition of protein denaturation is related to the inhibition of inflammatory activity, as denaturation of protein causes the production of auto-antigens in conditions such as rheumatic arthritis, cancer, and diabetes (Dharmadeva et al. 2018).

Hepatoprotective activity

The hepatoprotective potential has exclusively been reported to the P. crispa. The hepatoprotective role of methanol extract (80%) of P. crispa aerial parts was investigated in rats against CCl4-induced hepatotoxicity. This study showed that oral administration of the above extract (500 mg/kg) for seven days before CCl4 injection significantly attenuated the elevated serum markers of liver toxicity such as AST (aspartate aminotransferase), ALT (alanine aminotransferase), GGT (gamma-glutamyl transferase), and ALP (alkaline phosphatase) compared to the toxic group. Moreover, the above treatment also reversed the altered levels of total protein, MDA, and non-protein sulfhydryls (NP-SH) in the liver tissues of CCl4-exposed rats (Soliman et al. 2022). In another study, methanol extract of P. crispa aerial parts (30 mg/kg) reduced CPZ intoxicated increased levels of bilirubin level by 46%, including AST (10%) and ALT (24%) compared to animals treated with CPZ alone and this effect was similar to the standard hepatoprotective drug, silymarin (El-Sabagh et al. 2021). Similar to methanol extracts, ethanol extract (250 mg/kg, b.wt.) of P. crispa aerial parts was also found to have hepatoprotective potential in the CCl4-induced liver fibrosis rat model. This treatment exerted an anti-fibrotic effect by downregulating fibrosis and inflammatory signaling pathways in rat liver tissue. Moreover, this treatment significantly suppressed the toxicity-linked elevated levels of AST, ALT, alkaline phosphatase (ALP), total lipids (TP), total cholesterol (TC), triglycerides (TG), low-level glycoprotein-cholesterol (LDL-C), alpha-fetoprotein (AFP), MDA, nitric oxide (NO), tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6). Conversely, toxicity-linked decreased levels of high-density lipoprotein cholesterol (HDL-C), reduced glutathione (GSH), and superoxide dismutase (SOD) were also increased in treated groups (Morsy et al. 2021).

Antiviral activity

Antiviral activity is also only reported to the P. crispa. A study on HepG2.2.15 cells showed promising anti-hepatitis B virus (HBV) potential to the ethyl acetate extract of P. crispa (IC50: 14.45 μg/ml). This observed anti-HBV activity was time- and dose-dependent and could be due to its phytochemical composition, which includes flavonoids alkaloids, and tannins (Arbab et al. 2017). Similarly, HF obtained from methanolic extract of P. crispa aerial parts also exhibited a potent virucidal effect against influenza A virus at doses 125 and 250 µg/ml. These treatments were found to affect different stages of the virus lifecycle such as pre-treatment, post-infection, and competition (Abo-Elghiet et al. 2023).

Immunomodulatory activity

Like above, immunomodulatory potential has also been solely reported to P. crispa. It has been found that mice treated with intra-peritoneal injection of methanolic extract of P. crispa (33 ng/mouse) for 10 successive days followed by infecting every mouse with 100 S. mansoni cercariae showed significant reduction in S. mansoni worm burden and stimulated significant interleukin 2 (IL2) production, including IgG response that reacted in ELISA against bilharzial, E. coli and cancer bladder antigens (Maghraby et al. 2010). In another study, the immunomodulatory effect of P. crispa extract (ethanol) was investigated in lipopolysaccharide- (LPS-) stimulated human-monocytic THP-1 cells (Albrahim et al. 2020). Results of this study showed that exposure to P. crispa extract (100 μg/ml) significantly reduced THP-1cell proliferation, migration, and phagocytosis in LPS-stimulated cells (but not in unstimulated cells). It also significantly reduced the expression of various chemotactic and cell survival-related proteins (Albrahim et al. 2020).

Anti-gastric ulcer potential

Traditionally, Pulicaria species are used as anti-gastric ulcer agents (Fahmi et al. 2019a). The ethanol extracts (500 mg/kg b.wt., p.o.) of both P. crispa and P. undulata aerial parts were found effective in treating gastric ulcers in rats. Treatment with these extracts reversed ethanol-induced ulcer indices, oxidative stress, inflammatory index, and histopathology by improving antioxidant levels, certain mucosal marker enzymes, inflammatory parameters, and the histopathology of the gastric mucosa (Fahmi et al. 2019a, 2019b).

Antimalarial activity

Diluted aqueous extract (1:200) of P. crispa whole plant showed strong growth inhibition (100%) of the malaria parasite Plasmodium falciparum (Sathiyamoorthy et al. 1999). However, recently in another study, weak activity was also reported in the ethanolic extract (70%) of P. undulata against P. falciparum (3D7) with IC50 -18.9 μg/ml (Abdou et al. 2022).

Analgesic activity

Analgesic activity along with antipyretic effect has only been reported for the P. crispa. In a hot plate test, the methanol extract (80%) of P. crispa aerial parts showed considerable analgesic effect in mice at the dose of 500 mg/kg, p.o. This effect was comparable to that produced by 4 mg/kg indomethacin and could be due to its central cyclooxygenase-linked production of prostaglandin E2 (PGE2) blocking ability (Soliman et al. 2022).

Antipyretic activity

The antipyretic activity of methanol extract (80%) of P. crispa aerial parts was also investigated for antipyretic effects using yeast-induced pyrexia in rats. This extract treatment showed significant protection against hyperthermia at doses studied, 250 and 500 mg/kg, p.o. The observed antipyretic effect could be due to the extract's ability to inhibit the enzyme cyclooxygenase and reduce the levels of PGE2 within the hypothalamus (Soliman et al. 2022).

Nephroprotective activity

The ethanol extract of P. crispa aerial parts (at a dose, 250 mg/kg, p.o.) showed a nephroprotective effect in rats against CCl4-induced nephrotoxicity, mainly by reducing the elevated levels of oxidative stress markers (MDA), interleukin-18 (IL-18), serum creatinine, urea, and uric acid due to CCl4 toxicity (Aziz et al. 2022). This observed nephroprotective effect was attributed to its anti-oxidant and anti-inflammatory principles (Aziz et al. 2022).

Neuroprotective potential

The essential oil obtained from P. undulata aerial parts showed a neuroprotective effect in a rotenone-induced neurotoxicity rat model. The observed neuroprotective activity of P. undulata essential oil at doses, 100 and 200 mg/kg was attributed to its anti-inflammatory and anti-oxidant activities. Moreover, studied treatments also mitigated the induced neuroinflammation by various mechanisms such as down-regulating inducible nitric oxide synthase (iNOS) and α-synuclein gene expressions (Issa, 2020).

Antidiabetic activity

The antidiabetic activity of ethanol extract (70%) of P. crispa aerial parts was studied in alloxan-induced diabetic rats. The findings of this study showed that akin to antidiabetic medication glibenclamide, the above extract treatments (100 and 200 mg/kg, b.wt.) had a potent hypoglycaemic effect in a dose-dependent manner, and also prevented body weight reduction and significantly decreased cholesterol, urea, and creatinine levels (Daradka et al. 2021).

Antileishmanial and antitoxoplasmal activities

Leishmaniasis and toxoplasmosis are parasitic protozoal diseases that pose serious health concerns, especially for immunocompromised people. The P. undulata whole plant methanol extract and its fractions (petroleum ether, chloroform, ethyl acetate, n-butanol, and water) were tested for in vitro antitoxoplasmal (against Toxoplasma gondii) and antileishmanial (Leishmania major promastigote) activities. Among these, the chloroform fraction was the most potent against T. gondii (EC50: 1.4 μg/ml and SI: 12.1), L. major promastigotes (EC50: 3.9 μg/ml and SI: 4.4), and amastigotes (EC50: 3.8 μg/ml and SI: 4.5) (Khan et al. 2021).

Anticonvulsant

Intracerebroventricular injection of aqueous extract (125–500 μg/rat) and essential oil (0.125–0.5%) of P. gnaphalodes to rats was found to be beneficial in treating myoclonic and tonic–clonic seizures in a dose-dependent manner (Zendehdel et al. 2013).

Other activities

Besides the above biological and pharmacological activities, different enzyme inhibitory activities, especially those that have therapeutic significance in treating metabolic and neurodegenerative disorders have been reported to these Pulicaria species. In a recent study, α-amylase and horseradish peroxidase inhibitory activities have been reported to the phenolic extract of P. crispa, which suggests its potential in treating diabetes and thyroid diseases (Feriel et al. 2021). Similarly, lipase inhibitory activity (IC50: 1.33 ± 0.03 mg/ml) was also reported in the ethyl acetate fraction of P. crispa extract obtained from 70% aqueous acetone (Nia et al. 2014). Besides this, an aqueous extract of P. crispa leaves was found to be useful in the biological control of different developmental stages of Bulinus truncatus, a major snail intermediate host of urinary schistosomiasis (Ali et al. 2009).

Essential oil of P. undulata aerial parts showed a promising anti-acetylcholinesterase activity (IC50 = 139.2 μg/ml) in Ellman method (Mustafa et al. 2020). In another study, essential oil of P. undulata leafy stems also showed acetylcholinesterase (0.95 ± 0.06 mg galanthamine equivalents (GALAEs)/g), butyrylcholinesterase (1.19 ± 0.13 mg GALAEs/g) and α-glucosidase (32.59 ± 0.20 mg acarbose equivalents (ACAEs)/g) inhibitory activities, including inhibition of tyrosinase and α-amylase (Mohammed et al. 2020). Paniculoside IV, an ent-kaurane type diterpene glucoside isolated from P. undulata was reported to have α-glucosidase inhibitory activity (Rasool et al. 2008). Similarly, carvotanacetone, separated from the essential of P. undulata leaves showed remarkable anticholinesterase activity (Ali et al. 2012).

Toxicity

In the acute toxicity and lethal dose studies, the administration of 5000 mg/kg of ethanolic extract of P. crispa did not show any toxicity in mice and it was considered to be safe (Daradka et al. 2021). In another study, the cytotoxicity of whole plant extracts (methanol, chloroform, diethyl ether, acetone, and water) of P. crispa was investigated against Artemia salina (leach) larvae. Among these, diethyl ether and methanol extract had minimum and maximum toxicity at the highest dose studied of 1000 μg/ml (Ejaz et al. 2023).

Conclusions and future perspectives

Herein, Pulicaria species reported in Qatar are comparatively reviewed regarding their traditional uses, phytochemistry, and biological and pharmacological activities. In Qatar, the traditional uses of these species are almost identical and they all are used as herbal tea. Anti-inflammatory agents and insect repellents are some other traditional uses reported for these species in the Arabian/Persian region countries. Of these species, P. undulata and P. crispa are separately investigated for their phytochemistry, and biological and pharmacological activities in the literature, though P. crispa has merged into P. undulata decades ago and considered a single species. However, it is noteworthy that P. crispa is accepted as a subspecies of P. undulata, and it is a synonym of P. undulata subsp. undulata. The local taxonomists believe that there are two distinct species or perhaps subspecies of P. undulata in Qatar, but this has not yet been proven scientifically. After reviewing the literature, we found that traditional uses of both P. undulata and P. crispa are almost the same. Moreover, P. undulata and P. crispa can be differentiated at the subspecies level based on the known phytochemistry of their essential oils. In genome analysis studies, P. undulata and P. crispa are found to be distinct from each other as well (El-Kamali et al. 2010). However, more DNA barcoding and chemometric-based studies are essential to prove this special distinction clearly at the species and subspecies level, including identifying regional hybrids thereof.

Being aromatic plants, the chemical composition of essential oils of these species has been extensively studied. Essential oils are mostly extracted from  the aerial parts of these species; however, flowers and leaves are also used. Over 300 VOCs have been reported in the essential oils of these species. Among these, oxygenated monoterpenes and sesquiterpenes are the dominant VOCs. Over 147, 176, 64, and 54 VOCs have been reported in P. crispa, P. undulata, P. sicula, and P. gnaphalodes, respectively. Of these, nearly 83, 110, 37, and 22 VOCs are exclusively reported in the essential oils of P. crispa, P. undulata, P. sicula, and P. gnaphalodes, respectively. These VOCs can be used as marker compounds for the characterization of essential oils of each of these species.

Besides VOCs of essential oils, flavonoids and sesquiterpenes are the most reported classes of compounds in these species. Altogether, over 45 different flavonoids, and nearly 9 phenolic acids and other polyphenols have been identified in these species. Both flavonoid aglycones and flavonoid glycosides have been reported in P. crispa and P. undulata, and some of them are solely reported in each of these species. The occurrence of 6-oxygenation of flavonols is a unique feature of P. sicula. Thus far, p-anisic acid and 7 flavonoids are exclusively reported in the P. gnaphalodes. Among sesquiterpene, the occurrence of sesquiterpene lactones is a common feature of these species. Along with sesquiterpenes, diterpenes, and triterpenes are reported in these species. Whether these reported flavonoids and sesquiterpenes are exclusively occurring in respective species is not yet clear. Hence, further comparative studies are warranted in this regard.

In view of biological and pharmacological activities, P. crispa and P. undulata are highly investigated, respectively followed by P. gnaphalodes. Interestingly, there is only one reported biological activity of P. sicula, which is its antimicrobial activity against MRSA. So far, these species have been reported to exhibit antimicrobial, anticancer, antioxidant, anti-inflammatory, hepatoprotective, antiviral, immunomodulatory, antigastric ulcer, antimalarial, nephroprotective, neuroprotective, anticonvulsant, antidiabetic, antipyretic, analgesic, antileishmanial and antitoxoplasmal activities. Among these, antimicrobial, anticancer, and anti-oxidant activities are mostly investigated for P. crispa, P. undulata, and P. gnaphalodes. Hepatoprotective antiviral, immunomodulatory, nephroprotective, antidiabetic, antipyretic, and analgesic activities are solely reported in P. crispa. These activities are mainly reported to the essential oils, extracts (mainly methanolic extracts), and their fractions, as well as pure compounds isolated from these plants. Antimicrobial and anticancer activities reported to some of the pure compounds such as axillarin, quercetin, and 2α-hydroxyalantolactone, need to be investigated in detail for their potential use as medicine in the future.

At the moment, Pulicaria species are confined to very small geographic areas in Qatar due to rapid urbanization and industrial development in the last couple of decades. Moreover, species like P. sicula and P. gnaphalodes are rapidly becoming rare in Qatar. Considering this, immediate steps in the context of the protection and conservation of these species need to be undertaken.