A Review of the Ethnobotanical Use, Chemistry and Pharmacological Activities of Constituents Derived from the Plant Genus Geijera (Rutaceae)

Dugan, Deepika; Bell, Rachael J.; Brkljača, Robert; Rix, Colin; Urban, Sylvia

doi:10.3390/metabo14020081

Open AccessReview

A Review of the Ethnobotanical Use, Chemistry and Pharmacological Activities of Constituents Derived from the Plant Genus Geijera (Rutaceae)

by

Deepika Dugan

¹

,

Rachael J. Bell

¹,

Robert Brkljača

²

,

Colin Rix

¹ and

Sylvia Urban

^1,*

¹

Marine and Terrestrial Natural Product (MATNAP) Research Group, School of Science (Applied Chemistry and Environmental Science), RMIT University, GPO Box 2476, Melbourne, VIC 3001, Australia

²

Monash Biomedical Imaging, Monash University, Clayton, VIC 3168, Australia

^*

Author to whom correspondence should be addressed.

Metabolites 2024, 14(2), 81; https://doi.org/10.3390/metabo14020081

Submission received: 21 December 2023 / Revised: 16 January 2024 / Accepted: 17 January 2024 / Published: 23 January 2024

(This article belongs to the Section Thematic Reviews)

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Abstract

:

Geijera Schott is a plant genus of the Rutaceae Juss. (rue and citrus) family, comprising six species which are all native to Oceania. Of the plants belonging to this genus, the most significant species that has a customary use is Geijera parviflora, which was used by Indigenous Australians, primarily as a pain reliever. Herein, a comprehensive review of the literature published on the genus Geijera from 1930 to 2023 was conducted. This is the first review for this plant genus, and it highlights the chemical constituents reported to date, together with the range of pharmacological properties described from the various species and different parts of the plant. These properties include anti-inflammatory, anti-microbial, anti-parasitic, insect repellent, analgesic, neuroactive, and anti-cancer activities. Finally, a reflection on some of the important areas for future focused studies of this plant genus is provided.

Keywords:

Geijera; wilga; biological activity; pharmacology; customary use; analgesic; toothache; anti-cancer

Graphical Abstract

1. Introduction

The genus Geijera contains six accepted species that are native to Australia, New Guinea, and New Caledonia [1]. Although the International Plant Names Index has over twenty species names listed in association with this genus, a large proportion of these are either synonyms of the accepted species or names that have been superseded due to taxonomic reclassification. The six species of the genus are listed below in Table 1 [2,3]. The species of this genus are found in rainforests, dry rainforests, woodlands, dry scrub, and open inland areas [4].

To date, phytochemical investigations have only been conducted on four of the six Geijera species. The chemical constituents provided in this review are, therefore, limited to the studies conducted on Geijera parviflora Lindl., Geijera linearifolia (DC.) J.M. Black (both endemic to Australia), Geijera salicifolia Schott (endemic to Australia, Papua New Guinea, and New Caledonia) and Geijera balansae (Baill.) Schinz & Guillaumin (endemic to New Caledonia). No phytochemical information is available for Geijera cauliflora Baill., and Geijera tartarea T.G. Hartley ex Munzinger & Bruy, which are both endemic to New Caledonia. Phytochemical investigation of the latter two species has been neglected possibly due to their rarity, their inaccessibility, or that they occur in a remote location. Geijera tartarea is a newly described, rare, and endangered species [5]. The 117 reported compounds in this review have been grouped on the basis of their chemical class and are numbered sequentially in Table 2, Table 3, Table 4 and Table 5.

The flowering plants of most endemic Rutaceae species in Oceania occur as low scleromorphic shrubs, whereas all species of Geijera can be described as large sclerophyllous shrubs [6]. Figure 1 illustrates the geographical distribution of Geijera species in Oceania.

The customary use of plants has been occurring for at least 65,000 years by the Indigenous Australians [7]. Interest in the chemical constituents of the Geijera species, particularly G. parviflora, has been motivated by the customary use of this plant in Australian bush medicine. Commonly known as dogwood or wilga (‘Wilgarr’ in the Wiradjuri language, ‘Nhiitaka’ or ‘Katha’ in Paakantyi (Barkindji), ‘Puri’ or ‘Buri’ in Mutthi Mutthi and ‘Dhiil’ or ‘Dheal’ in the Gamilarray, Yuwaalaray and Yuwaalayaay language groups), G. parviflora is considered a sacred tree and is of cultural importance to the Indigenous people of Australia, especially during burials and ceremonies [8]. It is a hardy, long-lived species that grows about 8 m tall with a wide, dense canopy and it can live for over 100 years.

The leaves of G. parviflora were used to prepare a ceremonial smoke together with leaves from other trees such as ‘Badha’ or ‘Budda’ Native Sandalwood, Eremophila mitchellii Benth., ‘Coolabah’ Eucalyptus coolabah Blakely & Jacobs and ‘Gurraay’ White Cypress Pine Callitris columellaris F.Muell. [8]. G. parviflora leaves were also used in ceremonies where they were baked, powdered, and smoked with other plant materials to induce intoxication and drowsiness, akin to the effects of alcohol [9]. The leaves were also chewed or placed into dental cavities for the relief of toothache or crushed and used as an external pain reliever [10]. An infusion of the leaves was used both internally and externally to relieve pain [11,12]. Leaf infusions were also used for bathing to provide skin care and to relieve sore muscles; they were used cold for sore eyes and ears, and apart from this, they were drunk to cure blood disorders [13]. The hot leaves were used as a poultice on sores and boils, and the bark was steeped in water for use as a laxative [13]. The leaves were also burned around camp sites as an insect repellent and the wood was used for spears and boomerangs [13]. Apart from these uses, the tree was valued as a source of pollen and nectar for honey production, the fruits and flowers of G. parviflora were eaten, and its aromatic leaves were used during cooking as a flavoring for emu meat [14,15].

G. parviflora is the most extensively studied species of the genus Geijera and it exhibits considerable variability in the composition of its essential oils and other chemical constituents, such as its coumarins [16]. During an initial investigation by Penfold in 1930, he noted that morphologically indistinguishable specimens had different chemotypes based on the character of their leaf essential oils [17,18,19]. The leaves of G. parviflora were observed to exhibit selective palatability as fodder for sheep, wherein certain plants would be readily consumed by stock whilst others would not. Two coumarins, dehydrogeijerin 13 and geiparvarin 2 (Table 2), were later isolated by Lahey and Macleod from specimens deemed either ‘unpalatable’ or ‘readily eaten’ [20]. It was found that 13 was only present in the unpalatable variety, and that 2 was only in the readily eaten variety. It was also observed that the readily eaten variety ‘Tree wilga’, occurred in drier areas, while the variety deemed unpalatable, ‘Lavender bush’ occurred in areas with greater than 500 mm of rainfall per annum [16]. The connection that was drawn between the two different coumarins present in the specimens and their palatability to sheep has not been validated [21]. After further research conducted by Brophy and Goldsack [16], G. parviflora now has four established chemotypes, based upon differing compositions of the leaf essential oils of the plant, with another four possible chemotypes having been tentatively identified by Sadgrove et al. [16,22].

G. salicifolia (scrub wilga, greenheart, green satinheart) is a long-lived, drought-tolerant and hardy species, utilised mainly for its timber, which was used to make fishing rods and cabinetry [23]. Its wood was traditionally used for making implements, weapons, and jewellery [24]. According to the Dharawal pharmacopeia collection recorded by Auntie Frances Bodkin, a Dharawal elder, G. salicifolia is also commonly called wilga and (similarly to G. parviflora) its leaves have customary use by the Dharawal people for pain relief, whereby they are chewed to alleviate toothache [24]. The vapors from the hot leaves are also used to relieve headache [24]. Two chemotypes of this species have been identified based upon differing composition of its leaf essential oils [16].

Uses of the other species from the Geijera genus for medicinal or other purposes (apart from timber) have not been recorded.

The purpose of this study was to review the chemical constituents within the genus Geijera Schott as reported up to December 2023, this being the first such review on the genus. Geijera is a genus that belongs to the family Rutaceae Juss. (rue and citrus family), which contains about 2100 species in 154 genera [25]. Apart from providing important nutritional benefits, many members of the Rutaceae are valuable sources of bioactive compounds such as alkaloids, coumarins (notably furano- and pyrano-coumarins), volatile oils, flavonoids, and limonoids [26]. This review provides a detailed account of the chemical constituents reported from the Geijera genus to date. However, it is only representative of four of the six Geijera species, as no studies have been reported for the chemical constituents of G. cauliflora and G. tartarea. In addition to the description of the constituents isolated from Geijera, their reported pharmacological activities are also summarised. Although a detailed treatment of the various specific pharmacological activities reported from these compounds is beyond the scope of this review, a concise summary has been provided. Specifically, the pharmacological activities relevant to the traditional use of G. parviflora are summarised to aid identification of constituents, which might be responsible for the customary medicinal uses of G. parviflora in Australian bush medicine. Constituents with notable properties such as anti-cancer activity are also included. Subsequent database searching of the relevant chemical constituents provided an account of what main types of pharmacological activities have been reported in the literature. Therefore, the documented pharmacological activities in this review are not necessarily reported from within the same publications that identified the chemical constituents in the Geijera plant species.

2. Methodology

The scientific literature published on the genus Geijera from 1930 to 2023 has been reviewed with a particular focus on publications pertaining to the phytochemicals that are specific to this genus. The databases employed for compiling this review included Google, Google Scholar, ScienceDirect (147 results), SciFinderⁿ (50 results), Scopus (44 results), Springer Link (78 results), PubMed (12 results), Wiley (124 results), and the Web of Science (43 results). Within the results, there were approximately 20 publications specifically reporting the isolation of chemical constituents from this plant genus. The search terms or keywords included Geijera, Geijera parviflora, Geijera salicifolia, Geijera linearifolia, Geijera balansae, Geijera cauliflora, Geijera tartarea, and wilga.

3. Chemical Constituents in Geijera Species

A total of 117 plant compounds have been identified via phytochemical investigations of four plant species of the Geijera genus, covering G. balansae, G. linearifolia, G. parviflora, and G. salicifolia. The compounds can be generally assigned to the following classes: coumarins, alkaloids, phenolic compounds, a flavonoid, fatty alcohol esters, fatty acid esters, phenylpropanoids, terpenes and terpenoids, and these appear sequentially in Table 2, Table 3, Table 4 and Table 5.

Most of the compounds identified from the genus Geijera originate from G. parviflora, which has been studied more than the other species, mainly due to its traditional medicinal uses by Indigenous cultures, as well as its utility as stock fodder during times of drought in the early- to mid-20th century. As shown in Figure 2, the other Geijera species have had little study in comparison. Hence, there is clear potential for further compound identification and discovery, especially considering the various bioactivities displayed by the chemical constituents identified to date. It also shows that while 117 compounds have been identified among the four species, many of these occur across multiple species of Geijera.

The number of chemical constituents according to the compound classes identified from the four Geijera species studied is illustrated in Figure 3, showing that the terpenes represent by far the most frequently isolated compound class across these species. It also shows that G. balansae is the only species to not have any terpenes reported. Terpenes are dominant components in the plant kingdom, so it is unlikely that G. balansae does not contain terpenes, but rather is indicative that no terpenes have yet been reported because the extraction methods employed to study this species to date have specifically targeted the isolation of alkaloids [27,28]. Similarly with G. linearifolia, only terpenes have been reported; however, this does not suggest only terpene-like compounds are being produced by G. linearifolia, but that further study of G. linearifolia is needed to reveal additional compound classes present.

Investigations on the other three Geijera species have focused on the plant essential oils which were obtained via hydro-distillation, as well as other targeted extraction methods employed for the extraction of coumarins and alkaloids. Studies on G. linearifolia reported the presence of terpenes, but not any other compound classes because only the volatile component/essential oil from this species has been studied [16].

As a result of conducting this review, it became evident that more than 60% of the compounds that have been reported from this plant genus require further verification and validation using spectroscopic techniques and other isolation strategies. Several compounds (largely terpenes and terpenoids) were identified solely based on GC-MS retention times, molecular weights, and database comparison, which can be inadequate for the elucidation of geometric/structural/stereoisomeric structures. The formation of artefacts that can result from isolation procedures, where plant materials are subjected to thermal treatment during hydro-distillation and gas chromatography, is another consideration to bear in mind. An example of this is the sesquiterpene geijerene 70, which is accepted to be a thermal Cope rearrangement product that is formed from its precursor, pregeijerene 68, which is a major constituent of the essential oil of one G. parviflora chemotype [22,29].

Despite considerations like the ones stated above, most of the reported compounds have been included in this review due to the variety of pharmacological properties that they possess. Minor constituents present in less than 1% of the essential oils, as well as constituents of aged plant essential oils that have been reported via GC-MS analysis, were omitted from the review. The rationale for this was due to their insignificant quantity and/or high likelihood of them being artefacts formed by processes such as oxidation and polymerisation as the oils age over several months or years. An interesting comparison of the character of aged essential oils with fresh samples that was performed by Sadgrove et al., demonstrated that the antimicrobial activity of aged samples increased compared to that of the fresh samples [9].

3.1. Coumarins

Coumarins are common in the Rutaceae plant family, and they primarily act as phytoalexins and allelochemicals. Their physiological roles are diverse and include protection of the plant against traumatic injury, microorganism infection by inhibition of the growth of bacteria and fungi, facilitating iron uptake from soil, as well as providing protection by repelling herbivorous insects [30]. The Rutaceae produce a range of pyrano-, furano- and prenylated-coumarins, in addition to the simple coumarins, all of which frequently display potent pharmacological effects [31]. The activity of coumarins is often attributed to the reactivity of the benzofuran system in their molecular structure; however, many simple coumarins also possess potent activity, e.g., the toxicity of umbelliferone 1 (Table 2) against insect herbivores and rodents [31,32,33,34]. Amongst other functions, 1 is a key intermediate in prenylcoumarin biosynthesis, which gives rise to the furanocoumarins and pyranocoumarins such as angelicin (isopsoralen) 16 and xanthyletine 17 [35].

Within Geijera, coumarins have been identified in the leaves of G. balansae, G. parviflora and G. salicifolia as well as the bark of G. balansae. Nineteen coumarins have been reported from the genus, consisting of nine monosubstituted coumarins 1–9 including umbelliferone 1, and six disubstituted coumarins 10–15, furanocoumarin angelicin (isopsoralen) 16, and three pyranocoumarins 17–19. Compounds 11, 12, and 15–17 were identified by Sadgrove et al. in trace amounts, based on GC-MS analysis of extracts. The unequivocal identification of these five coumarins within G. parviflora requires further investigation using targeted extraction strategies, in conjunction with the application of spectroscopic techniques for structure identification/elucidation. Luvangentin 18 was isolated from the leaves and xanthoxyletin 19 was isolated from the bark of the New Caledonian species G. balansae by Mitaku et al. (Table 2).

The coumarins geiparvarin 2 and dehydrogeijerin 13 were isolated by Lahey and Macleod from G. parviflora specimens deemed either ‘readily eaten’ or ‘unpalatable’. It was found that 13 was only present in leaves of the unpalatable variety which occurs in wetter areas, and that 2 was only present in leaves of the readily eaten variety, which occurs in drier areas [16]. Further work is needed to establish the validity of the connection between the palatability of these two chemotypes and the coumarins present therein.

Geiparvarin 2 has been found only in G. parviflora and G. salicifolia, and being a major constituent of leaf extracts, it has been identified as one of the main contributors to the pharmacological activities of these plants [36]. Its derivatives, such as 2′,3′-dihydrogeiparvarin 6, parvifloranine A 8, parvifloranine B 9, and 6-(methoxyl) geiparvarin 14, have only been found in G. parviflora so far. This coumarin and its derivatives can be said to be chemotaxonomic markers for the two abovementioned Geijera species, although more phytochemical investigation is required to establish whether they are also present in the other species of the genus or elsewhere within other taxa.

Table 2. Coumarins identified within the genus Geijera.

Compound and Exact Mass (Da)	Source	Method of Identification	Reference	Pharmacological Activity of Compound (Various Sources)
1 umbelliferone	G. salicifolia (leaves)	Melting point, IR and ¹H NMR	[37]	Anti-inflammatory, antinociceptive, anti-hyperglycaemic, antibacterial, antifungal, inhibition of DPPH, hydroxyl, superoxide anion and ABTS radicals, molluscicide, antifeedant, anti-tumour, antimutagenic, fluorescent (sunscreen agent), bone-protective, anti-biofilm [38,39,40]

162.0317
2 geiparvarin	G. parviflora (leaves)	Combustion analysis, chemical derivatisation, UV, IR (G.p)	[20,37]	Anti-cancer, monoamine oxidase B inhibitor [41,42,43]
	G. parviflora (leaves)	Combustion analysis, chemical derivatisation, UV, IR (G.p)
326.1154	G. salicifolia (leaves)	IR and ¹H NMR (G.s)
3 auraptene	G. parviflora (fruit/seeds)	IR and ¹H NMR	[44]	Increases collagen I expression, anti-bacterial, anti-fungal, antileishmanial, anti-cancer, and antioxidant [45,46]

298.1569
4 marmin	G. parviflora (fruit/seeds)	IR and ¹H NMR	[44]	No significant anti-inflammatory activity [47]

332.1624
5 6′-dehydromarmin	G. parviflora (fruit/seeds)	IR and ¹H NMR	[44]	Anti-inflammatory, cytotoxic [10]

330.1467
6 2′,3′-dihydrogeiparvarin	G. parviflora (fruit/seeds)	IR and ¹H NMR	[44,48]	Anti-cancer [48,49]
	G. salicifolia (leaves)
330.1467	G. salicifolia (leaves)
7 (R)-6-O-(4-geranyloxy-2-hydroxy) cinnamoylmarmin	G. parviflora (leaves)	2D NMR	[10]	Cytotoxic, anti-inflammatory [10]

630.3193
8 parvifloranine A	G. parviflora (leaves)	2D NMR, ECD and MS	[50]	Anti-inflammatory [50]

453.1788
9 parvifloranine B	G. parviflora (leaves)	2D NMR, ECD and MS	[50]	No significant anti-inflammatory activity [50]

470.1689
10 geijerin	G. salicifolia (bark)	Chemical derivatisation, UV, and IR	[37,51]	Acetylcholinesterase inhibitor [52]
	G. parviflora (leaves)	Melting point, IR and ¹H NMR
260.1049	G. parviflora (leaves)	Melting point, IR and ¹H NMR
11 scoparone	G. parviflora (leaves)	GC-MS	[21]	Antifungal, anti-inflammatory, antioxidant, anti-apoptotic, anti-fibrotic, and hypolipidemic [53,54]

206.0579
12 suberosin	G. parviflora (leaves)	GC-MS	[21]	Anti-inflammatory and anticoagulant [55,56]

244.1099
13 dehydrogeijerin	G. parviflora (leaves)	Chemical derivatisation, UV, and IR (G.p)	[20,37]	Anti-inflammatory activity, acetylcholinesterase inhibitor [52,57]
	G. salicifolia (leaves)	IR and ¹H NMR (G.s)
258.0892	G. salicifolia (leaves)	IR and ¹H NMR (G.s)
14 6-(methoxyl) geiparvarin	G. parviflora (leaves)	¹³C and ¹H NMR	[10]	Anti-inflammatory, cytotoxic [10]

356.1260
15 osthole	G. parviflora (leaves)	GC-MS	[22]	Antitumour, anti-inflammatory, neuroprotective, anxiolytic, osteogenic, cardiovascular protective, antimicrobial, antiparasitic [58,59]

244.1099
16 angelicin (isopsoralen)	G. parviflora (leaves)	GC-MS	[22]	Anti-cancer, pro-osteogenic, antiviral, pro-chondrogenic, anti-inflammatory, erythroid differentiating, anti-periodontitis [60,61]

186.0317
17 xanthyletine	G. parviflora (leaves)	GC-MS	[22]	Antimicrobial, fungicide [62,63]

228.0786
18 luvangetin	G. balansae (leaves)	UV, IR, ¹H NMR, MS	[28]	Antiulcer, antifungal, anti-inflammatory, antibacterial [64,65]

258.0892
19 xanthoxyletin	G. balansae (bark)	UV, IR, ¹H NMR, MS	[28]	Anticonvulsant, anti-inflammatory, carbonic anhydrase inhibitor, anti-malaria, histone lysine methyltransferase G9a inhibitor [66,67]

258.0892

(Key: G.p—G. parviflora, G.s—G. salicifolia).

3.2. Alkaloids

The isolation of twenty-two alkaloids has been reported from the genus Geijera, which includes five anthranilic acid derivatives, sixteen quinolones/quinolines (also derived from anthranilic acid), and a phenylethylamine-derived proto alkaloid hordenine. The five anthranilic acid derivatives 20–24 were isolated from the leaves of G. parviflora [68]. Three furoquinolines 25–27 [28,69], two isopropyldihydrofuroquinolines 28–29 [28,69], eight quinolones 30–37 [10,28,44], two dihydropyranoquinolines, 38–39 [27] and one dimeric quinolone 40 [28] have been isolated from the leaves, bark, and wood of species of Geijera. The quinolone flindersine 30 was isolated from the seeds/fruits of G. parviflora as well as from the leaves of G. balansae [28,44]. Additionally, hordenine 41 was isolated from the leaves of G. balansae [28] (Table 3).

Anthranilic acid derivatives are widely distributed within the Rutaceae family, but are of restricted distribution outside of this plant family [70]. The known physiological roles of alkaloids are generally accepted as providing protection for plants from pathogens and predators through their toxicity, as well as being involved in cell signalling and regulation of plant growth [71]. Alkaloids of genus Geijera display antimicrobial (including some against drug-resistant strains), anti-inflammatory, and other specific pharmacological activities as summarised in Table 3. Alkaloids, such as flindersine 30 and its derivatives, display significant activity in the mediation of inflammation, and these properties could help to explain the customary use of G. parviflora [10]. The dimeric quinolone alkaloid geijedimerine 40 from the leaves of G. balansae is unique to this species and has not been found so far in other taxa.

Table 3. Alkaloids identified within the genus Geijera.

Compound and Exact Mass (Da)	Source	Method of Identification	Reference	Pharmacological Activity of Compound (Various Sources)
20 11′-hexadecenoyl anthranilic acid	G. parviflora (leaves)	HRESI-MS, IR, UV, ¹³C and ¹H NMR	[68]	Antibacterial vs. Gram positive bacteria [68]

373.2617
21 9′-hexadecenoyl anthranilic acid	G. parviflora (leaves)	HRESI-MS, IR, UV, ¹³C and ¹H NMR	[68]	Antibacterial vs. Gram positive bacteria [68]

373.2617
22 7′-hexadecenoyl anthranilic acid	G. parviflora (leaves)	HRESI-MS, IR, UV, ¹³C and ¹H NMR	[68]	Antibacterial vs. Gram positive bacteria [68]

373.2617
23 9,12,15-octadecatrienoyl anthranilic acid	G. parviflora (leaves)	HRESI-MS, IR, UV, ¹³C and ¹H NMR	[68]	Did not display significant antibacterial activity [68]

383.2460
24 hexadecanoyl anthranilic acid	G. parviflora (leaves)	HRESI-MS, IR, UV, ¹³C and ¹H NMR	[68]	Antibacterial vs. Gram positive bacteria [68]

375.2773
25 dictamnine	G. balansae (wood/bark)	¹H NMR, IR, UV, and MS	[28]	Antibacterial, antiviral, antifungal, antiprotozoal, anti-cancer, anti-inflammatory, antioxidant, cardiovascular, antiplatelet, antiosteoporosis, anti-anaphylactoid [72]

199.0633
26 skimmianine	G. salicifolia (leaves)	IR, melting point (G.s)	[28,69]	Anti-inflammatory, acetylcholinesterase inhibitor, anti-cancer [73,74,75]
	G. balansae (wood/bark)	¹H NMR, IR, UV, and MS (G.b)
259.0845	G. balansae (wood/bark)	¹H NMR, IR, UV, and MS (G.b)
27 γ-fagarine	G. salicifolia (leaves)	IR, melting point (G.s)	[28,69]	Antileishmanial [76]
	G. balansae (wood/bark)	¹H NMR, IR, UV, and MS (G.b)
229.0739	G. balansae (wood/bark)	¹H NMR, IR, UV, and MS (G.b)
28 platydesmine	G. salicifolia (leaves)	Melting point, combustion analysis, chemical degradation, IR, UV and ¹H NMR (G.s)	[28,69]	Antifungal [77]
	G. salicifolia (leaves)
259.1208	G. balansae (leaves)	¹H NMR, IR, UV, and MS (G.b)
29 platydesmine acetate	G. salicifolia (leaves)	Combustion analysis, chemical degradation, IR and ¹H NMR	[69]	No activity reported to date

301.1314
30 flindersine	G. parviflora (fruit/seeds)	IR and melting point (G.p)	[28,44]	Anti-inflammatory, collagen III suppression, antibacterial, antifungal [10,45,78]
	G. balansae (leaves)	¹H NMR, IR, UV, and MS (G.b)
227.0946	G. balansae (leaves)	¹H NMR, IR, UV, and MS (G.b)
31 4′-hydroxy-3′,4′-dihydroflindersine	G. balansae (leaves)	Chemical synthesis/derivatisation, ¹H NMR, IR, UV, and MS	[28]	No activity reported to date

245.1052
32 cis-3′,4′-dihydroxy-3′,4′-dihydroflindersine	G. balansae (leaves)	Chemical synthesis/derivatisation, ¹H NMR, IR, UV, and MS	[28]	No activity reported to date

261.1001
33 zanthobungeanine	G. balansae (leaves)	¹H NMR, IR, UV, and MS	[28]	Leishmanicidal activity on Leishmania Viannia panamensis intracellular amastigotes (EC₅₀: 8.7 µg/)mL and promastigotes (EC₅₀: 14.3 µg/)mL, respectively [79]

271.1208
34 8-(methoxyl)-flindersine	G. parviflora (leaves)	UV, IR, 2D NMR and MS	[10]	No activity reported to date

257.1052
35 N-(acetoxymethyl) flindersine	G. parviflora (leaves)	UV, IR, 2D NMR and MS	[10]	Anti-inflammatory, collagen III suppression [10,45]

299.1158
36 haplaphine	G. parviflora (leaves)	UV, IR, 2D NMR and MS (G.p)	[10,28]	Anti-inflammatory, cytotoxic [10]
	G. balansae (bark)	¹H NMR, IR, UV, and MS (G.b)
229.1103	G. balansae (bark)	¹H NMR, IR, UV, and MS (G.b)
37 4-methoxy N-methyl-2-quinolone	G. balansae (bark)	¹H NMR, IR, UV, and MS	[28]	Antimicrobial against MRSA, IC₅₀ 8.0 µM [80]

189.0790
38 geibalansine	G. balansae (leaves)	Chemical synthesis/derivatisation, ¹H NMR, IR, UV, and MS	[27]	Antispasmodic [81]

259.1208
39 O-acetyl geibalansine	G. balansae (leaves)	Chemical derivatisation, ¹H NMR, IR, UV, and MS	[27]	No activity reported to date

301.1314
40 geijedimerine	G. balansae (leaves)	Chemical derivatisation, ¹H NMR, IR, UV, and MS	[28]	No activity reported to date

454.1893
41 hordenine	G. balansae (leaves)	¹H NMR, IR, UV, and MS	[27]	Diuretic, disinfectant, antihypotensive agent. Used for treatment of dysentery. Antifeedant for grasshoppers [67].

165.1154

(Key: G.b—G. balansae, G.p—G. parviflora, G.s—G. salicifolia).

3.3. Terpenes and Terpenoids

In total, sixty-four different terpenes/terpenoids have been isolated from the genus Geijera including monoterpenes, 42–55, monoterpenoids, 56–66, sesquiterpenes, 67–86, sesquiterpenoids 87–104, and the triterpene β-sitosterol 105. Although many of the terpenes that have been reported within the Geijera species are minor constituents of the leaf essential oils, they have been included in this review due to the possibility that they might contribute to the overall biological activity displayed by the plant extracts through combined and/or synergistic action together with the other active constituents. It is evident that the unequivocal identification of several of the compounds reported via GC-MS analysis requires further characterisation using spectroscopic techniques to aid in the confirmation of their structures. This is especially important for the disambiguation of the structures of geometric isomers and stereoisomers that have been reported.

Initial investigations of the essential oils of G. parviflora conducted by Penfold determined the presence of at least two chemotypes; the first one (1) was dominated by the terpenes pinene (49, 50) and camphene 51, which constituted 80% of the essential oils; while the other (2) contained an abundance of brevifolin 106 (a phenolic ketone) and the sesquiterpene azulene 67 [17,18,19]. Azulene 67 has been isolated as part of both the leaf essential oils of G. parviflora and G. salicifolia, respectively. Azulene is unique as it is one of the few naturally occurring pigments that is blue in colour, and it is responsible for the deep blue colour of the leaf oil from its G. parviflora chemotype [16,18]. Brophy and Goldsack continued this research and identified a total of four G. parviflora chemotypes, the two previously identified by Penfold, together with (3) a chemotype in which the terpenoid linalool 61 and the sesquiterpenoid β-eudesmol 96 were dominant, and another (4) in which the sesquiterpenes pregeijerene 68, geijerene 70, and the terpenoid linalool 61 were the major constituents [16]. The brevifolin-dominated chemotype (2) also contained spathulenol 102, globulol 92, and viridiflorol 98 as major constituents, with a very small proportion of monoterpenes. However, since the sample subjected to investigation was a few years old, it is unclear if any of the volatiles/monoterpenes had been lost from the extract, and it is possible that the large proportion of spathulenol 102, globulol 92, and viridiflorol 98 could be artefacts formed by oxidation of bicyclogermacrene 77 [16].

Two chemotypes of G. salicifolia exist; one containing pinene (49, 50), camphene 51, and limonene 45 as the dominant compounds; while the second chemotype contains large amounts of the phenolic ketone, brevifolin 106. Brevifolin 106 forms a large proportion of the essential oil of this chemotype and is obtained from the leaves via hydro-distillation [16]. G. linearifolia has not been found to exhibit different chemotypes, and its essential oils are dominated by spathulenol 102, geranyl acetate 57, bicyclogermacrene 77, and (E,E)-farnesol 87 [16]. There is scope for characterisation of the terpenes from G. balansae, which has been neglected because the studies performed on this species only targeted the isolation of alkaloids.

Terpenes and terpenoids are ubiquitous in the plant kingdom and they form the most diverse and abundant classes of secondary metabolites found in nature. They exhibit a large variety of pharmacological activities such as anti-microbial, anti-inflammatory, neuroactive, psychoactive, anti-cancer, anti-oxidant, and pest resistance, as well as several other activities [82]. This is also reflected in the range of activities displayed by the terpenes/terpenoids that have been identified within the Geijera species.

Monoterpenes: To date, fourteen monoterpenes 42–55 have been identified from the Geijera species, all of which have been identified in the leaf essential oils of the plants (Table 4).

Monoterpenoids: Six acyclic monoterpenoids 56–61, and five cyclic monoterpenoids 62–66, have been identified as part of the leaf essential oils (Table 4).

Sesquiterpenes: Seven cyclic sesquiterpene 68, 70, 75, 76, 80–82, ten bicyclic sesquiterpenes 67, 69, 72–74, 77–79, 83–84, two tricyclic sesquiterpene 71, and 85, as well as one open-chain sesquiterpene, 86, have been isolated as part of the leaf essential oils (Table 4).

Sesquiterpenoids: Two acyclic sesquiterpenoids 87, 99, one cyclic sesquiterpenoid 89, seven bicyclic sesquiterpenoids 88, 94–97, 101, 103 and eight tricyclic sesquiterpenoids 90–93, 98, 100, 102 and 104 have been isolated from the leaves of G. parviflora, G. salicifolia and G. linearifolia (Table 4).

Triterpene: One triterpene, β-sitosterol 105 was isolated from the leaves of G. salicifolia (Table 4).

Table 4. Terpenes and terpenoids identified within the genus Geijera.

Compound and Exact Mass (Da)	Source	Method of Identification	Reference	Pharmacological Activity of Compound (Various Sources)
42 (E)-β-ocimene	G. linearifolia (leaves) G. salicifolia (leaves) G. parviflora (leaves)	GC-MS	[16]	Anticonvulsant, antifungal, antitumour, plant pest resistance and attraction of plant pollinators (semiochemical) [83]

136.1252
43 (Z)-β-ocimene	G. linearifolia (leaves) G. salicifolia (leaves) G. parviflora (leaves)	GC-MS	[16]	Anticonvulsant, antifungal, antitumour, plant pest resistance and attraction of plant pollinators (semiochemical) [83]

136.1252
44 myrcene	G. parviflora (leaves) G. salicifolia (leaves)	GC-MS	[16]	Sedative, muscle relaxant, anti-inflammatory, analgesic, anti-tumour, antioxidant, psychotropic, antibiotic, antimutagenic [84,85]

136.1252
45 limonene	G. salicifolia (leaves)	GC-MS	[16]	Anxiolytic, anti-carcinogenic [84]

136.1252
46 α-terpinene	G. parviflora (leaves) G. salicifolia (leaves)	GC-MS	[16]	Antioxidant, antimicrobial, acetylcholinesterase inhibition, sedative [85,86]

136.1252
47 γ-terpinene	G. parviflora (leaves) G. salicifolia (leaves)	GC-MS	[16]	Antioxidant, antimicrobial, acetylcholinesterase inhibition, antinociceptive, anti-inflammatory [86,87,88]

136.1252
48 terpinolene	G. parviflora (leaves) G. salicifolia (leaves)	GC-MS	[16]	Antioxidant, antimicrobial, larvicide, insecticide [86,89]

136.1252
49 α-pinene	G. parviflora (leaves) G. salicifolia (leaves)	Chemical derivatisation (G.p) GC-MS (G.s)	[16,18]	Anti-inflammatory, anti-tumour [84]

136.1252
50 β-pinene	G. parviflora (leaves) G. salicifolia (leaves)	GC-MS	[16]	Anti-inflammatory, anti-tumour [84]

136.1252
51 camphene	G. parviflora (leaves)	Chemical derivatisation	[18]	Antioxidant [90]

136.1252
52 sabinene	G. parviflora (leaves) G. salicifolia (leaves)	GC-MS	[16]	Antioxidant, anti-inflammatory [91,92]

136.1252
53 α-phellandrene	G. parviflora (leaves)	GC-MS	[16]	Antinociceptive, hyperthermic, promotes immune response, anti-cancer, antimicrobial, fungicide, pesticide [93]

136.1252
54 β-phellandrene	G. parviflora (leaves) G. salicifolia (leaves)	GC-MS	[16]	Acetylcholinesterase inhibitor, antifungal, expectorant [94,95]

136.1252
55 p-cymene	G. salicifolia (leaves) G. parviflora (leaves)	GC-MS	[16]	Antioxidant, anti-inflammatory, anti-cancer, antimicrobial [96]

134.1096
56 citronellyl acetate	G. linearifolia (leaves)	GC-MS	[16]	Pro-apoptotic activity in HepG2, fungicide, larvicide, bactericide, insect repellent/insecticide, antinociceptive [97]

196.1620
57 geranyl acetate	G. linearifolia (leaves)	GC-MS	[16]	Anti-cancer, antifungal [98,99]

196.1463
58 neryl acetate	G. linearifolia (leaves)	GC-MS	[16]	Fragrance and flavouring agent, strengthens skin barrier function [67,100]

196.1463
59 nerol	G. linearifolia (leaves)	GC-MS	[16]	Antimicrobial [101]

154.1358
60 geraniol	G. linearifolia (leaves)	GC-MS	[16]	Antimicrobial [101]

154.1358
61 linalool	G. linearifolia (leaves) G. salicifolia (leaves) G. parviflora (leaves)	GC-MS	[16]	Anxiolytic, antibacterial, anti-inflammatory [102,103,104]

154.1358
62 α-terpineol	G. parviflora (leaves) G. salicifolia (leaves)	GC-MS	[16]	Antioxidant, anti-cancer, anticonvulsant, antiulcer, antihypertensive, antinociceptive, enhances skin penetration, insecticidal properties [105]

154.1358
63 terpinen-4-ol	G. parviflora (leaves) G. salicifolia (leaves)	GC-MS	[16]	Anti-inflammatory, antifungal, anti-cancer, antibacterial [106,107,108,109,110]

154.1358
64 1,8-cineole (eucalyptol)	G. parviflora (leaves) G. salicifolia (leaves)	GC-MS	[16]	Anti-inflammatory, antioxidant, analgesic, antifungal [107,111,112]

154.1358
65 camphor	G. parviflora (leaves) G. salicifolia (leaves)	GC-MS	[22]	Insecticidal, antimicrobial, antiviral, anticoccidial, antinociceptive, anti-cancer, antitussive, skin penetration enhancer [113]

152.1201
66 borneol	G. salicifolia (leaves)	GC-MS	[22]	Enhances membrane permeability, antibacterial, antifungal, antispasmodic, choleretic, acesodyne, sedative [114,115]

154.1358
67 azulene	G. parviflora (leaves)	Chemical derivatisation	[18]	Anti-inflammatory [116]

128.0626
68 pregeijerene	G. salicifolia (leaves) G. parviflora (leaves)	Chemical derivatisation, degradative analysis, and UV	[29]	Antifeedant, oviposition deterrence [117]

162.1409
69 cogeijerene	G. salicifolia (leaves)	Chemical derivatisation, degradative analysis, and UV (G.s)	[29,118]	No activity reported to date
	G. salicifolia (leaves)	Chemical derivatisation, degradative analysis, and UV (G.s)
162.1409	G. parviflora (leaves)	Chemical derivatisation, degradative analysis, IR, and UV (G.p)
70 geijerene	G. parviflora (leaves)	Combustion analysis, chemical derivatisation, degradative analysis, IR (G.p)	[16,18,119]	Antifeedant, oviposition deterrence [117]
	G. parviflora (leaves)
164.1565	G. salicifolia (leaves)	GC-MS (G.s)
71 viridiflorene (ledene)	G. linearifolia (leaves)	GC-MS	[16]	Antifungal [120]

204.1878
72 α-selinene	G. parviflora (leaves)	GC-MS	[16]	No activity reported to date

204.1878
73 β-selinene	G. parviflora (leaves)	GC-MS	[16]	No activity reported to date

204.1878
74 selina-3, 7(11)-diene	G. parviflora (leaves)	GC-MS	[22]	No activity reported to date

204.1878
75 germacrene B	G. salicifolia (leaves)	GC-MS	[22]	Antimicrobial activity against Gram negative bacteria [121]

204.1878
76 germacrene D	G. linearifolia (leaves) G. salicifolia (leaves) G. parviflora (leaves)	GC-MS	[16,22]	Anti proliferative, scavenging activity towards the ABTS radical, antibacterial, antifungal, insecticidal, repels herbivores, attracts pollinators [122,123]

208.2191
77 bicyclogermacrene	G. linearifolia (leaves) G. salicifolia (leaves) G. parviflora (leaves)	GC-MS	[16]	Larvicidal activity [124]

204.1878
78 α-bergamotene	G. parviflora (leaves)	GC-MS	[16]	Antifeedant [125]

204.1878
79 δ-cadinene	G. parviflora (leaves)	GC-MS	[16]	Acaricidal, antiproliferative and apoptotic [126,127]

204.1878
80 β-elemene	G. linearifolia (leaves) G. salicifolia (leaves) G. parviflora (leaves)	GC-MS	[16]	Anti-cancer, antineoplastic, reproductive toxicity [128,129]

204.1878
81 γ-elemene	G. parviflora (leaves) G. salicifolia (leaves)	GC-MS	[16]	Larvicidal activity [130]

204.1878
82 α-caryophyllene (humulene)	G. salicifolia (leaves)	GC-MS	[22]	Antibacterial, anti-inflammatory, antitumor, analgesic [131,132,133]

204.1878
83 β-caryophyllene	G. linearifolia (leaves) G. salicifolia (leaves) G. parviflora (leaves)	GC-MS	[16]	Anti-inflammatory, analgesic, antimalarial, antifungal, antibacterial, anti-tumour [84,134]

204.1878
84 α-santalene	G. parviflora (leaves)	GC-MS	[22]	Insect repellent, semiochemical [125]

204.1878
85 aromadendrene	G. parviflora (leaves) G. linearifolia (leaves) G. salicifolia (leaves)	GC-MS	[16,22]	Antibacterial (MRSA and drug resistant pathogens) [135]

204.1878
86 (E,E)-α-farnesene	G. parviflora (leaves) G. linearifolia (leaves) G. salicifolia (leaves)	GC-MS	[16]	Semiochemical, antibacterial, anticariogenic, anti-cancer, anti-plasmodial, hepatoprotective, antioxidant, anti-inflammatory, antifungal [136,137]

204.1878
87 (E,E)-farnesol	G. linearifolia (leaves)	GC-MS	[16]	Antibacterial, antifungal [138,139]

222.1984
88 guaiol	G. parviflora (leaves) G. salicifolia (leaves)	GC-MS	[22]	Insecticide, antimicrobial, acaricidal, anti-cancer [140,141,142]

208.1827
89 elemol	G. parviflora (leaves)	GC-MS	[16]	Antifungal [143]
	G. salicifolia (leaves)
222.1984	G. salicifolia (leaves)
90 palustrol	G. linearifolia (leaves)	GC-MS	[16]	Semiochemical [144]

222.1984
91 ledol	G. parviflora (leaves)	GC-MS	[22]	Antifungal, toxic CNS effects, antitussive, expectorant [145,146]

222.1984
92 globulol	G. parviflora (leaves)	GC-MS	[16]	Antimicrobial [147]

222.1984
93 epi-globulol	G. parviflora (leaves)	GC-MS	[16]	Antimicrobial, semiochemical [148]

222.1984
94 τ-cadinol	G. linearifolia (leaves)	GC-MS	[16]	Antitrypanosomal, smooth muscle relaxant, inhibits effects of cholera toxins [149,150]

207.1749
95 α-eudesmol	G. linearifolia (leaves) G. parviflora (leaves) G. salicifolia (leaves)	GC-MS	[16]	Antitrypanosomal, anti-cancer, anti-neurogenic inflammation [151,152,153]

222.1984
96 β-eudesmol	G. linearifolia (leaves) G. parviflora (leaves) G. salicifolia (leaves)	GC-MS	[16]	Anti-cancer, sedative, hepatoprotective, anti-inflammatory, diuretic, inhibits platelet aggregation, insect repellent, anti-allergy [67,152,154,155,156,157]

222.1984
97 γ-eudesmol	G. linearifolia (leaves) G. parviflora (leaves) G. salicifolia (leaves)	GC-MS	[16]	Anti-cancer [152]

222.1984
98 viridiflorol	G. parviflora (leaves)	GC-MS	[16]	Anti-mycobacterial, anti-inflammatory, antioxidant [158]

222.1984
99 (E,E)-farnesal	G. linearifolia (leaves)	GC-MS	[16]	Semiochemical [159]

220.1827
100 caryophyllene oxide	G. linearifolia (leaves) G. salicifolia (leaves) G. parviflora (leaves)	GC-MS	[16]	Anti-cancer, analgesic [134]

220.1827
101 caryophylla-4(12), 8(13)-dien-5-ol	G. parviflora (leaves)	GC-MS	[22]	No activity reported to date

220.1827
102 spathulenol	G. linearifolia (leaves) G. parviflora (leaves) G. salicifolia (leaves)	GC-MS	[16,22]	Antioxidant, anti-inflammatory, antiproliferative, antimycobacterial, antimicrobial [160,161]

220.1827
103 eremophilone	G. parviflora (leaves)	GC-MS	[16,22]	Cytotoxic, insecticidal, insect repellent, antifeedant (against termites) [162,163]

218.1671
104 cyclocolorenone	G. parviflora (leaves)	GC-MS	[16,22]	Antifeedant, antimicrobial, allelopathic, anti-inflammatory, insect repellent [164]

218.1671
105 β-sitosterol	G. salicifolia (leaves)	Melting point and IR	[37]	Anti-cancer, anthelminthic, antimutagenic [165,166]

414.3862

(Key: G.l—G. linearifolia, G.p—G. parviflora, G.s—G. salicifolia).

3.4. Miscellaneous Compounds Isolated

Phenolic derivatives, brevifolin 106, and elemicin 107, have been identified within the leaf essential oils of G. parviflora. Brevifolin 106 also forms a large proportion of the essential oil from one chemotype of G. salicifolia, obtained from the leaves via hydro-distillation, and it is also present in the bark of G. balansae. A flavonoid 3,5,8,4′-tetrahydroxy-6,7-dimethoxyflavone 108; a benzyl alcohol ester 2-phenylethyl isobutyrate 109, fatty acid ester isoamyl isovalerate 110, cyclic ketone cis-jasmone 111, phenylpropanoid methyl eugenol 112; and a benzene dicarboxylic acid (phthalic acid) 113 were also isolated from the leaves of G. parviflora. Additionally, four phenolic compounds 114–117 (vanillin, methyl syringate, methyl and ethyl ferulates, respectively) were isolated from the wood of G. balansae (Table 5).

The miscellaneous compounds isolated from the Geijera species exhibit a variety of pharmacological activities, as summarised in Table 5.

Table 5. Miscellaneous compounds isolated from the genus Geijera.

Compound and Exact Mass (Da)	Source	Method of Identification	Reference	Pharmacological Activity of Compound (Various Sources)
106 brevifolin (xanthoxylin)	G. parviflora (leaves) G. balansae (bark) G. salicifolia (leaves)	GC-MS (G.p) ¹H NMR, IR, UV, and MS (G.b) Melting point (G.s)	[16,18,28]	Antioxidant, hepatoprotective, antibacterial, antifungal, antinociceptive, antiedematogenic and antispasmodic [167,168]

196.0736
107 elemicin	G. parviflora (leaves)	GC-MS	[9]	Psychotropic, antimicrobial, antioxidant, acetylcholinesterase inhibitor, antiviral [9,169,170]

208.1099
108 3,5,8,4′-tetrahydroxy-6,7-dimethoxyflavone	G. parviflora (leaves)	¹H and ¹³C NMR	[10]	No activity reported to date

346.0689
109 2-phenylethyl isobutyrate	G. parviflora (leaves)	¹H and ¹³C NMR	[10]	Odorant [171]

192.1150
110 isoamyl isovalerate	G. parviflora (leaves)	¹H and ¹³C NMR	[10]	Flavouring/odorant [172]

172.1463
111 cis-jasmone	G. parviflora (leaves)	GC-MS	[22]	Semiochemical [173]

164.1201
112 methyl eugenol	G. parviflora (leaves)	GC-MS	[22]	Attracts pollinator insects (semiochemical) [174]

178.0994
113 phthalic acid	G. parviflora (leaves)	GC-MS	[22]	Endocrine disruptor [175]

166.0266
114 vanillin	G. balansae (wood)	¹H NMR, IR, UV, and MS	[28]	Flavouring, pharmaceutical excipient, antioxidant, inhibits lipid peroxidation [67]

152.0473
115 methyl syringate	G. balansae (wood)	¹H NMR, IR, UV, and MS	[28]	Anti-diabetic, TRPA1 agonist [176,177]

212.0685
116 methyl ferulate	G. balansae (wood)	¹H NMR, IR, UV, and MS	[28]	Inhibits COX-2 expression, blocks p-p38 and p-JNK in primary bone marrow derived-macrophages [178,179]

208.0736
117 ethyl ferulate	G. balansae (wood)	¹H NMR, IR, UV, and MS	[28]	Antioxidative, antiapoptotic, antirheumatic, neuroprotective and anti-inflammatory [180,181]

222.0892

(Key: G.l—G. linearifolia, G.p—G. parviflora, G.s—G. salicifolia).

4. Pharmacological Activities of Geijera Constituents

Compounds that have been identified within the genus Geijera exhibit a variety of pharmacological behaviors which can be categorised into the following main types of activity:

Antimicrobial activity;
Antifungal activity;
Reduction in inflammation;
Reduction in pain;
Reduction in anxiety;
Muscle relaxant activity;
Anti-cancer and anti-tumour activity;

Antioxidant activity;
Acetylcholinesterase inhibition;
MAO-B inhibition;
Anticonvulsant activity;
Psychotropic activity;
Increase in membrane permeability;
Plant pest resistance/insecticidal/semiochemical activity.

The chemical constituents identified in the four studied Geijera species are enumerated in Table 6, according to the main types of activity reported. The pharmacological activities of novel alkaloids isolated from G. balansae, namely O-acetyl geibalansine 39 and geijedimerine 40, as well as the flindersine derivatives 4′-hydroxy-3′,4′-dihydroflindersine 31 and cis-3′,4′-dihydroxy-3′,4′-dihydroflindersine 32 are unknown, but in light of the activities reported from the other species of the genus, it would be worthwhile to examine these for any useful pharmacological properties.

The activities reported in Table 6 were obtained based on all the available literature for that chemical constituent. The purpose of this was to illustrate the range of pharmacological activities of these compounds, which can possibly support the customary uses of the plant.

4.1. Geijera Secondary Metabolites That Can Be Linked to Its Ethnobotanical Uses

The key pharmacological activities associated with the traditional use of G. parviflora are related to general analgesia, relief from toothache and infection, and the induction of psychoactive effects. These outcomes could arise from the following pharmacological activities as reported from specific secondary metabolites:

anti-inflammatory activity
analgesic/antinociceptive activity
antimicrobial, antifungal, and antioxidant activity
acetylcholinesterase inhibition, monoamine oxidase inhibition, muscle relaxant activity, sedative activity, anticonvulsant activity, and psychotropic activity (from neuro- and psycho-active compounds).

Although many of the active compounds identified are minor constituents, their combined activity (probable or possible synergistic activity) merits further investigation, in conjunction with the effects of compounds such as α-terpineol 62, camphor 65, and borneol 66, which increase membrane permeability and hence may facilitate greater uptake of the active compounds. It has been hypothesised that the observed activities of preparations from medicinal plants can be attributed not only to the pharmacological effects of the main constituents, but also to a synergy of action between the most and the less abundant active components found within these mixtures [182]. The occurrence of a large variety of active major and minor constituents as observed within G. parviflora, makes it an ideal candidate for studies to explore the validity and implications of this hypothesis. In addition, many of the pharmacological activities herein are only reported for in vitro assays. This further supports the necessity for further investigations to ascertain the suitability of specific lead compounds for therapeutic use.

4.1.1. Anti-Inflammatory, Analgesic, and Antinociceptive Compounds

Of the forty-four anti-inflammatory and analgesic compounds identified within the genus Geijera, thirty-four have been found in G. parviflora (Table 7). Since inflammation triggers cellular responses associated with pain and hyperalgesia, a decrease in inflammation should mitigate pain [183].

Several of the compounds in Table 7 display anti-inflammatory activity through the inhibition of inflammatory mediators. For example, caryophyllene oxide 100 was shown to inhibit cyclooxygenase and/or lipoxygenase, whereas compounds such as 13, 26, 30, and 35, act through the inhibition of nitric oxide and prostaglandin E₂ production [57,73,92,106]. Banbury et al. suggested that the anti-inflammatory activities of flindersine 30 and its derivative (N-acetoxymethyl) flindersine 35, which act through prostaglandin E₂ inhibition, could contribute significantly to pharmacological effects that justify the traditional use of the leaves of G. parviflora for analgesia [10].

In total, nine compounds occurring in G. parviflora leaves: 44, 47, 53, 62, 64, 65, 83, 100 and 106 have reported analgesic and/or antinociceptive activities, and these properties directly support the customary uses of this plant.

4.1.2. Antimicrobial, Antifungal, and Antioxidant Compounds

A total of sixty-one antimicrobial, antifungal, and antioxidant compounds were identified within the Geijera species. These compounds (from various sources) have reported activities against a broad range of microbial and fungal pathogens, as well as significant antioxidant activities which may serve to support healthy immune responses and decrease the incidence of inflammatory conditions and resultant pain. Of these compounds, forty-one have been identified in G. parviflora (Table 8).

The furanocoumarin angelicin (isopsoralen) 16, found in G. parviflora leaves, has reported activities against gamma-herpes viruses and periodontal disease [61,184], and these activities are congruent with the traditional use of the plant for toothache. Antimicrobial constituents such as hexadecanoyl anthranilic acid 24, and the mixture of three anthranilic acid derivatives 20, 21, 22 from G. parviflora leaves displayed antibacterial activity against several Gram-positive strains, including a methicillin-resistant strain of Staphylococcus aureus [68]. Of particular interest, is that a quinolone isolated from the bark of G. balansae, 4-methoxy N-methyl-2-quinolone 37, displays significant activity against Methicillin resistant Staphylococcus aureus (MRSA) with an IC₅₀ value of 8.0 µM [80].

4.1.3. Neuroactive and Psychoactive Compounds

The twenty-one compounds distributed within Geijera that display neuroactive and psychoactive effects are categorised in Table 9. In addition to these, the coumarin osthole 15 (from G. parviflora leaves) and the ferulic acid derivative ethyl ferulate 117 (from G. balansae wood) also possess neuroprotective properties [181,185]. A total of fifteen neuroactive and psychoactive compounds have been reported from G. parviflora.

In this group of compounds, geiparvarin 2 has been shown to be a strong and selective monoamine oxidase B inhibitor [43].

These constituents are present in minor quantities which may not be sufficient to produce psychoactive effects if taken orally (due to their metabolism in the digestive tract). However, the traditional use of G. parviflora for the purpose of inducing intoxication involves smoking the plant, and there may be high enough concentrations of actives (or pyrolysed actives) present within the smoke (which is absorbed directly into the bloodstream via the lungs) to induce intoxicating effects [22]. Preliminary investigation of smoke condensates from G. parviflora carried out by Sadgrove et al. did not yield definitive results [9]. Hence, there is scope for further work to be undertaken in order to refine the methodology devised to simulate the smoke preparations that are created during traditional use of G. parviflora, which are often produced in conjunction with other plant materials, so that any psychoactive constituents within these complex mixtures can be accurately determined and assayed for their combined activity, as well as their individual activities, in this context.

4.1.4. Anti-Cancer Compounds

The most noteworthy anti-tumour compound isolated from the genus Geijera is geiparvarin 2, which displays significant in vitro cytostatic activity and antiproliferative activity against various tumour cell lines [42,186]. The bioactivity of 2 was attributed to the furan-3 (2H) moiety, which was suggested by Borges et al. to act as an alkylating agent against bio-nucleophiles [41]. Geiparvarin 2 and 2′,3′-dihydrogeiparvarin 6 also display significant in vitro activity against human carcinoma of the nasopharynx [48,49]. Derivatives of geiparvarin 2 have been developed with increased cytotoxic activity, suggesting that this compound could provide a useful lead in the development of new anti-tumour agents [42].

In total, forty-one compounds displaying anti-cancer activities were reported within the genus Geijera, with thirty-three of these occurring in G. parviflora (Table 10). Although it is beyond the scope of this review to provide details of the various cancer cell lines that these compounds are active against, the number of compounds with anti-cancer activity present in G. parviflora especially, provides a good argument for the value and use of this plant in customary medicine.

4.1.5. Compounds That Offer Pest Resistance, Insecticidal and Semiochemical Benefits

There are twenty-six compounds identified within the genus Geijera which have been observed in other studies to display useful botanical activities, including the ability to confer resistance from plant pests, provide protection from deleterious insects, and provide other semiochemical benefits such as anti-feedant activity and attraction of pollinators. Of these, twenty-one such compounds occur in G. parviflora (Table 11).

It would be useful to test extracts or isolates obtained directly from the Geijera species for the same or additional activities, such as antiparasitic activity. Based on the activities displayed here, there is scope for the development of formulations based on the constituents of Geijera, which could provide beneficial alternatives to conventional insect repellents as well as insecticides and pesticides in agricultural settings.

4.2. Future Perspectives

The traditional use of G. parviflora as an analgesic is supported by the identification of over thirty compounds within the plant, which display relevant pharmacological activities in this area. A promising range of active compounds has been discovered within other species of the genus, giving impetus for further natural product characterisation. Exploratory studies into synergistic effects are also warranted.

Most of the compounds identified within the genus Geijera have been isolated from the leaves of the plants. However, on the basis of the variety of active constituents that have been found within this species and its genus, it would be prudent to study the parts of the plant which have not received as much scientific attention, namely the fruits/seeds, which have previously yielded the alkaloid flindersine 30 [44].

The two New Caledonian species G. cauliflora, and G. tartarea, which have not been studied to date, should also be prioritised for future study.

Improvements in NMR and mass spectroscopy, and the development of new technologies for analytical separations and chemical profiling (LC/MS) have occurred in the decades since these studies were first performed. These advances mean that further compounds, including new structure derivatives, could be discovered. This could provide useful information in terms of the structure–activity relationships (SAR) of the currently known active compounds. In addition, a chemical profiling study that is focused on lead-like compounds, which compares the chemical profiles of different parts of the plants such as the leaves, fruits, and bark/wood, would also be beneficial to perform as an aid in further compound discovery. Further studies exploring a greater range of biological/physiological activities, beyond the traditional applications, are also worthwhile. This would include examining the agrochemical potential and bioactivity in a range of assays beyond those listed in this review, as well as exploration of the synthesis of active metabolites and/or their large-scale production, such as implementation of callus cultures. No studies have been conducted on the effect of the growing conditions on the production of secondary metabolites, nor has there been enough study of the plants in this genus to be able to establish whether specific compounds/classes observed could be chemotaxonomic markers. It is important to note that the pharmacological activities of the novel alkaloids O-acetyl geibalansine 39 and geijedimerine 40, as well as the flindersine derivatives 4′-hydroxy-3′,4′-dihydroflindersine 31 and cis-3′,4′-dihydroxy-3′,4′-dihydroflindersine 32 isolated from G. balansae are unknown, but in the light of the activities reported from the other alkaloids of this genus, it would be helpful to examine these for useful pharmacological properties. This would include refining the methodology to extract these compounds, revisiting the complete characterisation of some of the compounds listed in this review, and exploring synthetic routes for their production.

5. Conclusions

Plants of the genus Geijera are a rich source of biologically active compounds which encompass terpenes, terpenoids, coumarins, quinolones, and anthranilic acid derivatives. The traditional use of G. parviflora in the Indigenous Australian context is supported by the presence of compounds with significant anti-inflammatory, analgesic, antioxidant, antimicrobial, and antifungal activity. The psychoactive, neuroactive, and neuroprotective aspects of constituents inferred from the traditional uses of G. parviflora, in conjunction with their reported activities, merit further detailed investigation. Studies undertaken in recent years have highlighted many of the biological activities of the chemical constituents within these plants including anti-cancer, antimicrobial, antifungal, and pest resistant properties. With such a wealth of bioactivity, compounds from the various species of Geijera still hold potential to provide new therapeutic agents. This justifies a thorough phytochemical investigation of the constituents of the two neglected species, G. cauliflora, and G. tartarea. Furthermore, based on the reported activities exhibited by their chemical constituents, additional research on the pharmacological potential of all the plant components, including the roots, stems, bark, leaves, and flowers, from the entire genus Geijera is justified.

Author Contributions

Investigation, D.D. and R.J.B.; writing—original draft preparation, D.D.; writing—review and editing, D.D., R.B., C.R. and S.U.; supervision, S.U. All authors have read and agreed to the published version of the manuscript.

Funding

This research is supported by an Australian Government Research Training Program (RTP) Scholarship.

Institutional Review Board Statement

Not Applicable.

Informed Consent Statement

Not Applicable.

Data Availability Statement

Not Applicable.

Acknowledgments

In the spirit of Reconciliation, the authors acknowledge the Traditional Custodians of country throughout Australia and their connections to land, sea, and community. The authors would like to acknowledge the Wurundjeri people of the Kulin Nations as the Traditional Owners of the land on which RMIT University stands. We pay our respect to their Elders past, present, and future and we extend that respect to all Aboriginal and Torres Strait Islander peoples.

Conflicts of Interest

The authors declare no conflict of interest.

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Figure 1. Occurrence of species from the genus Geijera Schott [3].

Figure 2. Total plant compounds identified to date from each of the studied Geijera species.

Figure 3. Distribution of plant compounds identified to date within Geijera species. The number denotes the number of compounds of each class within the Geijera species.

Table 1. Geijera plant species and their synonyms.

Species (Accepted Name)	Synonyms
Geijera balansae (Baill.) Schinz & Guillaumin	Zanthoxylum balansae
Geijera cauliflora Baill.	Dendrosma deplanchei Pancher & Sebert Geijera deplanchei (Pancher & Sebert) Däniker Geijera lateriflora Baill. ex Guillaumin
Geijera linearifolia (DC.) J.M.Black	Geijera parviflora var. crassifolia Benth. Eriostemon linearifolius DC. Geijera linearifolia Domin
Geijera parviflora Lindl.	Geijera pendula Lindl. Geijera parviflora var. parviflora Lindl. Zanthoxylum australasicum A.Juss.
Geijera salicifolia Schott	Geijera salicifolia var. augustifolia Maiden Geijera salicifolia Schott var. salicifolia Geijera salicifolia var. latifolia (Lindl.) Domin Geijera salicifolia var. angustifolia Maiden & Betche Geijera latifolia Lindl. Geijera salicifolia var. typica Domin Geijera floribunda Pancher ex Guillaumin
Geijera tartarea T.G.Hartley ex Munzinger & Bruy	None

Table 6. Constituents identified in Geijera species according to their pharmacological activity type.

Type of Activity	No. Compounds in Geijera	No. Compounds in G. balansae	No. Compounds in G. parviflora	No. Compounds in G. salicifolia	No. Compounds in G. linearifolia
Acetylcholinesterase inhibition	7	1	6	6	-
Anti-cancer	41	4	32	26	13
Anticonvulsant	4	1	3	3	2
Antifungal	25	5	16	13	9
Antimicrobial	45	9	29	19	12
Antioxidant	20	4	15	11	2
Increase in membrane permeability	3	-	2	3	-
Monoamine oxidase B inhibition	1	-	1	1	-
Muscle relaxant	5	2	2	3	1
Osteogenic	3	1	2	-	-
Plant pest resistance/semiochemical/ insecticide	26	1	21	14	9
Psychoactive	3	-	3	2	-
Reduction in anxiety	7	-	5	5	2
Reduction in inflammation	38	7	28	17	6
Reduction in pain	12	1	8	10	3

Table 7. Anti-inflammatory, analgesic, and antinociceptive compounds within the genus Geijera.

umbelliferone 1 S	xanthoxyletin 19 B	sabinene 52 P,S	β-caryophyllene 83 P,S,L
6′-dehydromarmin 5 P	dictamine 25 B	α-phellandrene 53 P	(E,E)-α-farnesene 86 P,S,L
(R)-6-O-(4-geranyloxy-2-hydroxy) cinnamoylmarmin 7 P	skimmianine 26 S,B	citronellyl acetate 56 L	α-eudesmol 95 P,S,L
parvifloranine A 8 P	flindersine 30 P,B	linalool 61 P,S,L	β-eudesmol 96 P,S,L
scoparone 11 P	N-(acetoxymethyl) flindersine 35 P	α-terpineol 62 P,S	viridiflorol 98 P
suberosin 12 P	haplaphine 36 P,B	terpinen-4-ol 63 P,S	caryophyllene oxide 100 P,S,L
dehydrogeijerin 13 P,S	myrcene 44 P,S	1,8 cineole 64 P,S	spathulenol 102 P,S,L
6-(methoxyl) geiparvarin 14 P	γ-terpinene 47 P,S	camphor 65 P,S	cyclocolorenone 104 P
osthole 15 P	α-pinene 49 P,S	borneol 66 S	brevifolin (xanthoxylin) 106 P,S,B
angelicin (isopsoralen) 16 P	β-pinene 50 P,S	azulene 67 P	methyl ferulate 116 B
luvangetin 18 B	p-cymene 55 P,S	α-caryophyllene (humulene) 82 S	ethyl ferulate 117 B

(Sources: P—G. parviflora, S—G. salicifolia, L—G. linearifolia, B—G. balansae).

Table 8. Antimicrobial, antifungal, and antioxidant compounds within the genus Geijera.

umbelliferone 1 S	zanthobungeanine 33 B	nerol 59 L	guaiol 88 P,S
auraptene 3 P	4-methoxy N-methyl-2-quinolone 37 B	geraniol 60 L	elemol 89 P,S
scoparone 11 P	hordenine 41 B	linalool 61 P,S,L	ledol 91 P
osthole 15 P	(E)-β-ocimene 42 P,S,L	α-terpineol 62 P,S	globulol 92 P
angelicin (isopsoralen) 16 P	(Z)-β-ocimene 43 P,S,L	terpinen-4-ol 63 P,S	epi-globulol 93 P
xanthyletine 17 P	myrcene 44 P,S	1,8 cineole 64 P,S	τ-cadinol 94 L
luvangetin 18 B	α-terpinene 46 P,S	camphor 65 P,S	α-eudesmol 95 P,S,L
xanthoxyletin 19 B	γ-terpinene 47 P,S	borneol 66 S	viridiflorol 98 P
11′-hexadecanoyl anthranillic acid 20 P	terpinolene 48 P,S	viridiflorene (ledene) 71 L	spathulenol 102 P,S,L
9′-hexadecenoyl anthranillic acid 21 P	camphene 51 P	germacrene B 75 S	cyclocolorenone 104 P
7′-hexadecanoyl anthranillic acid 22 P	sabinene 52 P,S	germacrene D 76 P,S,L	brevifolin (xanthoxylin) 106 P,S,B
hexadecanoyl anthranillic acid 24 P	α-phellandrene 53 P	α-caryophyllene (humulene) 82 S	elemicin 107 P
dictamnine 25 B	β-phellandrene 54 P,S	β-caryophyllene 83 P,S,L	ethyl ferulate 117 B
γ-fagarine 27 S,B	p-cymene 53 P,S	aromadendrene 85 P,S,L
platydesmine 28 S,B	citronellyl acetate 54 L	(E,E)-α-farnesene 86 P,S,L
flindersine 30 P,B	geranyl acetate 57 L	(E,E)-farnesol 87 L

(Sources: P—G. parviflora, S—G. salicifolia, L—G. linearifolia, B—G. balansae).

Table 9. Neuroactive and psychoactive compounds within the genus Geijera.

Acetylcholinesterase Inhibitors	Anxiolytics and Sedatives	Muscle Relaxants and Anticonvulsants	Psychoactive Compounds
geijerin 10 P,S	osthole 15 P	xanthoxyletin 19 B	geiparvarin 2 P,S
dehydrogeijerin 13 P,S	myrcene 44 P,S	geibalansine 38 B	myrcene 44 P,S
skimmianine 26 S,B	limonene 45 S	(E)-β-ocimene 42 P,S,L	elemicin 107 P
α-terpinene 46 P,S	α-terpinene 46 P,S	(Z)-β-ocimene 43 P,S,L
γ-terpinene 47 P,S	linalool 61 P,S,L	myrcene 44 P,S
β-phellandrene 54 P,S	borneol 66 S	α-terpineol 62 P,S
elemicin 107 P	β-eudesmol 96 P,S,L	borneol 66 S
		τ-cadinol 94 L
		brevifolin (xanthoxylin) 106 P,S

(Sources: P—G. parviflora, S—G. salicifolia, L—G. linearifolia, B—G. balansae).

Table 10. Anti-cancer compounds within the genus Geijera.

umbelliferone 1 S	dictamnine 25 B	p-cymene 55 P,S	β-caryophyllene 83 P,S,L
geiparvarin 2 P,S	skimmianine 26 S, B	citronellyl acetate 56 L	(E,E)-α-farnesene 86 P,S,L
auraptene 3 P	haplaphine 36 P,B	geranyl acetate 57 L	guaiol 88 P,S
6′dehydromarmin 5 P	(E)-β-ocimene 42 P,S,L	α-terpineol 62 P,S	α-eudesmol 95 P,S,L
2′,3′-dihydrogeiparvarin 6 P,S	(Z)-β-ocimene 43 P,S,L	terpinen-4-ol 63 P,S	β-eudesmol 96 P,S,L
(R)-6-O-(4-geranyloxy-2-hydroxy) cinnamoylmarmin 7 P	myrcene 44 P,S	camphor 65 P,S	γ-eudesmol 97 P,S,L
scoparone 11 P	limonene 45 S	germacrene D 76 P,S,L	caryophyllene oxide 100 P,S,L
6-(methoxyl) geiparvarin 14 P	α-pinene 49 P,S	δ-cadinene 79 P	spathulenol 102 P,S,L
osthole 15 P	β-pinene 50 P,S	β-elemene 80 P,S,L	eremophilone 103 P
angelicin (isopsoralen) 16 P	α-phellandrene 53 P	α-caryophyllene (humulene) 82 S	β-sitosterol 105 S
xanthoxyletin 19 B

(Sources: P—G. parviflora, S—G. salicifolia, L—G. linearifolia, B—G. balansae).

Table 11. Antifeedant, oviposition deterrent, insecticidal, and semiochemical compounds within the genus Geijera.

Insecticides	Semiochemicals	Antifeedants	Oviposition Deterrents
terpinolene 48 P,S	(E)-β-ocimene 42 P,S,L	umbelliferone 1 S	pregeijerene 68 S
α-phellandrene 53 P	(Z)-β-ocimene 43 P,S,L	hordenine 41 B	geijerene 70 S,P
citronellyl acetate 56 L	α-santalene 84 P	pregeijerene 68 S
α-terpineol 62 P,S	(E,E)-α-farnesene 86 P,S,L	geijerene 70 S,P
camphor 65 P,S	palustrol 90 L	α-bergamotene 78 P
germacrene D 73 P,S,L	epi-globulol 93 P	eremophilone 103 P
bicyclogermacrene 77 P,S,L	β-eudesmol 96 P,S,L	cyclocolorenone 104 P
δ-cadinene 79 P	(E,E)-farnesal 99 L
γ-elemene 81 P,S	cis-jasmone 111 P
guaiol 88 P,S	methyl eugenol 112 P
β-eudesmol 96 P,S,L
eremophilone 103 P

(Sources: P—G. parviflora, S—G. salicifolia, L—G. linearifolia, B—G. balansae).

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Dugan, D.; Bell, R.J.; Brkljača, R.; Rix, C.; Urban, S. A Review of the Ethnobotanical Use, Chemistry and Pharmacological Activities of Constituents Derived from the Plant Genus Geijera (Rutaceae). Metabolites 2024, 14, 81. https://doi.org/10.3390/metabo14020081

AMA Style

Dugan D, Bell RJ, Brkljača R, Rix C, Urban S. A Review of the Ethnobotanical Use, Chemistry and Pharmacological Activities of Constituents Derived from the Plant Genus Geijera (Rutaceae). Metabolites. 2024; 14(2):81. https://doi.org/10.3390/metabo14020081

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Dugan, Deepika, Rachael J. Bell, Robert Brkljača, Colin Rix, and Sylvia Urban. 2024. "A Review of the Ethnobotanical Use, Chemistry and Pharmacological Activities of Constituents Derived from the Plant Genus Geijera (Rutaceae)" Metabolites 14, no. 2: 81. https://doi.org/10.3390/metabo14020081

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A Review of the Ethnobotanical Use, Chemistry and Pharmacological Activities of Constituents Derived from the Plant Genus Geijera (Rutaceae)

Abstract

1. Introduction

2. Methodology

3. Chemical Constituents in Geijera Species

3.1. Coumarins

3.2. Alkaloids

3.3. Terpenes and Terpenoids

3.4. Miscellaneous Compounds Isolated

4. Pharmacological Activities of Geijera Constituents

4.1. Geijera Secondary Metabolites That Can Be Linked to Its Ethnobotanical Uses

4.1.1. Anti-Inflammatory, Analgesic, and Antinociceptive Compounds

4.1.2. Antimicrobial, Antifungal, and Antioxidant Compounds

4.1.3. Neuroactive and Psychoactive Compounds

4.1.4. Anti-Cancer Compounds

4.1.5. Compounds That Offer Pest Resistance, Insecticidal and Semiochemical Benefits

4.2. Future Perspectives

5. Conclusions

Author Contributions

Funding

Institutional Review Board Statement

Informed Consent Statement

Data Availability Statement

Acknowledgments

Conflicts of Interest

References

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