*2.7.1. Leonotis leonurus*

**2.7.** *Leonotis* **genus**

16 Terpenes and Terpenoids

Seven species were recorded in SA and two of them were extensively studied. Traditionally, this genus is used to substitute hemp and called as wild dagga; however, there is no much scientific biological evidences supporting such claim. The chemistry was started in early 60s of the last century by South African researchers. Many labdane diterpenes have been The chemistry of *Leonotis* was commenced in 1962 and some compounds were identified; marrubiin (**31**) compounds, X (**32**) and Y (**33**), the stereoisomers of premarrubiin (**34**) and (**35**) (the *C*-13 epimeric forms of premarrubiin). Leonurun (**36**) has been isolated and the relative stereochemistry was determined using single-crystal X-ray diffraction analysis [24, 25]. After two years, labdane (13*S*)-9*α*,13*α*-epoxylabda-6*β*(19),15(14)-dioldilactone (**37**) was isolated, this compound caused significant changes in blood pressure of anesthetized normotensive rats, and also was found to exhibit a negative chronotropic effect [26].

The organic extract of *L. leonurus* showed 99% growth inhibition against *M*. *tuberculosis* at 1.0 mg/mL, subsequent phytochemical studies resulted in the identification of three labdane-type diterpenoids: 9,13:15,16-diepoxy-6,16-labdanediol (**38**), 6-acetoxy-9,13-epoxy-15-methoxylabdan-16,15-olide (**39**), and 9,13-epoxy-6-hydroxylabdan-16,15-olide (**40**). None of the isolated compounds were active against *M*. *tuberculosis* [27].

Recently, Fang et al. [28] identified leonurenones A–C (**41–43**), in addition to 9,13:15,16 diepoxy-6,16-labdanediol (**38**) and nepetifolin (**44**). The leonurenones contain an uncommon α,*β*-unsaturated enone moiety in ring B. Compound **38** was isolated as epimeric form, (at C-16, ratio 3:1). Compound **41** was isolated from aqueous extract of the leaves and the authors proposed the possible formation of **43** as an artefact *via* oxidation and lactonization of the more polar intermediate (**41**) during the isolation process. The total aqueous extract, at concentration of 1.0 g/mL, showed an 81% inhibition in a binding assay at the GABAA site. Compounds **41** and **43** did not show activity (<50% inhibition) in this assay [28].

In the following year, Wu and co-workers (2013) were successful to isolate and identify eleven labdanoides, *viz* leoleorins D–J (**41**–**43**, **45**–**48**) and 16-epi-leoleorin F (**49**), leoleorin A [corresponding to compound Y (**33**)], leoleorin B (**50**) (anhydro derivative of compound Y), and leoleorin C [9,13-epoxy-6-hydroxylabdan-15,16-olide (**40**)]. The absolute configurations of leoleorin A (**33**) and D (**41**) were established by X-ray crystallographic analyses. It is important to indicate that new compounds "leoleorins G-I", which were isolated in this study, were reported in the previous work under the names of leonurenones A–C **(41**–**43)** (13C data showed exchange positions C12 and C14 for leonurenones C/leoleorin H between the two references) [29].

From *L*. *leonurus*' flowers, an acyclic diterpene ester, 1,2,3-trihydroxy-3,7,11,15-tetramethylhexadecan-1-yl-palmitate (**51**), along with geniposidic acid (**52**) were isolated, the compounds exhibited neither cytotoxicity on mammalian kidney fibroblasts (Vero cells) nor antimicrobial activities [30].

*2.7.2. Leonotis nepetaefolia*

The chemistry of *L. nepetaefolia* started almost simultaneously with *L. leonurus*. Leonotin (**53**), nepetaefuran (**54**), nepetaefuranol (**55**), nepetaefolin (**44**) methoxynepetaefolin (**56**), nepetaefolinol (**57**) and leonotinin (**58**) the dilactone (8*β*,17,9,13-diepoxylabdane-16,15,19,6*β*-diolactone, **59**) were characterized [31–36].

The isolated compounds were evaluated for their binding activities to a panel of CNS G-protein-coupled receptors including adrenergic, dopaminergic, histaminic, muscarinic, opioid, and serotonergic receptors and neurotransmitter transporters and showed no interesting activity.[39]. From the material collected from Japan, five iridoid glycosides: 10-*O*-(*trans*-3,4-dimethoxycinnamoyl) geniposidic acid (**76**), 10-*O*-(*p*-hydroxybenzoyl) geniposidic acid

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*L. ocymifolia* was studied under different synonyms *viz*; *L. dubia* (*L. ocymifolia*, var. *ocymifolia*), *L. leonitis*; *L. leonitis* var. *hirtfolia* (*L. ocymifolia*, var. *ocymifolia*) and *L*. *dysophylla* Benth. (*L. ocymifolia* var. *raineriana*) and *L. ocymifolia* var. *raineriana* (Burm f) Iwarsson var. *raineriana* (Visiani) Iwarsson. The chemical studies resulted in the isolation of dubiin (**73**), 9α,13(*S*)-epoxy-8*β*-hydroxylabdane-6*β*,19;16,15-diolide (**80**), and leonitin (**81**). 20-acetoxy-9α,l3-dihydroxy-15(16)-epoxylabd-14-en-6*β*(19)-lactone (**82**) and 6*β*-acetoxy-9α,l3α-epoxylabda-20(19),16(15)-diol-dilactone (**83**) are from the leaves, in addition to compound X (**32**)[24, 41] Finally, nepetaefolin (**44**), leonotinin (**58**), and leonotin (**53**) were identified from the material collected from Pretoria

(**77**), geniposidic acid (**52**), mussaenoside (**78**), and ixoside (**79**) were isolated [40].

*2.7.3. Leonotis ocymifolia*

(South Africa) [42].

From the species collected from India, nepetaefolinol (**57**), dehydrated nepetaefolinol (**60**) and isomeric tetrol (**61**) (15,16-epoxy-labda-13(16),14-diene-6*β*,9,17,19-tetrol: the reduction product of leonotinin) were identified [37]. Leonitinic acid (**62**) with free C-17 carboxyl group was also isolated [38].

From a commercially material, originally collected from Peru, five inseparable epimeric mixtures of bis-spirolabdane diterpenoids, resulted from biosynthetic epimerization of three different structures around C-13 and C-15, have been isolated and identified as leonepetaefolin A (**63**) and its epimeric isomer 15-epi-leonepetaefolin A (**64**) (ratio 1:1), leonepetaefolin B(**65**)/15-epi-leonepetaefolin B (**66**) (2:3), leonepetaefolin C(**67**)/15-epi-leonepetaefolin C (**68**) (1,1), leonepetaefolin D (**69**)/15-epi-leonepetaefolin D (**70**) (7,10), leonepetaefolin E (**71**)/15-epi-leonepetaefolin E (**72**) (2,3) [39]. Additionally, methoxynepataefolin (**56**), nepetaefolin (**44**), nepetaefuran (**54**), dubiin (**73**), 19 chlroro derivative of nepetaefolin (**74**), leonotinin (**58**), leonotin (**53**), and LS-1 (**75**) were isolated. The absolute configuration of the epimeric mixture **63** and **64** was determined by X-ray crystallographic analysis [39].

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The isolated compounds were evaluated for their binding activities to a panel of CNS G-protein-coupled receptors including adrenergic, dopaminergic, histaminic, muscarinic, opioid, and serotonergic receptors and neurotransmitter transporters and showed no interesting activity.[39]. From the material collected from Japan, five iridoid glycosides: 10-*O*-(*trans*-3,4-dimethoxycinnamoyl) geniposidic acid (**76**), 10-*O*-(*p*-hydroxybenzoyl) geniposidic acid (**77**), geniposidic acid (**52**), mussaenoside (**78**), and ixoside (**79**) were isolated [40].

#### *2.7.3. Leonotis ocymifolia*

*2.7.2. Leonotis nepetaefolia*

18 Terpenes and Terpenoids

were characterized [31–36].

crystallographic analysis [39].

also isolated [38].

The chemistry of *L. nepetaefolia* started almost simultaneously with *L. leonurus*. Leonotin (**53**), nepetaefuran (**54**), nepetaefuranol (**55**), nepetaefolin (**44**) methoxynepetaefolin (**56**), nepetaefolinol (**57**) and leonotinin (**58**) the dilactone (8*β*,17,9,13-diepoxylabdane-16,15,19,6*β*-diolactone, **59**)

From the species collected from India, nepetaefolinol (**57**), dehydrated nepetaefolinol (**60**) and isomeric tetrol (**61**) (15,16-epoxy-labda-13(16),14-diene-6*β*,9,17,19-tetrol: the reduction product of leonotinin) were identified [37]. Leonitinic acid (**62**) with free C-17 carboxyl group was

From a commercially material, originally collected from Peru, five inseparable epimeric mixtures of bis-spirolabdane diterpenoids, resulted from biosynthetic epimerization of three different structures around C-13 and C-15, have been isolated and identified as leonepetaefolin A (**63**) and its epimeric isomer 15-epi-leonepetaefolin A (**64**) (ratio 1:1), leonepetaefolin B(**65**)/15-epi-leonepetaefolin B (**66**) (2:3), leonepetaefolin C(**67**)/15-epi-leonepetaefolin C (**68**) (1,1), leonepetaefolin D (**69**)/15-epi-leonepetaefolin D (**70**) (7,10), leonepetaefolin E (**71**)/15-epi-leonepetaefolin E (**72**) (2,3) [39]. Additionally, methoxynepataefolin (**56**), nepetaefolin (**44**), nepetaefuran (**54**), dubiin (**73**), 19 chlroro derivative of nepetaefolin (**74**), leonotinin (**58**), leonotin (**53**), and LS-1 (**75**) were isolated. The absolute configuration of the epimeric mixture **63** and **64** was determined by X-ray

*L. ocymifolia* was studied under different synonyms *viz*; *L. dubia* (*L. ocymifolia*, var. *ocymifolia*), *L. leonitis*; *L. leonitis* var. *hirtfolia* (*L. ocymifolia*, var. *ocymifolia*) and *L*. *dysophylla* Benth. (*L. ocymifolia* var. *raineriana*) and *L. ocymifolia* var. *raineriana* (Burm f) Iwarsson var. *raineriana* (Visiani) Iwarsson. The chemical studies resulted in the isolation of dubiin (**73**), 9α,13(*S*)-epoxy-8*β*-hydroxylabdane-6*β*,19;16,15-diolide (**80**), and leonitin (**81**). 20-acetoxy-9α,l3-dihydroxy-15(16)-epoxylabd-14-en-6*β*(19)-lactone (**82**) and 6*β*-acetoxy-9α,l3α-epoxylabda-20(19),16(15)-diol-dilactone (**83**) are from the leaves, in addition to compound X (**32**)[24, 41] Finally, nepetaefolin (**44**), leonotinin (**58**), and leonotin (**53**) were identified from the material collected from Pretoria (South Africa) [42].

study of *O. amercanium* afforded four compounds of the copane series (copan-3-ol (**87**), cop-

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*Orthosiphon* genus comprises 40 species recorded from the old world: in tropical and subtropical regions including Southern Africa and Madagascar. Three species were found in SA. Three labdanoids (+)-*trans*-ozic acid (**91**), labda-8(17),12*E*,14-trien-2α,18-diol (**92**), and 2α-hydroxylabda-8(17),12*E*,14-trien-18-oic acid (**93**) have been isolated from an ethanol extract. Compound **93** exhibited activity against *M. tuberculosis*, while **92** showed cytotoxic activity against MCF-7 and decreased the production of all the pro-inflammatory cytokines. From the same source, pheophytin a, the acidic degradation product of chlorophyll a, was

Only one species was recorded in SA. From the ethyl acetate extract of *P. rotundifolium,* cas-

About 300 species distributed in tropical and warm regions of the old World, 45 species recorded in SA, from which 19 species were studied for their chemical and/or biological constituents. The genus is characterized by the presence of orange glands that distributed in the aerial parts and contain highly oxygenated (and modified) abietane-type diterpenoids. Others, e.g., kaurane, labdane, phyllocladane as well as the rare skeleton halimane diterpenoids were described.

The plant afforded a series of tetracyclic phyllocladane-type (= 13*β*-kaurane) diter-penoids: (16*R*)-2α-senecioyloxy-3α-acetoxyphyllocladan-16,17-diol (**95**), (16*R*)-2α-senecioyloxy-3α,17 diacetoxy-16-hydroxyphyllocladane (**96**), (16*R*)-2α-isovaleroyloxy-3α-acetoxyphyllocladan-16, 17-diol (**97**), (16*R*)-2α-isovaleroyloxy-3α,17-diacetoxy-16-hydroxyphyllocladane (**98**), (16*R*)-3α-acetoxyphyllocladan-16,17-diol (**99**), (16*R*)-2α-senecioyloxy-16,17-dihydroxyphyllocladan-3-one (**100**), and (16*R*)-2α,3α-diacetoxyphyllocladan-16,17-diol (**101**). The authors discriminated between phyllocladane and *ent*-kaurane tetracyclic skeletons after extensive spectroscopic inves-

Thymoquinone (**105**) was identified as an active nonpolar ingredient to suppress the expression of lipopolysaccharide-induced tumor necrosis factor-alpha (TNF-*α*) [50]. The total extract showed cytotoxic activity against MCF-7, using HPLC-based metabolomics approach, and 7α-acetoxy-6*β*-hydroxyroyleanone (**102**) was identified as the main active constituent. Other

minor compounds like coleon E (**103**) and royleanone (**104**) were also identified [51].

l1(12)-en-3-o1 (**88**), cop-3(15)-en-11-ol (**89**), and cop-l0(ll)-en-3,12-diol(**90**)) [44].

isolated and showed inhibition of HIV-1 protease [45, 46].

sipourol (**94**), *β*-sitosterol, and *α*-amyrin were identified [47].

**2.10.** *Orthosiphon* **genus**

**2.11.** *Paltstoma* **genus**

**2.12.** *Plectranthus* **genus**

*2.12.1. Plectranthus ambiguus*

*2.12.2. Plectranthus amboinicus*

tigation as well as chemical transformations [48, 49].

#### **2.8.** *Neophyptis* **genus**

*Neophyptis* genus is represented by *N paniculata* in SA. Isoneocembrene-A (**84**), *β*-caryophyllene oxide(**85**), *α*-himachalene (**86**), the isolates showed weak to moderate antibacterial activity against five strains of *S. aureus* [43].

#### **2.9.** *Ocimum* **genus**

*Ocimum* genus comprises 65 aromatic species, distributed in tropical and subtropical regions worldwide. Species belonging to this genus are popularly used in Africa and Asia for treating diabetic symptoms. The genus is represented by 16 species in SA and the phytochemical study of *O. amercanium* afforded four compounds of the copane series (copan-3-ol (**87**), copl1(12)-en-3-o1 (**88**), cop-3(15)-en-11-ol (**89**), and cop-l0(ll)-en-3,12-diol(**90**)) [44].
