Chemical and pharmacological research on the plants from genus Ajuga

Xia Qing 1 , Hui-Min Yan 1 , Zhi-Yu Ni 2 , Christopher J. Vavricka 3 , Man-Li Zhang 1 , Qing-Wen Shi 1 , Yu-Cheng Gu 4 ,  and Hiromasa Kiyota 3
  • 1 School of Pharmaceutical Sciences, Hebei Key Laboratory of Forensic Medicine, Hebei Medical University, Shijiazhuang, Hebei Province, 050017, China
  • 2 School Basic Medicine, Hebei Medicinal University, 361 Zhongshan East Road, 050017, Shijiazhuang, Hebei Province, China
  • 3 Graduate School of Environmental and Life Science, Okayama University, 1-1-1 Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan
  • 4 Syngenta Jealott’s Hill International Research Centre, Berkshire, RG42 6EY, UK
Xia Qing
  • School of Pharmaceutical Sciences, Hebei Key Laboratory of Forensic Medicine, Hebei Medical University, Shijiazhuang, Hebei Province, 050017, China
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, Hui-Min Yan
  • School of Pharmaceutical Sciences, Hebei Key Laboratory of Forensic Medicine, Hebei Medical University, Shijiazhuang, Hebei Province, 050017, China
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, Zhi-Yu Ni
  • School Basic Medicine, Hebei Medicinal University, 361 Zhongshan East Road, 050017, Shijiazhuang, Hebei Province, China
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, Christopher J. Vavricka
  • Graduate School of Environmental and Life Science, Okayama University, 1-1-1 Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan
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, Man-Li Zhang
  • School of Pharmaceutical Sciences, Hebei Key Laboratory of Forensic Medicine, Hebei Medical University, Shijiazhuang, Hebei Province, 050017, China
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, Qing-Wen Shi
  • Corresponding author
  • School of Pharmaceutical Sciences, Hebei Key Laboratory of Forensic Medicine, Hebei Medical University, Shijiazhuang, Hebei Province, 050017, China
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, Yu-Cheng Gu and Hiromasa Kiyota
  • Corresponding author
  • Graduate School of Environmental and Life Science, Okayama University, 1-1-1 Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan
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Abstract

The genus Ajuga, a member of the Lamiaceae family, is comprised of more than 300 species of annual and perennial herbaceous flowering plants mainly distributed throughout the temperate regions of Asia, Europe, Australia, North America and Africa. These plants are used as folk medicines effective for rheumatic fevers, dysentery, malaria, hypertension, diabetes and gastrointestinal disorders, as well as anthelmintic, astringent, febrifuge diuretic, antifungal and anti-inflammatory agents. A variety of constituents has been isolated from these plants. This review summarizes the phytochemical progress of the genus Ajuga and lists the compounds isolated up to 2014.

Introduction

The genus Ajuga, a member of the Lamiaceae family, is comprised of more than 300 species of annual and perennial herbaceous flowering plants mainly distributed throughout the temperate regions of Asia, Europe, Australia, North America and Africa. These species have been used as common house plants and are called bugle or bugleweed. They are mainly characterized by the color and shape of the flower. For example, the flower of Ajuga reptans is somewhat tall and blue, while that of Ajuga decumbens is short and purple. Many of these plants are of medicinal importance and are traditionally used as remedies for rheumatic fevers, dysentery, malaria, hypertension, diabetes and gastrointestinal disorders, as well as anthelmintic, astringent, febrifuge diuretic, antifungal and anti-inflammatory agents [1]. The genus Ajuga has attracted attention since the report in 1976 that Ajuga remota grown in Kenya is not attacked by African armyworms and contains three moderately strong antifeedants [2]. Since then, reports of the isolation of neoclerodanes and phytoecdysteroids, as the insect allelochemicals responsible for antifeedant activity from this genus, have appeared [3]. Several species of this genus have been chemically studied and a series of bioactive metabolites, including phytoecdysteroids, diterpenoids and iridoids have been isolated and characterized. Biological investigations demonstrate that some of these compounds display antibacterial [4], antifungal [5], antiplasmodial [6], cytotoxic, antitumor promoting [7], vasoconstricting [8], insect molting inhibitory, insect antifeeding [9] and enzyme-inhibitory [10] activities. This review summarizes phytochemical progress of the genus Ajuga covering the literature up to 2014. In addition, some biological activities of compounds obtained from this genus are also listed.

Chemical constituents

There have been many phytochemical investigations on the isolation of constituents from the Ajuga genus. This has resulted in the isolation and characterization of a series of secondary metabolites, including phytoecdysteroids, sesquiterpenoids, diterpenoids, triterpenoids, iridoids, withanolides and some other compounds. Phytoecdysteroids, the characteristic components of Ajuga plants, are discussed first.

Steroids

Phytoecdysteroids (Table 1, Figure 1)

Phytoecdysteroids are widespread in the genus Ajuga. These compounds display interesting physiological activities such as insect molting activity and other hormonal functions involving regeneration, metamorphosis, reproduction and differentiation in all arthropods. These compounds play important roles for defense against phytophagous insects. They also display antiulcer, antirheumatic, insulin regulation and diuretic or tonic activities in mammals [34]. Some of the successful applications of plants in folk medicine can be explained by the occurrence of phytoecdysteroids.

Table 1

Steroids 1: Phytoecdysteroids.

No.NameSourcePartRef.
1CyasteroneA. decumbenswhole plant[11]
A. turkestanicaleaf[12]
A. ivaaerial part[13], [14], [15]
A. chialeaf, stem[16]
A. chamaepityswhole plant[17]
A. multifloraaerial part[18]
A. taiwanensiswhole plant[19]
A. nipponensisaerial part[20]
A. macrosperma var. brevifloraroot[21]
2EcdysteroneA. decumbenswhole plant[11]
A. nipponensiswhole plant[11], [22]
A. turkestanicaleaf[12]
A. ivaaerial part[13], [14], [15]
A. chamaepityswhole plant[17]
A. multifloraaerial part[18]
A. macrosperma var. brevifloraroot[21]
A. reptanswhole plant[23], [24], [25]
A. remotaleaf, root[26]
3AjugalactoneA. reptanswhole plant[25]
A. turkestanicaroot[27]
422-AcetylcyasteroneA. turkestanicaroot[28]
5TurkesteroneA. turkestanicaroot[29]
6Ajugasterone AA. nipponensiswhole plant[22]
A. reptanswhole plant[23], [25]
7Ajugasterone BA. reptanswhole plant[25]
A. turkestanicaroot[29]
A. ivawhole plant[30]
8Ajugasterone CA. nipponensisaerial part[20]
A. japonicaleaf[31]
9Ajugasterone DA. nipponensiswhole plant[22]
10Stachysterone DA. nipponensiswhole plant[22]
11Makisterone AA. ivawhole plant[14], [32]
A. macrosperma var. brevifloraroot[21]
1229-NorcyasteroneA. reptanswhole plant[23], [24], [25]
1329-NorsengosteroneA. reptanswhole plant[23], [24], [25]
142-Acetyl-29-norcyasteroneA. reptanswhole plant[33]
153-Acetyl-29-norcyasteroneA. reptanswhole plant[33]
16SengosteroneA. reptanswhole plant[25]
1722-Dehydro-12-hydroxycyasteroneA. reptans var. atropurpereaaerial part[34]
1822-Dehydro-12-hydroxysengosteroneA. reptans var. atropurpereaaerial part[34]
1922-Dehydro-12-hydroxy-29-nor-cyasteroneA. reptans var. atropurpereaaerial part[34]
2022-Dehydro-12-hydroxy-29-nor-sengosteroneA. reptans var. atropurpereaaerial part[34]
21ReptansteroneA. reptans var. atropurperearoot[35]
2228-epi-SengosteroneA. reptans var. atropurperearoot[35]
235,29-DihydroxycapitasteroneA. reptans var. atropurperearoot[35]
242-DehydroajugalactoneA. reptans var. atropurperearoot[35]
253-DehydroajugalactoneA. reptans var. atropurperearoot[35]
26Ponasterone AA. remotaleaf, root[26]
2724,28-Dehydromakisterone AA. ivawhole plant[14]
2822-OxocyasteroneA. ivawhole plant aerial[14]
22-DehydrocyasteroneA. nipponensispart[20]
2924,25-DehydroprecyasteroneA. ivawhole plant[14]
A. reptans var. reptanswhole plant[36]
3020-Hydroxyecdysone 22-acetateA. nipponensisaerial part[20]
A. reptanswhole plant[37]
3120-Hydroxyecdysone 25-acetate (Viticosterone E)A. reptanswhole plant[37]
32AjusteroneA. pseudoivaleaf[38]
33Ajugalide-EA. taiwanensiswhole plant[19]
34IsocyasteroneA. taiwanensiswhole plant[19]
3524-HydroxycyasteroneA. ivawhole plant[30]
3622-Dehydrocyasterone 2-glucopyranosideA. nipponensisaerial part[20]
37Ajugacetalsterone AA. nipponensisaerial part[20]
38Ajugacetalsterone BA. nipponensisaerial part[20]
39Ajugacetalsterone CA. macrosperma var. brevifloraroot[21]
40Ajugacetalsterone DA. macrosperma var. brevifloraroot[21]
41BreviflorasteroneA. macrosperma var. brevifloraroot[21]
A. reptans var. reptanswhole plant[36]
4220-Hydroxyecdysone 2-acetateA. macrosperma var. brevifloraroot[21]
4320-Hydroxyecdysone 3-acetateA. macrosperma var. brevifloraroot[21]
44Reptanslactone AA. reptans var. reptanswhole plant[36]
45Reptanslactone BA. reptans var. reptanswhole plant[36]
46SendreisteroneA. reptans var. reptanswhole plant[36]
Figure 1
Figure 1

Steroids 1: Phytoecdysteroids.

Citation: Heterocyclic Communications 23, 4; 10.1515/hc-2017-0064

Compounds 1 and 2 are usually the most abundant phytoecdysones in the genus Ajuga, and they were reported in A. decumbens, Ajuga incisa, Ajuga turkestanica, Ajuga iva, Ajuga nipponensis, Ajuga chia, Ajuga chamaepitys and Ajuga multiflora [11], [12], [13], [16], [17], [18]. Compound 36 was reported as a 2-O-glucopyranoside [20]. Phytoecdysteroids bearing a γ-lactone ring at various positions, 41, 44 and 45, were also isolated [21], [36]. Derivatives with a δ-lactone ring, 3, 21, 2325, 29, 37, and 46 were reported as well [14], [25], [27], [35], [36]. In addition, the reduced forms, 37 and 46 with a THP ring, and 38 and 40 with a THF ring, were isolated as acetals or hemiacetals [20], [21], [36]. Two other similar compounds with a THF ring 9 and 10, are biosynthesized from precursors via intramolecular hydration [22]. In addition, ajugacetalsterone C (39) has a rare 6,8-dioxabicyclo[3.2.1]oct-2-ene structure presumably formed by an intramolecular acetalization [21]. Fujimoto and co-workers summarized biosynthesis of ecdysteroids as well as sterols in Ajuga hairy root in detail [39].

Withanolides (Table 2, Figure 2)

Withanolides are characteristic of Solanaceous plants, though there are rare reports on their isolation from other families. In 1999, Khan and co-workers isolated a new withanolide 47 from Ajuga parvifora. This is the first report of naturally occurring withanolides in Lamiaceae [40]. In subsequent studies on the chemical constituents of A. parvifora, the same research group obtained a series of new withanolides 48–56, along with known 57 [41], [42], [43], [44], [45].

Table 2

Steroids 2: Withanolides.

No.NameSourcePartRef.
47AjuginA. parviflorawhole plant[40]
48Ajugin AA. parviflorawhole plant[41]
49Ajugin BA. parviflorawhole plant[41]
50Ajugin CA. parviflorawhole plant[42]
51Ajugin DA. parviflorawhole plant[42]
52Ajugin EA. parviflorawhole plant[43]
53Ajugin FA. parviflorawhole plant[43]
543,14,17,20,28-Pentahydroxy-1-oxo-(20R,22R)-witha-5,24-dienolideA. parviflorawhole plant[44]
553,17,20-Trihydroxy-1-oxo-(20S,22R)-witha-5,14,24-trienolideA. parviflorawhole plant[45]
5628-Hydroxy-14,20-epoxy-1-oxo-(22R)-witha-2,5,24-trienolideA. parviflorawhole plant[45]
57Coagulin-JA. parviflorawhole plant[44]
58Bracteosin AA. bracteosawhole plant[46]
59Bracteosin BA. bracteosawhole plant[46]
60Bracteosin CA. bracteosawhole plant[46]
Figure 2
Figure 2

Steroids 2: Withanolides.

Citation: Heterocyclic Communications 23, 4; 10.1515/hc-2017-0064

Other steroids (Table 3, Figure 3)

Compounds 61 and 67, two C29 monohydroxy sterols, were isolated from A. reptans and their structures were elucidated by spectral methods [47]. From the aerial parts of Ajuga salicifolia, Akbay and co-workers isolated one new stigmastane-type sterol 72 and eight new sterol glycosides 70, 71, 73–78 [53], [54]. The whole plant of Ajuga relicta afforded two new steroids 79, 80, as well as two known compounds 61, 68 [49]. A steroidal glucopyranoside 64 was isolated from A. chamaepitys ssp. laevigata [51].

Table 3

Steroids 3: other steroids.

No.NameSourcePartRef.
61ClerosterolA. reptanswhole plant[47]
A. pseudoivaleaf[48]
A. relictawhole plant[49]
62Clerosterol 3β-O-(β-D-glucopyranoside)A. pseudoivaleaf[50]
63Mighavide (3-O-Butanoylclerosterol)A. pseudoivaleaf[48], [50]
643-O-β-D-Glucopyranosyl-stigmasta-5,25-dieneA. chamaepitys ssp. laevigatawhole plant[51]
65StigmasterolA. taiwanensiswhole plant[19]
66Stigmasterol 3-O-β-D-glucopyranosideA. taiwanensiswhole plant[19]
6722,23-DidehydroclerosterolA. reptanswhole plant[47]
68β-sitosterolA. relictawhole plant[49]
A. taiwanensiswhole plant[19]
69β-sitosterol 3-O-β-D-glucopyranosideA. decumbenswhole plant[52]
70Ajugasalicioside AA. salicifoliaaerial part[53]
71Ajugasalicioside BA. salicifoliaaerial part[53]
72AjugasalicigeninA. salicifoliaaerial part[54]
73Ajugasalicioside CA. salicifoliaaerial part[53]
74Ajugasalicioside DA. salicifoliaaerial part[53]
75Ajugasalicioside EA. salicifoliaaerial part[53]
76Ajugasalicioside FA. salicifoliaaerial part[54]
77Ajugasalicioside GA. salicifoliaaerial part[54]
78Ajugasalicioside HA. salicifoliaaerial part[54]
79(24S)-24-Ethyl-11α-hydroxycholesta-5,25-dien-1-oneA. relictawhole plant[49]
80(24S)-24-Ethyl-7α-hydroxycholesta-5,25-dien-3-oneA. relictawhole plant[49]
81Ergosterol 5,8-endoperoxideA. remotaaerial part[55]
Figure 3
Figure 3

Steroids 3: other steroids.

Citation: Heterocyclic Communications 23, 4; 10.1515/hc-2017-0064

Triterpenoids (Table 4, Figure 4)

In 1997, two lupan triterpenoids 82 and 83 were isolated from the aerial parts of Ajuga macrosperma [56]. Oleananes 84 and 85 were two known triterpenoids isolated from A. relicta [49]. From A. chamaepitys ssp. laevigata, two ursanes and one oleanane 86–88 were isolated [51].

Table 4

Triterpenoids.

No.NameSourcePartRef.
82Betulinic acidA. macrospermaaerial part[56]
833-epi-Betulinic acidA. macrospermaaerial part[56]
84Oleanolic acidA. relictawhole plant[49]
853-O-Acetyloleanolic acidA. relictawhole plant[49]
86α-AmyrinA. chamaepitys ssp. laevigatawhole plant[51]
87β-AmyrinA. chamaepitys ssp. laevigatawhole plant[51]
88Ursolic acidA. chamaepitys ssp. laevigatawhole plant[51]
Figure 4
Figure 4

Triterpenoids.

Citation: Heterocyclic Communications 23, 4; 10.1515/hc-2017-0064

Diterpenoids (Table 5, Figure 5)

Ajuga species are rich in diterpenoids. With respect to the carbocyclic skeleton, Ajuga diterpenoids roughly belong to two groups: neoclerodane and abietane types.

Table 5

Diterpenoids.

No.NameSourcePartRef.
89Ajugarin IA. remotaleaf[2]
A. nipponensisaerial part[57]
A. parvifloraaerial part[58]
A. decumbenswhole plant[59]
90Ajugarin IIA. remotaleaf[2]
A. parvifloraaerial part[58]
91Ajugarin IIIA. remotaleaf[2]
92Ajugarin IVA. remotaleaf[60]
A. ciliata var. villosioraerial part[61]
93Ajugarin VA. remotaleaf[62]
94ClerodinA. remota

leaf[63]
A. bracteosaaerial part[64]
95DihydroclerodinA. parvifloraaerial part[58]
A. bracteosawhole plant[46], [64]
A. remotaaerial part[65]
96AjugareptansinA. reptansaerial part[66], [67], [68]
97Ajugareptansone AA. reptanswhole plant[69], [70]
98Ajugareptansone BA. reptanswhole plant[69]
99Ivain IA. ivawhole plant[71]
100Ivain IIA. ivawhole plant[71]
A. bracteosaaerial part[64]
101Ivain IIIA. ivawhole plant[71]
102Ivain IVA. ivawhole plant[71]
103Ajugapitin (Clerodendrin D)A. chamaepityswhole plant[72], [73]
A. australisaerial part[74]
A. decumbensleaf[75]
A. remotaaerial part[65]
A. turkestanicaaerial part[76]
10414,15-DihydroajugapitinA. chamaepityswhole plant[72], [73]
A. pseudoivaleaf[77], [78]
A. bracteosawhole plant[46], [64], [79]
A. remotaaerial part[65]
105ChamaepitinA. chamaepityswhole plant[80]
A. turkestanicaaerial part[76]
106AjugamarinA. nipponensisleaf[81], [82], [83]
A. decumbenswhole plant[75], [84], [85], [86]
A. ciliatawhole plant[87]
107DihydroajugamarinA. nipponensisleaf[81]
A. decumbensleaf[75]
108Ajugamarin chlorohydrinA. nipponensisleaf[81]
A. ciliatawhole plant[87]
1092-Acetylivain IA. pseudoivawhole plant[77]
110Ajugamarin A2A. decumbenswhole plant[88]
A. nipponensisaerial part[83]
A. ciliatawhole plant[87]
111Ajugamarin B1A. ciliatawhole plant[87]
112Ajugamarin B2A. nipponensisaerial part[57], [83]
A. decumbenswhole plant[88]
113Ajugamarin B3A. nipponensisaerial part[57]
114Ajugamarin B4A. ciliata var. villosioraerial part[61]
115Ajugamarin B5A. ciliata var. villosioraerial part[61]
116Ajugamarin C1A. nipponensisaerial part[57]
A. taiwanensiswhole plant[89]
A. ciliatawhole plant[90]
117Ajugamarin D1A. nipponensisaerial part[57]
118Ajugamarin E1A. ciliata var. villosioraerial part[61]
119Ajugamarin E2A. ciliata var. villosioraerial part[61]
120Ajugamarin E3A. ciliata var. villosioraerial part[61]
121Ajugamarin F1A. ciliata var. villosioraerial part[61]
122Ajugamarin F2A. ciliata var. villosioraerial part[61]
123Ajugamarin F3A. ciliata var. villosioraerial part[61]
124Ajugamarin F4A. decumbenswhole plant[86], [88]
A. parvifloraaerial part[58]
A. nipponensisaerial part[83]
125Ajugamarin G1A. decumbenswhole plant[75], [88]
A. ciliatawhole plant[87]
126Ajugamarin H1A. decumbenswhole plant[75], [88]
A. ciliatawhole plant[87]
127Deacetylajugarin IVA. ciliata var. villosioraerial part[61]
A. remotaaerial part[65]
A. ciliatawhole plant[91]
128Ajugachin AA. chamaepitysaerial part[73]
A. reptansaerial part[68]
129Ajugachin BA. chamaepitysaerial part[73]
A. turkestanicaaerial part[76]
130Ajugacumbin AA. decumbenswhole plant[59], [85], [92], [93]
A. nipponensisaerial part[83]
A. ciliatawhole plant[87]
131Ajugacumbin BA. decumbenswhole plant[59], [92], [93]
A. nipponensisaerial part[83], [94]
A. macrospermawhole plant[95]
A. pantanthawhole plant[95]
132Ajugacumbin CA. decumbenswhole plant[85], [92]
133Ajugacumbin DA. decumbenswhole plant[85], [92]
134Ajugacumbin EA. decumbenswhole plant[84]
135Ajugacumbin FA. decumbenswhole plant[84]
A. ciliatawhole plant[87]
136Ajugacumbin GA. decumbenswhole plant[93]
137Ajugacumbin HA. decumbenswhole plant[85]
138Ajugacumbin JA. decumbenswhole plant[96]
139Ajugavensin AA. genevensisaerial part[97]
A. reptansaerial part[70]
140Ajugavensin BA. genevensisaerial part[97]
141Ajugavensin CA. genevensisaerial part[97]
142Ajugamacrin AA. macrospermawhole plant[98]
143Ajugamacrin BA. macrospermawhole plant[98]
A. taiwanensiswhole plant aerial part[89]
A. nipponensiswhole plant aerial part[83]
144Ajugamacrin CA. macrospermawhole plant[95]
A. pantanthawhole plant[95]
145Ajugamacrin DA. macrospermawhole plant[95]
A. pantanthawhole plant[95]
146Ajugamacrin EA. macrospermawhole plant[95]
A. pantanthawhole plant[95]
147Ajugapantin AA. macrospermawhole plant[95]
A. pantanthawhole plant[95]
A. taiwanensiswhole plant[89]
A. ciliatawhole plant[87]
148Deoxyajugarin-IA. parvifloraaerial part[58]
149Ajugarin-I chlorohydrinA. parvifloraaerial part[58]
1503β-Acetoxyclerodinin CA. parvifloraaerial part[58]
151Clerodinin AA. bracteosawhole plant[46]
152Clerodinin CA. parvifloraaerial part[58]
153Clerodinin DA. parvifloraaerial part[58]
15415-α-Ethoxy-14-hydroajugapitinA. parvifloraaerial part[58]
15515-β-Ethoxy-14-hydroajugapitinA. parvifloraaerial part[58]
156Lupulin AA. lupulinawhole plant[99]
A. bracteosawhole plant[46]
A. turkestanica

A. pseudoiva
aerial part

leaf
[76]

[78]
157Lupulin BA. lupulinawhole plant[99]
158Lupulin CA. lupulinawhole plant[99]
159Lupulin DA. lupulinawhole plant[99]
160Lupulin EA. lupulinawhole plant[4]
161Lupulin FA. lupulinawhole plant[4]
1622β-Hydroxy-2-methylbutanoyl-3α-lupulinA. lupulinawhole plant[100]
1636-Deacetylajugarin IVA. lupulina var. majorwhole plant[101]
164Ajugorientin (3β-Hydroxyajugavensin B)A. orientalis

A. reptans
aerial part

aerial part
[74]

[67], [68]
16514,15-Dihydro-15-hydroxyajugapitinA. australisaerial part[74]
A. bracteosawhole plant[64], [79]
A. remotaaerial part[65]
166Ajugatakasin AA. decumbensleaf[75]
A. nipponensisaerial part[83]
A. ciliatawhole plant[87]
167Ajugatakasin BA. decumbensleaf[75]
A. ciliatawhole plant[87]
16814,15-DehydroajugareptansinA. reptansaerial part[67]
1693α-Hydroxyajugamarin F4A. reptansaerial part[67]
170Ajugapyrin AA. pyramidalisaerial part[102]
171Areptin AA. reptansaerial part[68]
172Areptin BA. reptansaerial part[68]
173(15R)​-​14,​15-​Dihydro-​15-​hydroxyajugachin AA. laxmaniiaerial part[103]
174(15S)​-​14,​15-​Dihydro-​15-​hydroxyajugachin AA. laxmaniiaerial part[103]
175Hativene AA. pseudoivaleaf[78]
176Hativene BA. pseudoivaleaf[78]
177Hativene CA. pseudoivaleaf[78]
178Hativene DA. pseudoivaleaf[104]
179Ajugatansin A1A. reptansaerial part[70]
180Ajugatansin B1A. reptansaerial part[70]
181Ajugatansin D1A. reptansaerial part[70]
182Bracteonin-AA. bracteosawhole plant[79]
183AjugareptoneA. reptansleaf[105]
184Ajugalaevigatic acidA. chamaepitys ssp. laevigatawhole plant

[51]
185(13S)-15-Hydroxylabd-8(17)-en-19-oic acid (Imbricatoloic acid)A. chamaepitys ssp. laevigatawhole plant[51]
186Ajugalide AA. taiwanensiswhole plant[89]
187Ajugalide BA. taiwanensiswhole plant[89]
A. ciliatawhole plant[87]
188Ajugalide CA. taiwanensiswhole plant[89]
A. ciliatawhole plant[87]
189Ajugalide DA. taiwanensiswhole plant[89]
A. ciliatawhole plant[91]
190Ajuganipponin AA. nipponensisaerial part[83]
A. ciliatawhole plant[90]
191Ajuganipponin BA. nipponensisaerial part[83]
A. ciliatawhole plant[87]
A. decumbenswhole plant[86]
19214-Hydro-15-hydroxyclerodinA. remotaaerial part[65]
19314,15-Hihydroajugachin BA. turkestanicaaerial part[76]
19414-Hydro-15-methoxyajugachin BA. turkestanicaaerial part[76]
19515-epi-Lupulin AA. decumbenswhole plant[106]
19615-epi-Lupulin BA. bracteosaaerial part[64]
1976-O-DeacetylajugamarinA. decumbenswhole plant[106]
198Ajugadecumbenins AA. decumbenswhole plant[106]
199Ajugadecumbenins BA. decumbenswhole plant[106]
200Ajubractin AA. bracteosaaerial part[64]
201Ajubractin BA. bracteosaaerial part[64]
202Ajubractin CA. bracteosaaerial part[64]
203Ajubractin DA. bracteosaaerial part[64]
204Ajubractin EA. bracteosaaerial part[64]
2053-epi-CaryoptinA. bracteosaaerial part[64]
2063-epi-14,15-DihydrocaryoptinA. bracteosaaerial part[64]
20715-Hydroxyajubractin CA. bracteosaaerial part[64]
20814-Hydro-15-hydroxyajugachin AA. bracteosaaerial part[64]
209Ajugaciliatin AA. ciliatawhole plant[87]
210Ajugaciliatin BA. ciliatawhole plant[87]
211Ajugaciliatin CA. ciliatawhole plant[87]
212Ajugaciliatin DA. ciliatawhole plant[87]
213Ajugaciliatin EA. ciliatawhole plant[87]
214Ajugaciliatin FA. ciliatawhole plant[87]
215Ajugaciliatin GA. ciliatawhole plant[87]
216Ajugaciliatin HA. ciliatawhole plant[87]
217Ajugaciliatin IA. ciliatawhole plant[87]
218Ajugaciliatin JA. ciliatawhole plant[87]
A. decumbenswhole plant[59]
219(12S)-1β,6α,19-Triacetoxy-18-chloro-4α,12-dihydroxyneoclerod-13-en-15,16-olideA. ciliatawhole plant[91]
220(12S,2′S)-12,19-Diacetoxy-18-chloro-4α,6α-dihydroxy-1β-(2-methylbutanoyloxy)neoclerod-13-en-15,16-olideA. ciliatawhole plant[91]
221(12S)-6α,18,19-Triacetoxy-4α,12-dihydroxy-1β-tigloyloxyneoclerod-13-en-15,16-olideA. ciliatawhole plant[91]
222(12S)-6α-Acetoxy-4α,18-epoxy-12-hydroxy-19-tigloyloxyneoclerod-13-en-15,16-olideA. ciliatawhole plant[90]
2236α,18-Diacetoxy-4α-hydroxy-19-tigloyloxyneoclerod-13-en-15,16-olideA. ciliatawhole plant[90]
224Ajugamarin A2 chlorohydrinA. ciliatawhole plant[87]
2256α,19-Diacetoxy-4α-hydroxy-1β-tigloyloxyneoclerod-12-en-15-oic acid methyl ester-16-aldehydeA. decumbenswhole plant[59]
226(12S)-18,19-Diacetoxy-4α,6α,12-trihydroxy-1β-tigloyloxyneoclerod-13-en-15,16-olideA. decumbenswhole plant[59]
2274α,6α-Dihydroxy-18-(4′-methoxy-4′-oxobutyryloxy)-19-tigloyloxyneoclerod-13-en-15,16-olideA. decumbenswhole plant[59]
228(12S)-1α,19-Epoxy-6α,18-diacetoxy-4α,12-dihydroxyneoclerod-13-en-15,16-olideA. decumbenswhole plant[86]
229(12S)-6α,19-Diacetoxy-18-chloro-4α-hydroxy-12-tigloyloxyneoclerod-13-en-15,16-olideA. decumbenswhole plant[86]
230(12S,2′′S)-6α,19-Diacetoxy-18-chloro-4α-hydroxy-12-(2-methylbutanoyloxy)neoclerod-13-en-15,16-olideA. decumbenswhole plant[86]
231Ajugacumbin A chlorohydrinA. ciliatawhole plant[87]
A. decumbenswhole plant[59]
232Ajuforrestin AA. forrestiiwhole plant[107]
A. decumbensaerial part[7]
233Ajuforrestin BA. forrestiiwhole plant[107]
A. decumbensaerial part[7]
234Ajugaside AA. decumbenswhole plant[108]
235Ajudecumin AA. decumbensaerial part[7]
236Ajudecumin BA. decumbensaerial part[7]
237Ajudecumin CA. decumbensaerial part[7]
238Ajudecumin DA. decumbensaerial part[7]
239CarnosolA. forrestiiwhole plant[109]
240EpiisorosmanolA. forrestiiwhole plant[109]
2412,11,12-Trihydroxy-7,20-epoxy-8,11,13-abietatrieneA. forrestiiwhole plant[109]
242EpirosmanolA. forrestiiwhole plant[109]
2437-MethoxyrosmanolA. forrestiiwhole plant[109]
2447-EthoxyrosmanolA. forrestiiwhole plant[109]
2452α,3β,11,12-Tetrahydroxy-7β,20-epoxy-8,11,13-abietatrieneA. forrestiiwhole plant[109]
Figure 5
Figure 5

Diterpenoids.

Citation: Heterocyclic Communications 23, 4; 10.1515/hc-2017-0064

Neoclerodanes

Most of the neoclerodane diterpenoids produced by species of the genus Ajuga contain a substituted decalin with a 4α,18-oxirane ring and two oxygenated substituents bound to C(6) and C(19) [110]. The side chain features several moieties with the most common being: (i) a butenolide function (α-substituted α,β-unsaturated γ-lactone, or 13-en-15,16-olide) as in 89–93 isolated from A. remota [2], [60], [62]; (ii) a tetrahydrofurofuran as in 94 reported as a constituent of A. remota [63]; and (iii) a hexahydrofurofuran as in 95 reported as a component of Ajuga parviflora [58]. In 1983, three new bitter principles, 106–108, were isolated from the leaves of A. nipponensis. The β-hydrin structure of 108 was confirmed by treatment of 106 with methanolic HCl [81], [82]. In addition, by reinvestigation of the aerial parts of A. nipponensis, four new bitter neoclerodanes 112, 113, 116, 117 and a known diterpenoid 89 were isolated [57]. The configuration of methoxy group at C(15) (R5) of lupulin A (156) [99] was revised to be α by Huang and co-workers [106]. Consequently, hativene D (178) [104] is not 15-epi-lupulin (195) but lupulin (156). The structure of 15-epi-lupulin B (196) [64] with a 2β-OH group coincides with lupulin A 156.

Abietanes

A new abietane diglucopyranoside 234 was isolated from the whole plants of A. decumbens [108]. In the course of the search for bioactive metabolites with anticancer effects, Wang et al. isolated four new rearranged abietane hydroquinones 235–238, together with two known abietanes 232 and 233 from the aerial parts of A. decumbens collected in China [7].

Sesquiterpenoids (Table 6, Figure 6)

Only a few other sesquiterpenoids, bisabolene, eudesmanolides and seco-sesquiterpenoids, were reported. Compound 246, a bisabolene sesquiterpenoid, was isolated from the aerial parts of A. decumbens [7]. Research on Ajuga forrestii resulted in the isolation of four eudesmane sesquiterpene lactones 247–250. Among them, compounds 247–249 are new. Compound 249 exhibits weak cytotoxic activity against HepG2 and MCF-7 human cell lines [109]. Four megastigmane derivatives 251–254 and 257 were isolated in 2012 [7], [112]. A new ionone glycoside 255 was also isolated from this plant. This is the first report of the occurrence of ionone glycosides in Ajuga species [111].

Table 6

Sesquiterpenoids.

No.NameSourcePartRef.
246GlecholoneA. decumbensaerial part[7]
2473α-Acetoxy-1α,8β-dihydroxyeudesm-7(11)-en-8,12-olideA. forrestiiwhole plant[109]
2483α-Acetoxy-1α-hydroxyeudesm-8,7(11)-dien-8,12-olideA. forrestiiwhole plant[109]
2491α-Acetoxy-8α-oxyethyl-2-oxoeudesman-3,7(11)-dien-8,12-olideA. forrestiiwhole plant[109]
2501α-Acetoxy-8α-hydroxy-2-oxoeudesman-3,7(11)-dien-8,12-olideA. forrestiiwhole plant[109]
251(6R,7E,9R)-9-Hydroxy-4,7-megastigmadien-3-oneA. decumbensaerial part[7]
252(3S,5R,6S,7E)-5,6-Epoxy-3-hydroxy-7-megastigmen-9-oneA. decumbensaerial part[7]
253(6E,9S)-9-Hydroxy-4,6-megastigmadien-3-oneA. decumbensaerial part[7]
2546-Hydroxy-4,7-megastigmadiene-3,9-dioneA. decumbensaerial part[7]
2554β-Hydroxy-7,8-dihydro-3-oxo-β-ionol 9-O-β-D-glucopyranosideA. salicifoliaaerial part[111]
256Corchoionoside CA. salicifoliaaerial part[111]
257LoliolideA. decumbenswhole plant[112]
Figure 6
Figure 6

Sesquiterpenoids.

Citation: Heterocyclic Communications 23, 4; 10.1515/hc-2017-0064

Monoterpenoids (Table 7, Figure 7)

Major monoquiterpenoids isolated from the genus Ajuga belong to iridoids. In 1974, Guiso and co-workers isolated three iridoid glucopyranosides 258–260 from A. reptans. Compound 259 is an 8-O-acetyl derivative of 260 and a 6-epimer of 8-O-acetylmioporoside 271 [113], [117]. Four new iridoid glucopyranoside cis- and trans-p-coumaroyl esters 263–266 were isolated from methanol extract of the dried plant of A. decumbens, together with the known compounds 258 and 262 [116]. Compound 270, isolated from the leaves of Ajuga pseudoiva, possesses an unusual 13-membered macrocyclic structure [121].

Table 7

Iridoids.

No.NameSourcePartRef.
258ReposideA. reptanswhole plant[113], [114], [115]
A. decumbenswhole plant[116]
259AjugosideA. reptanswhole plant[117]
260AjugolA. reptanswhole plant[117]
261JaranidosideA. spectabiliswhole plant[118]
2628-O-AcetylharpagideA. multiflorawhole plant[119]
A. remotaaerial part[6]
A. decumbenswhole plant[116]
A. ivaaerial part[120]
A. reptanswhole plant[114], [115]
263Decumbeside AA. decumbenswhole plant[116]
264Decumbeside BA. decumbenswhole plant[116]
265Decumbeside CA. decumbenswhole plant[116]
266Decumbeside DA. decumbenswhole plant[116]
267HarpagideA. ivaaerial part[120]
A. reptanswhole plant[114], [115]
2686-DeoxyharpagideA. ivaaerial part[120]
269AjureptosideA. reptanswhole plant[114]
2707-O-6′-O-Malonylcachinesidic acidA. pseudoivaleaf[121]
2718-O-AcetylmioporosideA. salicifoliaaerial part[111]
272GaliridosideA. taiwanensiswhole plant[19]
273TeuhircosideA. taiwanensiswhole plant[19]
2746-Keto-8-acetylharpagideA. remotaaerial part[122]
2756,7-Dehydro-8-acetylharpagideA. remotaaerial part[122]
2767,8-DehydroharpagideA. remotaaerial part[122]
2778-Acetylharpagide 6-O-β-glucopyranosideA. remotaaerial part[122]
278Harpagide 6-O-β-glucopyranosideA. remotaaerial part[122]
2792′,3′-DiacetylharpagideA. remotaunderground part[123]
2806′-O-RhamnosylharpagideA. remotaunderground part[123]
2816′-O-Galloyl-7,8-dehydroharpagideA. remotaunderground part[123]
2826-O-Xylosylharpagoside-BA. remotaunderground part[123]
283Ajureptaside AA. reptanswhole plant[115]
284Ajureptaside BA. reptanswhole plant[115]
285Ajureptaside CA. reptanswhole plant[115]
286Ajureptaside DA. reptanswhole plant[115]
2876-epi-8-O-AcetylharpagideA. reptanswhole plant[115]
Figure 7
Figure 7

Iridoids.

Citation: Heterocyclic Communications 23, 4; 10.1515/hc-2017-0064

Flavonoids (Table 8, Figure 8)

Flavonoids 288–305 including flavones and flavonols isolated from the genus Ajuga are outlined in Table 8.

Table 8

Flavonoids.

No.NameSourcePartRef.
288LuteolinA. chiaaerial part[124]
A. lupulinwhole plant[101], [125]
289Luteolin 7-O-glucopyranosideA. chiaaerial part[124]
A. lupulinawhole plant[101], [125]
290ApigeninA. chiaaerial part[124]
A. multifloraaerial part[126]
A. forrestiiwhole plant[107]
291NaringinA. ivaaerial part[15]
292Apigenin ​7-​O-​neohesperidosideA. ivaaerial part[15]
293ChrysoriolA. lupulinawhole plant[125]
294DiosmetinA. lupulinawhole plant[125]
295KaempferideA. lupulinawhole plant[125]
296QuercetinA. lupulinawhole plant[125]
297AcacetinA. forrestiiwhole plant[107]
298Gnetifolin BA. forrestiiwhole plant[107]
299Apigenin 7-glucuronideA. multifloraaerial part[18]
300KaempferolA. taiwanensiswhole plant[19]
301Myricetin 3-O-rutinoside 4′-O-rutinosideA. remotaaerial part[122]
302Myricetin 3-O-rutinoside 3′-O-rutinosideA. remotaaerial part[122]
303Isorhamnetin 3-O-rutinoside 7-O-rutinoside 4′-O-β-glucopyranosideA. remotaaerial part[122]
3043,4′-Dihydroxy-3,6,7-trimethoxyflavoneA. bracteosawhole plant[127]
3057-Hydroxy-3,6,3′,4′-tetramethoxyflavoneA. bracteosawhole plant[127]
Figure 8
Figure 8

Flavonoids.

Citation: Heterocyclic Communications 23, 4; 10.1515/hc-2017-0064

Polyketides and alkaloids (Table 9, Figure 9)

From the leaves of A. iva, three new homologous 1,3-diglycerides 331–333 and compound 339 were obtained. In 1986, Takasaki and co-workers isolated three phenethyl alcohol glycosides 323–325, including a new derivative 323 [108]. A phenylalanine derivative 346 was isolated from this plant recently [96]. In addition, Yu and co-workers isolated a phthalic ester 321 from the aerial parts of A. multiflora [18].

Table 9

Polyketides and alkaloids.

No.NameSourcePartRef.
306Ethyl (1-acetoxy-4-oxo-2,5-cyclohexadien-1-yl)acetateA. parviflorawhole plant[128]
307Methyl (1-acetoxy-4-oxo-2,5-cyclohexadien-1-yl)acetateA. parviflorawhole plant[128]
308Ethyl (1-hydroxy-4-oxo-2,5-cyclohexadien-1-yl)acetateA. parviflorawhole plant[128]
309Methyl (1-hydroxy-4-oxo-2,5-cyclohexadien-1-yl)acetateA. parviflorawhole plant[128]
310(1-Hydroxy-4-oxo-2,5-cyclohexadien-1-yl)acetic acidA. parviflorawhole plant[129]
3112-Hydroxy-4β-methyl-4α-(β-D-glucopyranoside)-2,5-cyclohexadien-1-oneA. parviflorawhole plant[129]
312Methyl 2-(2,2-dimethyl-6-oxo-7-dihydro-1,3-benzodioxol-3(6H)-yl)acetateA. parviflorawhole plant[129]
3136,7-Dihydroxycoumarin (Esculetin)A. decumbenswhole plant[52]
314CoumarinA. laxmaniiaerial part[103]
315Vanillic acidA. decumbenswhole plant[112]
A. taiwanensiswhole plant[19]
316Melilotic acid methyl esterA. laxmaniiaerial part[103]
317Methyl caffeateA. decumbenswhole plant[112]
318Methyl (E)-4-acetoxy-3-methoxycinnamateA. pseudoivaleaf[38]
319Methyl (E)-4-acetoxycinnamateA. pseudoivaleaf[38]
320AjugananeA. bracteosawhole plant[127]
321Bis(2-ethylhexyl) phthalateA. multifloraaerial part[18]
322Bis(2S-methylheptyl) phthalateA. bracteosawhole plant[130]
323GalactosylmartynosideA. decumbenswhole plant[108]
324MartynosideA. decumbenswhole plant[108]
325Darendoside BA. decumbenswhole plant[108]
326LavandulifoliosideA. salicifoliaaerial part[111]
327Leonoside AA. salicifoliaaerial part[111]
328Leonoside BA. salicifoliaaerial part[111]
3291-Ethenylhexyl 6-O-β-L-arabinopyranosyl-2-O-β-D–glucopyranosyl-β-D-glucopyranosideA. decumbenswhole plant[52]
330Butyl β-D-fructopyranosideA. decumbenswhole plant[52]
331Ivade AA. ivaleaf[131]
A. pseudoivaleaf[48]
332Ivade BA. ivaleaf[131]
A. pseudoivaleaf[48]
333Ivade CA. ivaleaf[131]
A. pseudoivaleaf[48]
334Hizivaide AA. pseudoivaleaf[132]
335Hizivaide BA. pseudoivaleaf[132]
336Hizivaide CA. pseudoivaleaf[132]
337Hizivaide DA. pseudoivaleaf[132]
338Hizivaide EA. pseudoivaleaf[132]
339Methyl 3-hydroxyhexadecanoateA. ivaleaf[133]
340(10E,15Z)-9,12,13-Trihydroxyoctadeca-10,15-dienoic acidA. decumbenswhole plant[112]
341Heptacos-3-en-25-oneA. bracteosaaerial part[134]
342Bractic acidA. bracteosawhole plant[10]
343LigularinineA. parviflorawhole plant[44]
344SenecionineA. parviflorawhole plant[45]
345IntegerrimineA. parviflorawhole plant[45]
346Aurantiamide acetateA. decumbenswhole plant[96]
347Pheophytin-aA. taiwanensiswhole plant[19]
348Pheophytin-bA. taiwanensiswhole plant[19]
349132-Hydroxy(132-S)pheophytin-aA. taiwanensiswhole plant[19]
351Nicotinic acidA. taiwanensiswhole plant[19]
352Bractin AA. bracteosawhole plant[10]
353Bractin BA. bracteosawhole plant[10]

During the search for bioactive metabolites from A. pseudoiva leaves, Ben and co-workers isolated five novel monoglycerides 334–338, two novel cinnamic acids 318, 319 and one new steroid 63, along with five known compounds 61, 62, 331–333. Three compounds 331–333 show significant antifeedant activity, which might be associated with the presence of two β-hydroxyalkanoic moieties in each compound [38], [48], [50], [132]. A phytochemical investigation on A. parviflora resulted in the isolation of quinols 306–312 and pyrrolizidine alkaloids 343–345. Derivatives 306–308 are new compounds. Compound 309, isolated previously from the leaves and branches of Jacaranda species, display cytotoxic and antitumor activities. Three pyrrolizidine alkaloids 343–345 were reported for the first time from this plant [44], [45], [128], [129].

The plant of Ajuga bracteosa afforded several new compounds including unsaturated ketone 341, phthalic ester 322, phenolic compound 320, two sphingolipids 352, 353 and a long-chain polyhydroxy acid 342 [10], [130], [134].

Figure 9
Figure 9

Polyketides and alkaloids.

Citation: Heterocyclic Communications 23, 4; 10.1515/hc-2017-0064

Biological activity

Antifeedant and larvicidal activity

A neoclerodane 103 was isolated from the leaves of A. decumbens as a feeding stimulant for Athalia rosae ruficornis [75]. Three new neoclerodanes 164, 168, 169 were isolated from the aerial parts of A. reptans cv. catlins giant. Insect antifeedant testing revealed that 168 has significant activity against sixth stadium larvae of Spodoptera littoralis [67]. A series of active clerodanes 104, 156, 175–177 were isolated from the acetone extract of A. pseudoiva leaves by bioassay-guided chromatography. The behavioral responses of Spodoptera littoralis larvae to all clerodanes showed strong antifeedant activity at 100 to 1 mg/L. In addition, this study also indicated that a methoxy group at C(15), either in the α- or β-position, might decrease antifeedant activity [9]. Manguro and co-workers tested larvicidal activity of the extracts of A. remota using second instar Aedes aegypti larvae [123]. The ethyl acetate extract is toxic with LC50 value of 5.30 μg/L, while the methanol extract displays weak toxicity with an LC50 of 65.94 μg/L. Compound 81, obtained from the ethyl acetate extract, is the active component with an LC50 value of 4.40 μg/L.

Antimicrobial activity

Compounds 156–161 are six new neoclerodanes isolated from Ajuga lupulina. The diterpenoids 156 and 160 show strong activity against Pseudomonas aeruginosa and Escherichia coli (inhibitory zones are 3–5 mm and 3.5–4.5 mm, respectively, at a concentration of 0.02 mg/mL). In addition, 156 displays weak activity against Staphylococcus aureus (1.5 mm). The antibacterial activity of 161 against P. aeruginosa (2.1 mm) and E. coli (2.0 mm) is poor compared to 156 and 160. Compound 157 exhibits weak antibacterial activity against S. aureus and E. coli (1.2 mm) [4], [99]. In 2001, Kariba tested the extracts of A. remota for in vitro antifungal activity. The petroleum ether and methanol extracts exhibit antifungal activity against the dermatophytic fungi Trichophyton mentagrophytes and Microsporum gypseum [5]. Ergosterol 5,8-endoperoxide 81, isolated from the methanol extract of A. remota, shows activity against Mycobacterium tuberculosis [55].

Antimalarial activity

Ajuga remota is commonly used as medicinal herb for malaria treatment in Kenya. Three isolates, 81, 89 and 262, were tested for their in vitro antiplasmodial activity. Compound 89 is moderately active against a chloroquine-sensitive (FCA 20/GHA) strain of Plasmodium falciparum, with an IC50 of 23.0 μm, compared to a 0.041 μm IC50 for chloroquine. Compared to 89, compound 262 is approximately 3 times as potent. Compound 262 is also equally potent towards chloroquine-sensitive (FCA 20/GHA) and chloroquine-resistant (W2) strains [6]. An excellent review article summarizes antimalarial activity of compounds contained in A. remota and A. bracteosa [135].

Anti-inflammatory activity

Gautam et al. tested a 70% ethanol extract of A. bracteosa whole plants in a mice acute inflammation model based on topical application of TPA. The result showed that the extract exhibits a remarkable and dose-dependent anti-inflammatory activity at 0.5 and 1.0 mg/ear. In addition, it showed a significant in vitro COX-1 and COX-2 inhibitory activity at 25 and 50 μg/mL. Among the isolates from the bioactive extract, compound 156 exhibited the highest inhibition of COX-1, and compound 268 displayed the highest inhibition of COX-2 [136]. The compounds 342, 352, 353 exhibited remarkable inhibition of lipoxygenase. Compound 342 was more active than baicalein (IC50=22.4 μm) with an IC50 of 10.0 μm [10].

Hypoglycemic activity

Ajuga iva has been used as traditional medicine to control diabetes mellitus for many centuries. In 2002, a study to examine the hypoglycemic effect of A. iva was carried out, and the results demonstrated that A. iva aqueous extract exhibits strong hypoglycemic activity. Lyophilized aqueous extract of A. iva whole plant was found to decrease plasma glucopyranose levels of streptozotocin-induced diabetic rats from 337 to 102.2 mg/dL after 6 h of oral administration. Furthermore, repeated oral administration significantly reduced plasma glucopyranose levels after 1 week of treatment (112 mg/dL at 1 week vs. 337 mg/dL at the baseline values) [137].

Cytotoxic activity

Compounds 70–75 are five new sterol glycosides isolated from a methanol extract of the aerial parts of A. salicifolia. Their cytotoxicity against HeLa cells (KB), human T cell leukemia (Jurkat), and peripheral mononuclear blood cells (PMBC) have been evaluated. Compounds 70–74 significantly inhibit the viability and growth of Jurkat T cells at concentrations below 10 μm. Compound 73 is the most active substance with an IC50 values of 3 μm, followed by 70 (IC50=6 μm). An additional glucopyranose substituent leads to weaker cytotoxicity against Jurkat T cells, as observed for 71 (IC50=10 μm) and 74 (IC50=8 μm). Compound 70 induces cell-cell contacts in a Jurkat T cell population, and remarkably up-regulated mRNA levels of the cell-cycle regulator cyclin D1, which might be an indication for cell differentiation [53]. In 2003, Akbay and co-workers investigated the cytotoxicity of sterols obtained from A. salicifolia against KB (HeLa) and Jurkat T cancer cells. This study demonstrated that compound 72 is active against KB cells with an IC50 of 1 μg/mL, while the corresponding 3-O-β-glucopyranoside, compound 76, is less potent (IC50=13 μg/mL) [54]. Four new A. decumbens abietane diterpenoids, 235–238, were evaluated for in vitro inhibition of cell proliferation. The diterpenoids 235 and 237 exhibit moderate cytotoxic activities against MCF-7 cells (human breast cancer), with IC50 values of 19.4 and 12.5 μm, respectively [7].

Cholinesterase inhibitory activity

Compounds 95, 104, 151, 156, 342, 352 and 353 were obtained from A. bracteosa, and their enzyme-inhibitory potential was evaluated. The diterpenoids 95, 104, 151 and 156 display inhibitory activity against cholinesterase (AChE and BChE) with IC50 values in the range of 14.0–35.2 μm for AChE and 10.0–19.0 μm for BChE, respectively. Compound 104 is the most active against cholinesterase while 156 is comparatively less active, indicating that the presence of a MeO group at C(15) increases the cholinesterase inhibitory activity [10].

Antioxidative activity

Bouderbala and co-workers studied the effect of A. iva aqueous extract on lipid peroxidation and antioxidant enzyme activity in hypercholesterolemic rats. The results showed that A. iva extract is more effective at improving RBC antioxidant capacity relative to that of tissues. In addition, A. iva aqueous extract can reduce oxidative stress, which may prevent lipid peroxidation in hypercholesterolemic models by increasing antioxidant enzyme activity [138].

Vasorelaxant activity

El-Hilaly and co-workers investigated vascular activity of A. iva aqueous extract in normotensive Wistar rats. The aqueous extract displayed NO-mediated and NO-independent vasorelaxing properties in vitro. The A. iva extract contains more than one active compound. One of these compounds is responsible for inhibition of noradrenaline evoked contraction. Another compound was identified in vitro as a transient NO-dependent relaxation [8].

Conclusions

The plants of the genus Ajuga are widely distributed globally and many of these plants are used as traditional herbal medicines. The compounds isolated from this genus exert a broad spectrum of biological and pharmacological activities, however, our review indicates that phytochemical investigation has mainly focused on a few species. Further studies on the remaining species, their constituents and biological activities, should be carried out.

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This peer-reviewed journal publishes preliminary communications, research articles and reviews on developments in all phases of heterocyclic chemistry, including inorganic ring systems. The scope includes development of novel synthetic methods, rational design and synthesis of new drugs targeting specific biological receptors and development of new substrates and catalysts in materials chemistry.