3.1. Anticancer and Cytotoxic Activities
Cancer cells that avoid apoptosis continue to proliferate uncontrollably. Apoptosis is an ordered and orchestrated cellular process that occurs in physiological and pathological conditions. An understanding of the underlying mechanism of apoptosis is important as it plays a pivotal role in the pathogenesis of many diseases. Degenerative diseases are characterized by too much apoptosis, while in the case of cancer, too little apoptosis occurs. Thus, resisting apoptosis is a key process in cancer development and progression [
83]. Targeting the antiapoptotic proteins such as those of the Bcl-2 family members (Bcl-2, Bcl-xL, Bcl-w, Mcl-1, and A1) is essential for cancer treatment or preventive drug discovery. In addition, it has been shown that most cancers depend on more than one antiapoptotic Bcl-2 member for survival. The discovery of new selective inhibitors of antiapoptotic proteins is thus important for the search for anticancer drugs [
84,
85,
86,
87].
Endiandric acids derivatives isolated from
Beilschmiedia and
Endiandra species were screened for Bcl-xL and Mcl-1 binding affinities (
Table 5). Amongst the tested compounds, ferrugineic acid B (
38) exhibited the best binding affinity for Mcl-1 (85% inhibition at 100 μM) while ferrugineic acid C (
39) showed the highest binding affinity to Bcl-xL (93% inhibition at 100 μM). Two compounds, ferrugineic acids B (
38) and C (
39), exhibited significant binding affinities for both antiapoptotic proteins. Apart from tsangibeilin B (
29) and ferrugineic acid J (
46), the compounds that exhibited good binding affinity to Mcl-1 possess a C
13 fused tetracyclic ring system with Δ
4,5 and Δ
8,9 double bonds. In the group of compounds with an C
11 fused tetracylic ring system, only kingianic acid C (
61) showed significant binding affinity to Mcl-1. No binding was detected from the compounds of this last fused tetracylic ring system for Bcl-xL. After the correlation between the structures and activities of compounds with C
13 fused tetracyclic ring system, Appel and collaborators postulated that the length of the saturated carbon side chain, the β-oriented C-4 hydroxy group and the terminal 4-hydroxyphenyl ring, play a crucial role for Bcl-xL and Mcl-1 binding affinities [
24,
34].
Table 5.
Binding affinities of some endiandric acid derivatives to antiapoptotic proteins Bcl-xL and Mcl-1.
Table 5.
Binding affinities of some endiandric acid derivatives to antiapoptotic proteins Bcl-xL and Mcl-1.
Compound | Bcl-xL/Bak Binding Affinity | Mcl-1/Bid Binding Affinity |
---|
% at 100 μM | Ki μM | % at 100 μM | Ki μM |
---|
Tsangibeilin B (29) | 26 ± 2.5 | ND | 81 ± 2.4 | ND |
Ferrugineic acid A (37) | 22 ± 2 | >100 | 0 | 14 ± 33 |
Ferrugineic acid B (38) | 60 ± 6 | 19.2 ± 1.6 | 85 ±2 | 12.0 ±5.0 |
Ferrugineic acid C (39) | 93 ± 3 | 12 ± 0.2 | 82 ± 2 | 13.0 ± 5.0 |
Ferrugineic acid D (40) | 39 ± 3 | >100 | 82 ± 2 | 5.2 ± 0.2 |
Ferrugineic acid E (41) | 20 ± 1 | ND | 14.3 ± 3 | ND |
Ferrugineic acid F (42) | 7 ± 1 | ND | 0 | ND |
Ferrugineic acid G (43) | 17 ± 1 | ND | 3 ± 1 | ND |
Ferrugineic acid I (45) | 35 ± 1 | ND | 7 ± 2 | ND |
Ferrugineic acid J (46) | 58 ± 7 | 19.4 ± 3 | 81 ± 3 | 5.9 ± 0.5 |
Kingianic acid F (47) | 22 ± 2.9 | ND | 80 ± 0.7 | ND |
Kingianic acid G (48) | 19 ± 1.6 | ND | 47 ± 2.9 | ND |
Kingianic acid A (54) | 21 ± 1.8 | ND | 36 ± 2.3 | ND |
Endiandric acid M (56) | 10 ± 0.5 | ND | 39 ± 2.9 | ND |
Kingianic acid C (61) | 25 ±1.7 | ND | 75 ± 1.1 | ND |
Kingianic acid E (63) | 1 ± 0.8 | ND | 8 ± 5.5 | ND |
U-Bak (Ki) | | 0.0012 ± 10−3 | | ND |
U-Bid (Ki) | | | | 0.016 ± 0.002 |
ABT-737 (Ki) | 57 ± 10 nM | | 47 ± 22 nM | |
The binding affinity of the racemic mixtures of kingianin A–N (
112–
125) isolated from
E. kingiana was evaluated on Bcl-xL by competition against the fluorescently tagged BH3 domain of the protein Bak. Racemic mixtures of kingianins G–L (
118–
123) exhibited good binding affinity with kingianin G (
118) exhibiting the best potency with a K
i value of 2 ± 0 μM (
Table 6). The pure enantiomers of these active racemates obtained using chiral preparative HPLC were evaluated for their binding affinity. Taking into account the stereochemistry of the compounds, the binding affinity was significantly higher for the (−)-enantiomers compared to the (+)-enantiomers, as illustrated by the comparison of the K
i for (−) and (+)-kingianin derivatives (
Table 6) [
43].
Table 6.
Bcl-xL binding affinity of compounds 112–125 (Ki in μM).
Table 6.
Bcl-xL binding affinity of compounds 112–125 (Ki in μM).
Compound | Bcl-xL Ki |
---|
Racemic mixture | (−) Enantiomer | (+) Enantiomer |
---|
Kingianin A (112) | 213 ± 83 | 60 ± 1.5 | >300 |
Kingianin B (113) | >300 | | |
Kingianin C (114) | >300 | | |
Kingianin D (115) | >300 | | |
Kingianin E (116) | >300 | | |
Kingianin F (117) | 231 ± 47 | | |
Kingianin G (118) | 2 ± 0 | 1.0 ± 0.2 | 5.0 ± 1.0 |
Kingianin H (119) | 18 ± 7 | 4.0 ± 0.4 | 27.0 ± 0.6 |
Kingianin I (120) | 18 ± 3 | 12.0 ± 1.1 | 16.0 ± 2.2 |
Kingianin J (121) | 29 ± 6 | 9.0 ± 0.2 | 25.0 ± 3.2 |
Kingianin K (122) | 80 ± 36 | 6.0 ± 0.2 | 112 ± 45 |
Kingianin L (123) | 36 ± 11 | 4.0 ± 0.1 | 71.0 ± 10 |
Kingianin M (124) | 236 ± 34 | | |
Kingianin N (125) | 177 ± 9 | | |
Unlabeled Bak (BH3) | 0.90 ± 0.27 | | |
Endiandric acid analogues isolated from unidentified Gabonese
Beilschmiedia species were screened for their cytotoxicity against NCI-H460 (human lung cancer cell lines); PC-3 (prostate adenocarcinoma cell lines), and M14 (amelanotic melanoma cell lines) using an MTT assay. All the isolated compounds were inactive against PC-3, and M14 cell lines. Beilschmiedic acids K (
17), L (
19), M (
18), N (
20) and A (
8) exhibited moderate cytotoxicity against NCI-H460 human lung cancer cells with IC
50 values of 5.5; 5.9; 4.4; 8.7; 19; 6.1 μM, respectively. This was the first report of the cytotoxicity of this class of secondary metabolites [
48]. Subsequently, other endiandric acid derivatives kingianic acids A (
59), C (
61), E (
63), F (
47), G (
48), endiandric acid M (
56), and tsangibeilin B (
29) isolated from
E. kingiana were evaluated for their cytotoxicity activity against A549 (lung adenocarcinoma epithelial cell lines), HT29 (colorectal adenocarcinoma cell lines) and PC3 cell lines. As reported by Williams
et al. [
48], all compounds were inactive against prostate adenocarcinoma cancer cell lines. Kingianic acid A (
59) showed weak activity against HT-29 and A549 cell lines with IC
50 values of 35 ± 0.2 μM and 85.4 ± 0.2 μM, respectively. Kingianic acid E (
63) showed moderate cytotoxic activity against A549 and HT-29 cell lines with IC
50 values of 15.36 ± 0.19 μM and 17.10 ± 0.11 μM, respectively [
34]. The other tested compounds showed very weak or were devoid of cytotoxic activity against the cell lines tested.
Ferrugineic acids A–J (
37–
46) and K (
58), isolated from
B. ferruginea, were screened for cytotoxicity against HCT-116 (Human colorectal carcinoma) and K562 (human leukemia) cancer cell lines. All these compounds were devoid of cytotoxicity on the two cancer cell lines tested at concentrations up to 50 µM [
24].
The cytotoxicity activities of lignans and other constituents of the stem of
B. tsangii were evaluated
in vitro against P-388 and HT-29 cell lines. Beilschmin A (
133), B (
134), C (
135), tsangin A (
137), B (
138), 2,6,11-trimethyldodeca-2,6,10-triene (
179), α-tocopheryl quinone (
167) and α-tocospiro B (
217) were cytotoxic (IC
50 below 4 µg/mL) against the P-388 cell lines. Tsangin A (
137), B (
138) and α-tocospiro B (
217) were the most cytotoxic with IC
50 values of 0.81 ± 0.009, 0.42 ± 0.03, and 0.83 ± 0.09 µg/mL, respectively, against the P-388 cell lines while 2,6,11-trimethyldodeca-2,6,10-triene (
179) and α-tocospiro B (
217) exhibited the best potency against the HT-29 cell line amongst the isolated with IC
50 values of 2.2 ± 0.3 and 1.5 ± 0.2 µg/mL, respectively [
25].
Endiandrin A (
143), endiandrin B (
144), (−)-dihydroguaiaretic acid (
145) isolated from
E. anthropophagorum and the synthesized derivative cinbalansan (
223) were also evaluated for their cytotoxicity against A549 cell line. In high-content screening (HCS) assays, (−)-dihydroguaiaretic acid (
145) was found to be the most potent compound, displaying cytotoxicity against the A549 cell line with an IC
50 of 7.49 μM after 24 h incubation in both propidium iodide and Yo-PRO-1 assays. It effect was less pronounced in the mitotracker assay with IC
50 of 31.2 μM. Endiandrin A (
143), and B (
144) were found to have moderate effects with an inhibition of 76% and 75% at 100 μM, respectively. Cinbalansan (
223) was found to have much less effect with a maximum inhibition of 34% [
32].
Alkaloids isolated from the leaves of
B. brevipes exhibited cytotoxicity activity against P-388 murine leukemia cell lines. (6,7)-Dimethoxy-1-isoquinolinyl)-(4'-methoxyphenyl)methanone (
94),
O,
O-dimethylcoclaurine (
98),
O-methylvelucryptine (
97), (
R)-(−)-armepavine (
96) and (±)-
N-norarmepavine (
95) were active with IC
50 values of 18.7, 6.5, 17.3, 42.2 and 44.5, respectively [
45].
The stem bark and leaf extracts of
B. acuta were evaluated against a panel of human cancer cell lines, including various multidrug-resistant phenotypes. The leaf extracts showed IC
50 values below or around 30 mg/mL in 10 cell lines. Interestingly, among them were multidrug-resistant cell lines, e.g., P-glycoprotein overexpressing CEM/ADR5000, breast cancer resistance protein-transfected MDA-MB-231-BCRP, TP53 knockout cells (HCT116 p53
−/−), and mutation-activated epidermal growth factor receptor-transfected U87MG.ΔEGFR cells [
88].
(−)-Kunstleramide (
105) a dienamide from
B. kunstleri displayed cytotoxic effect in MTT assays against A375 (melanoma cell lines), A549, HT-29, PC-3 and WRL-68 (normal liver) cell lines with EC
50 values of 64.65, 44.74, 55.94, 73.87 and 70.95 μg/mL, respectively [
31]. Other amides
N-
trans-feryoloctopamine (
110) and beilschamide (
111) isolated from the stem of
B. erythrophloia exhibited cytotoxic effects
in vitro. They were active against CCRF-CEM (human lymphoblastic leukemia) cell line with IC
50 values of 10.3 and 21.2 μg/mL, respectively [
69].
The essential oil obtained from the leaf of
B. erythrophloia exhibited cytotoxic activity against human OEC-M1 (oral squamous cancer), J5 (hepatocellular carcinoma), A549, HT-29, UACC-62 (melanoma) and K562 (leukemic) cell lines. The results showed that treatment with the essential oil for 48 h reduced the viability of OEC-M1 cells, J5 cells, A549 cells, HT-29 cells, UACC-62 cells, and K562 cells, with IC
50 around 32.6, 48.6, 38.8, 18.9, 5.8, and 6.8 μg/mL, respectively [
77].
3.2. Antimalaria Activity
Malaria remains one of the most notorious infectious diseases in the world. It constitutes a public health problem in more than 90 countries, inhabited by about 40% of the world’s population. The World Health Organisation estimates that there are 300–500 million malaria cases annually, causing 2–3 million deaths, mostly among children under five years old. In the last decades, resistance of
Plasmodium falciparum, the causative agent of the most severe form of the disease, to several antimalarials, especially chloroquine and antifolates, became widely disseminated, while the cost of effective treatment is prohibitive for the large majority of the population in developing countries. For these reasons, new effective and affordable antimalarials are urgently needed [
89,
90,
91]. In this perspective, extracts and some compounds isolated from
Beilschmiedia species were screened for their antiplasmodial potency.
Cryptobeilic acids A–D (
33–
36) and tsangibeilin B (
29) isolated from
B. cryptocaryoides collected in Madagascar exhibited antiplasmodial activity
in vitro against the chloroquine-sensitive strain of
P. falciparum NF54 with IC
50 values of 17.7, 5.35, 14.0, 10.8 and 8.2 µM, respectively. However, the cytotoxicity of these compounds against the L6 cell lines indicated low selectivity [
52].
The antiplasmodial bioassay guided separation of the chemical constituents of the wood of the Indonesian medicinal plant
B. madang led to the isolation of the bisbenzylisoquinoline dehatrine (
100), that exhibited potent antiplasmodial activity against the chloroquine-resistant strain
P. falciparum k1 with IC
50 value of 0.17 μM, and which is comparable to that of the reference drug quinine against the same strain
in vitro [
12].
Pipyahyine (
107), 5-hydroxy-7,8-dimethoxyflavanone (
157), and betulinic acid (
174) isolated from
B. zenkeri exhibited antiplasmodial activity against the chloroquine-resistant strain of
P. falciparum W2 with IC
50 values of 3.7, 9.3 and 5.2 μM, respectively. Their activity were moderate compare to chloroquine (IC
50 value of 0.13 μM), which was used as the positive control [
18].
Lupeol (
171), which showed
in vitro inhibitory activity against the
P. falciparum 3D7 strain with an IC
50 value of 27.7 ± 0.5 μM, was shown to cause a transformation of the human erythrocyte shape toward that of stomatocytes [
92].
3.3. Anti-Asthmatic and Other Anti-Inflammatory Activities
Asthma is a disease of the immune system, which is expressed for example as bronchial asthma in the form of acutely occurring, paroxysmal dyspnea with expiratory ventilation disability. Studies reported that persistent inflammation is central to the pathogenesis of asthma. So far, asthma therapy uses drugs which alleviate the symptoms but do not inhibit the mechanism responsible for the expression of inflammatory mediators such as the cytokines interleukin-4 (IL-4), interleukin-13 (IL-13) and interleukin-5 (IL-5) [
93,
94]. Endiandric acid H (
7), obtained from the plant
Beilschmiedia fulva, and its synthetic derivatives, known as c-maf, and NFAT inhibitors are used for producing a medicament, in particular for the treatment of allergic disorders, asthmatic disorders, inflammatory concomitant symptoms of asthma and/or of diseases which can be treated by inhibiting c-maf and NFAT [
53,
54].
The anti-inflammatory activities of extracts of
B. tsangii have been studied. The methanol extract of the roots of
B. tsangii showed potent inhibition of nitrogen monoxide (NO) production. Amongst the compounds isolated from this extract by bioassay guided separation, endiandric acid analogues endiandramide A (
32) and B (
57) with
N-isobutylamide group exhibited potent iNOS inhibitory activities with IC
50 values of 9.59 and 16.40 μM, respectively. Other isolates, tsangibeilin A (
26), tsangibeilin B (
29), endiandric acid K (
54), endiandric acid M (
56), endiandric acid L (
55), and the lignans beilschminol A (
128), beilschminol B (
129), tsangin C (
139) and tsangibeilin D (
31), exhibited moderate anti-inflammatory activity with IC
50 values in the range of 30–96 µM [
22,
23].
Synthetic glucocorticoids are widely used as drugs to treat inflammatory conditions such as rheumatoid arthritis or dermatitis and as adjunctive therapy for conditions such as autoimmune diseases. However, current glucocorticoid drugs act non-selectively, with the potential of long-term impairment of many physiological anabolic processes. Therefore, research aiming at the discovery of selective novel glucocorticoid receptor (GR) binders may provide new and improved drug therapies [
95,
96,
97,
98]. The bioguided fractionation of the dichloromethane extract of
Endiandra anthropophagorum based on GR binding assay resulted in the isolation of the active lignans endiandin A (
143), nectantin B (
146) and (−)-dihydroguaiaretic acid (
145) which displayed IC
50 values of 0.9, 27 and 35 μM, respectively. The di-acetylated (
224) and di-methylated (
225) derivatives of endiandrin A also exhibited good activities with IC
50 of 34 and 13 µM, respectively. From the structure–activity correlation, David and collaborators suggested that the constrained four-membered which has implications in the spatial arrangements of the substituents is important for the potent GR activity. In addition, increasing the steric bulk of the C-4/C-4' substituents in the cyclobutane series was shown to significantly reduce the activity [
33].
3.4. Antimicrobial Activity
Antibacterial activity of extracts and a number of endiandric acid derivatives and other constituents isolated from Beilschmiedia and Endiandra species have been studied.
Beilschmiedic acid A (
8), B (
9), and C (
10), isolated from the stem bark of
B. anacardioides, exhibited antibacterial activities against a wide range of microorganisms (
Bacillus subtillis,
Micrococcus luteus,
Streptococcus faecalis) with minimum inhibitory concentrations (MICs) of 0.7–364 μM
. Compound
10 was found to be the most active derivative against the three tested strains with MICs of 5.6, 0.7 and 22.7 μM, respectively. Compounds
9 (MIC value of 11.3 μM) and
10 (MIC value of 5.6 μM) were found to be more active than the reference drug ampicillin (MIC value of 89.5 µM) against
B. subtillis. Compound
10 was also more active than the reference drug ampicillin (MIC value of 5.58 µM) against
M. luteus [
17].
Compound
8 and other endiandric acid derivatives beilschmiedic acids I–O (
15–
21), isolated from an unidentified Gabonese
Beilschmiedia species, exhibited potent antibacterial activity against a clinical isolate of methicillin-resistant
S. aureus (MRSA) with MIC values between 10 and 13 μg/mL [
48].
Cryptobeilic acids A (
33) and B (
34) isolated from
B. cryptocaryoides displayed antibacterial activity against
Escherichia coli 6r3 with MIC values of 10 and 20 μg/mL, respectively. Their activity were moderate compared to that of the reference drug ampicillin (MIC value of 5 μg/mL) [
52].
Endiandric acid erythrophloin C (
24) with phenyl in the side chain isolated from
B. erythrophloia exhibited antitubercular activity against
Mycobacterium tuberculosis with MIC of 50 μg/mL [
41].
In addition to endiandric acid derivatives, other constituents of
Beilschmiedia and
Endiandra genera have also exhibited antibacterial activity
in vitro against some strains of bacteria. The amide pipyahyine (
107) and beilschmieflavonoid B (
156) isolated from the stem of
B. zenkeri exhibited antibacterial activity
in vitro against
Bacillus subtilis,
P. agarici and
S. minor with MICs between 81.5–197.5 μM [
18].
Magnolol (
141), a neolignan isolated from different
Endiandra species, showed strong antibacterial activities against both
Propionibacterium acnes and
Propionibacterium granulosum, which are acne-causing bacteria with the MIC value of 9 μg/mL [
99].
Beilschmin A (
133) and B (
134), two lignans isolated from
B. tsangii, exhibited potent antitubercular activities with MICs of 2.5 and 7.5 μg/mL, respectively. These compounds were more active than their corresponding epoxy-analogues, 4α,5α-epoxybeilschmin A (
130) (IC
50 of 30 µg/mL) and 4α,5α-epoxybeilschmin B (1
31 (IC
50 of 40 μg/mL). As reported by Chen
et al. [
48], the epoxidation of the C4/C5 bond of compounds
133 and
134 considerably reduce their antibacterial activity against
M. tuberculosis. Beilschmin A (
133) with MICs of 2.5 μg/mL was most active than the reference compound, ethambutol (MIC of 6.2 µg/mL) [
26]. The sesquiterpene suberosol B (
180) isolated from
B. erythrophloia also exhibited potent antitubercular activity against
M. tuberculosis H37Rv
in vitro with MIC of 28.9 µg/mL [
41].
The methanol extract of the wood of
B. tovarensis showed significant antibacterial activity results against
Staphylococcus aureus and
Enterococcus faecalis [
13]. The methanol extract of the fruits of
B. obscura showed antibacterial activity against multi-resistant drugs strains of
Escherichia coli,
Enterobacter aerogenes,
Klebsiella pneumoniae,
Enterobacter cloacae,
Pseudomonas aeruginosa, and
Providencia stuartii with MICs between 16–128 μg/mL [
100].
Essential oils from the leaves and bark of
B. madang showed moderate antibacterial activity towards
B. subtilis and
S. aureus with identical minimum inhibitory concentrations (MIC), 125 μg/mL. They also exhibited activity towards
E. faecalis with MIC value of 250 μg/mL. Both oils were also found to be active against Gram-negative bacteria,
K. pneumoniae with MIC value of 250 μg/mL [
77].
The antifungal activities of extracts and the isolates from
Beilschmiedia and
Endiandra were also reported. The essential oils from the bark of
B. madang showed strong antifungal activity towards
Aspergillus niger and
A. fumigatus with identical MIC values, 62.5 μg/mL [
78].
The crude methanolic extract of
B. alloiophylla was found to be active against
Candida albicans in vitro. Alkaloids isolated from this extract boldine (
74), 2-hydroxy-9-methoxyaporphine (
81), laurotetanine (
82), secoboldine (
89), isoboldine (
80), asimilobine (
83), oreobeiline (
87), 6-epioreobeiline (
88), liriodenine (
90), (
S)-3-methoxynordomesticine (
91) and the triterpenoid β-amyrone (
174) exhibited good antifungal activity against the same strain with MICs in the range of 8–64 μg/mL [
29]. Paulo and collaborators reported moderate antifungal activity for laurelliptine (
79) and isoboldine (
80)
in vitro against
Tricophyton rubrum and
Microsporum gypseun [
101].
3.5. Other Activities
Essential oil from the leaves of
Beilschmiedia madang exhibited cholinesterase and tyrosinase inhibiting activities
in vitro with inhibition of 55.2%, 60.4%, and 53.1% for acetyl-, butyrylcholinesterase and tyrosinase at 1000 μg/mL, respectively [
78]. The crude methanolic extract of
B. alloiophylla inhibited acetylcholinesterase and α-glucosidase
in vitro. Four compounds from this extract, oreobeiline (
87), 6-epioreobeiline (
88), β-amyrone (
174), and (
S)-3-methoxynordomesticine (
91), displayed moderate inhibitory activity against α-glucosidase with IC
50 values of 8.0, 10.0, 20.0, and 10.0 μM, respectively. Other isolates from the same extract, 2-hydroxy-9-methoxyaporphine (
81), laurotetanine (
82) and liriodenine (
90), displayed strong inhibitory activity against AchE with IC
50 values of 2.0, 3.2 and 3.5 μM, comparable to that of the reference substance huperzine (IC
50 values of 1.8 μM) [
29].
The essential oils from the leaves of
B. tilaranensis and
B. brenesii exhibited enzyme inhibitory activities against cruzain, a potential therapeutic target for Chagas’ disease, a parasitic disease caused by
Trypanosoma cruzi and that occurs mostly in South and Central American countries, with IC
50 values of 23.6 μg/mL and 61.9 μg/mL, respectively [
102,
103,
104].
The crude methanolic extract of
B. alloiophylla was shown to exhibit antileishmanial activity
in vitro. Compounds isolated from this extract, 2-hydroxy-9-methoxyaporphine (
81), laurotetanine (
82), liriodenine (
91), boldine (
74), secoboldine (
90), isoboldine (
80), asimilobine (
83), oreobeiline (
87), 6-epioreobeiline (
88), β-amyrone (
174), and (
S)-3-methoxynordomesticine (
91) exhibited moderate activity with IC
50 values in the range of 10–50 μM [
29].
The essential oils from
B. madang exhibited weak DPPH radical scavenging activity (IC
50 leaf oil, 263.9 μg/mL; bark oil, 212.0 μg/mL) compared to standard antioxidant, butylated hydroxytoluene (IC
50 of 18.5 μg/mL) [
78]. (−)-Kunstleramide (
105) an dienamide from
B. kunstleri exhibited very poor dose-dependent inhibition of DPPH (2,2-diphenyl-1-picrylhydrazyl) activity, with an IC
50 value of 179.5 ± 4.4 μg/mL [
31].