A novel acylated flavonol tetraglycoside and rare oleanane saponins with a unique acetal-linked dicarboxylic acid substituent from the xero-halophyte Bassia indica

Article abstract of DOI:10.1016/j.fitote.2021.104907

In recent years, the scientific interest and particularly the economic significance of halophytic plants has been highly demanding due to the medicinal and nutraceutical potential of its bioactive compounds. A xero-halophyte Bassia indica is deemed to be

Full text of DOI:10.1016/j.fitote.2021.104907

Fitoterapia 152 (2021) 104907
Contents lists available at ScienceDirect
Fitoterapia
journal homepage: www.elsevier.com/locate/fitote
A novel acylated flavonol tetraglycoside and rare oleanane saponins with a
unique acetal-linked dicarboxylic acid substituent from the xero-halophyte
Bassia indica
a,
b
a,
c
a,*
Ahmed Othman , Yhiya Amen , Kuniyoshi Shimizu
a
Department of Agro-environmental Sciences, Graduate School of Bioresources and Bioenvironmental Sciences, Kyushu University, Fukuoka 819-0395, Japan
Department of Pharmacognosy, Faculty of Pharmacy, Al-Azhar University, Cairo 11371, Egypt
b
c
Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
A R T I C L E I N F O
A B S T R A C T
Keywords:
In recent years, the scientific interest and particularly the economic significance of halophytic plants has been
highly demanding due to the medicinal and nutraceutical potential of its bioactive compounds. A xero-halophyte
Bassia indica is deemed to be a very cheap source of natural entities without chemical or biological investigation.
In this context, a new acylated flavonol tetraglycoside, kaempferol-3-O-β-D-glucopyranosyl-(1→6)-O-[β-D-gal-
Halophytes
Bassia indica
Chenopodiaceae
Saponins
actopyranosyl-(1→3)-2-O-trans-feruloyl-
rare occurring flavonol triglycoside, isorhamnetin-3-O-β-D-glucopyranosyl-(1→6)-O-[
1→2)]-β-D-glucopyranoside (15), were isolated from the aqueous methanol extract of the aerial parts of
B. indica. The study also reported an optimal separation and characterization of a new seco-glycosidic oleanane
α
-L-rhamnopyranosyl-(1→2)]-β-D-glucopyranoside (14), together with
Anticholinesterase
α-L-rhamnopyranosyl-
(
′
′
′
′
′
′
saponin with 2 R,3 S stereocenters, identified as (2 R,3 S)-3-O-[2 -hydroxy-3 -(2"-O-glycolyl)-oxo-propionic acid-
β-D-glucuronopyranosyl]-28-O-β-D-glucopyranosyl-olean-12-en-3β-ol-28-oic acid (17), in addition to its deriv-
′
ative, 3-O-[2 -(2"-O-glycolyl)-glyoxylyl-β-D-glucuronopyranosyl]-28-O-β-D-glucopyranosyl-olean-12-en-3β-ol-28-
oic acid (16). The structures of all isolated compounds were elucidated based on 1D, 2D NMR, and HR-MS
analysis, as well as comparing with similar derivatives published in the literature. Furthermore, thirteen
known compounds were isolated and identified as β-sitosterol (1), vanillic acid (2), o-hydroxybenzoic acid (3),
р-hydroxybenzoic acid (4), 6,7-dihydroxycoumarin (5), methyl caffeate (6), caffeic acid (7), quercetin (8), uracil
(
(
9), thymidine (10), tachioside (11), isorhamnetin-3-O-β-D-glucopyranoside (12), kaempferol-3-O-rutinoside
13). The anticholinesterase activity of all isolated compounds was evaluated.
1
. Introduction
Natural product research continues to play a vital role in paving the
1400 species in 105 genera with several species growing in the Egyptian
ecosystem [4,5]. Several chemical compounds related to diverse
chemical classes were identified in Chenopodiaceae including alkaloids
[6], saponins [7], flavonoid glycosides [8], ecdysteroids [9,10], ses-
quiterpenoids [11], lignanamides [12], phenolic acids [13,14], and
coumarins [15]. Additionally, various members of this family have been
implied to contain various compounds that have shown several biolog-
ical activities such as antioxidant, anticholinesterase [16], anti-
inflammatory [17], analgesic [18], antihyperlipidemic [19], antihy-
pertensive [20], antitumor [21], hepatoprotective [22], antidiabetic
[23], and tyrosinase inhibitory activity [24].
way toward discovery of new sources of bioactive lead compounds
throughout history and has been applied in many fields of medicine and
pharmaceutical industry [1]. Up to date, there are many examples of
natural compounds that have been developed into effective drugs for
various diseases such as infectious diseases, Alzheimer, diabetes, and
cancer, etc. [2].
Halophytes are plants able to grow in dry and saline habitats. They
are regarded as a potential economic source of nutrients, bioactive
constituents, in addition to the ability to display substantial health
benefits [3]. The halophyte family Chenopodiaceae is comprising about
Bassia indica (Wight) A.J.Scott. (synonym: Kochia indica) is a xero-
halophyte herb belongs to the family Chenopodiaceae and widely
*
Corresponding author at: Department of Agro-environmental Sciences, Faculty of Agriculture, Kyushu University, Japan.
E-mail address: shimizu@agr.kyushu-u.ac.jp (K. Shimizu).
https://doi.org/10.1016/j.fitote.2021.104907
Received 15 March 2021; Received in revised form 14 April 2021; Accepted 16 April 2021
Available online 20 April 2021
0
367-326X/© 2021 Elsevier B.V. All rights reserved.

A. Othman et al.
Fitoterapia 152 (2021) 104907
distributed in Egypt. It has been reported to display antitumor, antiox-
idant, and cardiotonic activities [25]. However, the detailed chemical
composition and biological activities of B. indica have not been fully
investigated. The plant B. indica is commonly eradicated by rural people
which lead to waste of natural resources. Therefore, the utilization of
such halophyte extracts with high nutritional and pharmaceutical value
for their chemical and biological characterization represents a powerful
tool in drug discovery with much less cost.
2.3. Extraction and isolation
The dried aerial parts of B. indica (1 Kg) were extracted with 80%
MeOH till exhaustion followed by evaporation to give a semi-solid dark
brown residue (130 g, 13%). The obtained crude residue was suspended
in distilled water (500 mL) and subjected to fractionation successively
with n-hexane (500 mL × 6), EtOAc (500 mL × 6), and n-BuOH (500 mL
× 4) to yield 32, 4, and 22 g, respectively.
In continuation of our ongoing projects for the discovery of effective
substances from halophytic plants distributed in the Egyptian
ecosystem, a study was designed aiming at isolation, identification, and
characterization of compounds from B. indica growing in Egyptian
desert lands in order to valorize such kind of plants and to shed more
light toward the utilization of halophytes as a very cheap and promising
source of novel bioactive compounds.
The EtOAc fraction (3 g) was chromatographed over silica gel for CC
(75–150 μm, 2 × 65 cm) and eluted with n-hexane containing increasing
proportions of EtOAc and MeOH to obtain seven fractions (fractions 1 to
7).
Fraction 1 (136 mg) was chromatographed over Sephadex LH-20
column (30 g, MeOH; 150 mL) to afford compound 1 (23 mg). Frac-
tion 2 (220.4 mg) was chromatographed over Sephadex LH-20 column
(50 g, MeOH; 300 mL) to yield three subfractions (2–1, 2–2, and 2–3).
Subfraction 2–1 (112 mg) was further purified over MPLC with silica gel
The current study reports on the isolation and identification of 17
compounds, including one new acylated flavonol tetraglycoside, a rarely
occurring flavonol triglycoside, and two rare occurring seco-glycosidic
oleanane saponins. The anticholinesterase activity of the isolated com-
pounds was also determined.
2 2
flash column (2 columns; each 4 g) eluted with CH Cl -MeOH (9.5:0.5 v/
v) as a mobile phase to obtain compounds 2 (6 mg), 3 (12 mg), 4 (8 mg),
and 5 (10 mg), respectively. Subfraction 2–2 (62.2 mg) was further
purified over Sephadex LH-20 column (30 g, 100% MeOH) to afford
compound 6 (19 mg) and compound 7 (8.5 mg). Subfraction 2–3 (38.3
2
. Experimental
2
mg) was purified on preparative RP-TLC (H O-MeOH, 100 mL, 1:1 v/v)
2
.1. General experimental procedures
to afford compound 8 (3.3 mg).
Fraction 5 (1954 mg) was chromatographed on MPLC with RP-C18
flash column (40 m, 12 g) using gradient elution system of H O-
Optical rotations were obtained on a JASCO P-2200 polarimeter.
μ
2
NMR spectra were recorded on a DRX 600 spectrometer (Bruker Dal-
tonics, USA). Tetramethylsilane (TMS) was used as reference. Chemical
shift and coupling constant were recorded in δ (ppm) and J (Hz),
respectively. HR-ESI-MS data for compounds were recorded on a
quadrupole time-of-flight mass spectrometer (Agilent QTOF-LC-MS,
Agilent Technologies, USA). Fractionation and separation of com-
pounds was performed on column chromatography packed with silica
MeOH (9:1 to 0:1) as a mobile phase and a flow rate 10 ml/min to afford
five major subfractions (5–1 to 5–5). Subfraction 5–1 (100 mg) was
purified over Sephadex LH-20 column (30 g, MeOH; 150 mL) to afford 9
(10 mg). Subfraction 5–2 (162 mg) was purified over Sephadex LH-20
column (30 g, MeOH; 150 mL) then subjected to further purification
over NP-TLC using CH
compound 10 (6.2 mg) and compound 11 (4.5 mg) which was further
purified over silica gel CC (1 g, CH Cl
2 2
Cl -MeOH as an eluent (9:1, 100 ml) to obtain
gel (75–150
μm, Merck, Darmstadt, Germany), RP18 (38–63
μm, Wako
2
2
-MeOH, 8.5:1.5). Subfraction 5–5
Pure Chemical Corporation, Osaka, Japan), Sephadex LH-20 (Sigma
Aldrich, St. Louis, MO, USA), Diaion HP-20 (Mitsubishi Chemical Co.,
Tokyo, Japan), and Biotage selekt equipped with RP18 flash column
(1380 mg) was subjected to purification over Sephadex LH-20 column
(100 g, MeOH; 500 mL) to yield compound 12 (9 mg), while the rest of
fraction (1100 mg) was chromatographed over MPLC with RP-C18 flash
chromatography (Biotage Selekt, Sf a¨ r C18 Duo column, 30
μ
m, 30 g).
μ
2
column (40 M, 12 g) eluted gradually with H O-MeOH (9:1 to 0:1) to
Final purification of the isolates was further achieved by using medium
obtain four subfractions (6–1 to 6–4). Subfraction 6–3 (66 mg) was
purified over Sephadex LH-20 column (20 g, MeOH; 100 mL) to obtain
compound 13 (7.5 mg).
pressure liquid chromatography (Pure C-850 Flash prep®, Buchi,
Switzerland) with UV-ELSD detection, normal flash columns (40
RP18 flash columns (20 m), Preparative column (Zorbax Extend-C18
PrepHT, 21.2×150 mm, 5 m, Agilent, USA). Moreover, some isolates
μm),
μ
The n-BuOH fraction (21 g) was subjected to fractionation on open
column packed with Diaion HP-20 (100 g, 3 × 70 cm) flushed with five
μ
were purified on preparative NP-TLC (Wako Pure Chemical Corporation,
Osaka, Japan) and preparative RP-TLC (Merck, Darmstadt, Germany).
TLC investigation was carried out on plates precoated with silica gel
GF254 and RP18F254 (Merck, Darmstadt, Germany), then chromato-
grams were visualized under UV light at (254 and 365 nm) and sprayed
2
mobile phases of H O-MeOH (1:0, 4:1, 1:1, 1:4, 0:1, each 10 L) to afford
5 fractions (Bu1 to Bu-5).
Fraction Bu3 (1 g) was chromatographed over MPLC system with
μ
2
flash column RP-C18 (40 m, 12 g) eluted with H O-MeOH (8.5:1.5 to
7:3) with flow rate 10 ml/min to obtain four subfractions Bu3–1 to
Bu3–4. Subfraction Bu3–2 (180 mg) was further purified over MPLC
with 10% MeOH-H
2
SO
4
and/or Liebermann–Burchard reagents, fol-
◦
lowed by heating for 5 min at 105 C. Acetylthiocholine iodide (ACTI)
was purchased from Tokyo Chemical Industry (Tokyo, Japan). Galant-
amine hydrobromide and AChE from Electrophorus electricus (elec-
triceel), 518 U/mg, was purchased from Sigma (St. Louis, MO, USA).
system with flash column RP-C18 (40
system of H
ative HPLC column (Zorbax Extend-C18 PrepHT, 21.2×150 mm, 5
connected to MPLC system using H O-MeOH (4:1) with flow rate 5 ml/
μM, 4 g) eluted with an isocratic
2
O-MeOH (4:1) followed by final purification over prepar-
m)
μ
2
′
Ellman's reagent, 5,5 -dithiobis[2-nitrobenzoic acid] (DTNB), was ob-
min as an eluent to obtain compounds 14 (4.3 mg) and 15 (4.1 mg).
tained from Wako company (Osaka, Japan).
Fraction Bu4 (3.5 g) was fractionated over Biotage using RP-C18
μ
2
flash column (30 m, 30 g, 25 mL/min) flushed with H O-ACN (98:2
2
.2. Plant material
to1:1) to afford eleven subfractions (Bu4–1 to Bu4–11). Subfraction
Bu4–10 (402 mg) was chromatographed over MPLC system connected to
The flowering aerial parts of B. indica were collected from desert
μ
2
two flash columns RP-C18 (40 m, each 4 g) using H O-ACN (4:1 to 1:1)
areas south of Egypt (Cairo-Assiut desert road) in September 2019. The
plant was identified by Prof. Ibrahim A. El-Garf, Department of Botany,
Faculty of Science, Cairo University, Egypt. A voucher specimen (BIC-
to obtain three subfractions (Bu4–10-1 to Bu4–10-3). Subfractions
Bu4–10-2 (200 mg) was purified over an open column packed with
reversed phase silica (38–63
(7:3) to obtain 16 (11.5 mg) and 17 (12 mg).
μ
m, 1×50 cm) and eluted with H
2
O-ACN
2
019) was prepared and deposited at the herbarium of Pharmacognosy
Department, Faculty of Pharmacy, Al-Azhar University, Egypt.
2

A. Othman et al.
Fitoterapia 152 (2021) 104907
2
.3.1. Kaempferol-3-O-β-D-glucopyranosyl-(1→6)-O-[β-D-
B (50 mM Tris HCl, PH = 8, 0.1 M NaCl, 0.02 M MgCl2⋅6H2O), 50
buffer A (50 mM Tris-HCl, PH 8, 0.1% BSA) and 25 L of tested com-
pounds in concentration ranges from 1 to 250 g/mL (dissolved in 25%
μ
L of
galactopyranosyl-(1→3)-2-O-trans-feruloyl-
β-D-glucopyranoside (14)
α
-L-rhamnopyranosyl-(1→2)]-
μ
μ
2
5
-30.06 (c 0.02, MeOH); H and 13C NMR data,
1
Yellow needles; [
α]
D
DMSO) were allowed to react followed by measuring the absorbance
with a microplate reader (Biotek, Winooski, VT, USA) at 405 nm.
ꢀ
see Table 1; HRESIMS m/z 1093.3028 [M-H] , (calcd. for C49
H
57
O
28
,
1
093.3036).
Moreover, 25 L of AChE (0.25 U/mL in buffer A) was added and the
μ
absorbance was detected again. A solution of 25% DMSO was used as a
negative control. To exclude any increase in absorbance due to the
colored compounds or spontaneous hydrolysis of the substrate, the
absorbance before addition of the enzyme was subtracted from the
absorbance after adding the enzyme.
′
2
.3.2. 3-O-[2 -(2"-O-glycolyl)-glyoxylyl-β-D-glucuronopyranosyl]-28-O-
β-D-glucopyranosyl-olean-12-en-3β-ol-28-oic acid (16)
1
13
White powder; H and C NMR data, see Table 2; HR-ESI-MS m/z
ꢀ
9
25.4428 [M-H] (calcd. for C46
H
70
O
19 925.4433).
′
′
′
′
2
.3.3. (2 R,3 S)-3-O-[2 -hydroxy-3 -(2"-O-glycolyl)-oxo-propionic acid-
3. Results and discussion
β-D-glucuronopyranosyl]-28-O-β-D-glucopyranosyl-olean-12-en-3β-ol-28-
oic acid (17)
Phytochemical investigation of the aqueous methanol extract pre-
pared from the dried aerial parts of B. indica resulted in isolation of new
acylated flavonol tetraglycoside (14), alongside with a rare flavonol
triglycoside (15) and two rare triterpene seco-glycosidic oleanane sa-
ponins having a unique acetal-linked dicarboxylic acid substitution (16,
White powder; 1H and 13C NMR data, see Table 2; HR-ESI-MS m/z
ꢀ
9
55.4538 [M-H] (calcd. for C47
H
71
O
20 955.4539.
2
.4. Acid hydrolysis
1
7), in addition to 13 known compounds. The isolated compounds were
One milligram of each compound 14, 15, 16, and 17 was subjected
categorized into steroid, phenolic acids, phenolic glycoside, dihydrox-
ycoumarin, nucleic acids, flavonol aglycone, flavonol glycosides, and
oleanane saponins. The structures of isolated compounds (Fig. 1) were
◦
to acid hydrolysis by 2 M HCl in water (0.5 mL) and refluxed at 95 C for
h. Neutralization of the reaction mixture was performed by addition of
NH OH, then EtOAc was added four times to extract the aglycone, hence
2
1
elucidated based on different spectroscopic measurements including H,
4
1
3
sugars were remained in the aqueous solution. The aqueous solution was
then lyophilized and freeze dried to obtain a residue. The residue was
then dissolved in a few drops of MeOH and used for identification of the
sugar moiety by comparison with authentic sugar samples.
C, APT, HSQC, HMBC, COSY NMR and HR-MS analysis.
3
.1. Determination of isolated compounds
Structures of the known compounds were determined by comparison
2
.5. Anticholinesterase assay
of their NMR data with those reported in the literature and they were
identified as β-sitosterol (1) [27], vanillic acid (2) [28], o-hydrox-
ybenzoic acid (3) [29], p-hydroxybenzoic acid (4) [30], 6,7-dihydroxy-
coumarin (5) [31], methyl caffeate (6) [32], caffeic acid (7) [33],
quercetin (8) [34], uracil (9) [35], thymidine (10) [36], tachioside (11)
[37], isorhamnetin-3-O-β-D-glucoside (12) [38], kaempferol-3-O-ruti-
noside (13) [39].
The isolated compounds (1–17) were evaluated for their AChE
inhibitory effect by the in vitro spectrophotometric method of Ellman's
assay in 96-well plate [26]. AChE has the ability to hydrolyze the sub-
strate acetylthiocholine iodide resulting in the product thiocholine
which is then reacts with Ellman's reagent [5,5-dithiobis-(2-nitrobenzoic
acid), DTNB] to produce a yellow colored 5-thio-2-nitrobenzoate which
can be detected at 405 nm. Galantamine was used as a positive control.
Compound 14 was isolated as yellow needles. The optical rotation of
2
5
14 was [
α
]
D
-30.06 (c 0.02, MeOH). In HR-ESI-MS (Fig. S1), the mo-
28 based upon the
In a 96-well plate, 25
μL of 15 mM ACTI, 125
μL of 3 mM DTNB in buffer
lecular formula of 14 was deduced to be C49H O
58
Table 1
1
13
6
H (600 MHz) and C (150 MHz) NMR data of 14 (in DMSO‑d ).
No.
Aglycone
δ
H
(J in Hz)
δ
C
No.
δ
H
(J in Hz)
δ
C
No.
δ
H
δ
C
•
1
2
3
4
5
6
7
8
9
1
1
2
3
4
•
•
1
2
3
4
5
6
α
-L-rhamnopyranoside
• Feruloyl moiety
′
′
′
′
′
′
′′
′′′′′′
–
–
–
–
–
5.11 brs
99.8
72.3
84.5
72.3
68.6
18.1
1
–
126.2
111.7
148.3
149.5
115.7
122.9
115.9
144.8
166.2
56.1
′′
′′
′′
′′
′′
′′′′′′
156.9
133.2
177.8
161.7
99.1
4.84 t (8.6)
2
7.14 brs
′′′′′′
3.68 m
3
–
–
′′′′′′
3.04 m
4
′′′′′′
3.17 m
5
6.72 d (8.3)
6.96 brd
6.34 d (15.6)
7.43 d (15.6)
–
′′′′′′
6.17 d (1.6)
0.93 d (6.2)
6
′
′′′′′
–
164.4
94.1
• β-D-glucopyranoside
7
8
9
′
′
′
′′′
′′′
′′′
′′′′′′
′′′′′′
6.34 d (1.6)
1
2
3
4
5
6
4.30 d (7.6)
3.20* m
100.9
70.8
68.9
76.9
75.9
61.1
–
156.8
104.4
121.5
131.3
115.7
160.2
0
–
3.40 m
O-Me
3.78 s
′
′′′′
′′′′
′′′′
–
3.51* m
′
′
′
, 6
7.91 d (8.7)
6.89 d (8.7)
–
3.28 m
′
′
, 5
3.51–3.70 m
• β-D-galactopyranoside
′
′′′′
β-D-glucopyranoside
1
2
3
4
5
6
4.27 d (7.6)
3.03–3.33* m
3.33–3.40* m
3.18 m
103.5
70.7
77.4
68.7
76.8
61.5
′
′
′
′
′
′
′
′
′
′
′′′′′
′′′′′
′′′′′
′′′′′
′′′′′
1
2
3
4
5
5.59 d (7.6)
97.9
80.1
76.6
70.4
73.7
3.51 m
3.67 m
3.74 m
3.01 m
3.70* m
3.77 m
3
.83 m
′
′
6
3.57 m
66.5
3
.18 m
1
1
–
Chemical shifts are recorded in ppm, coupling constants (J) are given in Hz. The assignments were determined based on HSQC, HMBC, and H
*) refers to overlapped signals.
H COSY experiments.
(
3

A. Othman et al.
Fitoterapia 152 (2021) 104907
Table 2
signals resonated at δ
H
5.59 d (J = 7.6 Hz), 5.11 brs, 4.30 d (J = 7.6 Hz),
1
13
H (600 MHz) and C (150 MHz) NMR data of 16 and 17 (in D
2
O-Pyridine‑d
5
).
4.27 d (J = 7.6 Hz), in addition to signals at δ 3.05–4.84 for sugar
H
protons.
1
6
17
The 13C NMR (Table 1 and Fig. S3) of 14 exhibited 49 carbon reso-
nances that categorized into two methyls (one methoxy and one methyl
of rhamnose), 3 methylenes, 29 methines, and 13 quaternary carbon
No.
δ
H
(J in Hz)
δ
C
δ
H
(J in Hz)
δ
C
1
2
3
4
5
6
7
8
9
0.85 m
38.3
25.2
89.6
37.7
54.9
17.5
32.9
41.1
48.6
35.8
22.8
122.1
143.2
45.4
29.6
22.3
45.4
40.6
46.4
31.5
32.0
32.2
27.2
15.9
14.5
16.4
25.1
177.3
32.2
22.7
1.16 m
39.2
25.7
90.0
38.7
55.3
17.9
36.3
41.6
47.4
38.1
23.2
122.6
143.6
45.8
29.0
22.8
46.9
41.2
46.4
32.5
30.1
36.2
27.6
16.3
14.9
16.8
25.6
177.8
32.6
23.1
1.64 m, 1.93 m
1.73 m, 1.92 m
signals, as confirmed with the aid of HSQC experiment (Fig. S4). Ac-
3.11 dd (3.5, 11.6)
3.10 dd (3.5, 11.6)
1
cording to HSQC data, the four anomeric protons were detected in
H
–
–
0.46 brd
–
0.45 d (11.7)
–
NMR spectrum and found to be correlated with corresponding carbons
.59 d / 97.9, 5.11 brs / 99.8, 4.30 d / 100.8, 4.27 d / 103.5. Further-
18.1 indicated a rhamnose
5
1.15 m
–
–
–
1.14 m
–
–
–
more, one doublet proton at δ
H
0.93, δ
C
1
13
moiety. The H and C NMR spectral data as well as comparison with
previously published data exhibited a kaempferol glycoside [40,41].
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The 13C NMR also exhibited a methoxylated carbon signal at δ
56.1,
61.2–84.5 ppm. The
presence of feruloyl moiety with trans-geometry was deduced basically
from tow olefinic doublets δ 6.34 and δ 7.43 which were correlated
with carbons at δ 115.9 and 144.8 respectively.
The HMBC correlations (Fig. 2 and Fig. S5) of anomeric proton at δ
.59 and C-3 (δ 133.2) confirmed the glycosidic linkage at C-3 of the
1.55 m
5.14 brs
–
1.59 m
5.14 brs
–
C
alongside with glycoside carbon signals at δ
C
–
–
1.25 m
1.82 m
_____
1.24 m
1.83 m
–
H
H
C
H
2.82 m
1.22 m
–
2.83 m
1.22 m
–
1.05 m
1.53 m
1.01 s
0.77 s
0.59 s
0.72 s
0.75 s
_____
5
C
aglycone. Other HMBC and HSQC correlations revealed that the β-D-
glucopyranosyl sugar was the primary O-linked sugar at C-3. HMBC
1.05 m
1.53 m
1.01 s
0.77 s
0.59 s
0.72 s
0.75 s
–
′
′
cross peaks of anomeric protons at δ
H
5.11 and δ
H
4.30 with C-2 (δ
84.5
C
′′
8
0.1) and C-6 (δ
C
66.5), respectively. The deshielded signal at δ
C
′
′′
of C-3 of rhamnose moiety suggested that another sugar monomer is
′
′′′′
linked there, which was then confirmed by HMBC correlations of H-1
′
′′
(δ
H
4.27) with C-3 . Moreover, a feruloyl moiety was proved to be
′′′
attached at H-2 of rhamnose moiety as HMBC correlation was detected
0.94 s
0.71 s
0.94 s
0.71 s
between downfielded triplet proton observed at δ
group of the feruloyl moiety at δ 166.2. Additionally, long range HMBC
correlation between δ 6.34 (H-7'''''') and carbonyl group (C-9'''''') at δ
66.2 clearly confirmed the feruloyl moiety.
The sugar moieties were determined through the total acid hydro-
H
4.84 and carbonyl
C
3
-O-β-D-glucuronic acid
3-O-β-D-glucuronic acid
H
C
′
′
′
′
′
′
1
2
3
4
5
6
4.67 d (7.5)
3.84 m
3.97 m
3.82 m
4.05 m
–
104.5
73.6
84.4
72.1
76.9
175.2
4.68 d (7.5)
105.1
1
3.84 m
74.1
83.5
71.6
76.7
174.4
4.03 dd (9.5, 11.5)
3.82 m
lysis followed by examinations over TLC with authentic sugar samples
that indicated the presence of glucose, rhamnose, and galactose. Hence,
the absolute configuration of sugars has been determined as β- for
4.04 m
–
Substitution at C-3 of glucuronic
Substitution at C-3 of glucuronic
glucose and galactose and -for rhamnose [42,43]. Accordingly, from
α
acid
acid
the above mentioned data, 14 was identified as kaempferol-3-O-β-D-
glucopyranosyl-(1→6)-O-[β-D-galactopyranosyl-(1→3)-2-O-trans-fer-
′
′
′
′
′
′
1
2
3
–
174.4
101.4
66.4
–
177.6
74.1
5.43 s
4.58 d (2.5)
5.50 d (2.5)
uloyl-
α-L-rhamnopyranosyl-(1→2)]-β-D-glucopyranoside.
4.56 d (14.8)
104.9
4
.45 d (15.2)
Compound 15 was obtained as yellow powder. It is a rare flavonol
triglycoside as it has been reported previously only from Allium neapo-
litanum [44]. Hence, 15 was isolated and elucidated through comparing
the published NMR data [44] with our data, as well as HR-ESI-MS
′
′
′
4
5
–
177.1
4.70 d (15.5)
68.12
177.9
4
.40 d (15.4)
′
–
–
–
2
8-O-β-D-glucopyranoside
28-O-β-D-glucopyranoside
42 21
analysis (Fig. S7), and its molecular formula deduced to be C34H O
′
′
′
′
′
′
′′
′′
′′
′′
′′
′′
1
2
3
4
5
6
5.74 d (8.1)
94.2
71.1
69.4
77.0
77.0
60.6
5.73 d (8.2)
3.80 m
3.90 m
3.78 m
3.69 m
4.03 m
3.95 m
94.7
71.2
69.9
77.3
77.6
61.1
based upon the molecular ion peak in negative ion mode at m/z
3.80 m
ꢀ
785.2136 [M-H] , (calcd. for C34
H
41
O
2
785.2140). Consequently, 15
3.90 m
3.78 m
was identified as isorhamnetin-3-O-β-D-glucopyranosyl-(1→6)-O-[
α
-L-
3.69 m
rhamnopyranosyl-(1→2)]-β-D-glucopyranoside.
4.07 m
Compound 16 was obtained as white powder. Its molecular formula
3
.97 dd (6.6, 13.8)
was established by HR-ESI-MS (Fig. S13) to be C46
H
69
O
19 from the [M-
ꢀ
1
Chemical shifts are recorded in ppm, coupling constants (J) are given in Hz. The
H] ion at m/z 925.4428 (calcd. for C46
H
O
19 925.4433). The H NMR
70
1
1
H– H COSY
13
assignments were determined based on HSQC, HMBC, and
experiments.
(
(
Table 2 and Fig. S14), C NMR (Table 2 and Fig. S15), and HSQC
Fig. S16) spectra of 16 showed characteristic pattern for oleanolic acid
aglycone, seven tertiary methyl signals at δ
H
0.59 (H-25), 0.71 (Hꢀ 30),
ꢀ
molecular ion peak at m/z 1093.3028 [M-H] , (calcd. for C49
H
57
O
28
0.72 (H-26), 0.75 (H-27), 0.77 (H-24), 0.94 (H-29), 1.01 (Hꢀ 23),
1
093.3036). The 1H, C, HSQC, HMBC, 1
13
H
–1H COSY NMR spectra
olefinic proton at δ 5.14 (brs, H-12), in addition to two olefinic carbons
H
confirmed the presence of flavonol moiety, four sugar moieties, in
addition to feruloyl moiety. The 1H NMR spectrum (Table 1, Fig. S2)
showed several characteristic signals, one broad singlet aromatic proton
at δ 122.1, δ 143.2, and carbonyl signal at δC 177.3, which are char-
C
C
13
acteristic for triterpene oleanane aglycone [45,46]. The C NMR
spectrum exhibited seven methyls, twelve methylene, sixteen methine,
eleven quaternary carbons. The HSQC correlations of δH 5.74 (d, J = 8.1
Hz) and δH 4.67 (d, J = 7.5 Hz) with δ 94.2 and δ 104.5 confirmed the
at δ
d (J = 1.6 Hz), 7.91 d (J = 8.7 Hz), 6.89 d (J = 8.7 Hz), 6.72 d (J = 8.3
Hz), 6.96 brd (J = 8.5 Hz), two doublet olefinic protons at δ 6.34 d (J =
5.6 Hz), 7.43 d (J = 15.6 Hz), one singlet aromatic methoxyl proton at
3.78 s, and one doublet aliphatic methyl signal at δ 0.93 d (J = 6.2
Hz). Sugar moieties were identified by the presence of four anomeric
H
7.14, six doublet aromatic protons at δ
H
6.17 d (J = 1.6 Hz), 6.34
C
C
H
presence of two sugar monomers. HMBC cross peaks (Fig. 3 and
1
Fig. S17) of anomeric protons at δ 5.74 with δC 177.3 (C-28), δH 4.67
H
′
δ
H
H
with δC 175.2 (C-6 ) and δ 89.6 (C-3) revealed that two sugars, β-D-
C
glucose and β-D-glucuronic acid, were linked to C-28 and C-3,
4

A. Othman et al.
Fitoterapia 152 (2021) 104907
Fig. 1. Chemical structure of isolated compounds (1–17).
respectively. The deshielded signal at δ
′
C
84.4 of C-3 indicated that
another side chain is linked there, which was then proved by HMBC
′
′
′
′′
correlations of δ
H
5.43 (H-2 ) with δ
C
84.4 (C-3 ) and δ
C
66.4 (C-3 ). The
′
suggested seco-glycosidic dicarboxylic substitution at C-3 was further
confirmed by HMBC correlations of two protons at δ
H
4.56 (d, J = 14.8
′
′
′′
Hz), δ
H
4.45 (d, J = 15.2) with δ
C
101.4 (C-2 ) and 177.1 (C-4 ).
′
Finally, from the above-mentioned data, 16 was identified as 3-O-[2 -
′
′
(
2 -O-glycolyl)-glyoxylyl-β-D-glucuronopyranosyl]-28-O-β-D-glucopyr-
anosyl-olean-12-en-3β-ol-28-oic acid. It was found in a good agreement
with the isolated one in literature [47] and herein we report 16 as a
rarely occurring seco-glycosidic oleanane saponin and the hypothesis of
biosynthetic pathway of this compound is supported in supplementary
data (Fig. S25).
Compound 17 was obtained as white powder. The HR-ESI-MS
ꢀ
spectrum (Fig. S19) of 17 displayed a [M-H] ion at m/z 955.4538
(
calcd. for C47
lished to be C47
displayed seven methyl signals at δ
H
71
O
20 955.4539), hence the molecular formula estab-
20. The 1H and APT NMR (Table 2) spectra of 17
0.59 (H-25), 0.71 (H-30), 0.72 (H-
H
72
O
H
Fig. 2. Key HMBC
and COSY
correlations of compound 14.
5

A. Othman et al.
Fitoterapia 152 (2021) 104907
Fig. 3. Key HMBC
and COSY
correlations for 16 and 17.
2
3
1
1
6), 0.75 (H-27), 0.77 (H-24), 0.94 (H-29), 1.01 (H-23), one signal at δ
H
Table 3
Anticholinesterase activity (IC50) of isolated compounds (1–17) from B. indica
.10 (dd, J = 3.5, 11.5 Hz, H-3), one olefinic proton at δ
2), two olefinic carbons at δ
77.8 indicating a triterpene oleanane aglycone [45,46,48]. The signals
4.58 (d, J = 2.5 Hz), δ 5.50 (d, J = 2.5 Hz), δ 4.70 (d, J = 15.5
Hz), and δ
H
5.14 (brs, H-
a
C
122.6 and 143.6, and carbonyl signal at δ
C
Compound
IC50
(μg/mL)
at δ
H
H
H
1
2
3
4
5
6
7
8
9
55.8 ± 3.8
4.40 (d, J = 15.4) revealed the presence of oxo-propionic
88.3 ± 1.10
H
> 250 g (48.5%)*
μ
acid and glycolyl moieties. The APT NMR and HSQC data exhibited
the presence of 47 carbon signals including seven methyls, twelve
methylene, seventeen methine, eleven quaternary carbons. The HSQC
203.2 ± 4.5
3.6 ± 0.07
b
NA
correlations (Fig. S22) of δ
Hz) with δ 94.7 and δ 105.1 revealed the presence of two anomeric
H
5.73 (d, J = 8.2 Hz) and δ
H
4.68 (d, J = 7.5
112.9 ± 3.08
18 ± 1.3
C
C
NA
carbons for two sugar monomers, which is in a good agreement with the
1
1
0
1
45.7 ± 0.57
>250 (26%)*
93.2 ± 1.2
27.9 ± 0.8
>250 (40.6%)*
>250 (35%)*
63.1 ± 1.5
29.6 ± 1.7
12.5 ± 0.6
published data for very related saponin compounds in the literature
′
[
48]. The deshielded carbon signal at δ
C
83.5 of C-3 of glucuronic acid
12
13
14
suggested that another side chain is linked there, where the HMBC
′
correlations (Fig. 3 and Fig. S23) of δ
confirmed the acetal-linked dicarboxylic acid substitution at C-3 .
H
5.50 with δ
C
83.5 (C-3 )
1
1
1
5
6
7
′
Moreover, the seco-glycosidic acetal-linked substitution moiety was
′′
proved by other HMBC correlations of H-2 at δ
H
4.58 with δ
C
177.6 (C-
Positive control
(Galantamine)
′
′
′′
1
4
3
) and δ
C
104.9 (C-3 ), in addition to the correlations of protons at δ
H
′′
a
.70, δ
H
4.40 (H-4”a and H-4”b) with δ
). The two stereocenters of the 2 and 3 positions of seco-glycosidic
C
177.9 (C-5 ) and δ
C
104.9 (C-
The results are presented as the mean ± SD of values (n = 3). *Inhibitory
′′
′′
′′
b
activity expressed at a concentration 250
obtained at tested concentration.
μ
g/mL. NA means there is no activity
substitution were assigned to be R and S, respectively, based on com-
parison of the detailed NMR data with the related dimethyl ester de-
rivative previously published in the literature [49]. Based upon all the
′
′
′
above-mentioned evidences, 17 was elucidated as (2 R,3 S)-3-O-[2 -hy-
′
′′
droxy-3 -(2 -O-glycolyl)-oxo-propionic acid-β-D-glucuronopyranosyl]-
distributed in variety of foods and their daily intake with food has no
adverse effects [51]. As a result, the phenolic derived phytoconstituents
should be considered for the dietary prevention of AD.
2
8-O-β-D-glucopyranosyl-olean-12-en-3β-ol-28-oic acid.
As a comprehensive interpretation in this study, flavonoids as
quercetin (8) and similar flavonoids in aglycone form showed marked
inhibitory activity against AChE. Also, some flavonoid glycosides have
been reported for their activity against AChE. In our study, flavonoid
glycosides (12 and 13) exerted marked inhibitory activity, whereas the
activity is dramatically reduced with the presence of more sugar resi-
dues in the molecule as in compounds 14 and 15. The activity of
phenolic acids toward AChE was dependent mainly on the number and/
or position of OH groups and propenoic acid side chain. For instance, the
isolated compound 2 showed a relatively high activity in comparison
with 3 and 4. Also, compound 5 with catechol and cyclized pyrone
moieties showed potent inhibitory activity against AChE. In the litera-
ture, it was reported that the presence of propenoic (CH=CH-COOH)
group (caffeic acid) has a significant effect on the activity toward AChE
compared with CH -CH -COOH (hydrocaffeic acid) or COOH groups
3
.2. Anticholinesterase activity
Acetylcholine is the main neurotransmitter, responsible for cholin-
ergic signaling in the brain. Therefore, phytochemical constituents
which inhibit acetylcholinesterase (AChE) and restore acetylcholine
levels are highly targeted for treating symptoms of Alzheimer's disease
(
AD). In this context, the isolated compounds (1–17) were tested in vitro
for their AChE inhibitory activity (Table 3).
Among the isolates, compounds 5, 8, 13, and 17 exhibited significant
inhibitory activity toward acetylcholinesterase enzyme with IC50 3.6,
1
8, 27.9, 29.6
galantamine (12.5
and 12 exerted marked inhibitory activity with IC50 45.71, 55.8, 63.11,
8.3, 93.2 g/mL, respectively.
It was reported previously that phenolic acids and flavonoids are
μ
g/mL, respectively, compared to the standard drug
μg/mL). On the other hand, compounds 10, 1, 16, 2,
8
μ
2
2
(protocatechuic acid). Besides, the methylation of caffeic acid will lead
to a marked decline in the inhibitory activity [52].
capable to reduce the oxidative stress and consequently they are
considered as potential lead compounds for development of cholines-
terase inhibitor drugs that can be used for treatment of AD [50]. Hence,
the plant phenolic constituents can play an important role in the
improvement of cognitive symptoms and help to protect against
neurodegenerative disorders. Additionally, the phenolic acids have
some benefits over the well-known inhibitors as they are commonly
4. Conclusion
In summary, natural plants have long been regarded as useful source
of lead compounds for fighting various chronic diseases including AD.
6

A. Othman et al.
Fitoterapia 152 (2021) 104907
Owing to the lack of efficacy and severe side effects associated with the
current therapies for AD treatment, there is an urgent need for newer
molecules that are capable of inhibiting the acetylcholinesterase enzyme
for the treatment of AD.
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