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Molecules 2021, 26, 4664. https://doi.org/10.3390/molecules26154664 www.mdpi.com/journal/molecules
Review
The Genus Haplophyllum Juss.: Phytochemistry and
Bioactivities—A Review
Majid Mohammadhosseini
1,
*, Alessandro Venditti
2
, Claudio Frezza
3,
*, Mauro Serafini
3
,
Armandodoriano Bianco
2
and Behnam Mahdavi
4
1
Department of Chemistry, College of Basic Sciences, Shahrood Branch, Islamic Azad University, Shahrood,
Iran
2
Dipartimento di Chimica, Università di Roma “La Sapienza”, Piazzale Aldo Moro 5, 00185 Rome, Italy;
alessandro.venditti@gmail.com (A.V.); armandodoriano.bianco@fondazione.uniroma1.it (A.B.)
3
Dipartimento di Biologia Ambientale, Università di Roma “La Sapienza”, Piazzale Aldo Moro 5, 00185
Rome, Italy; mauro.serafini@uniroma1.it
4
Department of Chemistry, Faculty of Science, Hakim Sabzevari University, Sabzevar, Iran;
behnammahdavi@yahoo.com
* Correspondence: majidmohammadhoseini@gmail.com (M.M.); claudio.frezza@uniroma1.it (C.F.)
Abstract: Herein, a comprehensive review is given focusing on the chemical profiles of the essential
oils (EOs), non-volatile compounds, ethnobotany, and biological activities of different Haplophyllum
(Rutaceae family) species. To gather the relevant data, all the scientific databases, including Scopus,
ISI-WOS (Institute of Scientific Information-Web of Science), and PubMed and highly esteemed
publishers such as Elsevier, Springer, Taylor and Francis, etc., were systematically retrieved and
reviewed. A wide array of valuable groups of natural compounds, e.g., terpenoids, coumarins,
alkaloids, lignans, flavonoids, and organic acids have been isolated and subsequently characterized
in different organic extracts of a number of Haplophyllum species. In addition, some remarkable
antimicrobial, antifungal, anti-inflammatory, anticancer, cytotoxic, antileishmanial, and antialgal
effects as well as promising remedial therapeutic properties have been well-documented for some
species of the genus Haplophyllum.
Keywords: Haplophyllum Juss. genus; Rutaceae; phytochemistry; chemotaxonomy; ethnobotany;
bioactivities
1. Introduction
It is evident that herbal and medicinal plants play a vital role on the life of human
beings and have unique compartment in their lifestyles. Over the past few decades, a large
number of scientific investigations have been carried out on a wide spectrum of herbal
plants and these attempts have led to the isolation of a large number of valuable natural
compounds in different plant species [1,2]. In reality, medicinal plants are used in
different scientific disciplines, from food industries to the fragrance and cosmetics
domain, to different medicinal and pharmaceutical approaches [3,4].
Haplophyllum Juss. is a genus of plant species belonging to the Rutaceae family and
comprises 160 species of which only two are accepted, i.e., Haplophyllum dauricum (L.) G.
Don and Haplophyllum suaveolens Ledeb., whereas fifty species are considered to be
synonyms and one hundred and eight are unresolved names [5].
The etymology of the name derives from the union of two Greek words, απλοũς
(haplous), meaning simple, and φύλλον (phýllon), meaning leaf in the sense of a simple
leaf. These terms refer to the fact that the species belonging to this genus are characterized
by non-composite leaves.
Citation: Mohammadhosseini, M.;
Venditti, A.; Frezza, C.; Serafini, M.;
Bianco, A.; Mahdavi, B. The Genus
Haplophyllum Juss.: Phytochemistry
and Bioactivities—A Review.
M
olecules 2021, 26, 4664.
https://doi.org/10.3390/
molecules26154664
Academic Editors: Ioannis P.
Gerothanassis, Muhammad Iqbal
Choudhary, Hina Siddiqui
Received: 30 June 2021
Accepted: 28 July 2021
Published: 31 July 2021
Publisher’s Note: MDPI stays
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Copyright: © 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license
(http://creativecommons.org/licenses
/by/4.0/).
Molecules 2021, 26, 4664 2 of 40
From a botanical standpoint, these species appear mainly as perennial herbs even if
low shrubs also exist. They present cymose and bracteate inflorescences, with petals being
variably colored from light white to bright yellow. They have ten stamens and have free
filaments which are widely expanded below and are pubescent on the inner surface
(Figure 1) [6].
Figure 1. The photographs of Haplophyllum suaveolens Ledeb.
The distribution area of this genus is quite wide, ranging from Morocco and Spain to
China and passing through Romania, Somalia, Turkey, Iran, and Central Asia [6].
Additionally, many relevant species are endemic and some even occur in small, unlinked
populations. In particular, the latter characteristics concern the Iranian and Central Asian
species, and, for this reason, the genus is locally and partially considered to be very
susceptible to extinction [7].
In the present review article, we aimed to cover and discuss the available
phytochemical knowledge involving the composition of the chemical profiles of
Haplophyllum’s essential oils (EOs) as well as the characterized non-volatile compounds
and their relevant biological activities. This work represents an updating, an extension, as
well as a partial modification of the work by Prieto et al. [8] on the phytochemistry and
bioactivities of the same genus. To collect the corresponding data, Scopus (date of access:
20 January 2021 and revisited on 06 June 2021), PubMed (date of access: 10 January 2021
and revisited on 05 June 2021), ISI-WOS (date of access: 21 January 2021 and revisited on
05 June 2021), and a number of published reports dealing with different aforementioned
aspects were carefully studied. The keywords used for this research were Haplophyllum,
phytochemistry, ethnobotany, ethnopharmacology, pharmacology, and biological
activities, in combination between Haplophyllum and the rest of the mentioned keywords,
one by one. The systematic research was also conducted considering all the accepted or
unresolved names of Haplophyllum species, as reported in www.theplantlist.org (accessed
date 24 June 2021) [5], alone or in combination with the previous terms, one by one. All
the Haplophyllum species, now taxonomically considered to be synonyms of other species,
as reported in www.theplantlist.org [5], were not taken into consideration for this review.
In any case, all the existing works, abiding by these rules, were inserted in spite of the
years or types of publications.
2. Phytochemistry
The Haplophyllum species have been studied for their phytochemical constituents that
regard both the EOs and the polar fraction metabolites.
2.1. Essential oils of Haplophyllum species
EOs could be defined as hydrophobic liquid mixtures usually having a lower density
of water and comprising versatile natural compounds that are separated using different
approaches, e.g., expression, cold press, water-distilled extraction, steam distillation, and
numerous microwave-based techniques [9–11]. Within the past few decades, EOs have
gained much attention due to their widespread uses in a variety of phytochemical,
biological, medicinal, pharmaceutical, and food disciplines as well as in the flavour and
Molecules 2021, 26, 4664 3 of 40
fragrance industry [12,13]. In fact, a large number of reports could be found in the
literature highlighting the remarkable potential use of EOs for a wide spectrum of
applications [14,15]. Similar to many other herbal genera, Haplophyllum species are
considered as valuable sources of secondary metabolites such as EO components.
According to the literature, a large number of reports have argued the chemical profiles
of the EOs obtained from different organs of Haplophyllum species. Table 1 displays the
main compounds identified in the EOs of different Haplophyllum species.
Table 1. Main volatile constituents from different species of Haplophyllum genus worldwide.
Plant species Main components (%) OY a
Identified
compoundsDominant
group
Extraction
method
Analysis
method
Studied
organs Country Reference
Nr. %
H. acutifolium
(DC.) G. Don
α-Cadinene (25.1%), β-
cedrene (19.1%), sabinene
(8.1%), terpinen-4-ol
(5.7%), and 8,14-
cedranoxide (5.5%)
0.1 92 97.7 SH
b CHD
c GC, GC-
MS
Aerial
parts Iran [16]
H. buhsei Boiss.
β-Caryophyllene (12.9%),
limonene (9.7%), β-pinene
(7.9%), linalool (7.4%), α-
pinene (6.4%), and
1,8-cineole (5.5%)
0.35 36 92.2 MH
d CHD
GC, GC-
MS FAP e Iran [17]
H. furfuraceum
Bunge
Elemol (11.7%), β-
eudesmol (10.1%), 1,8-
cineole (9.3%), α-pinene
(8.5%), β-pinene (7.7%),
caryophyllene oxide
(5.9%), and p-cymene
(5.2%)
0.35 33 98.1 MH∼OS g CHD GC, GC-
MS
Aerial
parts Iran [18]
H. glaberrimum
Bunge
Myrcene (52.9%), elemol
(10.6), and β-caryophyllene
(8.9%)
0.08 10 93.9
MH CHD
GC, GC-
MS
Leaves
Iran [19]
Myrcene (65.1%), α-thujene
(5.4%), and trans-β-
ocimene (4.7%)
0.14 16 96.9 Aerial
parts
H. laeviusculum
C. C. Towns.
β-Pinene (20.1%), α-
phellandrene (11.7%), β-
caryophyllene (7.6%),
myrcene (6.8%), linalool
(6.1%), and limonene
(5.6%)
NA h 36 95.7 MH CHD GC, GC-
MS FAP Iran [20]
H. lissonotum
C.C. Towns.
Caryophyllene oxide
(26.9%), β-caryophyllene
(12.2%), humulene epoxide
II (8.3%), α-caryophyllene
(7.2%), and caryophylla-
4(14),8(15)-dien-5β-ol
(7.1%)
0.23 50 88.5 OS CHD GC, GC-
MS
Aerial
parts Iran [21]
H. megalanthum
Bornm.
Palmito-γ-lactone (45.8%),
octadecatrienoic acid
(10.7%), linoleic acid
0.1 58 91.7 NH CHD
GC, GC-
MS FAP Turkey [22]
Molecules 2021, 26, 4664 4 of 40
(6.5%), octadecatetraenoic
acid (6.3%), and
nonacosane (4.8%)
H. myrtifolium
Boiss.
PEE l:
β-Caryophyllene (14.6%),
decane (11.4%), and β-
phellandrene (7.0%)
-
47 69 -
SPME n
GC-MS
Aerial
parts
Turkey
[23]
CEAE m:
Havibetol (21.9%), eugenol
(19.1%), methyl- eugenol
(10.8%), trans-linalool
oxide (7.1%), and β-
cyclocitral (6.0%)
42 83.2 NH
Linalool (12.8%), β-
caryophyllene (10.3%), and
methyl eugenol (5.9%)
NR 97 85.3 - CHD GC-MS
Aerial
parts Turkey [24]
H. perforatum
Kar. & Kir.
Sabinene (52.7%), β-
caryophyllene (10.8%),
(2E,6E)-farnesyl acetone
(10.3%), hexadecanoic acid
(5.1%), β-pinene (5.0%),
and cis-sabinene hydrate
(4.9%)
-
9 95.9 MH
HS-SPME
o
GC, GC-
MS
Flowers
Iran [25]
Sabinene (24.7%), β-
caryophyllene (35.6%),
elemol (17.4%), α-
caryophyllene (4.6%), α-
pinene (4.5%), and 1,8-
cineole (4.3%)
10 99.7 SH Leaves
Sabinene (26.2%), β-
caryophyllene (8.8%),
camphor (7.4%), limonene
(6.3%), elemol (5.0%), β-
phellandrene (4.9%), and
α-pinene (4.6%)
19 81.3 MH Stems
H. robustum
Bunge
Sabinene (30.5%), β-pinene
(18.2%), and limonene
(12.1%)
0.5
23 86.1 MH
CHD
GC-MS
Aerial
parts
Iran
[26]
1,8-Cineole (38.1%),
myrcene (10.7%), α-pinene
(8.5%), terpinen-4-ol
(7.0%), and sabinene (6.1%)
30 99.2
OM p
Whole
plant [27]
cis-Sabinene hydrate
(23.2%), 1,8-cineole
(19.1%), γ-terpinene
(10.3%), limonene (7.3%),
and β-pinene (6.1%)
1.1 13 82.7
GC, GC-
MS
Leaves
[28]
1,8-Cineole (27.7%), γ-
terpinene (12.2%), cis-
sabinene hydrate (11.5%),
0.39 12 82.7 Stems
Molecules 2021, 26, 4664 5 of 40
limonene (11.1%), and β-
pinene (7.7%)
1,8-Cineole (45.1%),
limonene (12.3%), cis-
sabinene hydrate (12.0%),
γ-terpinene (6.7%), and β-
pinene (6.1%)
1.1 11 89.2 Flowers
1,8-Cineole (28.4%),
limonene (13.8%), cis-
sabinene hydrate (12.2%),
γ-terpinene (10.1%), and β-
pinene (8.7%)
2.1 12 83.4 Fruits
1,8-Cineole (38.1%),
myrcene (10.7%), α-pinene
(8.5%), terpinen-4-ol
(7.0%), sabinene (6.2%),
methyl-geranate (4.7%), γ-
terpinene (4.3%), and α-
terpinene (3.4%)
0.5 30 99.2 OM CHD
GC, GC-
MS
Aerial
parts Iran [29]
H. tuberculatum
Juss
Limonene (27.3%), and α-
pinene (21.9%) 0.35 18 79.7 MH CHD
GC, GC-
MS
Aerial
parts Iran [30]
α-Phellandrene (10.7-
32.9%), β-caryophyllene
(6.3-12.8%), β-pinene (7.6-
8.0%), limonene (4.0-9.6%),
and δ-3-carene (5.5-6.0%) q
0.03
23
r
80.2
r
MH
FAPCF
u
United
Arab
Emirates
[31]
29
s
78.7
s
Linalool (15.0%), linalyl
acetate (10.6%), β-
caryophyllene (9.7%), and
α-terpineol (6.7%) t
0.04 28 77.4 OM
β-Phellandrene (23.3%),
limonene (12.6%), β-
ocimene (12.3%), β-
caryophyllene (11.6%),
myrcene (11.3%), and α-
phellandrene (10.9%)
0.21 30 99.7
MH
GC-MS,
13C
NMR
FTF v Oman [32]
Linalool (15.5%), α-pinene
(7.9%), and limonene
(5.3%)
0.02 40 98.1
GC, GC-
MS
Aerial
parts Iran [33]
trans-p-Menth-2-en-1-ol
(19.2%), cis-p-menth-2-en-
1-ol (13.2%), myrcene
(10.1%), δ-3- carene (8.8%),
β-phellandrene (6.9%),
limonene (6.6%), cis-
piperitol (6.4%), piperitone
(4.1%), and trans-piperitol
(4.0%)
NR 37 96.4 OM FAP Saudi
Arabia [34]
Hexadecanoic acid (40.2%)
and oleic acid (26.8%) 1.54 18 93.5 NH Shoots Tunisia [35]
Molecules 2021, 26, 4664 6 of 40
2,4-Bis(1,1-dimethylethyl)-
phenol (28.3%), piperitone
(17. 8%), terpinen-4-ol
(3.2.%), hexadec-1-ene
(3.2%), β-phellandrene
(3.0%), p-cymene-8-ol
(2.9%), (1E,4E)-germacrene
B (2.1%), octadec-1-ene
(2.1%), and α-phellandrene
(2.1%)
0.91 26 82.5 OM
CHD
Aerial
parts Algeria [36]
α-Terpinene (26.4%), β-
terpinene (17.1%), β-
phellandrene (10.4%), γ-
terpinene (9.1%), 3,7-
dimethyl-cyclooctadiene
(6.0%), and myrcene (5.7%)
0.4 24 95.8
MH GC-FID,
GC-MS
Aerial
parts
Egypt [37]
α-Terpinene (24.4%), β-
terpinene (14.4%), β-
phellandrene (10.0%), γ-
terpinene (7.8%), 3,7-
dimethyl-cyclooctadiene
(6.7%), and myrcene (6.0%)
1.5 28 97.0 Flowers
cis-p-Menth-2-en-1-ol
(16.8%), trans-p-menth-2-
en-1-ol (16.2%), trans-
piperitol (12.1%), limonene
(8.1%), piperitone (6.7%) 1-
octyl acetate (5.4%), and
cis-piperitol (4.9%)
NR
32 94.4
OM GG-MS
Leaves
Tunisia [38]
Isobornyl acetate (13.8%),
cis-p-menth-2-en-1-ol
(12.4%), trans-p-menth-2-
en-1-ol (11.2%), trans-
piperitol (9.1%), piperitone
(8.5%), 1-octyl acetate
(7.4%), α-pinene (4.6%),
and cis-piperitol (4.0%)
24 94.3 Stems
Piperitone (9.1%), 1-octyl
acetate (8.8%), cis-p-menth-
2-en-1-ol (8.7%), trans-p-
menth-2-en-1-ol (8.2%),
isobornyl acetate (7.8%),
trans-piperitol (5.5%),
limonene (5.2%), cryptone
(4.5%), and α-pipene
(3.9%)
37 91.3
Leaves
and
stems
H. virgatum
Spach.
2-Nonanone (28.4%), 2-
undecanone (21.5%), 1,8-
cineole (9.5%),
caryophyllene oxide
(6.8%), and linalool
0.2 25 90.5 NH CHD
GC, GC-
MS
Aerial
parts
Iran
[18]
Molecules 2021, 26, 4664 7 of 40
(5.0%)
Valencene (14.6%), β-
pinene (13.1%), limonene
(8.8%), δ-3-carene (8.2%),
aromadendrene
(8.1%) ,and piperitone
(6.8%)
0.3 39 95.9 MH GC-MS [39]
a OY: Oil yield; b SH: Sesquiterpene hydrocarbon; c CHD: Classical hydrodistillation; d MH: Monoterpene hydrocarbon; e
FAP: Flowering aerial parts; f NH: Non-terpene hydrocarbon; g OS: Oxygenated sesquiterpene; h NA: Not available; i
NR: Not reported; j Plants collected in 1994; k Plants collected in 1997; l PEE: Petroleum ether extract; m CEAE:
Chloroform eluate of the alkaloidal extract; n SPME: Solid phase microextraction; o HS-SPME: Head space-solid phase
microextraction; p OM: Oxygenated monoterpene; q Plants collected in May (1997 and 2001); r May (1997); s May (2001); t
Plants collected in April (1998); u FAPIF: Fresh aerial parts, including flowers; v FTF: Fresh twigs and flowers.
Table 2 shows the distribution of the main volatile compounds in the Haplophyllum
spp. essential oils.
Table 2. Distribution of the main volatile phytochemicals in the Haplophyllum genus.
Phytochemical class Phytochemical compound Haplophyllum spp. References
Monoterpene hydrocarbons
α-Phellandrene H. laeviusculum
H. tuberculatum [20,31,32,36]
α-Pinene
H. buhsei
H. furfuraceum
H. perforatum
H. robustum
H. tuberculatum
[17,18,25,27–30,33,38]
α-Terpinene H. robustum
H. tuberculatum [29,37]
α-Thujene H. glaberrimum [19]
β-Ocimene H. tuberculatum [32]
β-Phellandrene
H. myrtifolium
H. perforatum
H. tuberculatum
[23,25,32,34,36,37]
β-Pinene
H. buhsei
H. furfuraceum
H. laeviusculum
H. perforatum
H. robustum
H. tuberculatum
H. virgatum
[17,18,20,25,26,28,31,39]
β-Terpinene H. tuberculatum [37]
γ-Terpinene H. robustum
H. tuberculatum [28,29,37]
δ-3-Carene H. tuberculatum
H. virgatum [31,34,39]
p-Cymene H. furfuraceum [18]
Cis-sabinene hydrate H. perforatum
H. robustum [25,28]
Isobornyl acetate H. tuberculatum [38]
Limonene H. buhsei
H. laeviusculum [17,20,25,26,28–34,38,39]
Molecules 2021, 26, 4664 8 of 40
H. perforatum
H. robustum
H. tuberculatum
H. virgatum
Myrcene
H. glaberrimum
H. laeviusculum
H. robustum
H. tuberculatum
[19,20,27,32,34,37]
Sabinene
H. acutifolium
H. perforatum
H. robustum
[16,25–27,29]
Trans-β-ocimene H. glaberrimum [19]
Non-terpene hydrocarbons
1-Octyl acetate H. tuberculatum [38]
2,4-Bis(1,1-dimethylethyl)-phenol H. tuberculatum [36]
3,7-Dimethyl-cyclooctadiene H. tuberculatum [37]
(2E,6E)-Farnesyl acetone H. perforatum [25]
2-Nonanone H. virgatum [18]
2-Undecanone H. virgatum [18]
β-Cyclocitral H. myrtifolium [23]
Decane H. myrtifolium [23]
Eugenol H. myrtifolium [23]
Havibetol H. myrtifolium [23]
Hexadec-1-ene H. tuberculatum [36]
Hexadecanoic acid H. perforatum
H. tuberculatum [25,35]
Linoleic acid H. megalanthum [22]
Methyl-eugenol H. myrtifolium [23,24]
Methyl-geranate H. robustum [29]
Nonacosane H. megalanthum [22]
Octadec-1-ene H. tuberculatum [36]
Octadecatrienoic acid H. megalanthum [22]
Octadecatetraenoic acid H. megalanthum [22]
Oleic acid H. tuberculatum [35]
Palmito-γ-lactone H. megalanthum [22]
Oxygenated monoterpenes
1,8-Cineole
H. buhsei
H. furfuraceum
H. perforatum
H. robustum
H. virgatum
[17,18,25,27–29,39]
α-Terpineol H. tuberculatum [31]
p-Cymene-8-ol H. tuberculatum [36]
Camphor H. perforatum [25]
Cis-p-menth-2-en-1-ol H. tuberculatum [34,38]
Cis-piperitol H. tuberculatum [34,38]
Cryptone H. tuberculatum [38]
Linalool
H. buhsei
H. laeviusculum
H. myrtifolium
H. tuberculatum
H. virgatum
[17,18,20,24,31,33]
Molecules 2021, 26, 4664 9 of 40
Linalyl acetate H. tuberculatum [31]
Piperitone H. tuberculatum
H. virgatum [34,36,38,39]
Terpinen-4-ol
H. acutifolium
H. robustum
H. tuberculatum
[16,27,29,36]
Trans-p-menth-2-en-1-ol H. tuberculatum [34,38]
Trans-linalool oxide H. myrtifolium [23]
Trans-piperitol H. tuberculatum [34,38]
Oxygenated sesquiterpenes
8,14-Cedranoxide H. acutifolium [16]
β-Eudesmol H. furfuraceum [18]
Caryophyllene oxide
H. furfuraceum
H. lissonotum
H. virgatum
[18]
Caryophylla-4(14),8(15)-dien-5β-ol H. lissonotum [21]
Elemol
H. furfuraceum
H. glaberrimum
H. perforatum
[18,19,25]
Humulene epoxide II H. lissonotum [21]
Sesquiterpene hydrocarbons
(1E,4E)-Germacrene B H. tuberculatum [36]
α-Cadinene H. acutifolium [16]
α-Caryophyllene H. lissonotum
H. perforatum [21,25]
β-Cedrene H. acutifolium [16]
β-Caryophyllene
H. buhsei
H. glaberrimum
H. laeviusculum
H. lissonotum
H. myrtifolium
H. perforatum
H. tuberculatum
[17,19–21,23–25,31,32]
Aromadendrene H. virgatum [39]
Valencene H. virgatum [39]
As it can be seen from Tables 2 and 3, the literature data concerning the chemical
profiles of the EOs of this valuable medicinal genus are abundant, in particular about its
most important species, i.e., H. tuberculatum (Forssk.) A. Juss. From a general survey of
these data, it could be clearly observed that the characterized chemical profiles of this
species differ widely from one another. Yet, these profiles were mainly seen to be
characterized by the presence of monoterpene hydrocarbons (MH), oxygenated
monoterpenes (OM), and non-terpene hydrocarbons (NH). Other reported classes are also
sesquiterpene hydrocarbons (SH) and oxygenated sesquiterpenes (OM), even if with
minor frequency. This same pattern was also reported in several other species such as two
Hyptis species (Lamiaceae family) [40], several Hypericum species (Hypericaceae family)
[41] and Helichrysum species (Asteraceae family) [42]. Not all the compounds were
reported in all the species. Nevertheless, the most reported compounds were β-
caryophyllene and β-pinene [17–21,23,25,26,28,31,32,39], whereas several compounds
were identified only in single species.
For what concerns the phytochemical profiles of H. tuberculatum, in some reports, the
major compounds were limonene, α-pinene, β-pinene, α-phellandrene, β-phellandrene,
myrcene, δ-3-carene, β-ocimene, α-terpinene [37], and β- and γ-terpinene [30–33,37],
Molecules 2021, 26, 4664 10 of 40
whereas, in others, the major components were linalool, linalyl acetate, 1,8-cineole, 4-
terpineol [37], trans-p-menth-2-en-1-ol, cis- and trans-p-menth-2-en-1-ol, piperitone, and
cis- and trans-piperitol [29,31,34,36–38]. As shown in Table 1, for what concerns the volatile
fractions and oils from H. myrtifolium specimens, monoterpene hydrocarbons [23] or non-
terpene hydrocarbons were the prevailing groups of natural compounds [23,24].
Monoterpene hydrocarbons and oxygenated monoterpenes were the main class of
constituting compounds of H. robustum Bunge [26–28]. On the other hand, some sporadic
reports dealt with the isolation and identification of the volatile essences of other species
of the genus Haplophyllum. In accordance with these reports, monoterpene hydrocarbons
were the most abundant compounds in H. glaberrimum, H. virgatum, H. laeviusculum, and
H. buhsei [17,19,39], whereas, for H. virgatum, H. buxbaumii, and H. megalanthum, non-
terpene hydrocarbons were found in the highest quantities [18,21,22]. H. acutifolium oil
consisted mainly of sesquiterpene hydrocarbons [16]. It is also interesting to note that the
total amounts of monoterpene hydrocarbons and oxygenated sesquiterpenes in the H.
furfuraceum oil were approximately the same [18]. Lastly, by using the headspace solid
phase microextraction (HS-SPME) approach, volatile fractions from the flowers and stems
of H. perforatum Kar & Kir. were observed to be mainly composed of monoterpene
hydrocarbons, whereas that of the leaves contained higher quantities of sesquiterpene
hydrocarbons [25].
2.2. Polar fraction metabolites of Haplophyllumn species
Regarding the non-volatile fraction metabolites, Haplophyllum species biosynthesize
compounds belonging to the class of terpenoids, saponins, alkaloids, coumarins, lignans,
flavonoids, and organic acids (Table 3 and Figures 2–14).
Table 3. Non-volatile compounds evidenced in Haplophyllum spp.
Plant species Compounds Extraction
solvent
Analysis
method Studied organs Country Reference
H. acutifolium
(DC.) G. Don
Haplacutine A,
haplacutine B,
haplacutine C,
haplacutine D, acutine,
haplamine, haplacutine
E, haplacutine F, and 2-
nonyl-quinolin-4(1H)-
one
Ethyl acetate
HPLC-PDA-MS,
SPE-NMR,
UV and IR
Aerial parts Iran [43]
Acutine, skimmianine,
and acetamide Chloroform CC, UV, TLC,
NMR and MS Epigeal parts Turkmenistan [44]
Skimmianine and
evoxine N.D. N.D. N.D. Tajikistan [45]
β-Sitosterol,
cholesterol, oleanolic
acid, haplophytin-A,
haplophytin-B,
haplotin, flindersine,
and kusunokinin
Methanol CC, UV, NMR
and MS Whole plant Pakistan [46,47]
Eudesmin Ethereal eluates
CC, IR, UV,
NMR, and MS Epigeal parts
Uzbekistan [46,48]
H. alberti-
regelii
Korovin
Diphyllin Methanol
CC, IR, UV,
NMR, and MS Tajikistan [49]
Molecules 2021, 26, 4664 11 of 40
H.
boissierianum
Beck
ECNP Methanol and
ethanol
Phytochemical
screening Aerial parts Serbia [50]
H. bucharicum
Litv.
Diphyllin
Methanol
CC, IR, UV,
NMR, and MS Epigeal parts Tajikistan [49]
β-Sitosterol,
stigmasterol,
campesterol,
cholesterol,
skimmianine,
bucharaine, and 3-
dimethylallyl-4-
dimethylallyloxy-2-
quinoline
CC, IR, NMR,
and MS
Aerial parts
Russia
(Dagestan
republic)
[49]
Diphyllin, 4-acetyl-
diphyllin, bucharaine,
skimmianine,
bucharaminol,
bucharidine, 4-
hydroxyquinolin-2-one,
4-methoxyquinolin-2-
onem and justicidin B
MP, CC, and
NMR
Uzbekistan
(different
districts)
[51]
Skimmianine,
dictamnine, γ-fagarine,
robustine, haplopine,
flindersine, and
haplamine
MP, CC, and
NMR Roots
Uzbekistan
(Surkhandari
nskii district)
[51]
Bucharaine,
skimmianine,
haplopine, folifine,
bucharidine, γ-
fagarine, robustine, and
benzamide
Chloroform and
phenolic partitions
CC, IR, UV, and
NMR
Mother liquor
from the roots Turkmenistan [52]
H. bungei
Trautv.
Skimmianine,
haplopine, haplamine,
γ-fagarine and POCS
Methanol
HPLC-UV Leaves Uzbekistan [53]
Dictamnine,
skimmianine, folimine,
robustinine, 4-
methoxyquinolin-2-
one, and haplobungine
CC, UV, IR, MS,
NMR, and MP
Epigeal parts
Kazakhstan [54]
Osthole, 7-(3’,3’-
dimethylallyloxy)-6-
methoxycoumarin, and
5-hydroxy-7-
methoxycoumarin
Chloroform MP, IR, and
NMR Turkmenistan [55]
Scopoletin,
isoscopoletin, and
bungeidiol
N.D. CC, MP, IR, and
NMR Azerbaijan [56]
Molecules 2021, 26, 4664 12 of 40
H.
canaliculatum
Boiss.
7-Isopentenyloxy-γ-
fagarine, atanine,
skimmianine,
flindersine, and
perfamine
Methanol CC, HPLC-UV,
and NMR Aerial parts Iran [57]
H.
cappadocicum
Spach
Isodaurinol, daurinol,
j
usticidin A, justicidin
B, diphyllin,
matairesinol,
dictamnine, robustine,
haplopine,
skimmianine,
scopoletin, and seselin
Ethanol
CC, NMR, UV,
and MS
Whole plant
Turkey [58]
(−)-Cappadoside, (−)-
cappodicin, and (−)-
haplodoside
IR, NMR, MS,
and UV Turkey [59]
(−)-haplomyrtoside, (−)-
majidine, (−)-lβ-
polygamain, and
vanillic acid
CC, UV, IR,
NMR, and MS Iran [60]
Malatyamine CC, IR, NMR
,
and MS Turkey [61]
H. dauricum
(L.) G. Don
Justicidin B, daurinol,
umbelliferone,
umbelliferone 7-O-β-D-
glucoside, 5,7-
dihydroxy-coumarin,
and dauroside D
Ripartition in
chloroform, CC,
IR, UV, NMR,
and MS Epigeal parts Mongolia
[62]
Dauroside A and
dauroside B
CC, UV, IR, αD,
NMR, and MS [63,64]
Diphyllin, scopoletin,
dauroside C, haploside
B, and haploside D
N.D. CC, IR, NMR,
and MS Whole plant N.D. [65]
Robustine, dictamnine,
γ-fagarine, haplopine,
skimmianine, 4-
methoxy-N-methyl-2-
quinolone, folimine,
robustinine, and
daurine
Methanol CC, UV, IR,
NMR, and MS Roots Mongolia [66]
H.
dshungaricum
Rubtzov
Seselin and xanthyletin
Ethanol
CC, TLC, MP, IR,
and NMR Whole plant Kazakhstan [67]
H. dubium
Korovin
Scopoletin, scopolin,
haploside B, and
haploside D
CC, MP, UV,
NMR, and MS
Epigeal parts
Tajikistan [68]
H. foliosum
Vved.
Foliosidine,
haplodimerine,
skimmianine, N-
methyl-2-phenyl-4-
Chloroform CC, IR, UV,
NMR, and MS N.D. [46]
Molecules 2021, 26, 4664 13 of 40
quinolone, foliosine,
and folimine
Folimine, foliosidine,
dubinidine, foliosine,
edulinine, folidine, and
ferulic acid
Methanol CC, IR, UV,
NMR, and MS Tajikistan [69,70]
Isorhamnetin,
haploside C, and
limocitrin-7-O-β-D-(6’’-
O acetyl)-glucoside
Ethanol CC, UV, NMR,
and MS
Aerial parts
Kyrgyzstan [71]
H.
glaberrimum
Bunge
ECNP N.D.
Phytochemical
screening Uzbekistan [72]
H.
griffithianum
Boiss.
Skimmanine,
dictamnine, dubinine,
dubinidine, gerphytine,
dubamine, and
N-methylhaplofoline
Methanol
CC, IR, UV,
NMR, MS, and
X-ray
Whole plant Uzbekistan [73,74]
Dubamine, dubinine,
dubinidine,
dictamnine,
skimmianine, N-
methylhaplofoline,
gerphytine, and
griffithine
CC, IR, UV,
NMR, and MS Aerial parts Uzbekistan [75]
Flindersine, folimine,
and evoxine
MP, TLC, UV, IR,
NMR, and MS
Epigeal parts Uzbekistan [76]
H. kowalenskyi
Stschegl.
Skimmianine and γ-
fagarine CC and TLC Epigeal parts Azerbaijan [77]
H. latifolium
Kar. & Kir.
Skimmianine, evoxine
haplopine, glycoperine,
7-isopentenyloxy-γ-
fagarine, haplamine,
haplamide,
haplamidine, and
haplatine
CC, UV, IR,
NMR, and MS Whole plant Kazakhstan [78,79]
Skimmianine,
haplopine, haplamine,
and POCS
HPLC-UV Leaves Uzbekistan [53]
H. leptomerum
Lincz. &
Vved.
Isorhamnetin and
haploside D
Ethanol
CC, MP, UV,
NMR, and MS
Epigeal parts
Tajikistan [68]
β-Sitosterol, γ-fagarine,
skimmianine, N-
methyl-2-phenyl-4-
quinolone, and
leptomerine
MP, CC, UV, and
NMR Tajikistan [80]
Skimmianine, γ-
fagarine, N-methyl-2-
phenyl-4-quinolone,
acutine, leptomerine, 2-
Methanol
CC, TLC, and
NMR Aerial parts Tajikistan [81]
Molecules 2021, 26, 4664 14 of 40
heptylquinolin-4-one,
and dictamnine
γ-Fagarine and
dictamnine
CC, TLC, and
NMR Roots Tajikistan [81]
H. multicaule
Vved.
β-Sitosterol, seselin and
xanthyletin
Ethanol
CC, TLC, IR,
NMR, and MP Whole plant Kazakhstan [67]
H. myrtifolium
Boiss.
Dictamnine, robustine,
γ-fagarine,
skimmianine, (-)-1β-
polygamain, 7-O-(3-
methyl-2-butenyl)-
isodaurinol, and
chrysosplenetin
CC, PTLC, UV,
NMR, and MS Aerial parts Turkey [82]
Haplomyrtin and (−)-
haplomyrfolin
CC, TLC, UV,
NMR, and MS Whole plant Turkey [83]
H.
pedicellatum
Bunge ex
Boiss.
Scopoletin, 6-
methoxymarmin,
7-geranyloxy-6-
methoxycoumarin, and
pedicellone
N.D. TLC, CC, αD
,
IR,
UV, and NMR N.D. N.D. [84]
γ-Fagarine,
skimmianine,
haplopine, haplamine,
and
POCS Methanol
HPLC-UV Leaves Uzbekistan [53]
Skimmianine, γ-
fagarine, haplopine,
and robustine
CC, IR, UV, and
NMR Epigeal parts Uzbekistan [52]
Haploside A, haploside
B, and haploside C Ethanol CC, UV, NMR,
and MS Ground parts Turkmenistan [71]
ECNP N.D. TFC methods Aerial parts Iran [72]
H. perforatum
Kar. & Kir.
Evoxine, haplopine,
haplamine,
skimmianine, and
haplosamine
Methanol
CC, IR. UV,
NMR, and MS Epigeal parts Kazakhstan [85]
Perforine,
skimmianine,
haplamine, haplopine,
bucharaine,
haplophyllidine,
flindersine, and γ-
fagarine
HPLC-UV Leaves
Uzbekistan
[53]
Evoxine, skimmianine,
haplophyllidine,
anhydroperlorine,
flindersine, haplamine,
and acetyl-
haplophyllidine
CC, IR, UV,
NMR, and MS Aerial parts Uzbekistan
[86]
skimmianine, evoxine,
7-isopentenyloxy-γ-
fagarine, perfamine,
CC, UV, MP,
NMR, and MS Epigeal parts Uzbekistan
[87]
Molecules 2021, 26, 4664 15 of 40
flindersine, haplamine,
and eudesmin
Haplosinine,
glycoperine,
glucohaplopine,
skimmianine, evoxine,
haplamine, and 7-
isopentenyloxy-γ-
fagarine
CC, MP, NMR,
and MS Romania [88,89]
7-Isopentyloxy-
γ
-
fagarine, skimmianine,
evoxine,
methylevoxine,
glycoperine,
haplamine, and
flindersine
CC, UV, IR,
NMR, and MS Seeds and roots Tajikistan [90]
Diphyllin CC, IR, UV,
NMR, and MS
Epigeal parts
Tajikistan [49]
Scopoletin, scopoletin
7-O-β-D-
glucopyranoside, and
haploperoside A
Ethanol CC, UV, αD, IR,
NMR, and MS Kazakhstan [91]
Haploperoside B Butanol
CC, UV, αD, IR,
NMR, and MS
Kazakhstan [91]
Haploside A, haploside
C, and haploside D
Ethanol
CC, αD, UV, IR,
NMR, and MS
Kazakhstan
[92,93]
Haploside E,
haplogenin, and
limocitrin-7-O-β-D-(6’’-
O-acetyl)-glucoside
CC, αD, UV, IR,
NMR, and MS
Kazakhstan
[94]
H. ptilosyylum
Spach
Justicin B, isodaurinol,
matairesinol,
arctigenin, (-)1β-
polygamain, 4-[6”,7”-
dihydroxygeranoyl]-
matairesinol, 4-
isopentylhaplomyrfolin
A, 4-
isopentylhaplomyrfolin
B, picropolygamain,
ptilostin, ptilostol, and
ptilin
Methanol
CC, αD, UV,
NMR, and MS Aerial parts Turkey [95–97]
H.
ramosissimum
(Paulsen)
Vved.
Skimmianine,
haplopine,
Haplamine, and γ-
fagarine
HPLC-UV Leaves Uzbekistan [53]
Skimmianine,
dictamnine, evoxine,
CC, MP, IR, UV,
NMR, and MS Epigeal parts Kazakhstan [98]
Molecules 2021, 26, 4664 16 of 40
scopoletin, and
scoparone
H. robustum
Bunge ECNP N.D.
Preliminary
qualitative
methods
Aerial parts Iran [72]
H.
schelkovnikovii
Grossh.
β-Sitosterol, obtusifol,
and POCS
Chloroform and
methanol
TLC, NMR, and
IR Epigeal parts
Azerbaijan [99]
Skimmianine and γ-
fagarine Methanol CC and TLC Azerbaijan [77]
H. sieversii
Fisch.
Flindersine, haplamine,
anhydroevoxine, and
eudesmin
Petroleum ether
CC, TLC, HPLC-
UV, NMR, and
MS
Aerial parts Kazakhstan [100]
H. suaveolens
Ledeb.
Flindersine, γ-fagarine,
kokusaginine, and
haplophyllidine
Chloroform and
benzene
CC, IR, UV,
NMR, and MS Whole plant Turkey [95]
ECNP Methanol and
ethanol
Phytochemical
screening Aerial parts Serbia [50]
H. tenue Boiss. Skimmianine and γ-
fagarine Methanol CC and TLC Epigeal parts Azerbaijan [77]
H. telephioides
Boiss.
7-Hydroxy-9-methoxy-
flindersine, diphyllin,
4-acetyl-diphyllin, and
haplomyrtin
Ethanol
CC, UV, IR,
NMR, and MS
Whole plant Turkey [96]
H. thesioides
(Fisch. ex
DC.) G.Don
Flindersine,
kokusaginine,
skimmianine, pteleine,
nkolbisine, haplopline,
haplosine, thesiolen,
seselin, scoparone, and
angustifolin
Chloroform CC, IR, UV,
NMR, and MS
Aerial parts
Turkey [97]
H.
tuberculatum
Juss.
γ-Fagarine,
skimmianine, and
evoxine
Hot ethanol CC, TLC, IR, UV,
NMR, and MS Iraq [101]
Flindersine and 3-
dimethylallyl-
4-dimethylallyloxy-2-
quinolone
n-Hexane CC, IR, UV,
NMR, and MS
Leaves and
stems Palestine [102]
(+)-Dihydroperfamine,
3-dimethylallyl-4-
dimethylallyloxy-2-
quinolone,
tubasenecine,
tubacetine, 7-hydroxy-
8-(3-methyl-2-butenyl)-
4-methoxyfuro2,3b-
quinoline, justicidin A,
and justicidin B
Dichloromethane CC, TLC, UV, IR,
NMR, and MS Aerial parts
Saudi Arabia [103]
Tuberine Petroleum ether
and chloroform
CC, IR, UV,
NMR, and MS Lybia [104,105]
Molecules 2021, 26, 4664 17 of 40
Skirnmianine, justicidin
A, and diphyllin Chloroform CC, IR, UV,
NMR, and MS Sudan [106]
ECNP N.D.
Preliminary
qualitative
methods
Iran [72]
Haplotubinone,
haplotubine, dyphyllin,
and N-(2-phenylethyl)-
benzamide
Dichloromethane
CC, IR, UV,
NMR, MS, and
X-ray
Saudi Arabia [107]
Skimmianine and γ-
fagarine Petroleum ether
CC, TLC, NMR,
and MS Iraq [108]
Ammoidin and POCS TLC, MP, and
HPLC-UV
1-Hydroxy-3-
(hydroxymethyl)-6,7-
dimethoxy-4-(3,4-
methylenedioxyphenyl)
-
2-naphthoic acid γ-
lactone, and (−)-
secoisolariciresinol
Methanol
CC, IR, HPLC-
UV, NMR, and
MS
Whole plant Egypt [109]
5,7,4’-Trihydroxy-6-
methoxy-3-O-glucosyl
flavone
Ethyl acetate
CC, IR, UV,
NMR, and MS
Aerial parts Sudan [106]
j
usticidin A, justicidin
B, tuberculatin, and
acetyl-tuberculatin
Methanol CC, TLC, NMR,
and HPLC-DAD Aerial parts Spain [110]
H. vulcanicum
Boiss. &
Heldr.
Vulcanine, dictamnine,
γ-fagarine, robustine,
haplopine,
skimmianine,
nigdenine, scopoletin,
umbelliferone, (−)-
haplomyrfolin,
kusunokinin, diphyllin,
syringarasinol,
tuberculatin,
haplomyrfolol, and
konyanin
Ethanol CC, IR, UV,
NMR, and MS Whole plant Turkey [111–113]
αD: Optical Rotation; CC: Column Chromatography; ECNP: Exact Compounds Not Specified; HPLC-DAD: High
Performance Liquid Chromatography Coupled to Diode Array Detector; HPLC-PDA-MS: High Performance Liquid
Chromatography Coupled to Photodiode Array Detector and Mass spectrometry; HPLC-UV: High Performance
Liquid Chromatography Coupled to Ultraviolet Spectroscopy; IR: Infrared Spectroscopy; MP: Melting Point; MS:
Mass Spectrometry; N.D.: Not Reported; NMR: Nuclear Magnetic Resonance spectroscopy; POCS: Plus Other
Compounds Not Specified; PTLC: Preparative Thin Layer Chromatography; SPE-NMR: Solid Phase Extraction with
Nuclear Magnetic Resonance Spectroscopy; TLC: Thin Layer Chromatography; UV: Ultraviolet Spectroscopy; X-ray:
X-Ray Spectroscopy.
As it can be seen from Table 3, not all the Haplophyllum species were studied for their
non-volatile components. Surely, alkaloids, coumarins, and lignans represent the most
represented classes of natural compounds in this genus, having been reported in most of
Molecules 2021, 26, 4664 18 of 40
them, often together, even if some exceptions are present (i.e., H. canaliculatum, H.
kowalenskyi and H. tenue, where only alkaloids were identified [57,77] and H.
dshungaricum, where only coumarins were identified) [67]. In addition, only for the species
H. alberti-regelii, one compound was identified [49], whilst for all the others, at least two
compounds were identified, even if they belonged to the same phytochemical class. For
some species and/or exemplars, the exact compounds were not specified since only a
phytochemical screening was performed such as for H. boissierianum, H. glaberrimum, H.
pedicellatum, and H. tuberculatum from Iran and H. robustum and H. suaveolens from Serbia
[50,72]. The extraction solvents are well-known as well as the analysis methods. Of course,
their choice depends on the kind of compounds that need to be extracted from the
Haplophyllum species. Ethanol proved to be a very effective solvent to extract different
classes of compounds, both polar and non-polar, whilst dichloromethane, methanol, n-
hexane, petroleum ether, chloroform, and ethyl acetate were perfect for extracting
compounds such as alkaloids, lignans, and coumarins. For what concerns the studied
organs, these are quite general, too, with a prevalence of aboveground organs. Indeed, for
what concerns the collection areas of the studied species, the general knowledge of the
Haplophyllum genus geographical distribution is respected since the majority of them were
collected in Asia.
H
HO
H H
H
β-sitosterol
H
HO
H H
H
cholesterol
COOHH
HO
H
H
oleanolic acid
H
HO
H H
H
stigmasterol
H
HO
H H
H
campesterol
Figure 2. Structure of the terpenoids identified in Haplophyllum species.
Molecules 2021, 26, 4664 19 of 40
OMeO O
osthole
O
O
O
seselin
O OO
xanthyletin
O
O
O
OMe
O
OH
obtusifol
O
O
O
thesiolen
OO O
ammoidin
OMe
OMe
OO
OMe
O
R
1
R
1
= C(OH)(CH
3
)
2
: ptilostol
R
1
= C(CH
3
)
2
OCH
2
CHC(CH
3
)
2
: ptilostin
R
1
= C(CH
2
)CH
3
: ptilin
Figure 3. Structure of the coumarins identified in Haplophyllum species—part 1.
O OR
3
R
1
R
1
= R
3
= OH, R
2
= R
4
= H: 5,7 dihydroxycoumarin
R
1
= OH, R
2
= R
4
= H, R
3
= OMe: 5-hydroxy-7-methoxycoumarin
R
1
= R
4
= H, R
2
= OMe, R
3
= O-3,3'dimethylallyl: 7-(3',3'-dimethylallyloxy)-6-methoxycoumarin
R
1
= R
4
= H, R
2
= OMe, R
3
= OH: scopoletin
R
1
= R
4
= H, R
2
= OMe, R
3
= O-β-D-Glc: scopoletin 7-O-β-D-glucopyranoside
R
1
= R
4
= H, R
2
= OH, R
3
= OMe: isoscopoletin
R
1
= R
4
= H, R
2
= OMe, R
3
= OCH
2
CHC(CH
3
)CH(OH)CH
2
CH
2
C(OH)(CH
3
)
2
: bungeidiol
R
1
= R
2
= R
4
= H, R
3
= OH: umbelliferone
R
1
= R
2
= R
4
= H, R
3
= O-β-D-Glc: umbelliferone 7-O-β-D-glucoside
R
1
= R
4
= H, R
2
= OMe, R
3
= 6'-acetyl-6-α-L-Rha-β-D-Glc: dauroside C
R
1
= R
4
= H, R
2
= OMe, R
3
= O-β-D-Glc: scopolin
R
1
= R
4
= H, R
2
= OMe, R
3
= OCH
2
CHC(CH
3
)CH
2
CH
2
CH(OH)C(OH)(CH
3
)
2
: 6-methoxymarmin
R
1
= R
4
= H, R
2
= OMe, R
3
= OCH
2
CHC(CH
3
)CH
2
CH
2
CHC(CH
3
)
2
: 7-geranyloxy-6-methoxycoumarin
R
1
= R
4
= H, R
2
= OMe, R
3
= OCH
2
CHC(CH
3
)CH
2
CH
2
C(O)C(OH)(CH
3
)
2
: pedicellone
R
1
= R
4
= H, R
2
= OH, R
3
= 6-α-L-Rha-β-D-Glc: haploperoside A
R
1
= R
4
= H, R
2
= OMe, R
3
= 4'-acetyl-6-α-L-Rha-β-D-Glc: haploperoside B
R
1
= R
4
= H, R
2
= R
3
= OMe: scoparone
R
1
= R
2
= H, R
3
= OH, R
4
= C(CH
3
)
2
CHCH
2
: angustifolin
R
1
= R
3
= OH, R
2
= β-D-Glc, R
4
= H: dauroside D
R
1
= R
2
= R
4
= H, R
3
= 4''-acetyl-6-α-L-Rha-β-D-Glc: dauroside A
R
1
= R
2
= R
4
= H, R
3
= 6-α-L-Rha-β-D-Glc: dauroside B
R
2
R
4
Figure 4. Structure of the coumarins identified in Haplophyllum species—part 2.
Molecules 2021, 26, 4664 20 of 40
N O
R
1
O
R
1
= OH, R
2
= Me: folifine
R
1
= H, R
2
= Me: N-methylhaplofoline
N
H
O
O
3-dimethylallyl-4-dimethylallyloxy-2-quinolone
NO
R
5
R
4
R
3
R
1
= R
2
= R
3
= H, R
4
= R
5
= OMe: γ-fagarine
R
1
= R
2
= H, R
3
= R
4
= R
5
= OMe: skimmianine
R
1
= R
2
= H, R
3
= OCH
2
CH(OH)C(OH)(CH
3
)
2,
R
4
= R
5
= OMe: evoxine
R
1
= R
2
= H, R
3
= OCH
2
CH(OH)C(CH
3
)
3,
R
4
= R
5
= OMe: methylevoxine
R
1
= R
2
= R
3
= R
4
= H, R
5
= OMe: dictamnine
R
1
= R
2
= R
3
= H, R
4
= OH, R
5
= OMe: robustine
R
1
= R
2
= H, R
3
= OH, R
4
= R
5
= OMe: haplopine
R
1
= R
2
= H, R
3
= O-β-D-Glc, R
4
= R
5
= OMe: haplopine
R
1
= R
4
= H, R
2
= R
3
= R
5
= OMe: kokusaginine
R
1
= R
2
= H, R
3
= O-isopententyl, R
4
= R
5
= OMe: 7-isopentenyloxy-γ-fagarine
R
1
= R
2
= H, R
3
= O-α-L-Rha, R
4
= R
5
= OMe: glycoperine
R
1
= R
2
= H, R
3
= OCH
2
CHC(CH
2
OH)CH
3
, R
4
= R
5
= OMe: haplatine
R
1
= R
2
= H, R
3
= O-α-L-Rha-β-D-Glc, R
4
=R
5
= OMe: haplosinine
R
1
= R
3
= R
4
= H, R
2
= R
5
= OMe: pteleine
R
1
= R
2
= H, R
3
= R
4
= OMe, R
5
= OCH
2
CH(OH)C(OH)(CH
3
)
2
: nigdenine
R
1
= R
4
= H, R
2
= OCH
2
CH(OH)C(CH
3
)
2
OH, R
3
= R
5
= OMe: nkolbisine
R
1
= R
2
= H, R
3
= OH, R
4
= CH
2
CHC(CH
3
)
2
, R
5
= OMe: 7-hydroxy-8-(3-methyl-2-butenyl)-4-methoxyfuro2,3b-quinoline
R
1
= R
2
= H, R
3
= OCH
2
CHC(CH
3
)CH
2
CH
2
CH(OH)C(CH
3
)
2
OH, R
4
= R
5
= OMe: haplotubine
R
2
R
1
Figure 5. Structure of the alkaloids identified in Haplophyllum species—part 1.
Molecules 2021, 26, 4664 21 of 40
R
1
= R
3
= R
4
= R
5
= H, R
2
= OCH
2
CH(OH)CH(C(OH)(CH
3
)
2
)CH
2
CHCHCH
3
, R
1
= R
3
= R
4
= R
5
= H: bucharaine
R
1
= R
3
= H, R
2
= R
4
= OMe, R
5
= Me: folimine
R
1
= R
5
= H, R
2
= R
3
= R
4
= OMe: haplobungine
R
1
= R
3
= R
5
= H, R
2
= R
4
= OMe: robustinine
R
1
= R
3
= R
4
= R
5
= H, R
2
= OH: 4-hydroxyquinolin-2-one
R
1
= R
3
= R
4
= R
5
= H, R
2
= OMe: 4-methoxyquinolin-2-one
R
1
= isopententyl, R
2
= OMe, R
3
= R
4
= R
5
= H: atanine
R
1
= R
3
= H, R
2
= OMe, R
4
= OCH
2
CH(OH)C(CH
3
)
2
OH, R
5
= Me: foliosidine
R
1
= CH
2
CH(R-OH)C(CH
3
)
2
OH, R
2
= OMe, R
3
= R
4
= H, R
5
= Me: edulinine
R
1
= CH
2
CH(OH)C(OH)(CH
3
)CH
2
OH, R
2
= OMe, R
3
= R
4
= H, R
5
= Me: ha plosamine
N O
R
5
R
2
R
4
R
3
R
1
N
H
O
O
R
1
= R
2
= R
3
= R
4
= H: flindersine
R
1
= R
3
= R
4
= H, R
2
= OMe: haplamine
R
1
= OMe, R
2
= R
3
= R
4
= H: haplophytin-A
R
1
= R
2
= H, R
3
= OCH
2
CH(OH)C(CH
3
)
2
OH, R
4
= OMe: haplophytin-B
R
2
R
1
R
3
R
4
O
O
NH
O
O
O
O
O
R = CHC(CH
3
)
2
= tubasenecine
R = Phenyl: tubacetine
R
Figure 6. Structure of the alkaloids identified in Haplophyllum species – part 2.
NO
OMe
R
1
O
OMe
R
1
= H: haplophyllidine
R
1
= Ac: acetyl-haplophyllidine
NO
OMe
O
OMe
(+)-dihydroperfamine
N
H
O
OH
O
O
haplotubinone
Figure 7. Structure of the alkaloids identified in Haplophyllum species—part 3.
Molecules 2021, 26, 4664 22 of 40
NO
OMe
O
MeO
perfamine
NO
OMe
OH
CH
2
OH
dubinidine
N
H
O
O
OH
OH
bucharaminol
N
HO
O
OHOH
bucharidine
N
H
O
COOH
3
malatyamin e
NH
O
O
N
O
OMe
MeO
MeO
haplodimerine
NO
OMe
OMe
OH
HO
perforine
H
N
N
vulcanine
Figure 8. Structure of the alkaloids identified in Haplophyllum species—part 4.
N
O
R
2
R
1
= H, R
2
= a: haplacutine A
R
1
= H, R
2
= b: haplacutine B
R
1
= H, R
2
= c: haplacutine C
R
1
= H, R
2
= d: haplacutine D
R
1
= H, R
2
= e: acutine
R
1
= H, R
2
= f: hapla cutine E
R
1
= H, R
2
= g: haplacutine F
R
1
= H, R
2
= h: 2-nonyl-quinolin-4(1H)-one
R
1
= Me, R
2
= i: foliosine
R
1
= Me, R
2
= phenyl: N-methyl-2-phenylquinolin-4-one
R
1
= Me, R
2
= propyl: leptomerine
R
1
= Me, R
2
= heptyl : 2-heptylquinolin-4-on e
OH
a
b
OH
c
OH
d
O
e
f
g
h
O
O
i
R
1
Figure 9. Structure of the alkaloids identified in Haplophyllum species—part 5.
Molecules 2021, 26, 4664 23 of 40
O
O
HH
R
4
O
OMe
OMe
OR
2
R
1
= R
3
= H, R
2
= R
4
= Me: eudesmin
R
1
= R
3
= OMe, R
2
= R
4
= H: syringaresinol
O
O
O
O
OMe
OMe
kusunokinin
O
O
O
MeO
MeO
O
justicidin B
MeO
OH
O
OMe
OR
1
O
R
1
= H: matairesinol
R
1
= Me: arctigenin
O
O
R
1
O
O
R
2
O
MeO
O
R
1
= β-D-Glc, R
2
= Me: (−)-cappadoside
R
1
= H, R
2
= Me: (−)-cappadocin
R
1
= β-D-Glc, R
2
= H: (−)-haplodoside
O
O
O
HO
O
(−)-haplomyrfolin
R
1
R
3
Figure 10. Structure of the lignans identified in Haplophyllum species—part 1.
O
O
O
O
O
O
(−)-1β-polygamain
MeO
O
O
OMe
OH
R
1
R
2
R
1
= O, R
2
= H: 4-isopentylhaplomyrfolin A
R
1
= H, R
2
= O: 4-isopentylhaplomyrfolin B
O
O
O
O
O
O
picropolygamain
O
OH
O
O
MeO
MeO
O
1-hydroxy-3-(hydroxymethyl)-6,7-dimethoxy-4-
(3,4-methylenedioxyphenyl)-2-naphthoic acid γ-
lactone
OH
OH
MeO
HO
OH
OMe
(−)-secoisolariciresinol
O
O
O
HO
HO
OH
haplomyrfolol
Figure 11. Structure of the lignans identified in Haplophyllum species—part 2.
Molecules 2021, 26, 4664 24 of 40
O
O
O
R1O
R2O
R3
O
R1 = R2 = Me, R3 = OH: diphyllin
R1 = R2 = Me, R3 = OAc: 4-acetyl-diphyllin
R1 = Me, R2 = R3 = H: daurinol
R1 = R3 = H, R2 = Me: isodaurinol
R1 = O-3-methyl-2-butenyl, R2 = Me, R3 = H: 7-O-(3-methyl-2-butenyl)-isodaurinol
R1 = R2 = Me, R3 = O-β-D-Api: tuberculatin
R1 = R2 = Me, R3 = 6-acetyl-O-β-D-Api: acetyl-tuberculatin
R1 = R2 = Me, R3 = H: justicidin B
R1 = R2 = Me, R3 = OMe: justicidin A
R1 = H, R2 = Me, R3 = OH: haplomyrtin
R1 = H, R2 = Me, R3 = O-β-D-Api: (−)-haplomyrtoside
R1 = R2 = Me, R3 = a: (−)-majidine
O
HO
OH
O
O
OH
OH
OH
a
Figure 12. Structure of the lignans identified in Haplophyllum species—part 3.
O
OH
R2O
R1
OH O
OMe
OH
R1 = OH, R2 = β-D-Glc: haploside B
R1 = OH, R2 = α-L-Rha-6-acetyl-β-D-Glc: haploside D
R1 = R2 = H: isorhamnetin
R1 = OMe, R2 = α-L-Rha-6-acetyl-β-D-Glc: haploside C
R1 = OMe, R2 = 6-acetyl-β-D-Glc: limocitrin-7-O-β-D-(6''-O-acetyl)-glucoside
R1 = OH, R2 = 6-acetyl-β-D-Glc: haploside A
R1 = OH, R2 = H: haplogenin
O
OGlc
HO
MeO
OH
OH
O
5,7,4'-trihydroxy-6-methoxy-3-O-glucosyl flavone
O
OMe
MeO
OH O
OMe
OH
MeO
chrysoplenetin
Figure 13. Structure of the flavonoids identified in Haplophyllum species.
Molecules 2021, 26, 4664 25 of 40
NH
2
O
acetamide
COOH
OH
OMe
vanillic ac id
CONH
2
benzamide
OH
MeO
HO
O
ferulic acid
NH
O
N-(2-phenylethyl)benzamide
Figure 14. Structure of the other compounds identified in Haplophyllum species.
Table 4 displays the distribution of the phytochemical compounds within the
Haplophyllum genus.
Table 4. Distribution of the non-volatile phytochemicals in the Haplophyllum genus.
Phytochemical
class Phytochemical compound Haplophyllum spp. References
Alkaloids
2-Heptylquinolin-4-one H. leptomerum [81]
2-Nonyl-quinolin-4(1H)-one H. acutifolium [43]
3-Dimethylallyl-4-dimethylallyloxy-2-quinoline H. bucharicum
H. tuberculatum [49,102,103]
4-Hydroxyquinolin-2-one H. bucharicum [51]
4-Methoxyquinolin-2-one H. bucharicum
H. bungei [51,54]
4-Methoxy-N-methyl-2-quinolone H. dauricum [66]
7-Hydroxy-9-methoxy-flindersine H. telephioides [96]
7-Hydroxy-8-(3-methyl-2-butenyl)-4-
methoxyfuro2,3b-quinoline H. tuberculatum [103]
7-Isopentenyloxy-γ-fagarine
H. canaliculatum
H. latifolium
H. perforatum
[57,78,87,89,90]
γ-Fagarine
H. bucharicum
H. bungei
H. dauricum
H. kowalenskyi
H. leptomerum
H. myrtifolium
H. pedicellatum
H. perforatum
H. ramosissimum
H. schelkovnikovii
H. suaveolens
H. tenue
H. tuberculatum
[51–53,66,77,80–
82,95,101,108,111]
Molecules 2021, 26, 4664 26 of 40
H. vulcanicum
N-methyl-2-phenyl-4-quinolone H. foliosum
H. leptomerum [43,80,81]
N-methylhaplofoline H. griffithianum [73,75]
(+)-Dihydroperfamine H. tuberculatum [103]
Acutine H. acutifolium
H. leptomerum [43,81]
Anhydroevoxine H. sieversii [100]
Anhydroperlorine H. perforatum
H. sieversii [86]
Acetyl-haplophyllidine H. perforatum [86]
Atanine H. canaliculatum [57]
Bucharaine H. bucharicum
H. perforatum [49,51–53]
Bucharaminol H. bucharicum [51]
Bucharidine H. bucharicum [51,52]
Daurine H. dauricum [66]
Dictamnine
H. bucharicum
H. bungei
H. cappadocicum
H. dauricum
H. griffithianum
H. leptomerum
H. myrtifolium
H. ramosissimum
H. vulcanicum
[51,53,54,58,66,73,
75,81,82,98,111]
Dubamine H. griffithianum [73,75]
Dubinine H. griffithianum [73,75]
Dubinidine H. foliosum
H. griffithianum [70,73,75]
Edulinine H. foliosum [70]
Evoxine
H. acutifolium
H. griffithianum
H. latifolium
H. perforatum
H. ramosissimum
H. tuberculatum
[45,76,78,85–
87,89,90,98,101]
Flindersine
H. acutifolium
H. bucharicum
H. canaliculatum
H. griffithianum
H. perforatum
H. sieversii
H. suaveolens
H. thesioides
H. tuberculatum
[47,51,53,57,75,
86,87,90,95,97,100,102]
Folidine H. foliosum [70]
Folifine H. bucharicum [52]
Folimine H. bungei
H. dauricum [46,54,66,69,76]
Molecules 2021, 26, 4664 27 of 40
H. foliosum
H. griffithianum
Foliosidine H. foliosum [46,69]
Foliosine H. foliosum [46,70]
Gerphytine H. griffithianum [74,75]
Glucohaplopine H. perforatum [89,90]
Glycoperine H. perforatum [89]
Griffithine H. griffithianum [75]
Haplacutine A H. acutifolium [43,44]
Haplacutine B H. acutifolium [43]
Haplacutine C H. acutifolium [43]
Haplacutine D H. acutifolium [43]
Haplacutine E H. acutifolium [43]
Haplacutine F H. acutifolium [43]
Haplamide H. latifolium [78]
Haplamidine H. latifolium [78]
Haplamine
H. acutifolium
H. bucharicum
H. bungei
H. latifolium
H. pedicellatum
H. perforatum
H. ramosissimum
H. sieversii
[43,51,53,78,85-87,
89,90,100]
Haplatine H. latifolium [79]
Haplobungine H. bungei [54]
Haplodimerine H. foliosum [46]
Haplophyllidine H. perforatum
H. suaveolens [53,86,95]
Haplopine
H. bucharicum
H. bungei
H. cappadocicum
H. dauricum
H. latifolium
H. pedicellatum
H. perforatum
H. ramosissimum
H. thesioides
H. vulcanicum
[51–
53,58,66,78,85,97,111]
Haplosamine H. perforatum [85]
Haplosinine H. perforatum
H. thesioides [88,97]
Haplotin H. acutifolium [46]
Haplotubine H. tuberculatum [107]
Haplotubinone H. tuberculatum [107]
Haplophytin-A H. acutifolium [47]
Haplophytin-B H. acutifolium [47]
Kokusaginine H. suaveolens
H. thesioides [95,97]
Leptomerine H. leptomerum [80,81]
Molecules 2021, 26, 4664 28 of 40
Malatyamine H. cappadocicum [61]
Methylevoxine H. perforatum [90]
Nigdenine H. vulcanicum [111]
Nkolbisine H. thesioides [97]
Perfamine H. canaliculatum
H. perforatum [57,87]
Perforine H. perforatum [53]
Pteleine H. thesioides [97]
Robustine
H. bucharicum
H. cappadocicum
H. dauricum
H. myrtifolium
H. pedicellatum
H. vulcanicum
[51,52,58,66,82,111]
Robustinine H. bungei
H. dauricum [54,62]
Skimmianine
H. acutifolium
H. bucharicum
H. bungei
H. canaliculatum
H. cappadocicum
H. dauricum
H. foliosum
H. griffithianum
H. kowalenskyi
H. latifolium
H. leptomerum
H. myrtifolium
H. pedicellatum
H. perforatum
H. ramosissimum
H. schelkovnikovii
H. tenue
H. thesioides
H. tuberculatum
H. vulcanicum
[44-46,49,51-
54,57,58,66,73,74,
77,78,80-82,85-87,
89,90,97,98,101,106,108,1
11]
Tubacetine H. tuberculatum [103]
Tubasenecine H. tuberculatum [103]
Tuberine H. tuberculatum [104,105]
Vulcanine H. vulcanicum [112]
Coumarins
5,7-Dihydroxy-coumarin H. dauricum [62]
5-Hydroxy-7-methoxycoumarin H. bungei [55]
6-Methoxymarmin H. pedicellatum [84]
7-(3’
,
3’-Dimethylallyloxy)-6-methoxycoumarin H. bungei [55]
7-Geranyloxy-6-methoxycoumarin H. pedicellatum [84]
Ammoidin H. tuberculatum [108]
Angustifolin H. thesioides [97]
Bungeidiol H. bungei [56]
Dauroside A H. dauricum [63,64]
Dauroside B H. dauricum [63,64]
Molecules 2021, 26, 4664 29 of 40
Dauroside C H. dauricum [65]
Dauroside D H. dauricum [60]
Haploperoside A H. perforatum [91]
Haploperoside B H. perforatum [91]
Isoscopoletin H. bungei [56]
Obtusifol H. schelkovnikovii [99]
Osthole H. bungei [55]
Pedicellone H. pedicellatum [84]
Ptilin H. ptilosyylum [96,97]
Ptilostin H. ptilosyylum [96,97]
Ptilostol H. ptilosyylum [96,97]
Scoparone H. ramosissimum
H. thesioides [97,98]
Scopoletin
H. bungei
H. cappadocicum
H. dauricum
H. dubium
H. pedicellatum
H. perforatum
H. ramosissimum
H. vulcanicum
[56,58,62,68,84,91,98,111
]
Scopoletin 7-O-β-D-glucopyranoside H. perforatum [91]
Scopolin H. dubium [68]
Seselin
H. cappadocicum
H. dshungaricum
H. multicaule
H. thesioides
[58,67,97]
Yhesiolen H. thesioides [97]
Umbelliferone H. dauricum
H. vulcanicum [62,111]
Umbelliferone 7-O-β-D-glucoside H. dauricum [62]
Xanthyletin H. dshungaricum
H. multicaule [67]
Flavonoids
5,7,4’-Trihydroxy-6-methoxy-3-O-glucosyl flavone H. tuberculatum [106]
Chrysosplenetin H. myrtifolium [82]
Haplogenin H. perforatum [94]
Haploside A H. pedicellatum
H. perforatum [71,102]
Haploside B
H. dauricum
H. dubium
H. pedicellatum
[65,68,71]
Haploside C
H. foliosum
H. pedicellatum
H. perforatum
[71,93]
Haploside D
H. dauricum
H. dubium
H. leptomerum
H. perforatum
[65,68,93]
Haploside E H. perforatum [94]
Isorhamnetin H. foliosum [68,71]
Molecules 2021, 26, 4664 30 of 40
H. leptomerum
Limocitrin-7-O-β-D-(6’’-O acetyl)-glucoside H. foliosum
H. perforatum [71,94]
Lignans
1-Hydroxy-3-(hydroxymethyl)-6,7-dimethoxy-4-(3,4-
methylenedioxyphenyl)-2-naphthoic acid γ-lactone H. tuberculatum [109]
4-[6”,7”-Dihydroxygeranoyl]-matairesinol H. ptilosyylum [95]
4-Acetyl-diphyllin H. bucharicum
H. telephioides
[51,96]
4-Isopentylhaplomyrfolin A H. ptilosyylum [95,96]
4-Isopentylhaplomyrfolin B H. ptilosyylum [95,96]
7-O-(3-Methyl-2-butenyl)-isodaurinol H. myrtifolium [82]
(−)-lβ-Polygamain
H. cappadocicum
H. myrtifolium
H. ptilosyylum
[60,82,95,96]
(−)-Cappodicin H. cappadocicum [59]
(−)-Cappadoside H. cappadocicum [59]
(−)-Haplodoside H. cappadocicum [59]
(−)-Haplomyrfolin H. myrtifolium
H. vulcanicum [83,111]
(−)-Haplomyrtoside H. cappadocicum [60]
(−)-Majidine H. cappadocicum [60]
(−)-Secoisolariciresinol H. tuberculatum [109]
Acetyl-tuberculatin H. tuberculatum [110]
Arctigenin H. ptilosyylum [95,96]
Daurinol H. cappadocicum
H. dauricum [58,62]
Diphyllin
H. alberti-regelii
H. bucharicum
H. cappadocicum
H. dauricum
H. perforatum
H. telephioides
H. tuberculatum
H. vulcanicum
[49,51,58,65,96,106,111]
Eudesmin
H. acutifolium
H. perforatum
H. sieversii
[46,48,87,100]
Haplomyrtin H. myrtifolium
H. telephioides [82,96]
Haplomyrfolol H. vulcanicum [111]
Isodaurinol H. cappadocicum
H. ptilosyylum [58,95,96]
Justicidin A H. cappadocicum
H. tuberculatum [58,103,106,110]
Justicidin B
H. bucharicum
H. cappadocicum
H. dauricum
H. ptilosyylum
H. tuberculatum
[51,58,62,95,96,103,110]
Konyanin H. vulcanicum [112]
Molecules 2021, 26, 4664 31 of 40
Kusunokinin H. acutifolium
H. vulcanicum [47,111]
Matairesinol H. cappadocicum
H. ptilosyylum [58,95,96]
Picropolygamain H. ptilosyylum [95,96]
Syringarasinol H. vulcanicum [111]
Tuberculatin H. tuberculatum [110]
Others
N-(2-Phenylethyl)-benzamide H. tuberculatum [107]
Acetamide H. acutifolium [44]
Benzamide H. bucharicum [52]
Ferulic acid H. foliosum [70]
Vanillic acid H. cappadocicum [60]
Terpenoids
β-Sitosterol
H. acutifolium
H. bucharicum
H. leptomerum
H. multicaule
H. schelkovnikovii
[47,49,67,80,99]
Campesterol H. bucharicum [49]
Cholesterol H. acutifolium
H. bucharicum [47,49]
Oleanolic acid H. acutifolium [47]
Stigmasterol H. bucharicum [49]
As it can be seen from Table 3, the distribution of the compounds is not equable in
all the Haplophyllum species. Alkaloids have been reported as the most representative
compounds in the genus, and they are also of the utmost importance from a
chemosystematic standpoint [114]. Skimmianine is the most reported compound of this
class in the genus, followed by γ-fagarine [44–46,49,51–54,57,58,66,73,75,77,78,80–82,85–
87,89,90,95,97,98,101,106,108,111]. Coumarins were also quite present in the Haplophyllum
genus, in particular scopoletin [56,58,62,68,84,91,98,111]. Coumarins also present
chemosystematic relevance in the Rutaceae family [115]. Our results fully confirm this
aspect. Flavonoids are widespread secondary metabolites in the plant kingdom with
specific functions and in less cases, they have chemotaxonomic relevance. Some of these
are rare derivatives with peculiar functionalizations such as that observed for the 8-
hydroxyflavone acetylated glycosides that own a restricted distribution among some
genera of the Lamioideae subfamily of Lamiaceae, e.g., Pogostemon, Sideritis, Stachys, and
Galeopsis [116–121]. In these genera, isoscutellarein and hypolaetin glycosides have been
recognized with glucose and allose as saccharidic moieties. Similarly, it seems that the
presence of acetylated 8-hydroxyflavone derivatives related to haplogenin might have a
chemotaxonomic relevance given that they represent quite common compounds in the
Haplophyllum genus. The functionalizations in these 8-hydroxyflavone derivatives
involved the presence of glucose and rhamnose as saccharidic units like in haplosides A,
B, C, D and limocitrin-7-O-β-D-(6’’-O acetyl)-glucoside [65,68,71,93,94]. In fact, haplosides
B and D have been observed in H. dauricum, which is one of the few accepted species in
the genus, but compounds related to haploside have also been recognized in other
Haplophyllum species which are of unresolved classifications [65,68,71,93]. Further studies
on the phytochemistry of other Haplophyllum spp. with a problematic classification are
desirable in the future since the distribution of these flavonoids might be of help for their
correct classification. The other classes of natural compounds observed in the
Haplophyllum genus were triterpenoids with β-sitosterol as the major compound
[47,49,67,80,99] and lignans with diphyllin as the major compound [49,51,58,65,96,106,111]
together with some phenolic acid derivatives. These classes have little chemotaxonomic
Molecules 2021, 26, 4664 32 of 40
relevance since they can be biosynthesized by many other plant genera and species such
as those belonging to the Araucariaceae [4], Lamiaceae [122], and Orobanchaceae [123]
families. Yet, the presence of ferulic acid from H. foliosum [69] should be underlined since
it is the biogenetic precursor of coumarins. In addition, it is noteworthy that several
lignans have been described for the first time in Haplophyllum, and these compounds
might have a chemotaxonomic relevance. However, further studies are still necessary to
confirm this hypothesis.
3. Ethnobotany and biological activities
The use of many Haplophyllum species in traditional medicine has a long history in
several countries of the world due to their significant pharmacological activities. In the
subsections, the specific ethnobotanical uses and pharmacological properties of
Haplophyllum species are presented and discussed as well as the pharmacological studies
carried out on its components.
3.1. H. acutifolium
The paste derived from its whole plant is used in the Iranian northern region of
Turkmen Sahra to treat dermal wounds and inflammations [124]. Its ethanolic extract has
been reported to be highly and moderately active as cytotoxic agent against RAMOS,
MCF-7, and U937 cancer cell lines with IC50 values equal to 23.7, 83.5, and 55.9 µg/mL,
respectively. This effect is most probably due to the high presence of alkaloids in this plant
[125]. In addition, two of its constituents, the alkaloids acutine and haplacutine E, isolated
by preparative-scale HPLC, exhibited moderate antiplasmodial activities with IC50 values
equal to 2.17 µM and 3.79 µM, respectively [43]. Eudesmin isolated from this species also
showed good germicidal activity against Candida albicans, Aspergillus flavum, Salmonella
typhi, Klebsiella pneumonia, and Fusarium oxysporium, with growth inhibition percentages
well above 50% [46]. Indeed, haplotyn-A, one of its other constituents, showed medium
germicidal activity against Candida albicans, Salmonella typhi, and Klebsiella pneumonia, with
growth inhibition percentages between 30 and 40%, except for K. pneumonia, where the
value was found to be 51% [46].
3.2. H. canalicatum
The methanolic extract of H. canalicatum from Iran exhibited moderate cytotoxic
activities against several cancer cell lines, e.g., HepG-2, MCF-7, MDBK, WEHI, and A-549,
with IC50 values higher than 50 µg/mL [126]. This effect has been observed to be mainly
due to the quinolinone alkaloids reported in this species. In fact, 7-isopentenyloxy-γ-
fagarine, atanine, skimmianine, flindersine, and perfamine were singularly tested for their
cytotoxic properties against several cancer cell lines, i.e., HepG-2, MCF, KG-1a, RAJI, and
JURKAT, and showed good results. In this context, 7-isopentenyloxy-γ-fagarine was
found to be the most active, with IC50 values against JURKAT, RAJI, and MCF-7 of 3.6, 1.5,
and 15.5 µg/mL, respectively. These values are below the positive control of doxorubicin.
In addition, the other compounds have proved to be active even if with a moderate effect.
Atanine was found to be more powerful than doxorubicin only against JURKAT (IC50 =
9.3 µg/mL). Instead, skimmianine, flindersine, and perfamine were always less potent
than doxorubicin against each tested cancer cell line [125]. In addition to this, two other
alkaloids isolated from this species, namely acutine and hapacutine E, showed moderate
in vitro antiplasmodial activity against chloroquine-sensitive Pfc (3D7 strain), with IC50
values of 2.17 and 3.79 µM, respectively [43].
3.3. H. myrtifolium
H. myrtifolium is used to treat warts, herpes, lichens, erysipelas, diarrhea, and some
types of tumors such as testicular cancer [125]. Moreover, its ethanolic extract was found
to be a potent antileishmanial agent against the species Leishmania tropica, with an IC50
Molecules 2021, 26, 4664 33 of 40
value of 10.9 µg/mL [127]. The same effect was also observed for two of its alkaloid
constituents, i.e., skimmianine and γ-fagarine, which showed IC50 values equal to 25.7 and
8.7 µg/mL, respectively [127]. Moreover, the aerial parts of this species extracted using
several solvents proved to possess strong α-glucosidase and α-amylase activities as well
as strong anti-acetyl cholinesterase and antidiabetic properties [128].
3.4. H. perforatum
H. perforatum Kar & Kir. displayed good antimicrobial activities against Bacillus
subtilis, Klebsiella pneumoniae, Morganella morganti, and Staphylococcus aureus [129].
Moreover, a paste prepared from the aerial parts of H. perforatum Kar & Kir. is used by the
local people in the Southern regions of Shiraz, Iran, to relieve severe toothaches [130]. It is
also noteworthy that the methanolic extract of the leaves of H. perforatum Kar & Kir. has
potent antifungal activity against Botrytis cinerea and Alternaria solani. The percentages of
growth inhibition were found to be 76.32 and 55.44%, respectively [131]. Indeed, the
alkaloids perforine and khaplamine isolated from this species grown in Azerbaijan have
been reported to have sedative action [132].
3.5. H. sieversii
Two different crude extracts of the aerial parts of H. sieversii (petroleum ether and
water) were found to have antifungal activity against Colletotrichum acutatum Simmonds,
C. fragariae Brooks, and C. gloeosporioides (Penz.) Penz. and Sacc., with inhibition zone
diameters below 10 mm [100]. Flindersine and haplamine showed antialgal activity
against Oscillatoria perornata Skuja with IC50 values, after 24 h, equal to 15.9 and 1.8 µM,
respectively. These two compounds were found to be also active against Selenastrum
capricornutum even if with lower IC50 values (17.8 and 15.9 µM, respectively). Haplamine
was also found to be active against Pseudanabaena LW397 having an IC50 value of 2.0 µM
after 24 h [100].
3.6. H. tuberculatum
H. tuberculatum has been used in Saudi Arabia for the cure of rheumatoid arthritis,
malaria, headaches, and some gynecological problems, as well as to remove warts and
freckles from the skin and to treat skin discoloration, infections, and parasitic diseases
[133,134]. It is also used in Sudan and Mongolia for the treatment of diarrhea and as an
antipyretic agent [135]. In Sudan, the herb is also employed as an antispasmodic, to treat
allergic rhinitis, gynecological disorders, asthma, and breathing difficulties [136]. In
Algeria, it has been used as an antiseptic, calming, vermifuge, and hypnotic neurological
and against injuries, ulcers, infertility, diabetes, bloating, fever, liver diseases, otitis,
rheumatism, obesity, constipation, colon, diarrhea, gases, hypertension, menstrual pains,
cardiac diseases, scorpion stings, flu, vomiting, throat inflammation, tonsillitis, cough,
and loss of appetite [137]. In the northern regions of Oman, the juice made with the leaves
has been used to treat headaches and arthritis for many years [138]. In Egypt, the
flowering parts are used as a drink to treat fever, abdominal upset, anemia, gastric pains,
intestinal worms, malaria, and as an aphrodisiac, while its decoction is used for rheumatic
pains [139]. Moreover, its ethanolic extract was observed to have high cytotoxic activities
against
RAMOS, U937, MCF-7, LNCap-FGC-10, 5637, and RPMI-8866 cancer cell lines. The
relative IC50 values were 25.3, 29.3, 57.2, below 7.81, 23.3, and 31.8 µg/mL, respectively.
This effect is mainly due to its alkaloid content [125]. The same extract is also able to
exhibit strong antimicrobial, anti-inflammatory and antifungal effects [136]. A strong
effect was also observed for the essential oil derived from the aerial parts against Aedes
aegypti. In particular, as reported, this oil could kill 100 % of its larvae at 250 and 125 ppm
[34]. In addition, a medium germicidal effect was observed for the same essential oil
against several Candida spp., Alternaria alternata, Curvularia lunata, Fusarium oxysporium,
Molecules 2021, 26, 4664 34 of 40
Stemphylium solani, and Aspergillus flavus with MIC values below 1 mg/mL [32]. Indeed,
against Escherichia coli, Staphylococcus aureus, Salmonella choleraesuis, and Bacillus subtilis,
the inhibition zone diameters were 17.6, 6.7, 17.3, and 12.3 mm, respectively. The n-hexane
extract of this species also showed medium antibacterial effects against Staphylococcus
aureus, Escherichia coli and Pseudomonas aeruginosa, with inhibition zone diameters of 12,
10, and 16 mm, respectively. The chloroform and methanol extracts were active, in this
sense, only against Pseudomonas aeruginosa, with inhibition zone diameters of 11 and 17
mm, respectively [35]. The main responsible compounds for this seem to be the alkaloids
and the lignans. The essential oil is also able to exhibit good antitumor activities against
lung carcinoma H1299 cell lines, with an IC50 value equal to 4.7 µg/mL [37]. The aqueous
extract of the leaves has also antispasmodic effects [140]. Additionally, one of its
constituents, the alkaloid tuberine, has shown high anti-microbial activity against Bacillus
subtilis and Saccharomyces cerevisiae at the concentration of 1 µg/mL [141]. Another alkaloid
constituent, dihydroperfamine, was found to have strong anxiolytic effects [103]. Indeed,
one of its lignans, 1-hydroxy-3-(hydroxymethyl)-6,7-dimethoxy-4-(3,4-
methylenedioxyphenyl)-2-naphthoic acid γ-lactone, has shown good selective antitumor
effects against the human lung cancer cell lines H-125M, with inhibition zone units equal
to 700 [109]. Lastly, its lignans justicidin A, justicidin B, tuberculatin, and acetyl-
tuberculatin possess strong cytotoxic effects against A375 cancer cell lines with GI50 values
equal to 25, 17, 3, and 3 µM, respectively [110]. Unfortunately, it is quite important to
highlight that the species is severely threatened and is at the verge of extinction in some
countries [142].
3.7. Other species
The lignan diphyllin, isolated from H. bucharicum, exhibited strong antileishmanial
activity, especially against intracellular amastigote forms (IC50 = 0.2 µM), while it did not
show remarkable activity against the promastigote forms (IC50 = 14.4 µM). Moreover, it
possesses moderate antiproliferative effects on human monocytes, with an IC50 value of
35.2 µM [143].
H. dauricum is employed mainly in Mongolia as an antitumor agent [144], especially
because of its coumarin content [145]. In addition, one of its lignan components, daurinol,
has shown remarkable cytotoxic properties (IC50 below 20 µM), being a potential catalytic
inhibitor of topoisomerase IIα and acting at the S phase, thus not causing DNA or RNA
damages [146,147].
H. leptomerum is used in Uzbekistan for its cytotoxic activities [148], mainly due to
one of its constituents, the alkaloid dictamine, which is able to exhibit strong cytotoxic
effects against the human cancer cell lines, e.g., HeLa and HCT-116, with IC50 values equal
to 65.0 and 85.0 µM, respectively [81].
H. pedicellatum has shown to possess antimicrobial activity against Pseudomonas
aeruginosa [129].
The lignan 1β-polygamain from H. ptilosyylum showed strong cytotoxic activity (IC50
= 111.7 pg/mL) against HIV-1 [95].
The infusion of H. robustum whole plant is frequently used in the Iranian northern
region of Maraveh Tappeh against dermal wounds as a beverage, thus acting from the
inside [149].
The ethanolic extract of H. stapfanum Hand.-Mazz. displayed high cytotoxic
properties against RAMOS, U937, and LNCap-FGC-10 cancer cell lines (IC50 values are
equal to 12.3, 15.6, and 28.3 µg/mL, respectively), as well as a moderate activity against
the 5637 and MCF-7 cancer cell lines (IC50 values are equal to 23.3 and 92.6 µg/mL,
respectively). These effects are thought to be due to its alkaloid content, but no precise
phytochemical analysis has been conducted on this species up to present [125].
H. telephioides is used in some areas of Turkey to treat flu [150].
H. tenue ethanolic extract and EO showed high radical scavenging activity, with IC50
values equal to 103.88 and 101.98 pg/mL, respectively. In addition, the ethanolic extract
Molecules 2021, 26, 4664 35 of 40
showed strong antimicrobial activity against Clostridium perfringens (IC50 = 16 pg/mL)
[151].
Lastly, the ethanolic extract of H. viridulum Soják from Iran displayed moderate
cytotoxic activities against RAMOS and U937 cancer cell lines, with IC50 values of 48.3 and
79.0 µg/mL, respectively) [125].
4. Conclusions
In the current review paper, the literature data have been systematically reviewed
and different aspects relating to the numerous Haplophyllum species have been discussed.
From a phytochemical point of view, a large number of bioactive natural compounds,
both volatile and non-volatile, have been characterized. In addition, as discussed earlier,
the ethnobotanical knowledge of Haplophyllum species is valuable, and these species are
widely prescribed in the traditional medicine of many countries, in particular in the
Middle East. The other aspect of Haplophyllum which deserves more attention is the
growing interest to study the potential biological activities of its species. In this sense,
Haplophyllum species, as well as their bioactive compounds, are able to exhibit many
pharmacological activities, among which the cytotoxic, antiviral, antifungal and
antimicrobial are the most important. However, it should be underlined that further
investigations are still required to confirm the real therapeutic potentials of these species
and to represent their remarkable phytochemical and biological potency. Summarizing,
the tabulated and argued data in the current review paper can attract the attention of the
scientific community towards the Haplophyllum species and prompt researchers in
phytochemical, pharmaceutical, and related areas to design and develop more attempts
on these valuable herbal plants.
Author Contributions: Conceptualization: M.M.; data collection: M.M., A.V., and C.F.; writing:
M.M., A.V., C.F., M.S., A.B., and B.M. All authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable
Informed Consent Statement: Not applicable
Conflicts of Interest: The authors declare no conflict of interest.
References
1. Mohammadhosseini, M. The ethnobotanical, phytochemical and pharmacological properties and medicinal applications of
essential oils and extracts of different Ziziphora species. Ind. Crop Prod. 2017, 105, 164–192.
2. Mohammadhosseini, M.; Venditti, A.; Sarker, S.D.; Nahar, L.; Akbarzadeh, A. The genus Ferula: Ethnobotany, phytochemistry
and bioactivities – A review. Ind. Crop Prod. 2019, 129, 350–394.
3. Mohammadhosseini, M.; Frezza, C.; Venditti, A.; Akbarzadeh, A. Ethnobotany and phytochemistry of the genus Eremostachys
Bunge. Curr. Org. Chem. 2019, 23, 1828–1842.
4. Frezza, C.; Venditti, A.; De Vita, D.; Toniolo, C.; Franceschin, M.; Ventrone, A.; Tomassini, L.; Foddai, S.; Guiso, M.; Nicoletti,
M.; Bianco, A.; Serafini, M. Phytochemistry, chemotaxonomy, and biological activities of the Araucariaceae family – a review.
Plants 2020, 9(888), 1-73.
5. The Plant List. Available online: www.theplantlist.org. (accessed on 24 June 2021).
6. Townsend, C. Taxonomic Revision of the Genus Haplophyllum (Rutaceae), Hooker’s Icones Plantarum. Bentham-Moxon Trust,
Kent, U.K, 1986.
7. Salvo, G.; Manafzadeh, S.; Ghahremaninejad, F.; Tojibaev, K.; Zeltner, L.; Conti, E. Phylogeny, morphology, and biogeography
of Haplophyllum (Rutaceae), a species-rich genus of the Irano-Turanian floristic region. Taxon 2011, 60, 513–527.
8. Prieto, J.,M.; Haplophyllum, A. Juss, a rich source of bioactive natural principles. In: Bitterlich, A., Fischl, S., editors. Bioactive
Compounds: Types, Biological Activities and Health Effects [Internet]. New York: Nova Science Publishers; 2012, pp. 341–380.
9. Nekoei, M.; Mohammadhosseini, M. Application of HS-SPME, SDME and cold-press coupled to GC/MS to analysis the essential
oils of Citrus sinensis CV. Thomson Navel and QSRR study for prediction of retention indices by stepwise and genetic algorithm-
multiple linear regression approaches. Anal. Chem. Lett. 2014, 4, 93–103.
Molecules 2021, 26, 4664 36 of 40
10. Hashemi-Moghaddam, H.; Mohammadhosseini, M.; Azizi, Z. Impact of amine- and phenyl-functionalized magnetic
nanoparticles impacts on microwave-assisted extraction of essential oils from root of Berberis integerrima Bunge. J. Appl. Res.
Med. Aromat. Pl. 2018, 10, 1–8.
11. Hashemi-Moghaddam, H.; Mohammadhosseini, M.; Salar, M. Chemical composition of the essential oils from the hulls of
Pistacia vera L. by using magnetic nanoparticle-assisted microwave (MW) distillation: Comparison with routine MW and
conventional hydrodistillation. Anal. Methods 2014, 6, 2572–2579.
12. Bakkali, F.; Averbeck, S.; Averbeck, D.; Idaomar, M. Biological effects of essential oils–A review. Food Chem. Toxicol. 2008, 46(2),
446-475.
13. Shaaban, H.A.; El-Ghorab, A.H.; Shibamoto, T. Bioactivity of essential oils and their volatile aroma components: Review. J.
Essent. Oil Res. 2012, 24(2), 203-212.
14. Sánchez-González, L.; Vargas, M.; González-Martínez, C.; Chiralt, A.; Cháfer, M. Use of essential oils in bioactive edible
coatings: A review. Food Engineer. Rev. 2011, 3, 1-16.
15. Aljaafari, M.N.; AlAli, A.O.; Baqais, L.; Alqubaisy, M.; Al Ali, M.; Molouki, A.; Ong-Abdullah, J.; Abushelaibi, A.; Lai, K.-S.;
Lim, S.E. An overview of the potential therapeutic applications of essential oils. Molecules 2021, 26(628), 1-27.
16. Asili, J.; Fard, M.R.; Ahi, A.; Emami, S.A. Chemical composition of the essential oil from aerial parts of Haplophyllum acutifolium
(DC.) G. Don from Iran. J. Essent. Oil-Bear. Pl. 2011, 14, 201–207.
17. Azadi, B.; Khaef, S. Volatile constituents of Haplophyllum buhsei Boiss. flowering aerial parts. Bull. Chem. Soc. Ethiopia 2015, 29,
327–330.
18. Biniyaz, T.; Habibi, Z.; Masoudi, S.; Rustaiyan, A. Composition of the essential oils of Haplophyllum furfuraceum Bge. ex Boiss.
and Haplophyllum virgatum spach. from Iran. J. Essent. Oil Res. 2007, 19, 49–51.
19. Bamoniri, A.; Mirjalili, B.B.F.; Mazoochi, A.; Naeimi, H.; Golchin, H.; Batooli, H. Study of the bioactive and fragrant constituents
extracted from leaves and aerial parts of Haplophyllum glabrrimum Bge ex Bioss from central Iran by nano scale injection. Dig. J.
Nanomater. Biostruct. 2010, 5, 169–172.
20. Azadi, B.; Khaef, S. The essential oil composition of Haplophyllum laeviusculum C. C. Towns. aerial parts. J. Chem. Pharm. Res.
2014, 6, 1002–1005.
21. Javidnia, K.; Miri, R.; Soltani, M.; Varamini, P. Volatile constituents of two species of Haplophyllum a. Juss. from Iran [H.
lissonotum C. Town. and H. buxbaumii (Poir.) G. Don. Subsp. Mesopotamicum (Boiss.) C. Town.]. J. Essent. Oil Res. 2009, 21, 48–51.
22. Ünver-Somer, N., Kaya, G.I.; Sarikaya, B.; Önür, M.A.; Özdemir, C.; Demircispi-Sup, B., Başer, K.H.C. Composition of the
essential oil of endemic Haplophyllum megalanthum Bornm. from Turkey. Rec. Nat. Prod. 2012, 6, 80–83.
23. Saglam, H., Gozler, T.; Kivcak, B.; Demirci, B.; Baser, K.H.C. Volatile compounds from Haplophyllum myrtifolium. Chem. Nat.
Compd. 2001, 37, 442–444.
24. Saglam, H.; Gozler, T.; Kivcak, B.; Demirci, B.; Baser, K.H.C. Composition of the essential oil of Haplophyllum myrtifolium. Chem.
Nat. Compd. 2001, 37, 439–441.
25. Mohammadhosseini, M.; Nekoei, M.; Mashayekhi, H.A.; Aboli, J. Chemical composition of the essential oil from flowers, leaves
and stems of Haplophyllum perforatum by using head space solid phase microextraction. J. Essent. Oil-Bear. Pl. 2012, 15, 506–515.
26. Masoudi, S.; Rustaiyan, A.; Azar, P.A. Essential oil of Haplophyllum robustum Bge. from Iran. J. Essent. Oil Res. 2004, 16, 548–549.
27. Gholivand, M.B.; Rahimi-Nasrabadiab, M.; Batoolic, H.; Samimid, H. Chemical composition and antioxidant activity of the
essential oil and various extracts of Haplophyllum robustum Bge. Nat. Prod. Res. 2012, 26, 883–891.
28. Bamonieri, A.; Safaei-Ghomi, J.; Asadi, H.; Batooli, H.; Masoudi, S.; Rustaiyan, A. Essential oils from leaves, stems, flowers and
fruits of Haplophyllum robustum Bge. (Rutaceae) grown in Iran. J. Essent. Oil Res. 2006, 18, 379–380.
29. Rahimi-Nasrabadi, M.; Gholivand, M.B.; Batooli, H. Chemical composition of the essential oil from leaves and flowering aerial
parts of Haplophyllum robustum Bge. (Rutaceae). Dig. J. Nanomater. Biostruct. 2009, 4, 819–822.
30. Yari, M.; Masoudi, S.; Rustaiyan, A. Essential oil of Haplophyllum tuberculatum (Forssk.) a. Juss. grown wild in Iran. J. Essent. Oil
Res. 2000, 12, 69–70.
31. Al Yousuf, M.H.; Bashir, A.K.; Veres, K.; Dobos, Á.; Nagy, G.; Máthé, I.; Blunden, G.; Vera, J.R. Essential oil of Haplophyllum
tuberculatum (Forssk.) A. Juss. from the United Arab Emirates. J. Essent. Oil Res. 2005, 17, 519–521.
32. Al-Burtamani, S.K.S.; Fatope, M.O.; Marwah, R.G.; Onifade, A.K.; Al-Saidi, S.H. Chemical composition, antibacterial and
antifungal activities of the essential oil of Haplophyllum tuberculatum from Oman. J. Ethnopharmacol. 2005, 96, 107–112.
33. Javidnia, K.; Miri, R.; Banani, A. Volatile oil constituents of Haplophyllum tuberculatum (Forssk.) A. Juss. (Rutaceae) from Iran. J.
Essent. Oil Res. 2006, 18, 355–356.
34. Al-Rehaily, A.J.; Alqasoumi, S.I.; Yusufoglu, H.S.; Al-Yahya, M.A.; Demirci, B.; Tabanca, N.; Wedge, D.E.; Demirci, F.; Bernier,
U.R.; Becnel, J.J.; Temel, H.E.; Baser, K.H.C. Chemical composition and biological activity of Haplophyllum tuberculatum Juss.
essential oil. J. Essent. Oil-Bear. Pl. 2014, 17, 452–459.
35. Debouba, M.; Khemakhem, B.; Zouari, S.; Meskine, A.; Gouia, H. Chemical and biological activities of Haplophyllum tuberculatum
organic extracts and essential oil. J. Essent. Oil-Bear. Pl. 2014, 17, 787–796.
36. Mechehoud, Y.; Chalard, P.; Figuérédo, G.; Marchioni, E.; Benayache, F.; Benayache, S. Chemical composition of the essential
oil of Haplophyllum tuberculatum (Forssk.) L.A. Juss. from Algeria. Res. J. Pharm. Biol. Chem. Sci. 2014, 5, 1416–1419.
37. Sabry, O.M.M.; Sayed, A.M.E.; Alshalmani, S.K. GC/MS analysis and potential cytotoxic activity of Haplophyllum tuberculatum
essential oils against lung and liver cancer cells. Pharmacog. J. 2016, 8, 66–69.
Molecules 2021, 26, 4664 37 of 40
38. Hamdi, A.; Majouli, K.; Vander Heyden, Y.; Flamini, G.; Marzouk, Z. Phytotoxic activities of essential oils and hydrosols of
Haplophyllum tuberculatum. Ind. Crop Prod. 2017, 97, 440–447.
39. Karimi, F.; Yousefzadi, M.; Mirjalili, M.H.; Rahmani, N.; Zaeifi, M. Chemical composition of the essential oil of Haplophyllum
virgatum var. virgatum from Iran. Chem. Nat. Compd. 2013, 49, 148–149.
40. Conti, B.; Canale, A.; Cioni, P.L.; Flamini, G.; Rifici, A. Hyptis suaveolens and Hyptis spicigera (Lamiaceae) essential oils:
Qualitative analysis, contact toxicity and repellent activity against Sitophilus granarius (L.) (Coleoptera: Dryophthoridae). J. Pest.
Sci. 2011, 84, 219–228.
41. Rouis, Z.; Laamari, A.; Abid, N.; Elaissi, A.; Cioni, P.L.; Flamini, G.; Aouni, M. Chemical composition and larvicidal activity of
several essential oils from Hypericum species from Tunisia. Parasitol. Res. 2013, 112, 699–705.
42. Najar, B.; Cervelli, C.; Ferri, B.; Cioni, P.L.; Pistelli, L. Essential oils and volatile emission of eight South African species of
Helichrysum grown in uniform environmental conditions. South Afr. J. Bot. 2019, 124, 178–187.
43. Staerk, D.; Kesting, J.R.; Sairafianpour, M.; Witt, M.; Asili, J.; Emami, S.A.; Jaroszewski, J.W. Accelerated dereplication of crude
extracts using HPLC-PDA-MS-SPE-NMR: Quinolinone alkaloids of Haplophyllum acutifolium. Phytochemistry 2009, 70, 1055–
1061.
44. Razzakova, D.M.; Bessonova, I.A.; Yunusov, S.Y. Alkaloids of Haplophyllum acutifolium. Chem. Nat. Compd. 1975, 9, 199–202.
45. Sadikov, Y.J.; Hojimatov, M. Alkaloids of Haplophyllum acutifolium (DC) G. Don. Fil. Plant Resour. 1988, 24, 77–81.
46. Ali, M.S.; Fatima, S.; Pervez, M.K. Haplotin: A new furanoquinoline from Haplophyllum acutifolium (Rutaceae). J. Chem. Soc. Pak.
2008, 30, 775–779.
47. Ali, M.S.; Pervez, M.K.; Saleem, M.; Tareen, R.B. Haplophytin-A and B: The alkaloidal constituents of Haplophyllum acutifolium.
Phytochemistry 2001, 57, 1277–1280.
48. Razzakova, D.M.; Bessonova, I.A.; Yunusov, S.Y. Eudesmin – A lignane from Haplophyllum acutifolium and H. perforatum. Chem.
Nat. Compd. 1972, 8, 646–647.
49. Nesmelova, E.F.; Razakova, D.M.; Akhmedzhanova, V.I.; Bessonova, I.A. Diphyllin from Haplophyllum alberti-regelii, H.
bucharicum, and H. perforatum. Chem. Nat. Compd. 1983, 19, 608.
50. Pavlović, D.R.; Zlatković, B.; Živanović, S.; Kitić, D.; Golubović, T. Serbian Rutaceae species: Comparison of chemical profiles
and radical scavenging activity. Biol. Nyssana 2018, 9, 37–43.
51. Bessonova, I.A. Components of Haplophyllum bucharicum. Chem. Nat. Compd. 2000, 36, 323–324.
52. Ubaidullaev, K.; Bessonova, I.A.; Yunusov, S.Y. Alkaloids of Haplophyllum pedicellatum, H. obtusifolium, and H. bucharicum.
structure of bucharamine. Chem. Nat. Compd. 1974, 8, 337–339.
53. Fiot, J.; Jansen, O.; Akhmedjanova, V.; Angenot, L.; Balansard, G.; Ollivier, E. HPLC quantification of alkaloids from
Haplophyllum extracts and comparison with their cytotoxic properties. Phytochem. Anal. 2006, 17, 365–369.
54. Bessonova, I.A.; Yunusov, S.Y. Alkaloids of Haplophyllum bungei. Chem. Nat. Compd. 1989, 25, 18–20.
55. Gashimov, N.F.; Orazmukhamedova, N.O. Coumarins of Haplophyllum bungei. Chem. Nat. Compd. 1979, 14, 563.
56. Abyshev, A.Z.; Gashimov, N.F. Coumarin composition of Haplophyllum bungei. Chem. Nat. Compd. 1982, 18, 615–616.
57. Varamini, P.; Javidnia, K.; Soltani, M.; Mehdipour, A.R.; Ghaderi, A. Cytotoxic activity and cell cycle analysis of quinoline
alkaloids isolated from Haplophyllum canaliculatum Boiss. Planta Med. 2009, 75, 1509–1516.
58. Gözler, B.; Arar, G.; Gozler, T.; Hesse, M. Isodaurinol, an arylnaphthalene lignan from Haplophyllum cappadocicum.
Phytochemistry 1992, 31, 2473–2475.
59. Gözler, B.; Önür, M.A.; Gözler, T.; Kadan, G.; Hesse, M. Lignans and lignan glycosides from Haplophyllum cappadocicum.
Phytochemistry 1994, 37, 1693–1698.
60. Gözler, B.; Gözler, T.; Saǧlam, H.; Hesse, M. Minor lignans from Haplophyllum cappadocicum. Phytochemistry 1996, 42, 689–693.
61. Arar, G.; Gözler, T.; Bashir, M.; Shamma, M. Malatyamine, a 4-quinolone alkaloid from Haplophyllum cappadocicum. J. Nat. Prod.
1985, 48, 642–643.
62. Batsurén, D.; Batirov, E.K.; Malikov, V.M. Coumarins of Haplophyllum dauricum. 5,7-Dihydroxycoumarin and its C-glucoside.
Chem. Nat. Compd. 1982, 18, 616–617.
63. Batsurén, D.; Batirov, E.K.; Malikov, V.M.; Yagudaev, M.R. Structures of daurosides A and B – New acylated coumarin
glycosides from Haplophyllum dauricum. Chem. Nat. Compd. 1983, 19, 134–138.
64. Vdovin, A.D.; Batsurén, D.; Batirov, É.K.; Yagudaev, M.R.; Malikov, V.M. 1H and 13C NMR spectra and the structure of a new
coumarin, C-glycoside dauroside D, from Haplophyllum dauricum. Chem. Nat. Compd. 1983, 19, 413–416.
65. Batirov, E.K.; Batsurén, D.; Malikov, V.M. Components of Haplophyllum dauricum. Chem. Nat. Compd. 1984, 20, 226–227.
66. Bessonova, I.A.; Batsurén, D.; Yunusov, S.Y. Alkaloids of Haplophyllum dauricum. Chem. Nat. Compd. 1984, 20, 68–70.
67. Tikhomirova, L.I.; Pimenov, M.G.; Kuznetsova, T.A. Coumarins from Haplophyllum dzhungaricum and H. multicaule. Chem. Nat.
Compd. 1975, 10, 403.
68. Yuldashev, M.P. Flavonoids and coumarins of Haplophyllum leptomerum and H. dubium. Chem. Nat. Compd. 2002, 38, 192–193.
69. Akhmedzhanova, V.I.; Bessonova, I.A.; Yunusov, S.Y. Alkaloids of Haplophyllum foliosum. Chem. Nat. Compd. 1980, 16, 574–576.
70. Akhmedzhanova, V.I.; Bessonova, I.A.; Yunusov, S.Y. Alkaloids of Haplophyllum foliosum. III. Structure of folidine. Chem. Nat.
Compd. 1985, 21, 782–783.
71. Yuldashev, M.P. Flavonoids of Haplophyllum foliosum and H. pedicellatum. Chem. Nat. Compd. 2001, 37, 288–289.
72. Aynehchi, Y.; Salehi Sormaghi, M.; Amin, G.; Soltani, A.; Qumehr, N. Survey of Iranian plants for saponins, alkaloids, flavonoids
and tannins. II. Int. J. Crude Drug Res. 1982, 20, 61–70.
Molecules 2021, 26, 4664 38 of 40
73. Kodirova, D.R.; Rasulova, K.A.; Abdullaev, N.D.; Bobakulov, K.M. Alkaloids from the plant Haplophyllum griffithianum. Chem.
Nat. Compd. 2011, 47, 856–857.
74. Kodirova, D.R.; Rasulova, K.A.; Turgunov, K.K.; Tashkhodzhaev, B.; Bobakulov, K.M.; Abdullaev, N.D. Gerphytine, a new
furanoquinoline alkaloid from Haplophyllum griffithianum. Chem. Nat. Compd. 2011, 47, 773–776.
75. Rasulova, K.A.; Kodirova, D.R.; Bobakulov, K.M.; Abdullaev, N.D. Griffithine, a new furanoquinolone alkaloid from:
Haplophyllum griffithianum. Chem. Nat. Compd. 2015, 51, 743–745.
76. Kodirova, D.R.; Rasulova, K.A.; Sagdullaev, S.S.; Aisa, H.A. Haplophyllum griffithianum as a source of quinoline alkaloids. Chem.
Nat. Compd. 2018, 54, 213–214.
77. Isaev, Y.I.; Bessenova, I.A. Alkaloids of Haplophyllum schelkovnikovii, H. villosum, H. tenue and H. kowalenskyi. Chem. Nat.
Compd. 1974, 6, 815.
78. Nesmelova, E.F.; Bessonova, I.A.; Yunusov, S.Y. Alkaloids of Haplophyllum latifolium the structure and synthesis of haplamide
and haplamidine. Chem. Nat. Compd. 1978, 14, 637–639.
79. Nesmelova, E.F.; Bessonova, I.A.; Yunusov, S.Y. Alkaloids of Haplophyllum latifolium the structure of haplatine. Chem. Nat.
Compd. 1978, 14, 645–650.
80. Akhmedzhanova, V.I.; Bessonova, I.A.; Yunusov, S.Y. Alkaloids of Haplophyllum leptomerum. I. The structure of leptomerine.
Chem. Nat. Compd. 1986, 22, 78–79.
81. Akhmedzhanova, V.I.; Angenot, L.; Shakirov, R.S. Alkaloids from Haplophyllum leptomerum. Chem. Nat. Compd. 2010, 46, 502–
503.
82. Saǧlam, H.; Gözler, T.; Gözler, B. A new prenylated arylnaphthalene lignan from Haplophyllum myrtifolium. Fitoterapia 2003, 74,
564–569.
83. Evcim, U.; Gozler, B.; Freyer, A.J.; Shamma, M. Haplomyrtin and (-)-haplomyrfolin: Two lignans from Haplophyllum myrtifolium.
Phytochemistry 1986, 25, 1949–1951.
84. Kuznetsova, G.A.; Gashimov, N.F. The structure of a new coumarin from Haplophyllum pedicellatum. Chem. Nat. Compd. 1974, 8,
649.
85. Rasulova, K.A.; Bessonova, I.A. Alkaloids of Haplophyllum perforatum. Chem. Nat. Compd. 1995, 31, 487–488.
86. Bessonova, I.A.; Acetylhaplophyllidine, A new alkaloid from Haplophyllum perforatum. Chem. Nat. Compd. 1999, 35, 589–590.
87. Razakova, D.M.; Bessonova, I.A.; Abdullaeva, K.A.; Yunusov, S.Y. Components of Haplophyllum perforatum. Chem. Nat. Compd.
1983, 19, 377–378.
88. Rasulova, K.A.; Bessonova, I.A.; Yagudaev, M.R.; Yunusov, S.Y. Haplosinine – A new furanoquinoline glycoalkaloid from
Haplophyllum perforatum. Chem. Nat. Compd. 1987, 23, 731–734.
89. Abdullaeva, K.A.; Bessonova, I.A.; Yunusov, S.Y. Alkaloids of Haplophyllum perforatum. II. Chem. Nat. Compd. 1978, 14, 179–182.
90. Rasulova, K.A.; Bessonova, I.A. Alkaloids of Haplophyllum perforatum. Chem. Nat. Compd. 1992, 28, 214–216.
91. Yuldashev, M.P.; Batirov, E.K.; Malikov, V.M. Coumarin glycosides of Haplophyllum perforatum. Chem. Nat. Compd. 1980, 16,
125–128.
92. Batirov, E.K.; Malikov, V.M. Haploside A – A new acylated flavonol glycoside from Haplophyllum perforatum. Chem. Nat. Compd.
1980, 16, 242–245.
93. Batirov, E.K.; Yuldashev, M.P.; Khushbatkova, Z.A.; Syrov, V.N.; Malikov, V.M. Flavonoids of Haplophyllum perforatum.
Structure and hypoazotemic activity of haploside C. Chem. Nat. Compd. 1987, 23, 54–57.
94. Yuldashev, M.P.; Batirov, E.K.; Malikov, V.M. Flavonoids of Haplophyllum perforatum. New glycosides of limocitrin. Chem. Nat.
Compd. 1985, 21, 179–182.
95. Ulubelen, A.; Gil, R.R.; Cordell, G.A.; Meriçli, A.H.; Meriçli, F. Cytotoxic lignans from Haplophyllum species. Pure Appl. Chem.
1994, 66, 2379–2382.
96. Ulubelen, A.; Meriçli, A.H.; Meriçli, F.; Kaya, Ü. An alkaloid and lignans from Haplophyllum telephioides. Phytochemistry 1994, 35,
1600–1601.
97. Ulubelen, A.; Mericli, A.H.; Mericli, F.; Sonmez, U.; Ilarslan, R. Alkaloids and coumarins from Haplophyllum thesioides. Nat. Prod.
Lett. 1993, 1, 269–272.
98. Bessonova, I.A.; Kurbanov, D.; Yunusov, S.Y. Components of Haplophyllum ramosissimum. Chem. Nat. Compd. 1989, 25, 39–40.
99. Abyshev, A.Z.; Denisenko, P.P.; Isaev, N.Y.; Kerimov, Y.B. Coumarins of Haplophyllum schelkovnikovii. Chem. Nat. Compd. 1979,
14, 564–565.
100. Cantrell, C.L.; Schrader, K.K.; Mamonov, L.K.; Sitpaeva, G.T.; Kustova, T.S.; Dunbar, C.; Wedge, D.E. Isolation and identification
of antifungal and antialgal alkaloids from Haplophyllum sieversii. J. Agric. Food Chem. 2005, 53, 7741–7748.
101. Al-Shamma, A.; Al-Douri, N.A.; Phillipson, J.D. Alkaloids of Haplophyllum tuberculatum from Iraq. Phytochemistry 1979, 18, 1417–
1419.
102. Lavie, D.; Danieli, N.; Weitman, R.; Glotter, E.J.T. A new quinolone type alkaloid from Haplophylum tuberculatum (Rutaceae).
Tetrahedron 1968, 24, 3011–3018.
103. Al-Yahya, M.A.; El-Domiaty, M.M.; Al-Meshal, I.A.; Al-Said, M.S.; El-Feraly, F.S. (+)-Dihydroperfamine: An alkaloid from
Haplophyllum tuberculatum. Int. J. Pharm. 1991, 29, 268–272.
104. McPhail, A.T.; McPhail, D.R.; Al-Said, M.S.; El-Domiaty, M.M.; El-Feraly, F.S. Revision of the stereochemistry of (+)-tuberine,
an alkaloid from Haplophyllum tuberculatum. Phytochemistry 1990, 29, 3055–3057.
105. Sheriha, M.G.; Abou Amer, M.K., Lignans of Haplophyllum tuberculatum. Phytochemistry 1984, 23, 151–153.
Molecules 2021, 26, 4664 39 of 40
106. Khalid, S.A.; Waterman, P.G. Alkaloid, lignan and flavonoid constituents of Haplophyllum tuberculatum from Sudan. Planta Med.
1981, 43, 148–152.
107. Al-Rehaily, A.J.; Al-Howiriny, T.A.; Ahmad, M.S.; Al-Yahya, M.A.; El-Feraly, F.S.; Hufford, C.D.; McPhail, A.T. Alkaloids from
Haplophyllum tuberculatum. Phytochemistry 2001, 57, 597–602.
108. Ali, A.-S.; Ekbal, A.-K.; Enas, J.; Diar, A. Qualitative and quantitative investigations of furocoumarin derivatives (psoralens) of
Haplophyllum tuberculatum (Rutaceae). AJPS 2005, 2, 24–36.
109. Youssef, D. Lignans from the aerial parts of Haplophyllum tuberculatum (Forssk) A. Juss. Bull. Pharm. Sci., Assiut Univer. 2005, 28,
261–267.
110. Al-Qathama, A.; Gibbons, S.; Prieto, J.M. Differential modulation of Bax/Bcl-2 ratio and onset of caspase-3/7 activation induced
by derivatives of Justicidin B in human melanoma cells A375. Oncotarget 2017, 8(56), 95999-96012.
111. Gözler, B.; Rentsch, D.; Gözler, T.; Ünver, N.; Hesse, M. Lignans, alkaloids and coumarins from Haplophyllum vulcanicum.
Phytochemistry 1996, 42, 695–699.
112. Gözler, T.; Gözler, B.; Linden, A.; Hesse, M. Vulcanine, a β-carboline alkaloid from Haplophyllum vulcanicum. Phytochemistry
1996, 43, 1425–1426.
113. Gözler, T.; Gözler, B.; Patra, A.; Leet, J.E.; Freyer, A.J.; Shamma, M. Konyanin: A new lignan from Haplophyllum vulcaniclm.
Tetrahedron 1984, 40, 1145–1150.
114. Waterman, P.G. Alkaloids of the rutaceae: Their distribution and systematic significance. Biochem. Syst. Ecol. 1975, 3, 149–180.
115. Gray, A.I.; Waterman, P.G. Coumarins in the Rutaceae. Phytochemistry 1978, 17, 845–864.
116. Tomas-Barberan, F.A.; Gil, M.I.; Ferreres, F.; Tomaslorente, F. Flavonoid p-coumaroylglucosides and 8-hydroxyflavone
allosylglucosides in some Labiatae. Phytochemistry 1992, 31, 3097–3102.
117. Venditti, A.; Bianco, A.; Frezza, C.; Serafini, M.; Giacomello, G.; Giuliani, C.; Bramucci, M.; Quassinti, L.; Lupidi, G.; Lucarini,
D.; Papa, F.; Maggi, F. Secondary metabolites, glandular trichomes and biological activity of Sideritis montana L. subsp. montana
from Central Italy. Chem. Biodivers. 2016, 13 1380-1390.
118. Venditti, A.; Bianco, A.; Maggi, F.; Nicoletti, M. Polar constituents composition of endemic Sideritis italica (MILL.)
GREUTER et BURTER from Central Italy. Nat. Prod. Res. 2013, 27, 1408–1412.
119. Venditti, A.; Bianco, A.; Nicoletti, M.; Quassinti, L.; Bramucci, M.; Lupidi, G.; Vitali, L.A.; Papa, F.; Vittori, S.; Petrelli, D.; Bini,
L.M.; Giuliani, C.; Maggi, F. Characterization of secondary metabolites, biological activity and glandular trichomes of Stachys
tymphaea Hausskn. from the Monti Sibillini National Park (Central Apennines, Italy). Chem. Biodivers. 2014, 11, 245–261.
120. Venditti, A.; Frezza, C.; Maggi, F.; Lupidi, G.; Bramucci, M.; Quassinti, L.; Giuliani, C.; Cianfaglione, K.; Papa, F.; Serafini, M.;
Bianco, A. Phytochemistry, micromorphology and bioactivities of Ajuga chamaepitys (L.) Schreb. (Lamiaceae, Ajugoideae): Two
new harpagide derivatives and an unusual iridoid glycosides pattern. Fitoterapia 2016, 113, 35–43.
121. Venditti, A.; Serrilli, A.M.; Bianco, A. A new flavonoid and other polar compounds from Galeopsis angustifolia Ehrh. ex Hoffm.
Nat. Prod. Res. 2013, 27, 412–416.
122. Frezza, C.; Venditti, A.; Serafini, M.; Bianco, A. Phytochemistry, chemotaxonomy, ethnopharmacology, and nutraceutics of
Lamiaceae. Stud. Nat. Prod. Chem. 2019, 62, 125–178.
123. Frezza, C.; Venditti, A.; Toniolo, C.; De Vita, D.; Serafini, I.; Ciccòla, A.; Franceschin, M.; Ventrone, A.; Tomassini, L.; Foddai, S.;
Guiso, M.; Nicoletti, M.; Bianco, A.; Serafini, M.; Pedicularis, L. genus: Systematics, botany, phytochemistry, chemotaxonomy,
ethnopharmacology, and other. Plants 2019, 8(306), 1-62.
124. Ghorbani, A. Studies on pharmaceutical ethnobotany in the region of Turkmen Sahra, north of Iran:(Part 1): General results. J.
Ethnopharmacol. 2005, 102, 58–68.
125. Varamini, P.; Doroudchi, M.; Mohagheghzadeh, A.; Soltani, M.; Ghaderi, A. Cytotoxic evaluation of four Haplophyllum species
with various tumor cell lines. Pharm. Biol. 2007, 45, 299–302.
126. Esmaeili, S.; Hamzeloo-Moghadam, M.; Ghaffari, S.; Mosaddegh, M. Cytotoxic activity screening of some medicinal plants from
south of Iran. Res. J. Pharmacog. 2014, 1, 19–25.
127. Östan, I.; Saǧlam, H.; Limoncu, M.E.; Ertabaklar, H.; Toz, S.Ö.; Özbel, Y.; Özbilgin, A. In vitro and in vivo activities of
Haplophyllum myrtifolium against Leishmania tropica. New Microbiol. 2017, 30, 439–445.
128. Zengin, G.; Sarikurkcu, C.; Aktumsek, A.; Ceylan, R.; Ceylan, O. A comprehensive study on phytochemical characterization of
Haplophyllum myrtifolium Boiss. endemic to Turkey and its inhibitory potential against key enzymes involved in Alzheimer, skin
diseases and type II diabetes. Ind. Crop. Prod. 2014, 53, 244–251.
129. Bazzaz, B.; Haririzadeh, G. Screening of Iranian plants for antimicrobial activity. Pharm. Biol. 2003, 41, 573–583.
130. Ahmadipour, S.; Mohsenzadeh, A.; Ahmadipour, S.; Eftekhari, Z.; Tajeddini, P. Ethnobotanical identification of medicinal
plants effective on toothache in Shiraz, South Iran. Pharm. Lett. 2015, 7, 419–426.
131. Bahraminejad, S.; Amiri, R.; Abbasi, S. Anti-fungal properties of 43 plant species against Alternaria solani and Botrytis cinerea.
Arch. Phytopathol. Plant. Protect. 2015, 48, 336–344.
132. Satritdinov, F.; Kurmukov, A. Pharmacology of the vegetable compounds and their uses in medicine, Tashkent, Uzbekistan,
1980.
133. Al-Yahya, M.A.; Al-Rehaily, A.J.; Ahmad, M.S.; Al-Said, M.S.; El-Feraly, F.S.; Hufford, C.D. New alkaloids from Haplophyllum
tuberculatum. J. Nat. Prod. 1992, 55, 899–903.
134. Ulubelen, A.; Öztürk, M. Alkaloids, coumarins and lignans from Haplophyllum species. Rec. Nat. Prod. 2008, 2(3), 54-69.
Molecules 2021, 26, 4664 40 of 40
135. Ali, M.B.; Mohamed, A.H.; Bashir, A.K.; Salih, A.M. Pharmacological investigation of Haplophyllum tuberculatum. Int. J. Pharm.
1992, 30, 39–45.
136. Raissi, A.; Arbabi, M.; Roustakhiz, J.; Hosseini, M. Haplophyllum tuberculatum: An overview. J. Herbmed Pharmacol. 2016, 5, 125–
130.
137. Hadjadj, S.; Bayoussef, Z.; El Hadj-Khelil, A.O.; Beggat, H.; Bouhafs, Z.; Boukaka, Y.; Khaldi, I.A.; Mimouni, S.; Sayah, F.; Tey,
M. Ethnobotanical study and phytochemical screening of six medicinal plants used in traditional medicine in the Northeastern
Sahara of Algeria (area of Ouargla). J. Med. Pl. Res. 2015, 9, 1049–1059.
138. Al-Snafi, A.E. Pharmacological importance of Haplophyllum species grown in Iraq – a review. IOSR J. Pharm. 2018, 8, 54–62.
139. Batanouny, K.; Aboutabl, E.; Shabana, M.; Soliman, F. Plants of potential medicinal value, wild medicinal plants in Egypt. Academy
of Scientific Research Technology, Egypt. The World Conservation Union, Switzerland, Swiss, 1999.
140. Tanira, M.; Ali, B.; Bashir, A.; Wasfi, I.; Chandranath, I. Evaluation of the relaxant activity of some United Arab Emirates plants
on intestinal smooth muscle. J. Pharm. Pharmacol. 1996, 48, 545–550.
141. Gnan, S.O.; Sheriha, G. A research note antimicrobial activity of (+)-tuberine. J. Food Prot. 1986, 49, 340–341.
142. Bidak, L.; Heneidy, S.; Shaltout, K.; Al-Sodany, Y. Current status of the wild medicinal plants in the Western Mediterranean
coastal region, Egypt. J. Ethnobiol. Ethnomed. 2013, 120, 566–584.
143. Di Giorgio, C.; Delmas, F.; Akhmedjanova, V.; Ollivier, E.; Bessonova, I.; Riad, E.; Timon-David, P. In vitro antileishmanial
activity of diphyllin isolated from Haplophyllum bucharicum. Planta Med. 2005, 71, 366–369.
144. Anonymous. World Health Organization: Medicinal plants in Mongolia. WHO Regional Office for the Western Pacific, Manila,
2013.
145. Tsetlin, A.; Niconov, G.; Shvarev, I.; Pimenov, M. Antitumor activity of natural coumarins. J. Rastit. Resur. 1965, 1, 507.
146. Kang, K.; Nho, C.W.; Kim, N.D.; Song, D.G.; Park, Y.G.; Kim, M.; Pan, C.H.; Shin, D.; Oh, S.H.; Oh, H.S. Daurinol, a catalytic
inhibitor of topoisomerase IIα, suppresses SNU-840 ovarian cancer cell proliferation through cell cycle arrest in S phase. Int. J.
Oncol. 2014, 45, 558–566.
147. Kang, K.; Oh, S.H.; Yun, J.H.; Jho, E.H.; Kang, J.H.; Batsuren, D.; Tunsag, J.; Park, K.H.; Kim, M.; Nho, C.W. A novel
topoisomerase inhibitor, daurinol, suppresses growth of HCT116 cells with low hematological toxicity compared to etoposide.
Neoplasia 2011, 13, 1043–1057.
148. Egamberdieva, D.; Mamedov, N.; Ovidi, E.; Tiezzi, A.; Craker, L. Phytochemical and pharmacological properties of medicinal
plants from Uzbekistan: A review. J. Med. Active Pl. 2017, 5, 59–75.
149. Mirdeilami, S.Z.; Barani, H.; Mazandarani, M.; Heshmati, G.A. Ethnopharmacological survey of medicinal plants in Maraveh
Tappeh Region, North of Iran. Iran. J. Plant. Physiol. 2011, 2, 327–338.
150. Tekin, M.; Eruygur, N. The structural studies on the medicinal plant Haplophyllum telephioides. Braz. J. Pharmacog. 2016, 26, 544–
552.
151. Eskandari, N.; Farjam, M.H.; Joukar, M. Comparative evaluation of antimicrobial and antioxidant activity of essential oil and
ethanolic extract of Haplophyllum tenue Boiss and Dalbergia sissoo. Adv. Environ. Biol. 2014, 175-180.
