Design and semisynthesis of new herbicide as 1,2,3-triazole derivatives of the natural maslinic acid

Article abstract of DOI:10.1016/j.steroids.2018.07.004

Interesting biological activities (anti-inflammatory, anticancer, antiviral, antioxidant, antidiabetic…) have been reported for maslinic acid (MA) and MA-based compounds. In continuation of our previous work on MA, herbicide potential of Tunisian plant extracts and 1,4-triazolyl derivatives of MA, we now wish to report semisynthesis of new MA-based triazole hybrid compounds with herbicide potential. These compounds were synthesized through Cu-catalyzed azide-alkyne cycloaddition (CuAAC) under microwave irradiation conditions between propargylated MA and a series of phthalimide azides. Here, the first partner of CuAAC reaction (propargylated MA) resulted from propargylation of C-28 carboxylic acid group of isolated MA from the well-known Mediterranean plant Olea europaea L. (Oleaceae). So far, phthalimide azide derivatives were achieved by trapping of N-acyliminium ion, in-situ generated under catalytic condition of Bi(OTf)₃, by aromatic nucleophiles. The cycloaddition reaction afforded regiospecifically 1,4-disubstituted triazoles in good yields. The latter hybrid compounds were shown to exhibit a high inhibition potential of seed germination. This constitutes the first step in development of potent herbicides since one of the final semisynthesized structures can serve as a promising lead candidate for further studies.

Full text of DOI:10.1016/j.steroids.2018.07.004

Steroids138(2018)102–107
Contents lists available at ScienceDirect
Steroids
journal homepage: www.elsevier.com/locate/steroids
Design and semisynthesis of new herbicide as 1,2,3-triazole derivatives of
the natural maslinic acid
Aymen Ben Nejmaa,b, Mansour Znatib, Adam Daicha, Mohamed Othmana, Ata Martin Lawsona,⁎
,
Hichem Ben Jannetb,⁎
a
Normandie Univ, France; UNILEHAVRE, URCOM, EA 3221, INC3M, FR 3038 CNRS, F-76600 Le Havre, France
b
Laboratory of Heterocyclic Chemistry, Natural Products and Reactivity (LR11ES39), Team: Medicinal Chemistry and Natural Products, Faculty of Science of Monastir,
University of Monastir, Avenue of Environment, 5019 Monastir, Tunisia
A R T I C L E I N F O
A B S T R A C T
Keywords:
Maslinic acid
Semisynthesis
1,3-Dipolar cycloaddition
Triazoles
Interesting biological activities (anti-inflammatory, anticancer, antiviral, antioxidant, antidiabetic…) have been
reported for maslinic acid (MA) and MA-based compounds. In continuation of our previous work on MA, her-
bicide potential of Tunisian plant extracts and 1,4-triazolyl derivatives of MA, we now wish to report semi-
synthesis of new MA-based triazole hybrid compounds with herbicide potential. These compounds were syn-
thesized through Cu-catalyzed azide-alkyne cycloaddition (CuAAC) under microwave irradiation conditions
between propargylated MA and a series of phthalimide azides. Here, the first partner of CuAAC reaction (pro-
pargylated MA) resulted from propargylation of C-28 carboxylic acid group of isolated MA from the well-known
Mediterranean plant Olea europaea L. (Oleaceae). So far, phthalimide azide derivatives were achieved by trap-
ping of N-acyliminium ion, in-situ generated under catalytic condition of Bi(OTf)3, by aromatic nucleophiles. The
cycloaddition reaction afforded regiospecifically 1,4-disubstituted triazoles in good yields. The latter hybrid
compounds were shown to exhibit a high inhibition potential of seed germination. This constitutes the first step
in development of potent herbicides since one of the final semisynthesized structures can serve as a promising
lead candidate for further studies.
Herbicide activity
1. Introduction
[8], we decided to take advantage of this high content of triterpenoids
in olive tree (Olea europaea). So far, since N-phenylphthalimide and
The use of insecticides, pesticides and herbicides [1] in the agri-
cultural sector remains one of the solutions to drastically reduce eco-
nomic losses in terms of crop yields. Nevertheless, these products,
particularly herbicides have also negative effects on the environment
and the health of living organisms, including humans [2]. Natural
herbicides and allelochemicals are increasingly used by farmers for
weeds management in intensive farming, organic agriculture, sustain-
able and family agriculture. In the light of these considerations, many
efforts are more and more devoted to the research in natural herbicides,
allelochemicals or natural products-based herbicides areas [3]. Most of
allelochemicals are secondary metabolites and belong, among others, to
phenolic compounds, long-chain fatty acids, organic cyanides and ter-
penoids [4]. Indeed, in the latter terpenoids class, pentacyclic skeletons
such as lupane, oleanane, and ursane triterpenes were reported for their
plant growth modulation potential [5–7]. As hydroxy pentacyclic tri-
terpene acids (HPTAs) are found in higher concentration (MA: 73.25%
and oleanolic acid: 25.75% (Fig. 1)) in the skin of olive fruit extracts
triazole derivatives were two different classes of herbicides such as
Flumioxazin Pestanal® and Amitrol Pestanal® (Fig. 2) [9], it was envi-
sioned through this work to connect these entities to a natural product
to design a new class of herbicides (Fig. 3). Based on our previous work
on MA [10], allelopathic potential of Tunisian plant extracts [11], 1,4-
triazolyl derivatives of MA [12] and oleanolic acid (OA) [13], the
present study aims to access novel modulators of plant growth based on
natural products such as MA (Fig. 3). This triterpene is mainly isolated
from Olea europaea L. under ultrasonic conditions in a large amount
[10]. Classified under Oleaceae family, Olea europaea plays a pivotal
role in Mediterranean diet and is considered to be a high economic
value plant that has accompanied the development of Mediterranean
civilization [14]. So far, olive tree, the major oil-producing crop in
Tunisia and the Mediterranean basin is used in traditional medicine
over the world. Decoctions of dried fruits and leaves are used to treat
diarrhea as well as respiratory and urinary tract infections whereas
fresh leaves infusion was reported for anti-inflammatory use [15]. As
⁎
Corresponding authors at: Normandie University, UNILEHAVRE, URCOM, EA 3221, INC3M, FR 3038 CNRS, F-76600 Le Havre, France (A.M. Lawson).
E-mail address: lawsona@univ-lehavre.fr (A.M. Lawson).
https://doi.org/10.1016/j.steroids.2018.07.004
Received 11 March 2018; Received in revised form 8 July 2018; Accepted 10 July 2018
0039-128X/©2018ElsevierInc.Allrightsreserved.

A. Ben Nejma et al.
Steroids138(2018)102–107
Fig. 1. Major compounds from Olea europaea: maslinic acid (MA) 1 and oleanolic acid (OA) 2.
Fig. 2. Herbicide marketed (Amitrol, Flumioxazin, Nijmegen-1).
Fig. 3. Triazole core as a linker in the design of a new class of herbicides.
described in literature, MA displayed several biological activities, such
as antioxidant [16], anti-inflammatory [17], antitumoral [18], anti-
diabetic [19], anti-allodynic [20] and anticancer activities [21].
Nevertheless, MA-based compounds have never been reported as
powerful herbicidal agents. Herein, is described the design and the
preparation of a series of novel MA linked to phthalimide derivatives
through 1,2,3-triazolo moiety as a spacer (Fig. 3). These compounds are
semisynthesized in moderate to good yields via Huisgen [3+2] cy-
cloaddition (“click reaction”) between a terminal alkyne and phthali-
mide-based azides. This copper-catalyzed 1,3-dipolar cycloaddition
reaction was regioselectively controlled and led to a series of novel MA-
based hybrid molecules that connect two distinct entities. The first
moiety has natural origin (MA) while the second part was synthesized
trough “N-acyliminium ion chemistry” (phthalimide derivatives) [22].
Since lupane triterpenes are known as Lactuca sativa L. growth
promoters [5,6], we expected through this work to shift this property
into inhibitory activity by adding a potential active moiety (triazolo-
methyl phtalimide part).
2. Materials and methods
2.1. Materials and reagents
Unless otherwise specified, reagents and starting materials were
purchased from traditional suppliers and were used without further
purification. Reactions were carried out in standard glassware. Solvents
were purified and dried using standard methods before their use.
Commercial TLC plates (Silica gel 60, F254, 0.2 mm-thick) were used to
monitor the progress of the reaction. Column chromatography was
performed with silica gel 60 (particle size 40–63 µm). HRMS were
103

A. Ben Nejma et al.
Steroids138(2018)102–107
Scheme 1. Synthesis of propargylated MA 3.
acquired with a LCT Premier XE mass spectrometer. For ESI experi-
ments, Leucine-enkephaline peptide was employed as a lock mass for
the LockSpray. 1H (300 MHz) and 13C (75 MHz) NMR spectra were
recorded at room temperature (rt) on a Bruker AM-300 Fourier
Transform spectrometer equipped with a 10 mm probe. Deuterated
chloroform (CDCl3) was used as solvent with all chemical shifts (δ),
reported in ppm, referred to residual non deuterated signal. Coupling
constants were measured in Hz and following abbreviations: s, singlet;
d, doublet; t, triplet; m, multiplet, etc., were used for 1H NMR signals.
a solid-liquid extraction (maceration in a mixture of Acetone/Water: 1/
1) followed by ultrasonic agitation. Under these conditions, large
amount of MA (6.0 g) was selectively obtained.
The structural analysis of compound 1 using spectroscopic methods
including 1D-NMR (1H, 13C and DEPT 135) showed the presence of
seven methyl groups in the higher field region (δH 0.46–1.04), an
ethylenic group at δH 5.20, two oxygenated carbons at δC 68.6 and 84.5
and acid function at δC 177.5 corresponding to the digital fingerprint
signals of MA. Moreover, this structural elucidation was confirmed by
the literature [23] and the presence of a pseudo molecular ion peak [M
+H]+ at m/z 473.3625 in ESI-HRMS analysis.
2.2. Extraction and isolation of compound 1
The pomace of Olea europaea L. was collected from the factory of
soap located in Sousse (Tunisia) and kept at room temperature in the
dark until its use. 2.5 kg of pomace was extracted once with Acetone-
Water (1:1) at room temperature for five days. Then the oil phase was
obtained after solvent evaporation under vacuum and a series of de-
cantation and separation. A white solid (10.5 g, yield 0.42%) has been
obtained after treatment of the oil phase with hexane under ultrasonic
agitation (30 min, bath at 25 °C). Compound 1 (6.0 g of MA, yield
0.24%) was purified by column chromatography (L: 100 cm, d: 2.5 cm)
over silica gel (elution: 100% pentane to pentane/ethyl acetate (1/1)).
3.1. Semisynthesis
After MA isolation, we turned our attention to the synthesis of the
Cu alkyne-azide cycloaddition (CuAAC) partners (propargylated MA
and N-(azidomethyl)phthalimide derivatives). Firstly, the propargy-
lated MA synthesis was conducted by engaging the isolated MA in the
propargylation of the carboxyl at C-28 position. The reaction was per-
formed in dry DMF by using NaH as base catalyst and provided the
desired alkyne 3 in 80% yield (Scheme 1). The comparison of spectral
data of compounds 1 and 3 showed the appearance of new signals such
as methylene at δH 4.69; 4.57 (dd, 2H, J = 15.6; 2.4 Hz, H1′) and me-
thylidyne group at δH 2.41 (d, J = 2.4 Hz, 1H, H3′) corresponding to the
added propargyl moiety. Also, the structure of dipolarophile 3 was
supported by its ESI-HRMS which showed a pseudo molecular ion peak
[M+H]+ at m/z 511.3778. On another hand, N-(azidomethyl)phtha-
limide derivatives (8a–8d) were synthesized in three steps starting from
commercially available N-chloromethylphthalimide (4) (Scheme 2).
The first step of the reaction sequence led to azide derivative 5 in ex-
cellent yield (93%) through nucleophilic substitution of the halogen
(Cl) by using NaN3 in DMSO at room temperature for 24 h. The latter
reaction was followed by one of the two carbonyl groups reduction by
using LiEt3BH in anhydrous dichloromethane (DCM) at −80 °C that
resulted in the N-acyliminium precursor hydroxy lactam 6 in 75% of
isolated yield. The 1H NMR spectrum of compound 6 revealed new
signals at δH 5.89 (s, 1H), 5.03 (d, J = 12.6 Hz, H10a) and 4.57 (d,
J = 12.6 Hz, H10b) corresponding respectively to an hydroxyl methine
and a methylene beside an asymmetric center. From this N-acyliminium
precursor, the acetoxy lactam 7 can be easily achieved by simple
acetylation (Scheme 2) under classical conditions [24]. The added
acetyl group was confirmed by observation of two new signals in the
13C NMR spectrum of compound 7 at δC 170.8 and 21.0 attributable to
carbonyl and methyl group, respectively, compared to 13C spectrum of
azide 6. Finally, the synthesized hydroxy lactams 5 were involved in π-
cyclisation of Friedel-Crafts type under bismuth (III) tri-
fluoromethanesulfonate-mediated conditions. This cyclization led to
different azides partners (8a–8d) required for the “click reaction” in
modest yields (42–48%), through the electron-rich aromatic ring attack
of the in situ formed N-acyliminium ion by mono-, di-, and tri-sub-
stituted aromatic nucleus. Additionally, this last step required only
5 mol% of Bi(OTf)3 which makes the latter more environmentally and
economically benign process. The structures of these azides partners
2.3. Bioassay (Herbicide potential)
Samples were dissolved in chloroform in order to test their herbicide
potential. 5 mL of each sample was dissolved at a concentration range
of 500 µg/mL. The solution was then put on a sheet of filter paper in a
Petri dish and evaporated to dryness for 24 h at 25 °C. The filter paper
was moistened with 5 mL of sterile distilled water. Then, 20 imbibed
seeds of Lactuca sativa were arranged in each Petri dish and were al-
lowed to grow in growth chamber in the dark at 25
2 °C for 7 days.
The same operation has been done for the control without adding the
sample. The germination and root length percentages of the targeted
species were measured for all seedlings in each Petri dish on day 7. The
data were transformed to inhibitory percent using the following equa-
tion.
Inhibition percentage % = [(control − sample)/control] × 100,
where sample represents the parameter measured in the presence of the
sample and control is the parameter measured in the presence of dis-
tilled water. Experiments were performed in triplicates.
2.4. Statistical analysis
The data from the experiments were subjected to analysis of var-
iance (ANOVA) using SPSS 13.0 for Windows. The percentage data
were transformed using arcsine-square root (arcsine √x) before ANOVA
analysis. Mean was calculated as 5% significance level by the least
significant difference test (Student's t-test).
3. Results and discussion
MA (Fig. 1) was isolated from the pomace of Olea europaea by using
104

A. Ben Nejma et al.
Steroids138(2018)102–107
Scheme 2. Synthesis of azides 5–7, 8a–8d.
were confirmed according to their spectral data since the comparison of
their 1H and 13C NMR spectra with those of compound 6 shows the
appearance of new signals in aromatic region corresponding to the in-
serted aromatic ring. In the other hand, the ESI-HRMS analysis revealed
the presence of a pseudo molecular ion peak [M+H]+ for each azide
formed. In the 1H NMR spectrum of azide 8a as an example, we ob-
served two new doublets at δH 7.00 (2H, J = 7.8 Hz) and 7.19 (2H,
J = 7.8 Hz) compared to 1H spectrum of compound 6. Indeed, these
protons corresponded satisfactorily to the added aromatic group. The
mass spectrometry of compound (8a) also confirmed this observation
by exhibiting a pseudo molecular ion peak for (C15H13N4O2)+ at m/z
281.1033.
Once the two partners were prepared, we were embarked in the
synthesis of 1,2,3-triazole moiety through ligation of azides and pro-
pargylated-MA terminal alkyne. In this perspective, two conditions of
Cu alkyne-azide cycloaddition (CuAAC) were used. Both conditions are
based on Cu(I) species as commonly used for “click reaction” (Scheme
3, conditions (a) and (b)). Nevertheless, in condition (a) the Cu(I) was
in-situ generated by the reduction of CuSO4 (Cu(II) salt) in organo-
aqueous (DCM/H2O) media. From the two tested conditions, we could
observe that condition (b) was more efficient and shorter in terms of
reaction time than condition (a) (Scheme 3). Indeed, under condition
(a) (CuSO4·5H2O, sodium ascorbate, DCM/H2O, 25 °C) the targeted
compounds were synthesized in modest yields ranged from 29% for 9g
to 36% for 9a. Concerning condition (b) that uses a 250 W microwave
irradiation (CuI, Et3N, DMF, MW-220 °C, 3–5 min) yields were 10–20%
higher than those of the previous conditions. Ranged from 39% for 9g
to 56% for 9a, the lowest yields (< 50%) for 9f (47%) and 9g (39%)
were probably due to steric hindrance of azide heterocycles through
dimethoxy or trimethoxyphenyl moieties. The synthesis of triazoles
9a–g was confirmed by 1D, 2D-NMR. The comparison 1H NMR spectra
of compounds 9a–g with propargylated-MA (3) showed the appearance
of new signals in aromatic region 6.83–7.90 ppm relative to aromatic
protons introduced by the azides used. It can be also noticed the dis-
appearance of the methylidyne signal in compound 3 and the appear-
ance of new singlet (1H) located in the region 7.80–7.95 ppm attribu-
table to the sole proton of triazole moiety. It is worth mentioning that
the reaction was regiospecific leading to 1,4-substituted triazolyl deri-
vatives 9a–9g (Scheme 3). The resulting 1,4-regioisomers were evi-
denced from the NOE H5′(triazole)/H6′(methylene), H5′(triazole)/H10′’(methylene)
and the absence of NOE between H5′(triazole)/H(methylene-MA). High Re-
solution Mass spectrometry (HRMS) data of all the formed derivatives
were also in agreement with the proposed structures.
3.2. Herbicide potential
After MA-based hybrid compounds being synthesized, their reg-
ulatory effects were evaluated on seed germination and on early growth
stages of Lactuca sativa L. used as a target plant. The results displayed in
Table 1 showed interesting herbicide potential (up to 100% of inhibi-
tion). At a first sight, using chloroform as solvent did not affect the
germination process of Lactuca sativa L. Therefore, the growth in-
hibitory effects could be really attributed to synthesized compounds.
Satisfactorily, the results indicated that targeted compounds have dif-
ferent degree of inhibitory effect on germination and seedling growth.
The latter fluctuation in the plant germination inhibition was closely
related to the nature and the structure of compounds. At the seventh
day, the maximum toxicity of these compounds was registered. Con-
cerning azide series 5–7 and 8a–8d, the percentage of inhibition varied
from 34.55 to 69.99%. This activity of the azide series (5–7) seems
105

A. Ben Nejma et al.
Steroids138(2018)102–107
Scheme 3. Synthesis of triazoles 9a–9g.
group by substituted aromatic groups through N-acyliminium chem-
istry, generally increased the inhibition percentage of azides
(59.75–69.99%) except for 8c (57.88%). The compound 8b showed in
this series, the highest percentage of inhibition with 69.99% and the
herbicide potential was probably due to the presence of the thiol group.
In MA-based series, firstly we noticed that free maslinic acid (1)
exhibited a very weak percentage of inhibition of 5.56%. On the other
hand, the propargylation of MA displayed a reverse effect, since com-
pound 3 lacked the phytotoxic effect and even slightly promoted the
germination and seedling growth of Lettuce (Lactuca sativa). This
compound can thus serves as reference in MA-based triazolophthali-
mide hybrid compounds. The phytotoxic effects of synthesized triazoles
9a–9g (Table 1) showed higher activities compared to the propargy-
lated MA (3) and azides (4–7, 8a–8d). Indeed, these hybrid compounds
displayed an important inhibition of total germination ranged from
91.79 to 100%. According to the literature and activities of the pro-
pargylated MA (3) and azides taken separately, the herbicide potential
of compounds 9a–9g as expected was mainly due to the added triazo-
lomethyl phtalimide part [9]. Interestingly, it's important to underline
that seed germination was completely inhibited in presence of com-
pound 9e (100%). As already hypothesized in phthalimide series, here
also the highest inhibitory activity of germination was probably due to
presence of the thiol group in the hybrid compound structure. Finally,
free MA (1) seems to have negligible inhibitory effect on Lactuca sativa
L. seeds germination while propargylated MA (3) tends to boost their
growth. Overall, it can be also noticed that phthalimide and methyl-
triazolo moieties are certainly responsible of this switch in the activity
of propargylated MA (3) into inhibitory activity observed for synthe-
sized hybrid compounds.
Table 1
Effects of compounds on total inhibition (GT), root length (RL) and shoot length
(SL) of Lactuca sativa L. Different letters in columns indicate significant differ-
ences among fractions at P < 0.05 (LSD test).
compound
GT
RL
SL
1
3
4
5
6
7
8a
8b
8c
8d
9a
9b
9c
9d
9e
9f
5.56
0.00
0.10g
0.00h
0.27f
0.27e
0.32f
0.20
97.81
100
0.20i
0.00j
95.70
100
0.21i
0.00j
46.70
58.89
49.15
34.55
64.20
69.99
57.88
59.75
91.79
96.00
92.44
94.85
100.00
95.79
98.21
01.89
15.55
42.75
61.00
66.50
20.50
19.70
32.13
30.24
09.0
03.85
06.85
05.09
00.0
0.29d
0.25g
0.38h
0.10h
0.30e
0.60d
0.19f
0.22f
0.05c
0.06a
0.09b
0.10b
0.0a
13.98
42.65
51.56
58.64
31.12
20.01
43.85
40.03
10.00
04.50
09.08
05.66
00.0
0.10d
0.10g
0.15h
0.11h
0.10f
0.15e
0.05g
0.10g
0.10c
0.07b
0.08c
0.05b
0.01d
0.12d
0.37e
0.32e
0.09c
0.05b
0.10c
0.10b
0.0a
0.0a
0.05b
03.0
02.23
98.57
0.04a
0.11a
0.14i
02.78
03.02
98.94
0.10a
0.12a
0.25i
a
9g
Control
0.08
0.07 h
The different letters (a–j) indicate a significant difference between the com-
pounds (p < 0.05).
mainly due to the presence of phthalimide group. Moreover, the
phthalimide-based azido adduct 5 (58.89%) increased the activity of N-
(chloromethyl)phthalimide 4 (46.70%), underlining the positive effect
of azide group in the germination inhibition. However, hydroxy lactam
6 (49.15%) and acetoxy lactam 7 (34.55%) did not provide higher
activity when compared to compound 5 (58.89%). Considering the
latter compound 5 as a reference, the replacement of one of its carbonyl
106

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Steroids138(2018)102–107
4. Conclusion
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In summary, maslinic acid (MA) was isolated from pomace olive
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identification and characterization, this well-known natural product
was employed as building block in the semisynthesis of new hybrid
molecules through a 1,3-dipolar cycloaddition involving propargylated
MA and phthalimide-based azides. The Cu alkyne-azide cycloaddition
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to good yieds in maximum 5 min of reaction time. The ability of these
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We are grateful to INC3M, to région Normandie and “Université Le
Havre Normandie” for support and technical help. We also thank
University of Monastir (Tunisia) for research facilities and financial
support to ABN.
Appendix A. Supplementary data
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