HANOI UNIVERSITY OF SCIENCE AND TECHNOLOGY

SCHOOL OF CHEMICAL ENGINEERING

Dept. of Pharmaceutical Chemistry and Pesticides Technology

*************************

SEMINAR
MIDTERM EXAM 20221
Subject: Synthesis of new coumarin derivatives and their anti-
inflammatory activity (CH4516E)

Lecturer: Assoc. Prof.Tran Khac Vu ......................

GROUP 5
Student’s Name Student’s Code
Lê Thị Thu Anh 20191346
Lê Thái Bình 20191344
Cao Bá Minh 20191366
Nguyễn Thùy Linh 20191364

Hanoi, Dember, 2022

1
Table of Contents
1. INFLAMMATORY...............................................................................................................................3
2. COUMARIN......................................................................................................................................4
2.1. Structure, physical, chemical property of coumarin....................................................................4
2.2. Pharmacological and Biochemical Characterization of Inflammation.......................................5
2.3. The basic synthesis reaction of coumarin.....................................................................................6
2.3.1. First synthesis by William Henry Perkin...............................................................................7
2.3.2. Pschorr coumarin synthesis....................................................................................................8
2.3.3. Pechmann reaction..................................................................................................................8
2.3.4. Knoevenagel reaction..............................................................................................................9
2.3.5. Wittig reaction.........................................................................................................................9
2.3.6. Telluride counterion..............................................................................................................10
3. NATURALLY OCCURING COUMARIN AND COUMARIN DERIVATIVES..........................10
3.1. Coumarin and Hydroxyl Derivatives of Coumarin........................................................................11
3.1.1. Coumarin................................................................................................................................11
3.1.2. 7-Methoxycoumarin derivative.............................................................................................11
3.1.3. Umbelliferone (7-hydroxy-[1]benzo[b]pyran-2- one) derivative........................................12
3.1.4. Scopoletin derivative..............................................................................................................12
3.2. Fused Coumarins..........................................................................................................................13
3.2.1. Xanthotoxin derivative..........................................................................................................13
4. SYNTHETIC COUMARIN DERIVATIVES....................................................................................13
4.1. Substituted Coumarins.................................................................................................................13
4.1.1. Synthesis 3-Benzylcoumarin.................................................................................................13
4.1.2. Synthesis of coumarin derivative from 7-Formyl-coumarin..............................................14
4.1.3. Synthesis carboxamide coumarin.........................................................................................15
4.1.4. Synthesis N-Aryl substituted 3-Carboxamidocoumarins 38 a-h........................................16
4.1.5. Synthesis 4-(7’-methoxy-2’-benzo[b]furanyl)coumarins 46a-f...........................................18
4.1.6. Synthesis coumarin derivative from 4-Formylcoumarin....................................................19
4.2. Hydroxyl Derivatives of Coumarin.............................................................................................20
4.2.1. Four diaminoether coumarin derivatives.............................................................................20
4.2.2. Synthesis coumarin derivative as TNFα inhibitors.............................................................21
4.3. Fused coumarin derivative...........................................................................................................21
4.3.1. Synthesis derivative of the angelicin.....................................................................................21

2
 4.3.2. Synthesis calophylloide..........................................................................................................22
REFERENCES........................................................................................................................................23

3
1. INFLAMMATORY
Doctor John Hunter – a Scottish surgeon in 18 th century, he observed the
inflammatory activity is not a disease, it is actually an unspecific response of the
body and initial activity of immune system. Through his microscopic examination
of important transparent membrane preparations, the German pathologist Julius
Cohnheim concluded that the inflammatory response is essentially a vascular
phenomenon [1].
The inflammatory symptom can be identified by five fundamental signals rubor
(redness), tumor (swelling), calore (heat), dolore (pain), and function aesa
(disturbance of function) and four elements that involved in the procedure are
inflammatory inducers (like infection, wound or tissue injury, or any other diseased
state), sensors (like mast cells, macrophages, dendritic cells, etc.), inflammatory
mediators (like various cytokines, biological amines, etc.), and the target tissues
[2].
There are several methods to regular the inflammatory responses by get rid of the
inducers, by blocking the sensors, by inhibiting the mediators, or by directly acting
on the target tissues, specifically by control inflammatory mediators such as
plasma proteases, arachidonic acid metabolites (like PGE2 and leukotrienes),
histamine, serotonin, nitric oxide, cytokines (such as lipoxins, interleukins 1–16,
and tumor necrosis factor-α ), chemokines (such as those belonging to the CXC,
CC, and C subsets), and colony-stimulating factors (CSFs). And processes involve
in producing these mediators are cyclooxygenases, caspases, and kinases (like
cyclindependent kinases, mitogen-activated protein kinase 38, c-jun N-terminal
kinase, mitogen-activated protein kinase/ extracellular signal regulated kinase,
serine threonine kinases, interleukin receptor-associated kinase 4, Janus kinases,
kinase insert domain receptor, NF-k β , lymphocyte specific kinase, spleen tyrosine
kinase, and TNFα kinase [1].
In brief, inflammation is a response and it is produced by host, it is considered as
normal and essential that prevents body from infection and noxious stimulus.
When the body undergo inflammatory condition, leucocytes and materials derived
from the serum is applied to the area of the tissue damge [3]. Although
inflammation is normal response of the body, its extreme severeness can bring
about tissue injury, physiological decompensation, organ dysfunction and even
death. There are two types of major inflammation based on timing and clinical
characteristics: acute and chronic inflammation [4].

4
2. COUMARIN
Coumarin named after tonka beans which has French word “coumarou”. They are
discovered nearly 600 genera of 100 plant families such as Rutaceae, Apiaceae,
Clusiaceae, Caprifoliaceae, Oleaceae, Nyctaginaceae. Almost all parts of plants
found coumarin’s substance and essential oil also. An example of findings of
coumarin is volatile oil which obtained from cinnamon barks, cassia leaves, and
lavender. Normally, coumarin is existence as odorless complex that conjugated to
sugars and acids, but is discharged by the action of acids, enzymes, or ultraviolet
(UV) radiation [5]. Apart from plants sources, coumarin also can be found to be
present in bacteria, fungi, or some marine organisms like sponges.
Coumarins can be divided into six groups as simple coumarins, furanocoumarins,
dihydrofuranocoumarins, pyranocoumarins (linear and angular type), phenyl
coumarins, and bi-coumarins [6].
In 1868, Coumarin was first synthesized after being initially isolated in 1822. It
was banned by the Food and Drug Administration in the 1950s, being classified as
a category 1 carcinogen and hepatotoxin, based on animal data [5]. However, this
may require revision in the light of subsequent animal data. Coumarin has many
biological characteristics, including: anti-microbial; anti-viral; anti-inflammatory;
antioxidant and enzyme inhibitory properties [7]. They are extensively utilized in
a variety of products, including food, dispersed fluorescent and lasers dyes,
pesticides, cosmetic, medications and optical brighteners [8].
2.1. Structure, physical, chemical property of coumarin
- Molecular formular: C9H6O2
- Molecular structure:

- IUPAC name: 2H-Chromen-2-one

- Molecular weight: 146.1427 g/mol

5
- Coumarin can be described as a benzene molecule with two adjacent hydrogen
atoms replaced by a lactone-like chain −(CH)=(CH)−(C=O)−O−, forming a second
six-membered heterocycle that shares two carbons with the benzene ring. It can be
categorized as a lactone and assigned to the benzopyrone chemical class.
* Physical property:
- Coumarin is a tasteless, white crystalline substance that has a vanilla-like
sweetness to its aroma.
- Freely soluble in ethanol, chloroform, and oils, while only sparingly soluble in
boiling water and only slightly soluble in cold water at 20°C.
- Coumarin has a UV absorption maximum of 272 nm in chloroform [5].
- Boiling point: 301.71 °C.
- Melting point: 71 °C.
* Chemical property:
Analysis structure of coumarin to brief SAR for derivatives activity [2]:
- At the C-8, adding anα , β -unsaturated carbonyl group or free hydroxyl to help
increases the activity.
- Major derivatives of coumarin are the constituents at 6-/7-monosubstituted, 6, 7-
disubstituted, or 6,7-fused coumarins which contain an oxygen atom (–OH or –
OR). That can explain at these positions, a polar moiety is very well active.
- When conducting the research about extracting plant, they still have no findings
the substituents at C-4.
- At C-3, a linear long chain hydrophobic moiety is well tolerated.
2.2. Pharmacological and Biochemical Characterization of Inflammation
Because of several stimuli, it can result in tissue swelling that was approved to be
reduced by coumarin. For example, a research from the Department of Zoology,
University of Adelaide, South Australia, the effects of coumarin and of external
lymphatic drainage were examined with the electron microscope in rat hind legs
and mouse ears that were injured by heat [9]. The research demonstrated by
plethysmography that has been shown that both coumarin treatment and external
lymph drainage lead to a significant protective effect in thermal oedema.
Furthermore, as benzopyrones chemical class, coumarin increasing the numbers of

6
macrophages and their normal proteolysis which bring about reduce all high-
protein oedemas like lymphoedema or elephantiasis [10]. Thus, coumarin have
been used in many clinical trials on a variety of high-protein oedemas.
However, coumarin has been shown greatly reduce high-protein edemas, including
burns, it had negligible effects on the capillary permeability as well as the
mechanism is not clear [11]. They are likely to be transported through leaky
microvessels into the tissue spaces. A reasonable explanation for the treatment of
coumarin is their protein carrier are phagocytosed by macrophages, leads to
reducing extravascular protein. Another way is the released lysosomal enzymes
bring about effects of macrophage activation and proteolysis.
Other studies showed that the anti-inflammatory effect of coumarins is probably
due to their ability to alter the function of enzymatic systems as cyclooxigenase
and lipooxygenase, and prevent the generation of free radicals known to be
involved in inflammatory processes [2]. Variety function of coumarin in
inflammation had been reported as depicted in Fig.1.

Fig. 1 Inflammatory targets of coumarin derivatives [2].

2.3. The basic synthesis reaction of coumarin
Many researchers found that coumarin had many effects on pharmaceutical fields,
hence, many studies have been carried out to synthesis this substance.
7
2.3.1. First synthesis by William Henry Perkin
The first synthesis of coumarin had been done by William Henry Perkin in 1868 by
the reaction between salicylaldehyde (2), sodium acetate (4) and acetic anhydride
(3) which was first marketed in 1876 (Scheme 1) [12].

Scheme 1. First synthesis of coumarin by William Henry Perkin [12]

However, the research was conducted by Department of Chemistry in Faisalabad
replaced acetic anhydride by acetic acid because of their misuse in narcotics
synthesis [12]. In reaction, acetic acid (5) and water were produced as side
products (Scheme 2). Four trials with different amounts of reactant were
conducted as Table 1 listed below:
Table 1: Four samples of synthesis coumarin experiments [12]
Sample No. Salicylaldehyde Sodium acetate Acetic acid
Sample-1 8 ml 10g 20 ml
Sample-2 20 ml 10g 20 ml
Sample-3 20 ml 10g 10 ml
Sample-4 20 ml 20g 20 ml

Scheme 2. Synthesis coumarin by Department of Chemistry in Faisalabad

This research had been shown that the yield of Perkin reaction of sample four is
highest but overall, four trials with acetic acid are very low and reaction with acetic
acid obtained less product than with anhydride acetic.

8
2.3.2. Pschorr coumarin synthesis
Coumarin synthesis by Pschorr. The Pschorr is a traditional ring closure method
for combining two aryl moieties to create polycyclic systems. Phenols (7) and beta
keto esters (8) react during the Pschorr coumarin synthesis in the presence of a
condensing agent (Scheme 3) [13].

Scheme 3: Synthesis coumarin by Pschorr [13]

Survey of the more recent literature shows that Pschorr cyclization was selected as
the method of choice in numerous cases in the synthesis of biologically important
carbocyclic and heterocyclic targets.
2.3.3. Pechmann reaction
The synthesis of coumarins can be accomplished by a variety of techniques. The
Pechman reaction is one of the industrial processes used to make coumarin. Many
of these types for Pechmann reaction is considered to be one of the most important
one as it requires simple starting materials with simple phenols and ester
compounds containing compounds have β-carbonyl group. In Pechmann reaction,
they prepared a number of coumarin derivatives by condensation phenol
compounds or products with compounds beta - keto ester with sulfuric acid [14].
Coumarin synthesis from reaction between the phenol compounds (7) and
compounds of β-keto esters (9) by Pechmann condensation (Scheme 4) [14].

Scheme 4. Synthesis coumarin by Pechmann reaction [14]

9
It has recently been demonstrated that the Pechman reaction can be carried out fast
by irradiating the reagents with microwave energy in a standard household
microwave oven [14] .
2.3.4. Knoevenagel reaction
The Knoevenagel reaction involves the condensation of benzaldehydes with
activated methylene compounds in the presence of an amine, and is used to
overcome the inherent difficulties associated with the synthesis of coumarins via
the Perkin reaction [15].
In the presence of piperidine (13), condensation of salicyaldehyde (11) or its
deravatives with various deravatives of ethyl acetate (12) results in the synthesis of
coumarins by sovent-free process while being exposed to microwave radiation
(Scheme 5) [15].

Scheme 5. Synthesis coumarin by Knoevenagel reaction [15]

2.3.5. Wittig reaction
In the past, coumarins have been synthesized by several routes including
Pechmann, Perkin, Knoevenagel. These reactions often require strongly acidic or
strongly basic reaction conditions and high temperature for longer reaction times,
which makes them less suitable for the synthesis of coumarins with complex
substitution patterns. A good alternative is the Wittig reaction [16].
An aldehyde or ketone is combined with a Witig reagent ( A triphenyl
phosphodium ylide) in an organic chemical reaction to produce an alkene and
tryphenylphosphine oxide. Georg Wittig, a German chemist who discovered this
reaction. [16]
In synthesis of coumarin through the Wittig reaction, the reaction times up to 17-
34 h under refluxing conditions in benzene or xylene as very toxic solvents
(Scheme 6) [16].

10
Scheme 6. Synthesis coumarin by Wittig reaction [16]
Or in another typical Wittig reaction (Scheme 7)

Scheme 7. Another typical Wittig reaction [16]

2.3.6. Telluride counterion
A change from sodium to lithium reduced reaction times and increased the yield of
coumarin to 75%. The R-bromopropionate of salicylaldehyde (18) gave the
expected coumarins in 41-64% yields (Scheme 8) [17].

Scheme 8. Synthesis coumarin by Telluride reaction [17]

3. NATURALLY OCCURING COUMARIN AND COUMARIN

DERIVATIVES
Substitution can occur at any of the six available sites. There are many possible
permutations offered by substitution and conjugation and this could explain, why
so many coumarin derivatives occur naturally.

11
3.1. Coumarin and Hydroxyl Derivatives of Coumarin
3.1.1. Coumarin
Dipteryx odorata is a species of plant in the legume family Fabaceae. It is native to
Central America and northern South America [18]. Dipteryx odorata‘s seeds are
called tonka beans. They are black, wrinkled, and have a smooth, brown interior.
They have a strong aroma similar to that of sweet wood due to their high coumarin
content [19]. August Vogel isolated coumarin for the first time from tonka beans in
1820 by bioassay guided fractionation. He mistook coumarin for benzoic acid [20].
In the same year, the French pharmacist Nicholas Jean Baptiste Gaston Guibourt
discovered the mistake and named the new compound “Coumarin” (from the
French name for tonka beans, coumarou) [21].
Coumarin (1) have been research to be derived from Torresea cearensis which is a
widespread plant in the northeast region of Brazil [22]. They found that in its stem
bark and seeds are largely used as an anti-inflammatory. This study performed an
experiment using T. cearensis extract to investigate the antiemetic and anti-
edematous effects of hydroalcoholic and coumarin extracts. The in-study model
used pain sensation in rats and carrageenan- and dextran-induced leg edema in rats.
The study found that compound 1 (10 and 20 mg/kg, p.o.) significantly inhibited
carrageenan-induced edema in rats [22].
3.1.2. 7-Methoxycoumarin derivative
Anti-inflammatory effect of coumarin (1) together with 7-methoxycoumarin
(Figure 2) had been researched biologically through the extraction from the aerial
parts of Lavandula latifolia VILL. (Labiatae) which is the Paraguayan crude drug
named “Alhucema” [23]. In study, substance had inhibitory activity when it was
applied topically to carrageenin-induced paw edema (CPE) in rats. The 70%
ethanolic extract was partitioned between chloroform and water to give an active
chloroform soluble fraction which showed inhibition to CPE and was
chromatography on a silica gel column by using elution with a chloroform –
methanol mixture to give an effective fraction. The fractions’ anti-inflammatory
was tested in the CPE test using topical application. Coumarin (1) showed a
weakly positive effect on CPE [23].

Figure 2. Herniarin (7-Methoxycoumarin) [23]

12
3.1.3. Umbelliferone (7-hydroxy-[1]benzo[b]pyran-2- one) derivative
Another study depends on the extract of Justicia pectoralis Jacq. var Stenophylla
Leonard (Acanthaceae) is an herb from the Northern and Northeastern regions of
Brazil and its main compounds are coumarin (1) and umbelliferone (7-hydroxy-
[1]benzo[b]pyran-2- one) (Figure 3) [24]. They found that this plant can cure
inflammation mainly due to the presence of coumarin. Coumarin (1) and
umbelliferone were performed an experiment to test the anti-edematous activities
on writhing acetic acid in rats and on carrageenan and dextran-induced leg edema
in rats. Fresh leaves of prepared J. pectoralis grown in Brazil were dried before
extraction with 330ml of ethyl alcohol and 660ml of distilled water. Finally, the
study found that coumarin and umbelliferone exhibited anti-sensitization effects
and exhibited significant anti-edema effects in the carrageenan model but only
coumarin reduced rat leg mass in the dextran model [24].

Figure 3. Umbelliferone (7-hydroxy-[1]benzo[b]pyran-2- one) [24]

3.1.4. Scopoletin derivative
The coumarins, umbelliferone and scopoletin (Figure 4) are the main ingredients
in Lomatia hirsuta (Lam.) Dielsex Macbr. (Proteaceae) were extracted. This herbal
plant native to Chile is used in traditional medicine and also occurs in Argentina,
Ecuador and Peru [24]. The leaves after planting from Chile were dried and
extracted with organic solvents such as n-hexane, chloroform, ethyl acetate and
methanol and the efficiency compared with each other. When extracted with
chloroform and ethyl acetate, coumarins, umbelliferone and scopoletin (0.012 and
0.001% dry weight) were found. Therefore, leaf infusion of L. hirsuta showed an
anti-inflammatory efficacy of up to 29.2% induced by λ-carrageenan and 53.5% of
the maximum efficacy observed with naproxen sodium (4 mg/kg) in the same
experimental conditions [24].

Figure 4. Scopoletin [24]

13
Another study looked at different herbs containing scopoletin. Compound was
obtained from the dichloromethane extract of Solanum ligustrinum (Solanaceae)
also native to Chile [25]. As usual, this plant is used in folk remedies to treat fever
and inflammation. The second extract showed 16% anti-inflammatory activity,
while the impure scopoletin fraction showed 65% anti-inflammatory activity at the
50 mg/kg dose, and the positive control naproxen sodium fraction showed 54.6%
activity in dose of 4 mg/kg. Anti-inflammatory activity was assessed using
carrageenan-induced leg edema [25].
3.2. Fused Coumarins
3.2.1. Xanthotoxin derivative
The aerial parts of the Sideritis taurica Stephanex WILD – a plant that grows in
Egypt was extracted with dichloromethane to give xanthotoxin (Figure 5) [26].
The plant after the extract process was proved non-toxic (in doses up to 1.5 g/kg b.
wt) with LD50= 2.205 g/kg b. wt. [95% fiducial limits (f.f.) = 1.977 and 2.434]. In
this experiment, using indomethacine as the reference substance (in doses of 5
mg/kg)] in the model of the carrageenan-induced rat paw edema test and this study
has found significantly anti-inflammatory activity [51.2% and 69.5% protection (in
doses of 200 and 300 mg/kg respectively)][26].

Figure 5. Xanthotoxin [26]

4. SYNTHETIC COUMARIN DERIVATIVES

4.1. Substituted Coumarins
4.1.1. Synthesis 3-Benzylcoumarin
3-Benzylcoumarin (23) has various biological activities and is synthesized in one
step general instead of the long route with three steps before [27]. This simple and
general reaction was conducted under mild conditions and the complex of amide
(22) with POCl3 (21) and salicylic aldehyde (20), was then reflux in chloroform
with a temperature of 66℃ (compared to the severe temperature 220-250°C in the
prior technique) with an 80% yield of product (Scheme 9).

14
Scheme 9. Synthesis 3-Benzylcoumarin [27]
4.1.2. Synthesis of coumarin derivative from 7-Formyl-coumarin
Synthesis of coumarin derivative with 7-Azomethine linkage was initiated from 7-
Formyl-coumarin (25) [28]. 7 – Formylcoumarin (25) was prepared using SeO2
oxidation of 7-Methylcoumarin (24) wih exception of solvent at high temperature
(180-190℃ ). And from 7-Azomthine, it formed some imino derivatives like the
oxime (26), the O-Methyloxime (27), the N-Phenylhydrazone (28), the
dihydrazone (29), the N-Methylhydrazone (30), the N-Phenylimine (31) and the N-
Methylnitrone (32) (Scheme 10). These compounds, together with coumarins 24,
25, were investigated for anti-inflammatory action in rats by inhibiting induced
carrageenan paw edema (CPE). Among these compounds, coumarins 24, 26, 29,
and 30 provided considerable protection against CPE (55.1%, 58.5%, 54.0%, and
54.7%, respectively) [28].

15
 H3C O O
24
N
HON
C O O SeO 2
O 32 C O O
H
26
MeNH OH.HCl NH 2OH.HCl

O MeONH 2. HCl
C O O
PhNH 2 25
H

PhN MeON
C O O C O O
H H
27
31 MeNHNH 2
PhNHNH 2. HCl

H 2NNH 2.HCl

PhNHN
MeNHN
C O O
C O O H
H 28
30

29

O O C N N C O O
H H

Scheme 10. Synthesis of coumarin derivative from 7-Formyl-coumarin [28]

4.1.3. Synthesis carboxamide coumarin
The research conducted reaction between salicylaldehyde (33) with carbon
suboxide (34) to give carboxamide coumarin (35) (Scheme 11) [29]. Furthermore,
carboxamide coumarin (35) displayed high biological activity in the acetic acid
writhing test [45-80% inhibition at a dosage of 5 mg/kg, indomethacine (50.3% at
the same dose)], a test in which nonsteroidal anti-inflammatory medications are
active.

16
 Scheme 11. Synthesis carboxamide coumarin [29]
4.1.4. Synthesis N-Aryl substituted 3-Carboxamidocoumarins 38 a-h
A succession of two types of coumarin derivatives N-Arylsubstituted 2-imino-2H-
1-benzopyran-3-carboxamides 36a and b and 2-oxo-2H-1-benzopyran-3-
carboxamides 38-a-h were prepared and studied about their anti-inflammatory
activity in carrageenan-induced rat paw edema model and use albino rats to test
acetic acid-induced peritonitis [30]. Through the Knoevenangel condensation, the
reaction between nitriles 36a, b and salicylaldehyde 2 and reaction between esters
39 and salicylaldehydes 2 in the presence of piperidine 13 in ethanol. Besides, 2-
oxo-2H-1-benzopyran-3-carboxamides 38a-h were synthesized by acidic
hydrolysis of the corresponding imino analogs 37a, b, using carboxamides 38c-h
was obtained in one-step from the starting materials Scheme 12. In research, they
use piroxicam as the reference compound to compare the anti-inflammatory with
synthesized coumarin compound. Pharmacological results on anti-inflammatory
activities and acute toxicity of the benzopyran derivatives 36a, b and 38a–h and
piroxicam are summarized in Table 2.

17
Table 2 Anti-inflammatory activity and acute toxicity of the benzopyran
derivatives 36a, b and 38 a-h
Acute toxicity
Approximate LD50 (mg/kg) Anti-inflammatory activity
(in mice)
Compound
Carrageenan-
Acetic acid
po ip induced paw
peritonitis
oedema
36a >1000 >700 19±2.11 40±6.43
36b >1000 >700 51±5.05 32±6.89
38a >1000 >700 44±7.21 39±5.09
38b >1000 >700 48±7.21 35±1.02
38c >1000 >700 38±1.01 42±7.20
38d >1000 >700 30±6.96 18±4.63
38e >1000 >700 41±6.42 32±7.01
38f >1000 >700 35±7.11 29±5.58
38g >1000 >700 54±6.05 35±4.88
38h >1000 >700 47±7.13 31±3.31

Scheme 12. Synthesis N-Aryl substituted 3-Carboxamidocoumarins 38 a-h

[30]

18
Compounds 38g, 36b, 38b, and 38h were shown to be the most active in
carrageenan-induced rat paw edema experiments, with 546.5%, 515.05%,
486.51%, and 477.13% inhibition, respectively (at dosages of 10 mg/kg p.o.,
piroxicam demonstrated 576.61%) inhibition. In acetic acid peritonitis tests, the
most active compounds 38c, 36a and 38a showed 42±7.20%, 40±6.43% and
39±5.09% inhibition respectively (at doses of 10 mg/kg p.o., piroxicam revealed a
protection of 29±7.24%). All tested compounds were essentially non-toxic at the
highest dose graded.
4.1.5. Synthesis 4-(7’-methoxy-2’-benzo[b]furanyl)coumarins 46a-f
The reaction between 4-(bromomethyl)coumarins 40a-f and vanillin (41) afforded
ethers 42a-f which joined in Knoevenagel condensation with ethyl cyanoacetate
(43) to obtain unsaturated cyanoesters 44a,b [31]. Besides, another approach used
orthovanillin to react with 40a-f under analogous conditions to give the formation
of ethers 45a-f. After that, conducting reflux in alcoholic K2CO3 and an
intramolecular aldol reaction occurred, resulting in the production of 4- (7'-
methoxy-2'-benzo[b]furanyl)coumarins 46a-f (Scheme 13). In testing procedure,
they took compounds 42a-d, 44a, 45a, and 46a for the trial of anti-inflammatory
activity in the carrageenan-induced rat paw edema method. Especially, when
compared with compounds the standard drug phenylbutazone with 79% less than
coumarin compounds 44a, 42c, and 46a active [87%, 81% and 80% inhibition
respectively in 5h in doses of 100 mg/kg] which are the most active substances.
Furthermore, these compounds were studied in pellet granuloma method and
demonstrated considerable inhibition of inflammation. Among all substances,
compound 44a was the most active (64.6% inhibition, while phenylbutazone as a
reference showed 64.74% inhibition) [31].

19
Scheme 13. Synthesis 4-(7’-methoxy-2’-benzo[b]furanyl)coumarins 46a-f [31]
4.1.6. Synthesis coumarin derivative from 4-Formylcoumarin
Three coumarins derivatives were synthesized from 4-Formylcoumarin (47) to
identify the potential anti-inflammatory of those substances [32]. First, compound
(47) reacted with carbethoxymethylene(triphenyl)phosphorane, aniline and
omethylhydroxylamine to give the coumarin derivatives 48, 51 and 53
respectively. Then, alkene 48 was reacted with 1,3-Dipolar cycloaddition nitrile
oxides 49 a,b to give dihydroisoxazoles 50a,b. Similarly, reaction between imine
51 and 49a,b was conducted to give dihydrooxadiazoles 52a,b. Finally, oxadiazole
was synthesized by the reaction between coumarin 53 with 4-
20
Methoxybenzonitrileoxide 49b (Scheme 14). The research carried out the
carrageenan rat paw edema in vivo and in vitro for anti-inflammatory activity
through their antiproteolytic activity and their ability to inhibit b-glucuronidase and
soybean lipoxygenase. The synthesized coumarins were tested by interacted with
1,1-Diphenyl-2-picrylhydrazyl (DPPH). Therein, using indomethacine (53.3%) as
reference compound; products 50a, 51, 52a, 53 could inhibit in vitro proteolysis,
and compounds 48, 51, 52a, b, 53 showed significant inhibition at the in vivo
experiments (54.0-64.6%). Among of all substances, compound 52b showed the
best biological activity [32].
CO2Et N
R
O
H N OMe H C
C
MeONH2 .HCl
H
C
O
C H 49a,b H
CO2Et

Ph3P CHCO2Et H
RC N O

O O O O O O
O O

53 47 48 50a,b

49b PhNH2
OMe

N
N
O
R
49,50,52
O
H N Ph
N Ph
a: R=Me
N C H

49a,b
b: R=4-MeOC6H4
O O
O O O O

51 52a,b
54

Scheme 14. Synthesis coumarin derivative from 4-Formylcoumarin [32]

4.2. Hydroxyl Derivatives of Coumarin
4.2.1. Four diaminoether coumarin derivatives
Four new diaminoether coumarin derivatives were prepared by a reaction between
4-Hydroxycoumarin or 7-Hydroxycoumarin and 1,3-Bromochloropropane that
leads to two intermediate compounds 4- or 7- Chloropropyloxycoumarins 55a, b
[33]. Then, they were reacted with 1,2- Ethylediamine 56a or 1,3-
Propylenediamine 56b afforded the four diaminoether derivatives 58a-d (Scheme
15). Consequently, the effect of those compounds was tested as having impact
inhibitory effect on inflammation (37-55%) using the carrageenan-induced rat paw
edema model was studied.

21
 HO Cl(H2C)3O H2Nn(H2C)HN(H2C)3O

Br(CH2)3Cl

H2N(CH2)3NH2
O O K2CO3 O O O O
57 a,b
55 a: 4-substituted 56 a,b 58 a-d
a: n=2; b: n=3
b: 7-substituted a: n=2, b: n=3 (4-sub)

c: n=2, d: n=3 (7-sub)

Scheme 15. Four diaminoether coumarin derivatives [33]
4.2.2. Synthesis coumarin derivative as TNFα inhibitors
Coumarin derivatives, such as (59) [R1= (un)substituted aryl methylene; R2=H,
alkyl, aryl, heteroaryl, HO, OMe; R3=H, X, OH, alkoxy, acylamino; R4=H, X, OH,
alkoxy, alkyl, CN, NO2, CHO; R5=alkyl, alkenyl; R6=H, X, alkyl, CHO] were
prepared for the use of such compounds as TNF α inhibitors which is a
proinflammatory cytokine secreted by various cells and related to the autoimmune
system [34]. The reaction was conducted as 4-Chlororesorcinol with ethyl 2-
Benzylacetoacetate to give the intermediate (60), then reacted with
dimethylcarbamoyl chloride and obtained the coumarin derivative (61) (Scheme
16). As a result, compound 61 demonstrated IC50=0.09 mM against 50%
inhibition of TNFα level.

Scheme 16. Synthesis coumarin derivative as TNFα inhibitors [34]

4.3. Fused coumarin derivative
4.3.1. Synthesis derivative of the angelicin
Derivatives 64 and 65 of the angelicin were synthesized by the reaction of quinone
62 with acetylmethylene (triphenyl)phosphorane (63) [28] (Scheme 17). The
research had been shown that coumarins 64, 65 had anti-inflammatory activity in
vitro.

22
Scheme 17. Synthesis derivative of the angelicin [28]
Another pharmacological study had been researched to find out other biological
activities of synthesis of angelicin herteroanalogues by replacing furan with
thiophene or a 1-substituted pyrazole moiety [35]. Reaction was conducted by
reaction between malonic esters 67 a,b and the enaminoketones 66a,b to
dihydrocoumarins 68a-d. After that, aromatization by 5,6-Dichloro-2,3- dicyano-p-
quinone (DDQ) to [7, 8]-Fused pyrazolocoumarins 69a-d (Scheme 18). Among
various derivatives that had been studied in this research, compound 69a-d showed
good anti-inflammatory activity by conducting carrageenan-induced rat paw edema
model.

Scheme 18. Another angelicin heteroanalogues [35]

4.3.2. Synthesis calophylloide
Another substance that showed anti-inflammatory is calophylloide (74), it acts as
prevented a prolonged inflammatory process by down-regulation of the pro-
inflammatory cytokines—IL-1β, IL-6, TNF-α, but up-regulation of the anti-
inflammatory cytokine, IL-10 [36]. Reactions were started from phloroglucinol by
Pechmann reaction with ethylbenzoylacetate and gave 5,7-Dihydroxy-4-
phenylcoumarin (70). After that, by Friedel-Crafts acylation/Fries rearrangement,
they conducted a reaction with 2- Methylbutanoylchloride to give the keto-
derivative (71). 1,1-Dimethoxy-3-methylbutan-3-ol in pyridine was heated with

23
(71) and then carried out methylation with methyliodie to obtain the formation of
pyrano-moeity 72. Finally, 72 was reacted with hydrobromic acid, bromine and
triethylamine lead to precursor bromoderivative 73 as reacted with DBU to give
dehydrobromination and the desired calophylloide 74 (Scheme 19).

Scheme 19. Synthesis calophylloide [36]

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