A PROJECT ON

“RECENT ANALOGS OF BENZOFURAN IN THE TREATMENT OF

ALZHEIMERS DISEASE”

A project report submitted in partial

fulfilment of the requirement for

the degree of

BACHELOR OF PHARMACY

By

KUNAL KUMAR
(Roll No. 1909080500047)

Under the Guidance of

DR. RAKHI MISHRA
(Professor)

Noida Institute of Engineering and Technology

Pharmacy Institute
Greater Noida-201306, Uttar Pradesh, India

to the Faculty of Pharmacy

Dr. A.P.J Abdul Kalam Technical University, LUCKNOW

1
 ACKNOWLEDGEMENTS
It is a great pleasure for me to acknowledge all those who have contributed
towards the conception, origin and nurturing of this project.
With a deep sense of gratitude and respect, I thank my esteemed research guide
Dr. Rakhi Mishra, Professor ,Noida Institute of Engineering and Technology
Pharmacy Institute, Greater Noida for his inestimable guidance, valuable
suggestions and constant encouragement during the course of this study.
I am thankful to Dr. Avijit Mazumder, Director and Dr. Rupa Mazumder, Dean
for their constant moral support, valuable suggestions directions and selfless
support throughout the investigation.
At this moment, I thank my friends and classmates for their moral support,
constant encouragement and patience absolutely needed to complete my entire
study. I am indebted infinitely to care, support and trust being shown by my
parents without whom it would not be possible to complete this project.

KUNAL KUMAR
(ROLL NO: 1909080500047)

2
 STATEMENT OF THE CANDIDATE
As required by university regulations. I wish to state that this work embodied in the
report title “Recent Analogs of Benzofuran in the Treatment Of Alzheimer’s
Disease” form, my own contribution to the work carried out under the guidance of
Dr. Rakhi Mishra

This work has been submitted for any degree to this or any other university, where
references have been made to previous work of the others.

KUNAL KUMAR
(1909080500047)
BPHARM 8TH SEM, 4TH YEAR

3
 CERTIFICATE

This is to certify that project work entitled “Recent Analog Of Benzofuran In The
Treatment of Alzheimer’s Disease” is a Bonafide research work done by Kunal
Kumar, under the supervision and guidance of Dr. Rakhi Mishra, Assistant
Professor, Noida Institute of Engineering and Technology Pharmacy Institute. The
work is completed and ready for evaluation in partial fulfilment for the award of
Bachelor of Pharmacy during the academic year 2022-2023. The project report has
not formed the basis for the award of any Degree/Diploma/Fellowship or other
similar title to any candidate of any University.

Date: -

Signature of Student

Signature of Internal Examiner Signature of External Examiner

4
 DECLARATION

I hereby declare that the work embodied in this project report entitled “RECENT
ANALOG OF BENZOFURAN IN THE TREATMENT OF ALZHEIMER’S
DISEASE” in Partial fulfilment of the requirements for the award of Bachelor of
Pharmacy, is a record of original and independent research work done by me
during the academic year 2021-22 under the supervision and guidance of DR.
RAKHI MISHRA. Professor, Noida Institute of Engineering and Technology
Pharmacy Institue, Greater Noida. I have not submitted this project for award of
any other degree or diploma of any other Institute or University

5
 CHAPTER NAME OF THE
S.NO. PAGE NO.
NO. CHAPTER

1 CHAPTER I INTRODUCTION 10

2 CHAPTER II AIM AND OBJECTIVE 21

3 CHAPTER III LITERATURE REVIEW 23

4 CHAPTER IV METHODOLOGY 40

5 CHAPTER V RESULTS AND DISCUSSION 42

6 CHAPTER VI CONCLUSION 46

7 CHAPTER VII REFERENCE 48

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RECENT ANALOGS OF BENZOFURAN IN TREATMENT OF
ALZHEIMER’S DISEASE

ABSTRACT

The prevalence of Alzheimer’s disease (AD), a neurobiological disorder that

affects both motor and cognitive function, is on the rise in the modern world, with
a male to female ratio of between 1.2 and 1.5. There are many factors that can
contribute to the development of AD, including head trauma, poor education, poor
diet and nutrition, poor sleep, and poor cardiac rhythm. Due to excessive toxicity,
poor solubility, and slow absorption, previously accessible medications like tacrine
were pulled from the market after failing to demonstrate their usefulness. Among
them, benzofuran-based drugs make a significant contribution because they are one
of the significant pharmacophores found both synthetically and naturally in
heterocyclic compounds, with a wide range of therapeutic applications in the field
of drug discovery that offers many opportunities for further improvement in Anti-
Alzheimer agents by acting in a similar manner to the pharmacophores found in
heterocyclic compounds. This project work include information summarising the
detail of recent analog of benzofuran in the treatment of Alzheimer disease which
are used in the report

KEYWORDS: Alzheimer disease, synthesis of benzofuran. Derivatives,

biomarkers, synthetic scheme

7
 List of Tables

S. No. Title Page No.

1. Physical Property of Benzofuran 14
2. List of patented drug having benzofuran moity. 16
3. List of potential marketed drug having benzofuran moity. 17
4. Inhibitory activity of synthesized cholinesterase inhibitor. 31

8
 List of Figures

S. No. Title Page No.

1 Gender Based Graph 12
2 Naturally obtain from .benzofuran derivatives 14
3. Scheme 1: Synthesis of benzofuran 26
4. Scheme 2: Synthesis of compound 2-acetyl benzofuran. 26
5. Scheme 3: Synthesis of derivatives of benzofuran. 27
6. Scheme 4: Synthesis of benzofuran derivative with one pot 27
method.
7. Scheme 5: benzofuran synthesis in ionic liquid by a PdCl2-heck 28
reaction
8. Scheme 6: formation of benzofuran with buch-wald condition. 28
9. Scheme 7:microwave-assisted route for synthesis of 2- 292
substituted benzofuran
10. Scheme 8: 2- alkyl- aryl benzofuran synthesis. 29
11. Scheme 9: Benzopyranones as a synthons for synthesis of 30
benzofuran.
12. Scheme 10: Synthesis of benzofuran by cyclization of 2alkoxy- 30
acetophenone

9
 CHAPTER-1
INTRODUCTION

10
Alzheimer’s disease (AD) is a neurological condition that worsens over time and
results in mortality by causing severe behavioural abnormalities, language
deterioration, and lifelong cognitive loss. By 2050, 14 and 130 million individuals
in Europe and the rest of the world are anticipated to have Alzheimer’s disease
(AD), which is one of the main causes of dementia in the elderly . It is
characterised by an ever-growing memory deficit and cognitive dysfunction
brought on by synaptic degeneration and neuronal death, particularly in the
hippocampus. .
Alzheimer’s disease (AD) has a complex and poorly understood pathogenesis.
Several factors, including low acetylcholine (ACh) values [5, 6], aberrant amyloid
(A) peptide deposition, oxidative stress, tau protein hyperphosphorylation and
biometal dyshomeostasis, contribute to AD. Since the early 1990s, when an
amyloid protein was found in postmortem patients and the amyloid cascade theory
was put forth, research into Alzheimer’s disease has advanced at an exponential
rate.
Currently, about 20,000 publications have been published on AD research [10].
This statistic is already rising at an alarming rate; around 6 million new instances
in current scenario of Alzheimer’s disease which is detected each year in the older
population. In 2013, approximately 85,000 people died from Alzheimer’s disease
which is the sixth biggest causes of mortality in the United States .
According to reports, Alzheimer’s disease (AD), which is believed to be the
primary cause of ongoing dementia in the ageing population, accounts for 65-70%
of all cases [13]. Men to women ratios have been reported to be between 1.2 and
1.5, with women having a higher frequency of Alzheimer’s disease. . According to
the study, one in five, or nearly 20%, of women and one in ten (10%) of males,
respectively, had an anticipated lifetime risk of Alzheimer’s disease at age 45.As

11
Graph 1 has already demonstrated. Gender bias can be apparent in the odds at 65,
which were somewhat higher for both sexes .

Gender based graph

25.00%

20.00%

15.00%

10.00%

5.00%

0.00%
MEN WOMEN MEN WOMEN
Age 45 Age 65

Fig 1: Estimated risk of Alzheimer’s dementia,at ages 45 and 65 in both men and women
.

Therapies available now for Alzheimer’s disease (AD) An NMDA receptor

antagonist (memantine) plus a cholinesterase powerful inhibitor (donepezil,
galantamine, etc.) have been shown to slightly improve memory and cognitive
function. But they are unable to halt or stop the progressive neurodegeneration .
There is yet no information available regarding how AChE interacts with amyloid
plaques. Nevertheless, experimental studies showed that the presence of AChE
changes its enzymatic and pharmacological properties, and that avoiding this
association may be helpful in treating Alzheimer’s disease patients. Aggregation
can lead to cytotoxicity through four basic routes, including permeability of the
lipid membranes, oxidative stress, endoplasmic reticulum (ER) stress, and
dysfunctional mitochondrial activity . Extracellular matrix (ECM) is a major
Neuroinflammation can be caused by an increase of astrocytes and activated
microglia in the lipid membrane. . Combination therapy is necessary due to the
complex pathophysiology of Alzheimer’s disease, which has been previously

12
mentioned. One strategy is to create multi-targeted drugs that are effective at many
routes simultaneously. The possibility of treating this condition due to the
availability of multi-target anti-Alzheimer treatment alternatives, which include
amyloid beta peptide (Ab)accumulation, has already recently changed due to the
disease's multifactorial nature. Reactive oxygen species (ROS) are produced when
ache inhibition, metal dyshomeostasis modulation, and MAO inhibition are
inhibited . Despite being taken off the market due to liver problems, tacrine (TAC)
was the first medication developed for the potential treatment of AD as an Ache
inhibitor. It has been by far the most often used Ache inhibitory moiety in the
development of a number of multi-target anti-AD medications, despite its severe
toxic effects at therapeutic dosages.

Very significant amounts of heterocyclic compounds are present in many drugs

and have established an essential foundation for medicinal chemistry due to their
adaptability and unique physicochemical properties. Many physiologically active
natural medications and synthetic chemical raw materials have a heterocyclic
molecule with a benzofuran ring at their core . Fomannoxin, a natural benzofuran
molecule, demonstrated outstanding neuroprotective abilities in accordance with an
amyloid-b peptide model (Figure 2). This discovery is significant since anti-
amyloid therapies are thought to be a good alternative to currently available
Alzheimer’s medications. As a result, we shall examine benzofuran-based
compounds in this paper as a potential alternative therapy choice for Alzheimer’s
disease.

13
 Fig. 2: Naturally obtain from Aleudiscusvitellinus.(benzofuran derivatives)

With a molecular weight of 118.13, benzofuran is a significant family of

heterocyclic chemicals. It can be thought of as benzene fused with a furan ring and
is described as a colourless liquid with a pleasant aromatic smell (as shown in
Figure 3). It also has melting and boiling points of -0.4 °F and 345 °F, respectively.
Along with medications and polymers, it can be discovered in a wide range of
bioactive natural products . It is recognised as one of the most significant
heterocyclic rings due to its extensive biological profile. Antiarrhythmic,
antitussive, antitubercular, antidepressant, anti-gout, antifungal, and
antihypertensive medicines are just a few of the medical uses for benzofuran .

Fig. 3: Chemical structure of benzofuran.

Table1:Physical Property of Benzofuran .

S.no Solubility Boiling Melting Refractive Pka Molecular Molecular
point point index formula weight
1 0.815mg/ml 173 °C −18 °C 34.9 m3·mol-1 -2.9 C8H6O 118.1326
(343 °F;
(0 °F;
446 K)
255 K)

14
1.1 Causes associated with Alzheimer’s disease.
A recent study found that Alzheimer’s disease is inherited since people with a
family history of the condition are more likely to develop it later in life. Education,
Education levels are associated with a decreased incidence of Alzheimer’s.
Activities that involve the body, mind, and group work A lower incidence of
dementia has been associated with a number of activities, including physical,
cognitive, social, and recreational ones.

dieting and nutrition It has only recently started to receive in-depth research as a
risk factor for Alzheimer’s disease, despite reports that trans fats and saturated fats
may increase risk, while green vegetables, a limited amount of vitamin other
minerals may reduce risk.

The 24-hour cycle and sleep There is proof that sleep is essential for clearing
amyloid, therefore less sleep is linked to amyloid build-up in the brain. However,
the relationship seems to be a two-way street because amyloid pathology can
disrupt sleep cycles.
Diabetes, for instance, is significantly associated with an increased risk of
Alzheimer’s disease, despite conflicting findings from clinical and pathologic
studies. Numerous studies have concluded that there is no connection between
diabetes and Alzheimer’s disease.

Trauma to the head, TBI has been associated to have higher risk for dementia ,
However, whether AD is more likely to lead to pathologic outcomes than other
neurodegenerative disease processes, such as the recently discovered chronic
traumatic encephalopathy, is being examined.

15
Patent of benzofuran based derivative which has potential to become an alternative
drug and is tabulated in table 2 also list of benzofuran based derivatives which has
potential to become an alternative with the marketed drugs.

Table 2: List of patented drug having benzofuran moity

S. no. Patent no. Patent Inventors Description

date
1. EP1945622B1 2011-28-12 William E. Klunk, Jr. Isotopically-labelled
Chester A. Mathis benzofuran
compounds as
imaging agents for
amyloidogenic
proteins.
2. JP6330011B2 2018-05-23 Steven Martin, Steven Kynurenin-3-
Martin Courtney, Michael monooxygenase
Prime, Michael Prime, inhibitor,
William Mitchell, William pharmaceutical
Mitchell, Christopher John composition thereof,
Brown, K Wristfer John and method of use
Brown, Agia Pena, Paula thereof.
Se. Duagia Pena, Paula Se.
Dopeter Johnson, Peter
Johnson, Celia Dominguez,
Celia Dominguez, Leticia
Em. Toledo Sherman,
Leticia Em. Toledo
Sherman, Ignacio Munos,
Ignacio Munos,
3. USRE44354E1 2013-07-09 HankF.Kung, Mei Amyloid plaque
PingKung, Zhi-Ping aggregation
Zhuang,VirginiaM.Y.Lee, inhibitors and
JohnQ.Trojanowski,Daniel diagnostic imaging
M. Skovronsky Agents.

4. CN105294662 2018-04-20 Li Xingshu, Wang Zhiren, Benzofuran

B Huang Ling and Chen quinolone derivative
Xinzi and application of

16
 benzofuran
quinolone derivative
in preparation of
medicine for treating
Alzheimer’s disease.
5. AU200528092 2011-05-19 Makoto Jitsuoka, Norikazu Carbamoyl-
1B2 Ohtake, substituted spiro
NagaakiSatoShigeruTokita, derivative.
Daisuke Tsukahara
6. US200900824 2009-03-26 Jonathan Laird Gross, Dihydro
34A1 Marla Jean Williams, Gary benzofuranyl
Paul Stack, Hong Gao, Alkanamine
Dahul Zhou Derivatives and
Methods for Using
Same.
7. KR101662853 05-10-2016 Didier RochegisleMutanno Benzofurane,
B1 Ingo benzothiophene,
KoberphrancesComtarseju benzothiazol
Christman- derivatives as fxr
FrancisaumitraCentaguptar modulators.
ameshSistlaoGumadiBenka
teshawar

8. JP5767211B2 2015-08-19 Johann Andershon, Helena

Yübeckanf, Johansson
Christian, Erik Lindejonas,
MalmströmgunnarNordwal
gitteTelputachanaWeigelt
9. EP1497279B1 2011-03-09 Oliver Schadt, Henning
Böttcher, Joachim
Leibrock, Kai Schiemann,
Timo Heinrich, Günter
Hölzemann, Christoph Van
Amsterdam, Gerd
Bartoszyk, Christoph
Seyfried
10. DE60310753T 11/10/2007 Ana Martinez Gil, Isabel
2 Dorronsoro Diaz, Laura
Rubio Arrieta, Diana
Alonso Gordillo, Ana
Fuertes Huerta, Susana
Morales-Alcelay, Maria
Del Monte Millan, Esther
17
2-Carboxamide-7-
piperazinyl-
benzofuran
derivative 774
Substituted indoles
and their use as 5ht-
reuptake inhibitors
and as 5ht ligands
dual binding
acetylcholinesterase
inhibitors for the
treatment of
alzheimer.
 Garcia Palomero, Paola
Usan Egea, Celia De
Austria, Miguel Medina
Padilla
11. US7741354B2 2010-06-22 Michael Thormann, Novel Inhibitors of
Michael Altmstetter, Glutaminyl Cyclase
Andreas Treml, Ulrich
Heiser, Mirko Buchholz

Table 3: List of potential marketed drug having benzofuran moity.

S. Name of drug Primary target Chemical structure Referenc

No. e
1. 99mTc]BAT- β-amyloid plaques
bp-1

2. 5-bromo-2-(4 Butyrylcholinestera
hydroxybenzy se Inhibitor
l)benzofuran

3. Benzofuran- Inhibit Aβ
tetrazole aggregation

4. Benzofuran– inhibit Ab fibril

Chalcone formation, directly
Hybrids scavenge (ROS).

18
5. Tacrine−Benz AchEand BChE
ofuran Inhibitor
Hybrids

6. Coumarin- Inhibit Aβ
Benzofuran aggregation and
Hybrids AChE

7. 2- anti-
benzylidene- acetylcholinesteras
benzofuran-3 e
(AChE)/butyrylcho
linesterase
8. Benzofuran- Inhibition of
Based Hybrid Cholinesterase
based on Activity, β-
SKF-64346 Amyloid
Aggregation.
9. MMBO Inhibit
neurofibrillarytangl
es, tau
phosphorylation.

10. 2-aryl Anti-

Benzofuran acetylcholinesteras
e

1.2 Biomarkers
Even in specialised facilities, 20% or more of patients have incorrect clinical
diagnoses of Alzheimer’s disease. Because positive biomarkers improve diagnosis
accuracy, their involvement
19
1.2.1 Structural imaging
Since neuroimaging detects nondegenerative causal abnormalities reported in
about 5% of all patients with complaints related cognitive impairment, the
American Academy of Neurology (AAN), whose primary focus is on neurology,
advises having structural imaging for the brain for people with objective cognitive
impairment .

1.2.3CSF.
The American Academy of Neurology (AAN), whose primary focus is on
neurology, advises having structural imaging for the brain for people with
objective cognitive impairment because neuroimaging detects nondegenerative
causal abnormalities reported in about 5% of all patients with complaints related
cognitive impairment.

20
 CHAPTER II
AIM AND OBJECTIVE

21
The aim of developing benzofuran compounds for the treatment of Alzheimer’s
disease is to identify potential therapeutic agents that can effectively mitigate the
symptoms or slow down the progression of the disease. Alzheimer’s disease is a
neurodegenerative disorder characterised by the accumulation of amyloid-beta
plaques and neurofibrillary tangles in the brain, leading to cognitive decline and
memory loss.
Thus the aim of this project work is to include information summarizing the detail
of recent analog of benzofuran in the treatment of Alzheimer's disease which are
used in this project

22
 CHAPTER III
LITERATURE REVIEW

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 Hiremathad Asha, et.al 2014 The most frequent form of dementia,
Alzheimer’s disease (AD), is a neurological disorder that is characterised by a
steady decline in memory and cognition. The multifaceted character of AD has
been shown to be the primary issue in its current lack of a cure. Therefore, the
creation of novel hybrids is absolutely necessary in the fight against the illness.
In light of this, novel coumarin-benzofuran hybrids have been created and
tested as potential treatments for Alzheimer’s disease. The goal is to find an
acetylcholinesterase inhibitor that is an efficient mimic of donepezil.

 He Jin Ha, et.al 2011 We created a benzofuran analogue (8, MDR-1339) that
is orally active and blood-brain barrier permeable with significant
antiaggregation activity. Compound 8 improved the learning and memory
function of AD model mice by lowering the A aggregates in their brains in
addition to restoring cellular viability from A-induced cytotoxicity. 8 will offer
a novel framework for an A-aggregation inhibitor that may provide an
alternative treatment for AD, given the excellent bioavailability and brain
permeability shown in our pharmacokinetic tests.

 Soumitra Agasthi, et.al 2015 Heterocyclic compounds are frequently present

in the fundamental components of a number of medications, natural goods, and
agrochemicals, which has sparked extensive research towards milder and
easier methods of synthesising them. Many alternative methods have been
developed over time in an effort to create these heterocyles. In this regard,
techniques that guarantee both step and atom efficiency have attracted a lot of
attention. These expectations were found to be met by the multiple C-H
activation method of synthesising heterocyclic moieties, which also ensures the
utilisation of readily available starting materials. The present state of
24
 benzofuran and indole synthesis employing various C-H functionalization
techniques is the main topic of this paper.

 YU Hang Miao, et.al There are many different types of benzofuran chemicals
in nature. Numerous investigations have demonstrated that the majority of
benzofuran compounds has potent biological properties, including anti-tumor,
antibacterial, anti-oxidative, and anti-viral properties. Benzofuran compounds
have gained the interest of chemical and pharmaceutical experts all over the
world due to their biological activities and numerous potential applications,
making them promising natural medicine lead compounds.

 Litvinova A. Valeriya, et.al We discuss current developments in the creation

of heterocyclization processes that result in derivatives of benzofuran-3-
carboxylic esters in this microreview. The five most recent and important
publications are discussed.

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1.3General Synthetic Scheme for Benzofuran Analogues: -
Since the medicinal significance of benzo[b]furans is very broad, major efforts
have been made to find novel synthetic techniques for their synthesis.

scheme 1: synthesis of benzofuran Salicylaldehyde(1a) reacts with chloroacetic

acid to produce o-formylphenoxyacetic acid(1b). When acetic anhydride and
glacial acetic acid are refluxed, it produces benzofuran(1c).

Scheme1: synthesis of benzofuran

Scheme2: synthesis of compound 2-acetyl benzofuran.

Salicylaldehyde (2a) and 1-chloropropan-2one (2b) were combined to make 1,8-
diazabicycloundec-7ene, which served as an activator to create 2-acetylbenzofuran
(2d) (Scheme 2) .

Scheme2: Reaction for the production of compound 2-acetyl Benzofuran.

26
Scheme3: synthesis of derivatives of benzofuran.
By cyclizing closed alkynes2(3b) in the presence of a CuBr catalyst with N-
tosylhydrazones generated from ortho hydroxybenzaldehyde(3a), the synthesis of
benzofurans derivatives is made possible. Numerous functional groups across the
board can endure the reaction circumstances (Scheme 3).

Scheme 3: synthesis of derivatives of benzofuran.

Scheme 4: synthesis of benzofuran derivative with one pot method.

An effective ligand for Pd catalysis that forms benzofuran derivatives (4c) and (4f)
in one pot, as well as 2chlorophenols (4a) coupled with alkynes (4b), when
hydroxyterphenylphosphine is available (Scheme 4).

27
 Scheme 4: synthesis of benzofuran derivative with one pot method.
Scheme 5: benzofuran synthesis in ionic liquid by a PdCl2-heck reaction
The production of benzofuran analogues via the Heck reaction with Pd catalysis is
well-known(5b). It is easy to see the advantages of intramolecular Heck reaction-
Pd-catalyzed through ionic liquid catalysis (Scheme 5).

Scheme 5: benzofuran synthesis in ionic liquid by a PdCl2-heck reaction

a:5% PdCl2, (nBu)3N, NH4O2CH

Scheme 6: formation of benzofuran with buch-wald condition.

First, we put our one-pot method to the test by reacting acetophenone (6a) with
under modified Buchwald conditions, using acetonitrile rather than dioxane
(Scheme 6). Through hydrolysis, O-aryloxime(6e) synthesis, [3,3]cyclization, and
rearrangement, benzofuran(6f) was produced at a yield of 91%.

Scheme 6: synthesis of benzofuran with buch-wald condition

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Scheme 7:microwave-assisted route for synthesis of 2-substituted benzofuran
An effective and mild microwave-assisted process for converting COOH(7a)
directly into ortho-substituted benzofurans(7d). enables the synthesis of
2,4,6trichloro(1,3,5)triazine(7b), non-racemized N-protected amino acids from
alkyl2benzofuran-methane amines (Scheme 7).

Scheme 7:Microwave-assisted route for synthesis of 2-substituted benzofuran

Scheme 8: 2-alkyl-aryl benzofuran synthesis.

One-pot visible-light-driven intermolecular attachment and cyclization was carried

out for a 5-endodig ortho-halophenol derivative (8a) in water with closing alkynes
generated by Pd in order to produce large amounts of 2aryl or alkyl benzofurans
(8b) without the assistance of Ru or Ir complexes or any other potential component
(Scheme 8).

29
 Scheme 8: synthesis of 2-aryl/alkyl benzofuran
Scheme 9: Benzopyranones as a synthons for synthesis of benzofuran.
Benzopyranones(9a) or coumarins (LI) can be utilised as synthons for the Fittig-
Ebert-Perkin reaction or pyrolysis to produce benzofurans(9c).

Scheme 9: Benzopyranones as a synthons for synthesis of benzofuran

Scheme 10: Synthesis of benzofuran by cyclization of 2alkoxy-acetophenone

There are various ways that 2-alkoxyacetophenones (10a) can be cyclized

intramolecularly to produce 2-R-3-methylbenzofurans (10b). In the polar
solvent/environment, Na and K alcoholates or alkalis are used as condensing
agents.

Scheme 10: Synthesis of benzofuran by cyclization of 2alkoxy-acetophenone

30
ANTI-ALZHEIMERACTIVITYOFBENZOFURAN-
BASEDDERIVATIVEANDTHEIRSYNTHETICSCHEME.

2.1 Ab fibril formation inhibitor

2014 H. Khanam et al. Byun et al. provided numerous suggestions for possible
approaches to creating ligands with very high binding affinity to Ab fibrils. They
have described the inhibitory effects of their novel line of amino-styryl benzofuran
analogues on the development of Ab fibrils. To evaluate the effectiveness of
synthetic drugs against the fibrillation of Ab, the thioflavin T (ThT) assay is used.
Compounds (A)as well as(B) (Fig.4) showed better inhibitory actions (IC50 14
0.07 and 0.08 mM, respectively) than the curcumin (IC50 14 0.80 mM) and IMSB
(IC50 14 8.00 mM) as reference compounds [104-106].

Fig.4 Ab fibril formation inhibitor benzofuran analogues.

2.2 2-Arylbenzofurancholinesterase inhibitor

In 2021, Y. YUN ET AL. reported,In order to research its anti-AD effectiveness,
2-arylbenzofurans were created. Due to their wide range of biological and
therapeutic properties, such as anti-inflammatory anti-bacterial , hypoglycemic ,

31
antioxidant , anti-tumor , anti-cholinesterase , anti-fungal , anti-monoamine
oxidase , and others, benzofuran compounds have drawn a lot of attention. The
aetiology of Alzheimer’s disease is complex, and multi-targeted medicines work
better in this condition than single-targeted ones.

Numerous substances based on benzofuran have recently been shown to be

effective acetylcholinesterase inhibitors. The current study examines the synthesis
and in vitro activity of analogues of the 2arylbenzofuran as BACE1 and ChE
inhibitors. In three processes, substituted 2hydroxy-benzaldehyde was converted to
2-arylbenzofuran. The synthesis processes for analogues of 2aryl-benzofuran are
shown in Scheme. An technique from Drozdzik and colleagues that has been
somewhat modified is used to synthesise the 2-aryl-benzofuran molecule.

Scheme: Synthesis of 2-arylbenzofuran,

a) K.Cos (b)10%KOH, CH.OH (c)AGO, AcONa (d)ChaCN, Al

32
2.3 Benzofuran analogue (MDR-1339) with anti-aggregation activity
An oral active, blood-brain-barrier (BBB) permeable benzofuran derivative with a
sizable anti-aggregation effect was created by Hee-Jin et al. in 2017 and is known
as MDR-1339. Not only does 2-(3,4-dimethoxyphenyl)-5-(3-methoxypropyl)
benzofuran restore cellular viability following Amoloid beta-induced cytotoxicity,
but it also improves adaptive learning and memory in model mice for AD by
reducing the build up of Amoloid beta in the brains.

Scheme: Synthesis of benzofuran analogue with anti-aggregation activity.

a) DBU, CH, CN (b) L, KaCO3(c) LiOH, MeOH-H2O (d) (i) NaBHA
(ii) L, € Mel t-BuOK

33
2.4 Anticholinesterase inhibitory activity
F. Abedinifar Et. Al reported in 2018 that (AchE) and (BchE) architectures are
remarkably similar, with 65% amino acid sequence similarity. By restoring Ach
levels, the inhibition of acetylcholinesterase and butyrylcholinesterase enzymes
alleviated symptoms related to Alzheimer’s and including cognitive level and also
include short-term memory. Benzofurans are an important heterocyclic category
with a diverse spectrum of bioactivity. The anticancer, antimicrobial, anti-
hyperlipidemic, AchE inhibitor, antibacterial, and anti-allergic rhinitis
characteristics of benzofuran-2-carboxamide derivatives are additional benefits.
The given scheme depicts the synthesis approach toward benzofuran-2-
carboxamide with pyridinium moiety. In the presence of K2CO3, the condensation
process of salicylaldehyde derivatives 1 and ethyl bromoacetate produced [128],
ethyl benzofuran-2-carboxylates(4c) was produced via hydrolysis in aqueous
ethanol/KOH. The amidation with (methylamino) pyridine or 4-(methylamino)
pyridine in the availability of hydroxybenzotriazole (HOBt) and [129] was
obtained from N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride
(EDC). Later, the compounds were N-benzylated with suitable benzyl halides in
acetonitrile at reflux temperature, yielding benzyl pyridinium halide salts of the
intended products 6a-6o [130]. Using a modified Ellman’s technique [131], the
inhibitory activity of AchE and BchE of the compound 6a-o, series of derivatives
were assessed of benzofuran-carboxamide benzyl pyridinium. Table 1 summarises
the findings, which include target compound IC50 and percent inhibition at 56 M.
(Table 5). None of the drugs inhibited AchE better than donepezil, however with
the exception of 6j, all of them are having superior inhibitory activity of BchE. 6k
inhibited AchE the best of the target drugs, but 6h inhibited BchE more efficiently

34
than donepezil, with an IC50 value of 0.054 M, which is about 100 times greater
than the positive control.

Fig.5: Compound having anti-cholinesterase activity.

Scheme: Benzofuran-2- carboxamide synthesis

35
Table 4: Inhibitory activity of synthesized cholinesterase inhibitor.
Compound R1 R2 X AchE BchE
Inhibitor Inhibitor
6a H H Br 5.50+-0.3 0.29+-0.01
6b H 3-Me Br 13.8+-0.5 0.11+-0.01
6c H 4-Me Br 19.8+-0.8 0.65+-0.04
6d H 2-NO2 Br 3.5+-0.3 0.15+-0.01
6e H 4-NO2 Br 40.0+-4.0 0.76+0.05
6f H 4-F Br 12.3+-0.3 0.37+-0.01
6g H 2,4-Cl2 Cl 4.4+-0.3 0.37+-0.01
6h H 2-F-6-NO2 Br 33.8+-1.2 0.054+-0.002
6i Ome H Cl 4.7+-0.4 0.87+-0.07

Donepezil - - - 0.031+-0.005 5.4+-0.1

2.5 PET Imaging of beta-Amyloid Plaques

Masahiro Ono Et. Al reported in 2018 (scheme)the synthesis of benzofuran
derivatives for PET imaging of beta-amyloid plaques. A reaction called
Intramolecular Wittig reaction between the compound triphenylphosphonium salt
and 4-nitrobenzoyl chloride performed the critical step in the synthesis of the
benzofuran backbone fig.. 3-methoxy-5-hydroxybenzyl alcohol and
triphenylphosphine hydrobromide were used to efficiently synthesise the required
Wittig reagent (yield 84 percent ). Wittig reactions yielded 33 percent of the
necessary benzofuran backbone, 4. 5 was converted into the compound mono-
36
methylamino derivative 7, initially by removing the nitro group to an amino group
with the accompany of SnCl2and then monomethylating the amino group using a
previously published process. Compound 5 was also able to efficiently transformed
to the dimethylamino derivative, 9, using paraformaldehyde, sodium
cyanoborohydride [132] and Acetic acid (produce 39 percent ). By treating
compounds 5, 7, and 9 with BBr3, the O-methyl groups were removed, yielding 6,
8, and 10 with yields of 47, 39, and 7%, respectively.

; (g) Scheme: Benzofuran derivatives are synthesised.

(a) EtOH, NaBH (b) acetonitrile, PPh, HBr; (c) toluene, 4-nitrobenzoyl chloride,
Nets; (d) EtOH, SnCk2; €CH,Cl, Bbra; (f) MeOH, NaOMe, (CH,O),
NaBH4CHCl2, BBr3
2.6 Anti cholinesterase activity
Dawood Et. Al. reported in 2018 Seong et al. investigated the anti-Alzheimer’s
disease (AD) effect of moracin mentioned below in fig. derivatives 120-123 (Fig.6)
via in vitro suppression of BACE1 and cholinesterase. A computer-assisted drug
design and modelling application was used to investigate the mechanism of action
of moracin derivatives. With a Ki value of 1.28 M, 112 of the moracin compounds

37
showed the strongest BACE1 inhibitory activity. The availability of the phenyl
scaffold in the compound 2-aryl benzofuran structure was crucial for BACE1
inhibition, according to SAR studies [106]. A total of twenty-two 1,5-
benzothiazepine derivatives 113 based on benzofuran were synthesised and tested
as cholinesterase inhibitors. The majority of the 113 compounds inhibited
butyrylcholinesterase (BchE) selectively, with IC50 values ranging from 1.072nM
to 1.072nM.

38
 CHAPTER IV
MATERIALS AND METHODOLOGY

39
Information of benzofuran analoge and their uses in treatment and
management of Alzheimer disease collected with the search engine like
Google Chrome, Yahoo, Wikipedia, Pub med, Quora, Scholar, NCBI.in
Different software are used for completing the data which are Microsoft
Word, Adobe, Quillbot, Dash

40
 CHAPTER-V

RESULT AND DISCUSSION

41
Various Scheme which are obtained from literature study for the synthesis of
benzofuran are listed in the table.

S.N SCHME RESULT

O
1 Benzofuran

2 2-acetyl Benzofuran

42
3 Ortho
hydroxybenzaldehyde

4 hydroxyterphenylphos
phine

5 PdCl2 Heck reaction

43
6 O-aryloxime

7 2,4,6,trichloro1,3,5tria
zine

8 2 aryl benzofuran

9 benzofuran

44
10

2alkoxy-
acetophenolone

CHAPTER-6
45
 CONCLUSION

Alzheimer’s disease (AD) is a neurobiological disorder that impairs motor and

cognitive function that is rapidly spreading in the current scenario with a male:
female ratio of 1.2 to 1.5 due to various causes associated with it such as
education, diet and nutrition, sleep and cardiac rhythm, and head trauma, among
others. It is the third greatest cause of mortality, and treating Alzheimer’s disease is
a huge issue due to the lack of an effective medicine. However, data suggests that
the benzofuran derivative has strong bioactivity against Alzheimer’s disease.

46
CHAPTER-7

47
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