A Project on

“RECENT ANALOG’S OF BENZOFURAN IN TREATMENT OF

ALZHEIMER’S 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

MS. RAKHI MISHRA

(Assistant 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
 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
Ms. RAKHI MISHRA, Department of Pharmacy, Noida Institute of Engineering
and Technology, Greater Noida for his inestimable guidance, valuable suggestions
and constant encouragement during the course of this study.
I am thankful to Dr. AVIJIT MAZUMDER and Dr. RUPA MAZUMDER 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)
 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 TREATMENT OF
ALZHEIMER’S DISEASE” form, my own contribution to the work carried out
under the guidance of Ms. 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
 CERTIFICATE

The work described in this initiated “RECENT ANALOGS OF BENZOFURAN

IN TREATMENT OF ALZHEIMER’S DISEASE by KUNAL KUMAR.
I certify that this is his bona fide work. This work described is original and has not
been submitted for any degree to this or any other university.

Date: -

Signature of Student

Signature of Internal Examiner Signature of External

Examiner
 DECLARATION
I hereby declare that the work embodied in this project report entitled “RECENT
ADVANCEMENT OF BENZOFURAN IN 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 MS RAKHI MISHRA. Assistant Professor, NOIDA INSTITUTE

OF ENGINEERING AND TECHNOLOGY ,GREATER NOIDA. . I have not submitted this
project for award of any other degree or diploma of any other Institute or University
 CHAPTER NAME OF THE
[Link]. PAGE NO.
NO. CHAPTER

1 CHAPTER I INTRODUCTION 1-2

2 CHAPTER II AIM AND OBJECTIVE 3-4

3 CHAPTER III LITERATURE REVIEW 5

4 CHAPTER IV METHODOLOGY 6-7

RESULTS AND
5 CHAPTER V 8-11
DISCUSSION

6 CHAPTER VI CONCLUSION 12

7 CHAPTER VII REFERENCE 13-14

 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.

KEYWORDS: Alzheimer disease, synthesis of benzofuran. Derivatives, biomarkers, synthetic

scheme
 CHAPTER-1

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

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.N SOLUBILIT BOILIN MELTIN REFRACTIV pK MOLECULA MOLECULA
O Y G G POINT E INDEX A R R WEIGHT
POINT FORMULA
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)

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.
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 date Inventors Description

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 inhibitor,
Prime, Michael Prime, pharmaceutical
William Mitchell, William composition thereof, and
Mitchell, Christopher John method of use thereof.
Brown, K Wristfer John
Brown, Agia Pena, Paula
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 [Link], Mei Amyloid plaque
PingKung, Zhi-Ping aggregation inhibitors and
Zhuang,[Link], diagnostic imaging
[Link],Danie Agents.
l M. Skovronsky

4. CN105294662B 2018-04-20 Li Xingshu, Wang Zhiren, Benzofuran quinolone

Huang Ling and Chen derivative and application
Xinzi of benzofuran quinolone
derivative in preparation
of medicine for treating
Alzheimer's disease.
5. AU2005280921 2011-05-19 Makoto Jitsuoka, Carbamoyl-substituted
B2 Norikazu Ohtake, spiro derivative.
NagaakiSatoShigeruTokit
a, Daisuke Tsukahara
6. US2009008243 2009-03-26 Jonathan Laird Gross, Dihydro benzofuranyl
4A1 Marla Jean Williams, Alkanamine Derivatives
Gary Paul Stack, Hong and Methods for Using
Gao, Dahul Zhou Same.
7. KR101662853B 05-10-2016 Didier Benzofurane,
1 RochegisleMutanno Ingo benzothiophene,
KoberphrancesComtarseju benzothiazol derivatives
Christman- as fxr modulators.
FrancisaumitraCentagupta
rameshSistlaoGumadiBen
kateshawar

8. JP5767211B2 2015-08-19 Johann Andershon,

Helena Yübeckanf, 2-Carboxamide-7-
Johansson Christian, Erik piperazinyl-benzofuran
Lindejonas, derivative 774
MalmströmgunnarNordwa
lgitteTelputachanaWeigelt
9. EP1497279B1 2011-03-09 Oliver Schadt, Henning Substituted indoles and
Böttcher, Joachim their use as 5ht-reuptake
Leibrock, Kai Schiemann, inhibitors and as 5ht
Timo Heinrich, Günter ligands
Hölzemann, Christoph
Van Amsterdam, Gerd
Bartoszyk, Christoph
Seyfried
10. DE60310753T2 11/10/2007 Ana Martinez Gil, Isabel dual binding
Dorronsoro Diaz, Laura acetylcholinesterase
Rubio Arrieta, Diana inhibitors for the
Alonso Gordillo, Ana treatment of alzheimer.
Fuertes Huerta, Susana
Morales-Alcelay, Maria
Del Monte Millan, Esther
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 Reference

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

2. 5-bromo-2-(4 Butyrylcholinesteras
hydroxybenzyl) e Inhibitor
benzofuran

3. Benzofuran- Inhibit Aβ
tetrazole aggregation

4. Benzofuran– inhibit Ab fibril

Chalcone formation, directly
Hybrids scavenge (ROS).

5. Tacrine−Benzo AchEand BChE

furan Hybrids Inhibitor
 6. Coumarin- Inhibit Aβ
Benzofuran aggregation and
Hybrids AChE

7. 2-benzylidene- anti-
benzofuran-3 acetylcholinesterase
(AChE)/butyrylcholi
nesterase

8. Benzofuran- Inhibition of
Based Hybrid Cholinesterase
based on SKF- Activity, β-Amyloid
64346 Aggregation.

9. MMBO Inhibit
neurofibrillarytangle
s, tau
phosphorylation.

10. 2-aryl Anti-

Benzofuran acetylcholinesterase

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
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.
 CHAPTER II
AIM AND OBJECTIVE
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.
 CHAPTER III
LITERATURE REVIEW
 Hiremathad Asha, et, all 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, all 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, all, 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
benzofuran and indole synthesis employing various C-H functionalization
techniques is the main topic of this paper.

 YU Hang Miao, et, all 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, all 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.
 CHAPTER IV
MATERIALS AND METHODOLOGY
[Link]

[Link]

[Link]

Search Engines used:

 Google Chrome
 Yahoo
 Wikipedia
 Pubmed
 Google Scholar
 [Link]
 Quora
 Science Direct

Softwares Used:
 Microsoft Word
 Adobe Reader
 Quillbot
 Dash This
 CHAPTER V
RESULTS AND DISCUSSION

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.

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).

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

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).

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

CHAPTER III
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 , 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) [Link] (b)10%KOH, [Link] (c)AGO, AcONa (d)ChaCN, Al

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

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 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
Table 4: Inhibitory activity of synthesized cholinesterase inhibitor.

Compound R1 R2 X AchE Inhibitor BchE 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-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 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.
 CHAPTER-3

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.
 CHAPTER-4

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