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DOI: 10.1055/a-2522-0970
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Small Molecules in Medicinal Chemistry

Advances in Synthesis and Anti-Alzheimer’s Disease Potential of Functionalized Benzofurans: A Recent Overview

Pragati Kushwaha∗
a   Department of Chemistry, University of Lucknow, Lucknow-226007, Uttar Pradesh, India
,
Rashi Rashi
a   Department of Chemistry, University of Lucknow, Lucknow-226007, Uttar Pradesh, India
,
Ayush Bhardwaj
a   Department of Chemistry, University of Lucknow, Lucknow-226007, Uttar Pradesh, India
,
Danish Khan∗
b   Department of Chemistry, Indian Institute of Technology, Roorkee-247667, Uttarakhand, India
› Author Affiliations

P.K. expresses gratitude to the Council of Science and Technology, U.P. (No. CST/D-795) and the University Grants Commission (UGC), New Delhi (F.30-507/2020(BSR)) for financial assistance.
› Further Information
 
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Abstract

Alzheimer’s disease (AD) comes under progressive neurodegenerative disorders which is the leading cause of dementia affecting the aged population. The available drugs for AD treatment are just palliative and not curative, further these drugs have severe side effects. Therefore, there is a significant demand for novel, potent, and safe molecules as anti-Alzheimer’s disease agents with diverse mechanisms of action. Benzofuran derivatives are one of the versatile and ubiquitous scaffolds being developed as potential candidates against AD. While benzofuran analogues have not yet resulted in widely approved AD treatments, these molecules remain a significant focus of AD drug discovery because of their multitargeted approach and promising preclinical results. The ongoing research into these molecules holds potential for future clinical applications as anti-AD agents. In light of this, the present review outlined recent advances of the synthesis and potent anti-AD activities reported. The sole purpose of this review is to shed light on the design and development of these molecules with high efficacy and reduced toxicity against AD.

1 Introduction

2 Synthesis

3 Benzofuran-Based Scaffolds against AD

4 Naturally Occurring Benzofurans for Treatment of AD

5 Future Perspectives

6 Conclusion


#

Key words

benzofuran - synthesis - electrochemical - Alzheimer’s disease - AChE - β-amyloid
1

Introduction

Heterocyclic compounds can be traced into a large number of drug molecules because of their versatile and unique physicochemical properties. These structures have become an important foundation for medicinal chemists.[1] Among heterocyclic molecules, benzofuran derivatives have garnered significant attention in medicinal chemistry because of their structural versatility and wide-ranging biological activities. Benzofuran is characterized by a benzene ring fused with a furan ring, this unique fusion of an aromatic benzene ring with the oxygen-containing furan ring delivers distinct electronic and chemical properties to benzofurans, creating the possibility of various functionalizations at multiple sites on the molecule (Figure [1]).[2] Therefore, benzofuran is modest yet highly versatile, attractive framework for the development of new therapeutic agents.

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Figure 1 Structure of benzofuran

The benzofuran moiety is ubiquitous in a large number of biologically active synthetic compounds.[3] These derivatives have been long associated as anticancer,[4] [5] antimicrobial,[6,7] anti-inflammatory,[8] antiprotozoal,[9] antiosteoporotic,[10] antileishmanial,[11] and many more activities.[12] [13] [14] This heterocyclic ring can be evidenced in a large number of well-established and clinical trial drugs, related to wide range of diseases. Some of the examples are enlisted in Table [1].

The diverse medicinal importance of benzofuran derivatives attract the scientific community to exert more from this opulent nucleus. One of the most extensively researched applications of benzofuran derivatives lies in their anti-Alzheimer’s disease activity. Neurodegenerative disorders are typically characterized by the gradual and progressive loss of neuronal cells, leading to nervous system dysfunction. Particularly, Alzheimer’s disease (AD) is the reason for around 80% of cases of dementia in aged population.[25] Dementia refers to a notable decline in cognitive function that goes beyond the normal neurodegenerative effects of age. According to World Alzheimer Reports, dementia is currently the seventh most common cause of death worldwide and one of the diseases with the largest societal costs.[26] Around 57.4 million individuals are thought to be affected by AD globally as of now, with 152.8 million expected by 2050.[27] The accurate pathophysiology of AD is still elusive, however, during the last decade, better understanding of the disease mechanism have been achieved. The studies have been clarified that etiology of AD is linked with multiple mechanisms, including inadequate cholinergic neurotransmission, impaired metabolism of β-amyloid (Aβ) peptides, τ protein phosphorylation, and the participation of oxidative and inflammatory processes.[28] Aβ plaques and the formation of τ-containing intracellular neurofibrillary tangles (NFT) are the pathological hallmark of AD.[29] Enzymes including acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and monoamine oxidase (MAO) are typically the focus of medicinal chemists developing AD drugs because of their importance in AD pathogenesis. Currently, approved anti-AD drugs are basically AChE inhibitors (Figure [2]); however, these therapeutic options only provide temporary relief from symptoms. Additionally, none of the available treatments halts the progression of this terminal disease. Further, the growing elderly population of the world is leading to an ever-increasing number of populations afflicted with neurodegenerative diseases including AD.[30] Therefore, there is a huge demand to create novel, efficient, and less hazardous medications to treat this debilitating disease.

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Figure 2 Currently available drugs for AD

Table 1 Benzofuran-Based Drug Molecules

Entry

Name

Structure

Uses

1

amiodarone[15]

antiarrhythmic

2

escitalopram[15]

antidepressant

3

dronedarone[15]

antiarrhythmic agent

4

budiodarone[15]

antiarrhythmic

 5

vilazodone[15]

antidepressant

 6

benzbromarone[15]

uricosuric agent

 7

2-MAPB[16]

empathogenic effects

 8

6-(2-aminopropyl)benzofuran[17]

serotonin-norepinephrine-dopamine reuptake inhibitor

 9

(–)-benzofuranylpropylaminopentane(BPAP)[18]

monoaminergic activity enhancer

10

brofaromine[15]

antidepressant

11

dimemebfe (5-MeO-BFE)[19]

agonist for serotonin receptors

12

5-(2-aminopropyl)benzofuran[17]

serotonin reuptake inhibitor

13

5-MAPB [1-(benzofuran-5-yl)-N-methylpropan-2-amine][20]

serotonin reuptake inhibitor

14

5-EAPB [1-(benzofuran-5-yl)-N-ethylpropan-2-amine][21]

serotonin reuptake inhibitor

15

Bromo-DragonFLY (or 3C-Bromo-Dragonfly, DOB-Dragonfly)[15]

potent hallucinogen

16

TFMFly[22]

agonist at the 5HT2A serotonin receptor

17

YM-348[23]

selective 5-HT2C receptor agonist

18

mycobacterium protein tyrosine phosphatase B (mPTPB)[24]

antibacterial and antifungal

19

6-benzofuryl purines[24]

antimycobacterial

20

2-(4-methoxy-2-methyl phenyl)-3H-benzofuro[3,2-e]benzofuran[24]

antibacterial and antifungal

21

4b,9b-dihydroxy-7,8-dihydro-4bH-indeno[1,2-b]benzofuran-9,10(6H,9bH)-dione[24]

antibacterial and antifungal

22

MEN-11066[24]

against breast cancer

The past decade has endured the considerable upsurge of interest to design and develop novel molecules against AD. As research progresses, benzofuran-based molecules have grown enormously and shown improved AChE inhibition as well as a wide spectrum of anti-AD activities.

As discussed previously, benzofuran molecules represent a highly versatile and functional class in medicinal chemistry with a wide spectrum of biological activities and therapeutic potentials. The pivotal role of benzofurans in medicinal chemistry motivates researchers to search for advance synthetic methodologies to develop these molecules which may serve as new biologically active leads. Undoubtedly, there are various review articles which are available to explain the spectrum of therapeutic importance of benzofuran derivatives including a few that discuss the anti-AD properties of benzofuran derivatives.[31] [32] However, there is a literature gap in the recent times for an article which provide a collective report on the synthetic advancements and a clear insight about various categories of benzofuran derivatives against AD which is an important parameter for structural modifications for further optimization. Therefore, the focus of this review is to embark on synthetic strategies via advanced synthetic routes and anti-AD activities of various benzofuran derivatives. In this review we have selected articles from 2019–2024.


# 2

Synthesis

Benzofuran derivatives are conventionally synthesized by a variety of methods, such as Perkin benzofuran synthesis, o-alkylation followed by cyclization of salicylaldehydes, McMurry reaction and cycloisomerization of alkyne ortho-substituted phenols, etc.[33] However, in recent times, there have been various modifications reported to these traditional methods.[32] Some of the advanced reaction procedures are outlined below.

2.1

Metal-Free Synthesis of Benzofuran Derivatives

Metal-free reactions have numerous advantages over metal-catalyzed reactions such as cost effectiveness, minimal waste, simple procedures, environmental friendliness, etc.[34] Because of these advantages the significance of metal-free reactions is growing rapidly.

Wang et al. reported an efficient metal-free approach to form disubstituted 2-aryl benzofurans 2 in excellent yields.[35] It was also applicable to 2-aryl indoles. The procedure was based on tert-butoxide-mediated condensation reaction and proceeded via an intermediate vinyl sulfoxide (Scheme [1]).

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Scheme 1 Metal-free synthesis of benzofuran derivatives

In 2022, Song et al. reported another transition-metal-free synthetic route for benzofuran derivatives 4 using o-bromobenzylketones. The reaction was executed via potassium tert-butoxide promoted intramolecular cyclization.[36] The reaction procedure was operationally simple and afforded good yields with broad substrate scopes (Scheme [1]).

The Wang group reported an HNTf2/TMSOTf-catalyzed cascade reaction started with o-alkenyl phenols and aldehydes.[37] The reaction was performed in DMF at 25 °C. 2,3-Disubstituted benzofurans 6 were obtained in good to excellent yields (Scheme [1]).


# 2.2

Microwave-Assisted Synthesis of Benzofuran Derivatives

Microwave-assisted reactions have remarkable advantages over other methods by reducing reaction times potentially (often from multiple hours to few minutes), because of the fast and uniform heating. This method improves yields and selectivity by increasing reaction efficiency and use of less solvent, which is an important aspect of green chemistry. It is a useful tool for both industrial and scientific purposes due to its simplicity of scalability and reproducibility.

The Ashok group reported a novel series of 4-aminophenyl-1H-1,2,3-traizole-based benzofuran analogues 9 and evaluated for anticancer and antimicrobial activities.[38] These molecules were synthesized in multiple steps and the last step afforded the benzofuran ring. The reaction was performed in taking potassium carbonate as base and dry acetone as solvent under microwave irradiation. These molecules have shown good anticancer activity against MCF-7, PC-3, and HeLa cell lines. Additionally, they have considerable antimicrobial activity against few gram-positive, gram-negative bacterial, and fungal strains (Scheme [2]).

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Scheme 2 Microwave-assisted synthesis of benzofuran derivatives

In 2023, the Mancini group reported the one-pot synthesis of 9-methoxynaphtho[1,2-b]benzofuran (12) by using 1-naphthol (10) and 1-bromo-4-methoxy-2-nitrobenzene (11) under microwave conditions.[39] In this reaction potassium tert-butoxide was used in dimethyl sulfoxide solvent. The reaction was kept for 2 h at 160 °C (Scheme [2]).


# 2.3

Light-Mediated Synthesis of Benzofuran Derivatives

The past years have endured a potential upsurge of interest in the use of visible-light-mediated chemical reactions for synthetic organic chemistry. The application of these methods to synthesize benzofuran derivatives have also received a considerable attention during past decade.[40]

The Wei group discovered a novel visible-light-mediated protocol to synthesize sulfonylated benzofurans 15.[41] The reaction was performed under 3 W blue-light irradiation at room temperature in the presence of 1-(phenylethynyl)-2-(vinyloxy)benzene (13) and arylsulfinic acid (14). The reaction was catalyzed by eosin Y (Scheme [3]).

Zoom Image
Scheme 3 Light mediated synthesis of functionalized benzofurans.

Hashmi et al. reported an interesting visible-light-induced methodology to synthesize benzofuran-based benzylic gem-diboronates 17.[42] These types of geminal diboronate molecules have distinct structures and reactivity. The reaction was proceeded via carbocyclization/borylation of iodoalkynes 16 in the presence of B2Pin2, [Au2(μ-dppm)2](OTf)2, and Na2CO3 in the presence of acetonitrile solvent (Scheme [3]).

In 2023, Wu and his group discovered another excellent procedure to synthesize polyarylated furan derivatives 20.[43] The reaction was performed with allenylphosphine oxide (18) and bromophenol or bromonaphthol (19) as starting materials in the presence of the base K2CO3 in DMF. In the next step Pd(OAc)2, 1,3 bis(diphenylphosphino)propane (DPPP), and K2CO3 in DMAc were added under blue-light irradiation (Scheme [3]).

In 2022, Yu and co-workers discovered a photoinduced three-component reaction for the synthesis of dihydrobenzofuran derivatives.[44] It was a photocatalyst-free reaction and showed a wide substrate scope. In this reaction, 1-ethynyl-2-isopropoxybenzene and N-allylbromodifluoroacetamides were used as reactants, DABCO·(SO2)2 as the sulfur dioxide surrogate, NaHCO3 as the base, and DMA as solvent. It was performed under blue-light irradiation for 12 h at room temperature (Scheme [3]).


# 2.4

Electrochemical Synthesis of Benzofuran Derivatives

Electrochemical reactions offer an efficient and sustainable alternative to traditional synthetic approaches by using electricity as the energy source, reducing the need for stoichiometric oxidants or reductants. These reactions allow precise control over selectivity and reactivity, enabling unique changes under mild reaction conditions. Additionally, these electrochemical reaction methods reduce waste materials with fewer byproducts.

The Wilden group reported the electrochemical iodocyclization of 2-allyl phenols 25 to afford benzofuran derivatives 26.[45] The reaction involved an in situ generated iodinating agent. One benefit of this strategy is that the halogen is added to the reaction mixture gradually, guaranteeing low amounts to avoid halogenating reactive aromatic rings. In this reaction, it was possible to produce a Zn(II) salt in situ, the Lewis acid needed to facilitate this reaction, from a graphite electrode covered with zinc in a clean and energy-efficient way (Scheme [4]).

Zoom Image
Scheme 4 Electrochemical synthesis of functionalized benzofurans.

Shi et al. reported an electrochemical intermolecular cross-dehydrogenative coupling reaction between phenols 27 and β-dicarbonyl compounds 28 to synthesize benzofuran derivatives 29.[46] The reaction was free of transition metals and external oxidants. n-Bu4NBF4 as the electrolyte and hexafluoroisopropanol (HFIP) as the solvent were the key elements for the reaction (Scheme [4]).

Guo et al. reported another electrochemical protocol to synthesize C-3-halogenated benzofuran 31 and benzothiophene derivatives.[47] The reaction was started with 2-alkynylanisoles or 2-alkynylthioanisoles 30 with potassium halides. It was an electrochemical reaction with no requirement of transition metal and additional oxidant. A carbon plate was used as anode, and a platinum plate was used as cathode in this process (Scheme [4]).

Recently, the Sun group have reported an electrochemical protocol to synthesize benzofuran-2-carboxaldehydes 33 which started with propargylic aryl ethers 32.[48] The reaction was performed in the presence of dialkyl(aryl) diselenides in acetonitrile solvent at 25 °C (Scheme [4]).


# 2.5

NPs-Catalyzed Synthesis of Benzofuran Derivatives

Nanoparticles (NPs) catalyzed reactions provide various advantages over conventional catalysis as it provides increased surface area-to-volume ratios. This led to the enhancement of catalytic activity with improvement of reaction rates. Their reusability and stability make them sustainable and affordable.

The Yang group synthesized a novel recyclable heterogeneous catalyst with Pd-NPs supported on N,O-dual-doped hierarchical porous carbon derived from naturally available and renewable biomass-bamboo shoots.[49] The catalyst was used for synthesizing 2-benzofuran derivatives 36 with o-iodophenols 34 and terminal alkynes 35. The reaction was copper- and additional ligand-free and provided excellent yields of the desired products (Scheme [5]).

Zoom Image
Scheme 5 NPs-catalyzed synthesis of functionalized benzofurans

#
# 3

Benzofuran-Based Scaffolds against AD

Synthetic benzofuran analogues have been extensively studied by researchers because of their easy synthetic procedures and possibilities to diverse functionalization by various substitutions at different positions. There are reports that have shown that these analogues are the potent inhibitors of acetylcholinesterase/butyrylcholinesterase and therefore they have been extensively used to develop anti-AD agents.

3.1

2-Arylated Benzofuran Scaffolds

The Rampa group have reported a novel 2-arylbenzofuran series including previously identified active pharmacophores[50] [51] and assessed their activity as AChE/BuChE inhibitors.[52] In the process of improving the neuroprotective effects the previously reported molecules, these molecules were rationally modified. Among the synthesized library of eighteen molecules, compounds 37 and 38 were showing the most promising results. It exhibited β-amyloid antiaggregation properties and anticholinesterase activity with some other neuroprotective effects towards human neuronal SH-SY5Y cells. The inhibitory activity toward human recombinant AChE (hAChE) and BuChE from human serum (hBuChE) was executed according to Ellman’s method. The IC50 (half maximal inhibitory concentration) values of compound 37 have been found to be 40.7 ± 3.5 μM and 38.1 ± 2.2 μM, respectively, against hAChE and hBuChE. On the other hand, for compound 38 the IC50 values were found as 60.8 ± 1.1 μM and 13.4 ± 0.5 μM, respectively. Further, the experimental results were validated through molecular docking studies. The docking results of compound 38 revealed that it can be efficiently accommodated inside the active site gorge with a docking score of –10.7 kcal/mol and can bind to the catalytic active site (CAS) and the peripheral anionic site (PAS) of hBuChE and induce its activities. Additionally, compound 37 exerted good selectivity and moderate affinity for CB1 receptors, too (Figure [3]).

Zoom Image
Figure 3 2-Arylbenzofurans against AD

In another interesting report the Choi group have studied the 2-arylbenzofurans substituted with a prenyl, geranyl, and/or farnesyl group at different positions isolated from the root bark of Morus alba as anti-AD agents.[53] These molecules, which are abundant in M. alba, have been reported frequently in enzyme inhibition and also used to increase the cellular permeability.[54] [55] In this study these molecules were assessed for triple inhibitory potential against AChE, BACE1, and GSK-3β. Among the molecules, compound 39 was the most effective against AChE, with an IC50 value of 4.61 ± 0.08 μM, followed by compound 41 (IC50, 13.92 ± 1.98 μM) and compound 42 (IC50, 23.05 ± 1.15 μM). Compound 39 was also found to be the most potent against BChE with an IC50 value of 1.51 ± 0.09 μM. The IC50 values for compounds 40, 41, and 42 were found to be 19.14, 6.12, and 64.51 μM, respectively. Additionally, BACE1 inhibition results revealed that all the molecules were efficient at micromolar concentrations and showed better results than the standard drug quercetin. In a similar manner, the IC50 values of these molecules against GSK-3β were below 10 μM and confirmed their efficacy. The combined biological results demonstrated that compound 39 was most potent among the series against AChE, BChE, BACE1, and GSK-3β enzymes showing IC50 values of 4.61, 1.51, 0.73, and 6.36 μM, respectively. In Aβ-aggregation assays, compound 39 inhibited self- and AChE-induced Aβ aggregation in a concentration-dependent manner. The results of Aβ aggregation were found superior than reference drugs (Figure [4]).

Zoom Image
Figure 4 Novel series of 2-arylbenzofurans against AD
Zoom Image
Figure 5 2-Arylated benzofuran derivatives against AD

In 2021, the Sun group explored another series of 2-arylbenzofurans as potential multitargeted ligands against AD.[56] The in vitro ChE inhibitory activity of these molecules was assessed using Ellman’s method taking donepezil as reference drug. Among the series compound 45 displayed the strongest activity with an IC50 value of 0.086 ± 0.01 μmol L–1 which is comparable to donepezil 0.085 ± 0.01 μmol L–1 and better than baicalein 0.404 ± 0.04 μmol L–1. Further, for BuChE inhibitory activity, compound 45 has exhibited an IC50 =16.450 ± 2.12 μmol L–1, i.e., slightly lower than donepezil (IC50 = 7.100 ± 0.23 μmol L–1), however, better than baicalein (IC50 = 31.624 ± 0.01 μmol L–1). Almost all the compounds have shown good BACE1 inhibition in which the three compounds 43, 44, and 45 displayed better inhibition than baicalein. Additionally, the cytotoxicity of these molecules has been assessed and found that these molecules are nontoxic to cell growth. Compound 45, which was found most potent in all aspects, could effectively reduce the level of reactive oxygen species. Overall, this study highlights the role of 2-arylbenzofurans as anti-AD agents (Figure [5]).

The neuropathological markers of AD include amyloid precursor protein (APP) deposits including several other hall marks. The APP mismetabolism and defective Aβ clearance set-off a series of processes that include hyperphosphorylated τ-mediated disruption of microtubular assembly result into synaptic failure. The τ protein is a naturally unfolded, soluble phosphoprotein. It is a major microtubule-associated protein (MAP) in neurons, which is fully differentiated or cannot be further divided (mature), which interact with tubulin to stabilize axonal microtubules and promote microtubule assembly in the brain. On the other hand, the motor tends to fully separate from the microtubule when kinesin attached itself to τ protein strips. Likewise, τ protein helped to regulate the balance of nerve cell trafficking, disorders like AD and Parkinson diseases.[57] In 2023, the Pujol group synthesized a benzofuran or an indole nucleus containing resveratrol analogues and studied their activities against various biological parameters.[58] Among the synthesized compounds 46 and 47 exhibited an inhibition of 58% and 55% of τ protein, respectively, at concentrations of 40 μM. Resveratrol itself has little activity (21.34 %) against the τ protein. These molecules were showing better results than resveratrol. The group expected that these compounds have better bioavailability compared to resveratrol because of the presence of methoxy/hydroxy groups (Figure [5]).

Wu et al. investigated Cortex Mori Radiois and isolated several molecules including ten 2-aryl benzofuran derivatives 48–57.[59] These benzofuran derivatives displayed decent BChE inhibitory activities on the basis of their structural diversity. Compounds 48 and 51 without isopentenyl group did not inhibit BChE at the concentration of 100 μM, while the prenylated derivatives 49 and 52 exhibited potent activity with IC50 values of 27.9 μM and 13.5 μM, respectively. Most potent compound 55 exhibited BChE inhibiting activity with an IC50 value of 2.6 μM, on the other hand, other two diprenylated analogues without the cyclization of isopentenyl, compounds 56 and 57 weakly inhibited BChE, with IC50 values of 27.1 μM and 32.8 μM, respectively. This referred that methylation at the phenolic OH has little effect on inhibitory potency and decreases the effect of compound 56 and 57. When the AChE activities were evaluated, among these molecules, only compound 50 and 52 exhibited moderate activity having IC50 values of 81.2 μM and 40.5 μM, respectively. For the first time, compound 55 was found to possess potent and selective inhibitory activity to BChE in a competitive manner with K i = 1.7 μM. Molecular docking studies revealed that compound 55 could insert itself into the catalytic pocket, resulting several intermolecular interactions with different amino acid residues. Further molecular dynamic simulations showed that compound 55 could engage in π–π interactions with Trp82 and form a hydrogen bond with Asn68, which collectively contributed to BChE inhibition (Figure [6]).

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Figure 6 Cortex Mori Radiois derived 2-arylated benzofurans as ChE inhibitors

# 3.2

Benzofuran-Chalcone-Based Scaffolds

α,β-Unsaturated carbonyl compounds hold a significant position in drug discovery and development process. These molecules undergo many synthetic transformations and are also used in the synthesis of heterocyclic compounds. A major part of medicinal chemistry research in the 21st century has been focused on these entities because of their various pharmacological potential.[60] Additionally, there are several reports of benzofuran-chalcone-based molecules against AD.

The Peuchmaur group reported few indanone and aurone derivatives (58, 59) and evaluated these molecules on the aggregation of the τ -AcPHF6 model.[61] It was found that the tridimensional shape of molecules has an impact on whether or not it functions as a fiber-binding or fiber-elongation inhibitor. Molecules having a dihedral structure, akin to myricetin 60, have been found to be significant inhibitors where three hydroxyl groups are substituted. Further, structure–activity relationship studies evidenced a notable effect of positions and the number of OH substituents for the interaction with AcPHF6. The kinetic experiments were not performed on the AcPHF6 model but performed with the full-length τ protein. The results demonstrated that few molecules among the series retained the fibrillation inhibitory effects (Figure [7]).

Zoom Image
Figure 7 Polyhydroxylated aurone derivatives with fibrillation inhibitory effects

The Abd El-Karim group designed nineteen benzofuran-chalcone derivatives and evaluated them against AChE.[62] Five compounds 61–65 among the synthesized series displayed most potent DPPH scavenging activity. Additionally, compounds 61 and 62 exhibited excellent AChE inhibition with IC50 values of 0.058 μM and 0.086 μM, which was comparable to the standard drug donepezil with an IC50 value of 0.049 μM. Compound 61 was selected for further bioevaluation. Acute and chronic toxicity experiments suggested that compound 61 displayed no toxicity and no significant differences in the blood profile. The docking experiments have shown that compounds 61 and 62 were displaying very good binding modes in the active pocket of AChE, which was comparable to donepezil (Figure [8]).

Zoom Image
Figure 8 Benzofuran-chalcone derivatives as AChE inhibitors

Jiménez et al. synthesized fifteen benzodihydrofuran-chalcone derivatives utilizing the Claisen–Schmidt condensation.[63] These molecules were synthesized by the reaction of natural fomannoxine, which already have neuroprotective activities, and various methyl aromatic ketones. These molecules were tested for cytotoxicity against the toxicity associated with Aβ using PC-12 cells. The cytotoxicity experiment revealed that only 4-bromo-substituted compound 66 was cytotoxic. The three molecules 67–69 exhibited a cytoprotective effect against Aβ toxicity (over 37%). Further, compound 69 was found the most potent among the series with cytoprotective impact more than 60 ± 5% of recovery of cellular viability. Structure–activity relationship (SAR) studies revealed that F substitution was more effective for cytoprotective activity. Moreover, F substitution at 3,5-positions was found particularly effective for cytoprotection. Additionally, these fluorine-substituted molecules inhibited aggregation of Aβ (Figure [9]).

Zoom Image
Figure 9 Benzodihydrofuran-chalcone derivatives against AD
Zoom Image
Figure 10 Benzofuran-tetrazole hybrids against AD

# 3.3

Benzofurans with other Heterocyclic Molecules

In 2018, Sashidhara et al. have synthesized and characterized hybrids of benzofuran and tetrazoles by employing the Ugi-azide reaction.[64] The group has utilized the molecular hybridation technique to incorporate benzofuran, tetrazole, and pyrazole moieties in one frame. The synthesized molecules were assessed using the Caenorhabditis elegans strain CL4176. Among the examined compounds 70–75 were found effective with 67.1%, 46.7%, 56.5%, 42.1%, 45.39%, and 63.81% inhibition value for Aβ toxicity, respectively. Further, the AChE inhibitory activity was also checked and found efficient. It was observed that compound 74 showed maximum potential against AChE. Further, molecular docking demonstrated that tetrazole and pyrazole cores show bonding and nonbonding. On the other hand, SAR was performed based on Aβ aggregation observations that concluded that >40% inhibition was essentially found when the tert-butyl group was attached to the tetrazole moiety, with benzofuran ring substitution not affecting the activity. The substitution of H and halogen were favored on the phenyl ring of pyrazole (Figure [10]).

The Mphahlele group developed two series of novel 2-carbo-substituted 5-oxo-5H-furo[3,2-g]chromene-6-carbaldehydes and their 6-(4-trifluoromethyl)phenylhydrazono analogues.[65] The efficacy of all eighteen synthesized compounds were analyzed against human AChE and BChE. Compounds 76, 77, 78, 79, and 80 were found the most active ones among the series. The IC50 values for AChE and BChE were 5.5 ± 0.05, 6.4 ± 0.04 and 9.4 ± 0.01, 5.1 ± 0.02 μM for 76 and 77, respectively, and for 78, 79, and 80 7.6 ± 0.03, 11.2 ± 0.02, 18.3 ± 0.04, 7.2 ± 0.03, and 5.4 ± 0.02, 9.6 ± 0.05 μM, respectively. Further, these most active compounds of both the series were evaluated against enzyme targets elaborated in AD, i.e., β- BACE-1, lipoxygenase-15 (LOX-15), and also their antioxidant potentials. The results demonstrated that compound 76 was found effective against β-secretase with IC50 = 21.6 μM and for LOX-15 with IC50 = 16.3 μM. Further, compound 78 where the 6-carbaldehyde group was replaced with the hydrazone functionality displayed increase in β-secretase inhibition (IC50 = 17.3 μM) but reduction in antilipoxygenase (IC50 = 21.6 μM ) and antioxidant activity as compared to compound 76. Compounds 77 and 80 exhibited β-secretase inhibition with IC50 = 15.4 μM and IC50 = 25.3 μM, respectively. Further, against LOX-15 IC50 values were found 9.6 μM and 26.5 μM, respectively, with a reduced antioxidant effect (Figure [11]) All these results were compared with the reference drug quercetin.

In 2019, Fancellu et al. constructed a novel series of tacrine-benzofuran hybrid molecule following a multitargeted approach and these molecules have shown very good activity.[66] TAC (tacrine) is a well-known AChE inhibitor, and benzofuran derivatives have also been reported to reduce self-aggregation of Aβ peptide as well as AChE inhibitors. The group has selected these moieties to synthesize a new class of hybrid molecules. Among the series, compounds 81, 84, and 86 were the most potent compounds against AChE with IC50 values of 0.12 μM, 0.13 μM, and 0.13 μM, respectively. Molecular docking studies revealed that the benzofuran moiety has the dual binding capacity by interacting with the CAS and PAS of enzymes. SAR revealed that molecules with shorter propylic linker and chloride substituent at TAC demonstrated the best activity. The studies against self-aggregation of Aβ peptide revealed that compounds 82, 83, 84, and 85 were the most effective. Further, it was also observed that OH containing compounds showed a decrease in self-aggregation inhibition in the presence of Cu2+. With all the results, it was concluded that compounds 84 and 86 offered the best activity in terms of cell neuroprotectivity (Figure [12]).

In 2021, the Escolano group have synthesized and evaluated ten benzofuranyl-2-imidazole derivatives as imidazoline I2 receptor ligands against AD.[67] The chemical character, 3D quantitative SAR, and ADMET in silico affinity against human brain imidazoline I2 receptors (I2-IR) were studied. The synthesized molecules 88 and 89 with a methoxy substituent showed the I2-IR binding values of pK i = 6.41 ± 0.16 and pK iH = 6.77 ± 0.29 and pK iL = 4.58 ± 0.39, respectively. Compound 90 with 5-bromine substitution showed similar affinity as garsevil (87, pK i = 8.63 ± 0.51 and pK iL= 5.85 ± 0.18). Garsevil (acute treatment in mice with 2-(2-benzofuranyl)-2-imidazole) was reported having nonwarning properties in the ADMET and the finest pharmacokinetic profile. Further, compounds 91 and 92, derivatives of hydroxybenzofuran-2-imidazole, reported pK i = 5.48 ± 0.11 and pK iH = 9.57 ± 0.63 and pK iL= 4. 6 ± 0.26. Compounds 93, 94, and 95 having an N-alkylated imidazole framework showed improved affinity with pK iH = 6.99 ± 0.28, pK iL= 5.35 ± 0.21 and pK iH = 6.95 ± 0.16 and pK iL= 4.16 ± 0.12, respectively (Figure [13]).

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Figure 11 Furochromone carbaldehyde derivatives against AD
Zoom Image
Figure 12 Tacrine-benzofuran derivatives against AD
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Figure 13 Benzofuranyl-2-imidazole derivatives
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Figure 14 Benzofuran piperidine derivatives against AD

Fu et al. have synthesized and characterized few benzofuran piperidine derivatives as Aβ antiaggregants.[68] Most of the synthesized molecules in the series exhibited Aβ antiaggregating properties in the range of 17.02–56.49% at 100 μM. Compounds 96, 97, 98, and 99 were found most potent among all molecules and displayed strong inhibition towards Aβ25–35 aggregation as 40.41%, 53.91%, 52.12%, and 56.49%, respectively. Further, molecular docking studies discovered that compounds 97 and 98 can bind with the ‘steric zipper’ region of the Aβ antiaggregant property. On the other hand, compounds 96 and 97 were binding with PAS of AChE. Additional properties of these selected compounds for AD comprised neuroprotection (75.17–105%), LDH (lactate dehydrogenase) release (285–324.05%), and ATP (adenosine triphosphate) production (95.49–104.56%), revealed multifunctionality of compounds 96, 97, and 98. In addition, these compounds were also subjected to th reactive oxygen species (ROS) inhibition and apoptotic ratio test and were positive towards ROS intracellular inhibition/cell death to Aβ25–35 peptides (Figure [14]).

In 2022, Sanad et al. have developed two novel series of piperazine-based molecules bis(thieno[2,3-b]pyridines) 100 and bis(pyrazolo[3,4-b]pyridines) 101.[69] These molecules were assessed for inhibiting AChE and DPPH scavenging activity. AChE inhibitory activity was checked using the Ellman method where the bis(thieno[2,3-b]pyridine) 100 series was found to be more effective than the bis(pyrazolo[3,4-b]pyridines) 101 series at a concentration of 50 μM. Except for two hybrids (100b and 100c), all hybrid molecules showed inhibition percentages ranging from 18.7 to 38.5. On the other hand, the 101 series has an inhibition percentage range from 8.3 to 33.4. Considering the data obtained at the tested concentration (100 μM), compound 100b was found most potent for AChE inhibition with the value 88.4% and 100c with 79.9%. For 101c and 101d the obtained percentage range was 54.7 and 50.8, respectively, and others 101a, 101b, and 101e exhibited in the range of 12.6–29.3%. Further, the results of DPPH radical scavenging at a concentration of 25 μM for the 100 series was found to be above 50%. However, 100b and 100c had the best inhibition percentage as 81.5 and 77.2, respectively (Figure [15]).

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Figure 15 Piperazine-linked bis(thieno[2,3-b]pyridines) and bis(pyrazolo[3,4-b]pyridines) as anti-AD agents

In 2022, the Sahin group reported a series of donepezil analogues bearing benzofurans and amines.[70] These molecules were evaluated for AChE and BuChE inhibition to mimic donepezil actions. It was observed from the biological evaluation that methoxy-group-containing compounds (103–106, 109, and 110) were about ten times more effective with respect to other molecules among the series. Four compounds 107–110 were observed to be most effective against acetylcholinesterase enzyme. These molecules carried the benzyl moiety on piperazine. However, compounds 102 and 103 contain secondary amines at piperazine that exerted good results on AChE. The IC50 values for the most active compounds 110, 109, 103, and 102 are 0.98 μM, 1.07 μM, 1.80 μM, and 1.14 μM, respectively. Further, 103, 109, and 110 showed good antiaggregation potential on Aβ1–40. Interestingly, compound 110 has shown a better antiaggregation effect compared to standard drug rifampicin (Figure [16]).

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Figure 16 Benzofuran-piperazine derivatives against AD

Foroumadi et al. have discovered a novel multifunctional series of 3-aminobenzofuran derivatives and assessed their anti-AD effects.[71] The synthesized molecules were targeted against acetylcholinesterase, butyrylcholinesterase, and β-amyloid aggregation. The inhibition of cholinesterase was evaluated via Ellman’s method. Experimental results stated that almost all molecules showed moderate to good inhibition with an IC50 in the range of 0.64–81.06 μM. Among the series, compound 111 was most efficient inhibitor against AChE (IC50=0.64 μM) and BuChE (IC50 = 0.55 μM). Further, the SAR study revealed that electron-donating substitutions on the molecules reduced the inhibition whereas electron-withdrawing groups enhanced the inhibition. Thus, compounds 111 and 112 had efficient enzymatic inhibitory activity with an IC50 in the range of 0.64–1.68 μM. In addition, β-amyloid aggregation results demonstrated that compounds 111 and 112 were most active with 30.1% and 35.6% inhibitory activity of self-induced Aβ1–42. These results were better than the reference drug donepezil (25.7%). Further molecular docking studies concluded that the peripheral anionic site could be positioned by 3-aminobenzofuran and the catalytic anion site of AChE was bound by an N-benzylpyridyidium fragment (Figure [17]).

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Figure 17 3-Aminobenzofuran derivatives for treatment of AD
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Figure 18 Few hydrazone derivatives as anti-AD agents

The Osmaniye group synthesized and evaluated ten novel hydrazone derivatives incorporated with different heterocyclic rings.[72] These molecules were evaluated against cholinesterases by the help of Ellman’s spectrophotometric method. It was observed that all the synthesized molecules have shown more than 50% inhibition against AChE at 10–3 M concentration. In addition, compounds 114 and 115 have shown better activity results than the reference donepezil at this concentration. However, only compounds 114 and 115 showed more than 50% inhibition at a concentration of 10–4 M with IC50 values of 0.034 μM and 0.027 μM, respectively. Further BChE enzyme inhibition reported that none of the compounds showed notable inhibition against BChE. The studies have demonstrated that these molecules can pass through blood brain barrier, the in vitro PAMPA tests revealed that compound 115 have high BBB permeability. The SAR studies revealed that 4-fluorobenzyl-containing derivatives 114 and 115 showed more activity in comparison to 4-fluorophenyl derivatives 113 (Figure [18]).

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Figure 19 2,3-Disubstituted benzofuran derivatives as potential anti-AD agents
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Figure 20 Benzofuran-based 1,2,4-triazole derivatives for the treatment of AD

In 2023, Radwan and co-workers developed a novel series of 2,3-disubstituted benzofuran derivatives as multifunctional molecules for the treatment of AD.[73] These molecules were synthesized by fusing benzofuran as core and 8-hydroxyquinoline moieties which were linked via a piperazine spacer. At doses of 1 μM with thioflavin T (20 μM) all synthesized molecules 116–122 were tested for Aβ-amyloid aggregation. The results of the thioflavin T assay demonstrated that the synthesized molecules 116–122 could effectively inhibit the growth of the fibrils. These molecules have shown Aβ-peptides aggregation inhibition in the range of 54.12–67.52%. Among the series, compound 116 has shown the most potent value, while compound 122 has shown the lowest value for aggregation. Further, Lipinski’s rule was applied to determine the solubility and permeability for medication uses. The values of compounds 116–119 and 121 were within the bioavailability score 0.55, but 120 and 122 violated the rule. On the other hand, molecular docking analysis was performed for all synthesized molecules on monomer and fibril structures of Aβ-peptides to validate the experimental results (Figure [19]).

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Figure 21 Benzofuran-based scaffold for treatment of AD

Recently, the Bhat group synthesized a series of benzofuran-based 1,2,4-triazole hybrid molecules.[74] These molecules were evaluated as anti-AD agents where most of them showed moderate to good inhibitory potential against AChE. After analysing all the synthesized molecules, compounds 123 and 126 were reported to have the strongest AChE inhibition with IC50 values of 0.88 ± 0.50 μM and 0.55 ± 1.00 μM, respectively. Compounds 124, 125, and 127 have IC50 values of 1.50 ± 1.00 μM, 2.28 ± 1.75 μM, and 1.98 ± 0.25 μM, respectively, with moderate inhibition. The SAR studies of these molecules conferred that introduction of an electron-donating group enhanced the AChE inhibition effect. However, compound 123 having an unsubstituted phenyl ring was the second most active derivative. Compound 125 with a nitro substituent on the N-phenylacetamide decreased the activity. Further, these molecules were also tested for their antibacterial potential and showed moderate to excellent activity (Figure [20]).

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Figure 22 Benzofuran-based molecules as cholinesterase inhibitors

# 3.4

Other Benzofuran-Based Scaffolds

In 2019, Musumeci and co-workers synthesized and characterized the biological activity of benzodifuran derivative 128.[75] Compound 128 was tested for interaction with the Aβ42 peptide, and the results suggested that it partly suppresses the β-sheet structure of Aβ42 leading to new structural elements. This analysis was done with the help the of the thioflavin T assay, circular dichroism, and electron microscopy. Additionally, it has been checked for antiproliferative activity on human cancer cell and found significant (Figure [21]).

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Figure 23 Benzofuran-oxime frameworks against AD

Khan et al. have synthesized benzofuran hybrids and discovered the inhibitory activity with respect to cholinesterase enzymes.[76] The in vitro ChE inhibitory effect of thirty synthesized molecules were performed, and the results revealed good to moderate potential. Among the tested compounds 129–134 were observed to have excellent inhibition. The IC50 value of compound 129 against AChE was 21.04 ± 0.51 μM and against BChE 22.2 ± 0.51 μM, for compound 130 35.86 ± 0.23 μM and 36.16 ± 0.33 μM, respectively. Compound 131 has an IC50 value of 24.86 ± 0.23 μM and 25.16 ± 0.13 μM, respectively. Further compounds 132–134 have IC50 values in the range of 31–41 μM against AChE and 32–42 μM against BChE. Further, for the SAR study all the molecules were divided into four categories where the most potent compounds 129–131 were placed in category A, 132 and 133 were placed in category B, and compound 134 was placed in category C. Category A derivatives consist of nitro substitution at the para position of the phenyl ring, which enhanced the activity. On the other hand, 130 has a bromo group at the para position, and 131 has a chloro group at the para position and showed good inhibition potential. In addition, in category B, molecules with chloro and bromo substitution at the para position also showed good inhibition. In category C, molecules containing an ethoxy group at the benzofuran rings have potent inhibition compared to the methyl group at the phenyl ring. Furthermore, most of the compounds with an OH group substitution were inactive, with the exception of 135 with an aryl substitution at the para position of the phenyl ring. Additionally, a kinetic study report of five most active compound revealed that the selected compounds were following uncompetitive type mechanism of inhibition (Figure [22]).

Yilmaz et al. designed and synthesized nineteen benzofuran-oxime derivatives and evaluated them as anti-AD agents.[77] According to enzyme inhibition results compounds 136, 138–140, 107, 109, and 110 have very strong inhibition against both AChE and BChE. Compounds 142 and 145–149 were found to be active against AChE only. However, compound 137 was a very good inhibitor of the BChE enzyme. Compounds which showed AChE and BChE inhibition activity comprised of IC50 values in the range of 12.25 ± 0.12 μM to 39.90 ± 1.25 μM and 7.48 ± 0.09 μM to 28.55 ± 0.71 μM, respectively. Those compounds which were only AChE active have IC50 values in the range of 8.05 ± 0.29 μM to 27.16 ± 0.61 μM. Lastly, compound 137 was found to have an IC50 value of 8.848 ± 0.04 μM for BChE inhibition. Further, the SAR report stated that the benzofuran-(phenyl)carbamoyl-oxime framework bearing compounds 136, 138–141, 143, and 144 showed best potential against both cholinesterase enzyme. While other molecules bearing cholorophenyl, nitrophenyl, methylphenyl, or chloropyridine substitution were selectively active against AChE enzyme (142, 145–149). Lastly, compound 137 with no substitution on the benzofuran ring and the p-methylphenyl ring was only active against BChE (Figure [23]).

In 2024, Rao and co-workers synthesized N-phenylbenzofuran-2-carboxamide and N-phenylbenzo[b]thiophene-2-carboxyamide derivatives.[78] In the SAR study it was reported that the compounds were modified by regioselective substitution of methoxyphenol, 3,4-dimethoxyphenyl, and 4-methoxyphenyl substituents. Further, fluorescence and biophysical investigation was performed which revealed that the 3-hydroxy-4-methoxyphenyl or 4-hydrox-3-methoxyphenyl ring containing compounds showed 41–54% inhibition towards Aβ42 aggregation (compounds 150, 151, 153, and 155). A 2-fold increase in inhibition against Aβ42 was observed when 4-methoxyphenyl incorporation was performed in compounds 152 and 154. In addition, antioxidant DPPH scavenging activity was reported to be in the range of 45–56% at 25 μM for compounds 150, 151, and 153–155. On the other hand, a molecular docking study of these compounds validated the experimental results (Figure [24]).

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Figure 24 N-substituted (phenyl)benzofuran-2-carboxamide and benzo[b]thiophene-2-carboxamide derivatives

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# 4

Naturally Occurring Benzofurans for Treatment of AD

Benzofuran derivatives can be tracked in various medicinal plants which already been known for their antioxidant, anti-inflammatory, and AChE inhibitory properties. Additionally, naturally occurring benzofuran derivatives exhibit antiamyloidogenic activity, which may prevent the formation and accumulation of β-amyloid plaques, a hallmark of AD pathology. Molecules such as moracin derivatives from the Morus species (mulberry) and others from the Euphorbiaceae and Asteraceae families have exerted their beneficial effects in preclinical studies, highlighting their ability to reduce oxidative stress and Aβ aggregation.

The Choi group has studied the effects of moracin derivatives 156–159 isolated from Morus alba as anti-AD agents.[79] Along with these properties their antioxidant and antiglycation activities were also evaluated. Among the molecules compound 156 exhibited the most potent BACE1 inhibitory activity. These molecules decreased the AGE levels and amyloid cross-β structures. Among these four, 156 and 159 exhibited better inhibition than the other two. The SAR studies concluded that the prenyl moiety in 2-arylbenzofurans is essential for the BACE1 inhibition. Furthermore, the addition of an extra ring to 2-arylbenzofurans offsets the antioxidant and antiglycation activities as well as the BACE1 inhibitory activity. Additionally, molecular docking studies confirmed the experimental results (Figure [25]).

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Figure 25 Moracin derivatives as potential anti-AD agents

The Suttisansanee group compared the amounts of phytochemicals in twentyseven different Morus spp. cultivated in the same geographical area for the better understanding of the biological profiles.[80] The study was aimed to compare the phytochemicals, antioxidant activities, and inhibitory effects against AChE, BChE, and BACE-1. The findings indicated that Morus sp. code SKSM 810191 displayed most potent activities with high TPCs, anthocyanins and anthocyanidin contents, antioxidant activities, and inhibition of the AD key enzymes.


# 5

Future Perspectives

As discussed above, benzofuran derivatives have appeared as potent molecules in the quest for anti- AD drugs because of their favorable pharmacokinetic properties and excellent biological activities. These molecules are appealing candidates for further studies against AD due to their potential to suppress amyloid plaques, prevent neurofibrillary tangles, and combat oxidative stress. The future of benzofuran derivatives in AD treatment will likely hinge on sophisticated drug design methodologies, including structure-based drug design, molecular docking, and machine learning algorithms. Key enzymes and receptors implicated in AD pathogenesis can be precisely targeted with these approaches. For example, the therapeutic efficacy of benzofuran-based molecules may be enhanced by the addition of substituents that promote selectivity towards cholinesterase enzymes. Benzofuran analogues have demonstrated potential in the treatment of cholinergic dysfunction seen in AD patients, which requires selective inhibition of these enzymes. Furthermore, molecular modeling may make it possible to adjust pharmacokinetic characteristics to enhance drug retention in the central nervous system (CNS) and blood-brain barrier (BBB) permeability, which is a problem frequently faced in AD treatment.

Additionally, AD is multifactorial disease involving a complex network of biochemical pathways. Some benzofuran-based molecules have been shown not only to inhibit AChE, but also to reduce oxidative stress which is a significant factor in AD progression. The MTDL approach aligns well with the structural versatility of benzofuran analogues, which can be easily modified to provide the molecules that can act on multiple targets. This strategy has the potential to improve clinical outcomes. The pathophysiology of AD is significantly influenced by oxidative stress and neuroinflammation, which lead to synaptic dysfunction and neuronal death. Analogues of benzofuran are also well-known for their anti-inflammatory and antioxidant properties. Antioxidant moieties, including phenolic or nitroxide groups, can be added to the benzofuran scaffold to scavenge reactive oxygen species (ROS) and reduce oxidative stress. These analogues may be able to suppress important inflammatory pathways, including the cyclooxygenase (COX) and nuclear factor κ-light-chain enhancer of activated B cells (NF-κB) pathways, by combining antioxidative activity with anti-inflammatory properties.

Benzofuran derivatives have a lipophilic nature, which makes them inherently more likely to cross the BBB than more polar compounds. However, further optimization of their chemical structures is required to increase their CNS bioavailability and reduce off-target effects. Future research may focus on developing benzofuran derivatives that can efficiently cross the BBB and selectively target oxidative and inflammatory pathways within the CNS, providing a dual therapeutic approach to mitigate neuroinflammation and oxidative stress.

The ultimate future goal is the translation of benzofuran analogues from preclinical studies to clinical applications. The in vitro results have been excellent, and the efficacy and safety of benzofuran-based compounds in animal models need to be validated in human trials. To guarantee the sustainability of these substances as AD treatments, future studies should concentrate on pharmacokinetics, toxicity, and possible adverse effects. Clinical trials should also investigate biomarkers of AD pathology, including reduction of τ and Aβ levels. Future research could also focus on isolating and optimizing novel natural benzofuran derivatives or synthesizing structurally similar analogues and studying their anti-AD properties. Combining synthetic and natural derivative studies may yield hybrid compounds with enhanced potency and reduced toxicity.


# 6

Conclusion

Alzheimer’s disease is an emerging challenge worldwide due to unclear understanding of the exact pathophysiology associated with the disease. Therefore, there is always a need for novel anti-AD agents with maximum efficacy, improved specificity, and reduced toxicity. In medicinal chemistry, heterocyclic rings hold a crucial position by demonstrating the significant biological activities, as evident by drugs available in the market. Benzofuran is a heterocyclic ring known for its multifaceted biological activities, leading to ongoing research using these scaffolds in drug designing and discovery. The future of benzofuran analogues as anti-AD agents is highly optimistic, owing to their structural versatility, multitargeted behavior, and ability to be tailored for specific therapeutic roles.

The current review article focused on synthetic advancements and new benzofuran derivatives with potent anti-AD activity that were published recently between 2019 and 2024. This review will help the scientific community to design and synthesize molecules with superior anti-AD activity via multitargeted approach, molecular hybridization, etc. This article explored about 2-arylbenzofurans which have potential as anti-AD agents. Furthermore, benzofurans containing α,β-unsaturated groups have also exerted beneficial effects against AD. Several benzofuran derivatives isolated from natural sources also have moderate to excellent anti-AD activities. In some cases, in addition to benzofuran, the presence of other heterocyclic molecules such as tetrazole, pyrazole, imidazole, piperidine, quinoline, etc. boosted the activity. In summary, this review discussed the active compound structures, biological activities, and SARs of few reported derivatives with good anti-AD activity. The primary aim of this review is to provide a clear insight and highlight the current status of benzofuran derivatives against AD and to facilitate the design and development of novel drug candidates for the treatment of this debilitating disease in the near future.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

The authors convey their profound thanks to Department of Chemistry, University of Lucknow, and IIT Roorkee for the facilities, support and encouragement to complete this work.


Corresponding Authors

Pragati Kushwaha
Department of Chemistry, University of Lucknow
Lucknow-226007, Uttar Pradesh
India   

Danish Khan
Department of Chemistry, Indian Institute of Technology
Roorkee-247667, Uttarakhand
India   

Publication History

Received: 09 December 2024

Accepted after revision: 21 January 2025

Accepted Manuscript online:
21 January 2025

Article published online:
12 March 2025

© 2025. Thieme. All rights reserved

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Figure 1 Structure of benzofuran
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Figure 2 Currently available drugs for AD
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Scheme 1 Metal-free synthesis of benzofuran derivatives
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Scheme 2 Microwave-assisted synthesis of benzofuran derivatives
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Scheme 3 Light mediated synthesis of functionalized benzofurans.
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Scheme 4 Electrochemical synthesis of functionalized benzofurans.
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Scheme 5 NPs-catalyzed synthesis of functionalized benzofurans
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Figure 3 2-Arylbenzofurans against AD
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Figure 4 Novel series of 2-arylbenzofurans against AD
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Figure 5 2-Arylated benzofuran derivatives against AD
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Figure 6 Cortex Mori Radiois derived 2-arylated benzofurans as ChE inhibitors
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Figure 7 Polyhydroxylated aurone derivatives with fibrillation inhibitory effects
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Figure 8 Benzofuran-chalcone derivatives as AChE inhibitors
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Figure 9 Benzodihydrofuran-chalcone derivatives against AD
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Figure 10 Benzofuran-tetrazole hybrids against AD
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Figure 11 Furochromone carbaldehyde derivatives against AD
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Figure 12 Tacrine-benzofuran derivatives against AD
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Figure 13 Benzofuranyl-2-imidazole derivatives
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Figure 14 Benzofuran piperidine derivatives against AD
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Figure 15 Piperazine-linked bis(thieno[2,3-b]pyridines) and bis(pyrazolo[3,4-b]pyridines) as anti-AD agents
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Figure 16 Benzofuran-piperazine derivatives against AD
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Figure 17 3-Aminobenzofuran derivatives for treatment of AD
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Figure 18 Few hydrazone derivatives as anti-AD agents
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Figure 19 2,3-Disubstituted benzofuran derivatives as potential anti-AD agents
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Figure 20 Benzofuran-based 1,2,4-triazole derivatives for the treatment of AD
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Figure 21 Benzofuran-based scaffold for treatment of AD
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Figure 22 Benzofuran-based molecules as cholinesterase inhibitors
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Figure 23 Benzofuran-oxime frameworks against AD
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Figure 24 N-substituted (phenyl)benzofuran-2-carboxamide and benzo[b]thiophene-2-carboxamide derivatives
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Figure 25 Moracin derivatives as potential anti-AD agents