R. Sahu1*, K. Shah1, A. Misbah, Deepika Paliwal, Neha Sharma and Tara Rani2

Department of Pharmaceutical Chemistry, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh 201310, 1Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh 281406, 2Department of Paramedical and Allied Sciences, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh 201310, India

*Corresponding Author:
R. Sahu
Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh 281406, India
E-mail: rakeshsahu1100@gmail.com
Date of Received 04 June 2022
Date of Revision 16 February 2023
Date of Acceptance 04 December 2023
Indian J Pharm Sci 2023;85(6):1539-1550

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DOI: 10.36468/pharmaceutical-sciences.1208

Abstract

Alzheimer's disease is a neurodegenerative disease that impairs motor and cognitive function it is spreading very quickly in the current scenario with a male:female ratio between 1:2 to 1:5 due to various causes associated with it which include education, diet and nutrition, sleep and cardiac rhythm and head trauma etc. Previously available drugs like tacrine failed to prove their efficacy and later were withdrawn from the market due to excess toxicity, lower solubility, and slow bioavailability. Among them, benzofuran-based drugs make a significant contribution because they are one of the important 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 on numerous prominent receptors. So, this article focuses on various benzofuran derivatives and their advancement in the treatment of Alzheimer’s disease with a summary of the synthesis of benzofuran and benzofuran-based derivatives which assist scientists in developing successful medications with the necessary pharmacological action.

Keywords

Alzheimer’s disease, benzofuran, derivatives, biomarkers, synthetic scheme

Alzheimer's Disease (AD) is a progressive neurological disease that causes permanent cognitive decline, linguistic degradation and severe behavioural abnormalities before death[1]. It is also reported as one of the primary causes associated with dementia in old age, with 14 to 130 million people expected to be affected in Europe and globally by 2050[2,3]. The pathophysiology of AD is difficult and poorly understood. However, several variables are considered bioindicators such as low Acetylcholine (ACh) value[4,5], abnormal-amyloid peptide deposition, oxidative stress, tau protein hyperphosphorylation[6,7] and biometal dyshomeostasis. In 2013, approximately 85 000 people died from AD which is the sixth biggest cause of mortality in the United States[8,9]. It is reported as the most common cause of continued dementia in the aging population, contributing to 65 %-70 % of all cases[10]. Furthermore, women have a higher frequency of AD, with men-to-women ratios found between 1:2 to 1:5[11,12]. The various study revealed that the expected lifetime risk for alzheimer's at 45 age was found to be around one in five which is almost (20 %) for women and shows one in ten (10 %) for men at 65 age. This has been illustrated graphically in which the chances increased slightly for both genders and can be seen as a gender bias[13].

Acetylcholinesterase (AChE) inhibitor therapy has dominated the management of AD, consequently, memory and cognitive performance have improved slightly. By restricting ACh turnover and restoring synaptic levels of this neurotransmitter, these medications make up for the loss of cholinergic neurons and provide symptomatic relief[14,15]. Current AD therapy options memory and cognitive performance have improved slightly with cholinesterase potent inhibitor[14] and an N-Methyl-D-Aspartate receptor antagonist (memantine). However, they do not prevent or stop the progressive neurodegeneration. Nonetheless, experimental investigations revealed that when an AChE inhibitor is associated with the therapy, it modifies its enzymatic and pharmacological characteristics and preventing such connection may be advantageous in the treatment of AD patients[16,17].

Benzofuran is an important family of heterocyclic chemicals that can be understood as benzene fused with furan ring and has formula C8H6, its chemical structure is shown in fig. 1[18]. It may be found in various bioactive natural items, medicines, and polymers[19]. Because of its broad biological profile, it is regarded as one of the most significant heterocyclic rings[20]. Benzofuran has several medicinal applications, including antiarrhythmic, antitussive, antitubercular[21], antidepressant[22], anti-gout, anti-fungal and antihypertensive agents[23]. According to an amyloid-β peptide model, fomannoxin is a natural benzofurancontenting compound, showing exceptional neuroprotective capabilities. The significance of this discovery stems from the fact that antiamyloid treatments are seen as a viable alternative to present Alzheimer's drugs[24]. As a result, in this article, we will look into benzofuran-based derivatives as a viable alternative therapeutic option for AD. Some important physicochemical properties are tabulated in Table 1[25,26].

IJPS-benzofuran

Fig. 1: Chemical structure of benzofuran

S No. Molecular weight Solubility Boiling point Melting point Refractive index pKa
1 118.1326 g/mol Soluble in organic solvent and insoluble in water and 173° (343°F; 446 K) -18° (0°F; 255 K) 34.9 m3.mol-1 -2.9

Table 1: Physical Property of Benzofuran

Classification of Antibiotics

According to a recent study, the causes of AD are hereditary, since a family history of Alzheimer’s dementia has been linked to the late onset of AD[27]. Education, higher levels of education are linked to having a lower risk accounting for AD[28]. Physical, mental and a variety of activities including cognitive, social and recreational activities have been linked to a reduced risk of dementia[29-32]. Additionally, some important factors also associated with AD like sleep and the 24 h cycle there is evidence that sleep is crucial for amyloid clearance and less sleep is therefore associated with amyloid build-up in the brain. However, the relationship appears bidirectional since amyloid disease can disturb sleep patterns[33]. Trauma to the head, traumatic brain injury has been associated with a higher risk for dementia[34]. However, whether AD is more likely to lead to pathologic outcomes than other neurodegenerative disease processes such as the recently discovered chronic traumatic encephalopathy[35-44].

The patent of benzofuran-based derivative which has the potential to become an alternative drug is tabulated in Table 2. Also, a list of benzofuranbased drugs which has recently been marketed is in Table 3.

S no. Patent no Patent date Inventors Description
1 JP6330011B2 May 23, 2018 Steven Martin, Steven Martin Courtney, Michael Prime, Michael Prime, William Mitchell, William Mitchell, Christopher John 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 Kynurenin-3-monooxygenase inhibitor, pharmaceutical composition thereof, and method of use thereof.
2 CN105294662B April 20, 2018 Li Xingshu, Wang Zhiren, Huang Ling and Chen Xinzi Benzofuran quinolone derivative and application of benzofuran quinolone derivative in preparation of medicine for treating alzheimer's disease.
3 KR101662853B1 May 10, 2016 Didier RochegisleMutanno Ingo KoberphrancesComtarsejuChristman-FrancisaumitraCentaguptarameshSistlaoGumadiBenkateshawar Benzofurane, benzothiophene, and benzothiazol derivatives as fxr modulators.
4 JP5767211B2 August 19, 2015 Johann Andershon, Helena Yübeckanf, Johansson Christian, Erik Lindejonas, MalmströmgunnarNordwalgitteTelputachanaWeigelt 2-Carboxamide-7-piperazinyl-benzofuran derivative 774
5 USRE44354E1 July 09, 2013 HankF.Kung, Mei PingKung, Zhi-Ping Zhuang,VirginiaM.Y.Lee, JohnQ.Trojanowski,Daniel M. Skovronsky Amyloid plaque aggregation inhibitors and diagnostic imaging agents
6 EP1945622B1 December 28, 2011 William E. Klunk, Jr. Chester A. Mathis Isotopically-labeled benzofuran compounds as imaging agents for amyloidogenic proteins.
7 DE60310753T2 November 10, 2007 Ana Martinez Gil, Isabel Dorronsoro Diaz, Laura Rubio Arrieta, Diana Alonso Gordillo, Ana Fuertes Huerta, Susana Morales-Alcelay, Maria Del Monte Millan, Esther Garcia Palomero, Paola Usan Egea, Celia De Austria, Miguel Medina Padilla Dual binding acetylcholinesterase inhibitors for the treatment of alzheimer.
8 AU2005280921B2 May 19, 2011 Makoto Jitsuoka, Norikazu Ohtake, NagaakiSatoShigeruTokita, Daisuke Tsukahara Carbamoyl-substituted spiro derivative.
9 EP1497279B1 March 09, 2011 Oliver Schadt, Henning Böttcher, Joachim Leibrock, Kai Schiemann, Timo Heinrich, Günter Hölzemann, Christoph Van Amsterdam, Gerd Bartoszyk, Christoph Seyfried Substituted indoles and their use as 5ht-reuptake inhibitors and as 5ht ligands
10 US7741354B2 June 22, 2010 Michael Thormann, Michael Altmstetter, Andreas Treml, Ulrich Heiser, Mirko Buchholz Novel inhibitors of glutaminyl cyclase
11 US20090082434A1 March 26, 2009 Jonathan Laird Gross, Marla Jean Williams, Gary Paul Stack, Hong Gao, Dahul Zhou Dihydro benzofuranyl Alkanamine Derivatives and Methods for Using Same.

Table 2: List of Patented Drugs having Benzofuran Moiety

S No. Name of drug Primary target Chemical structure Reference
1 99mTc]BAT-bp-1 β-amyloid plaques Image [35]
2 5-bromo-2-(4 hydroxybenzyl)benzofuran Butyrylcholinesterase Inhibitor Image [36]
3 Benzofuran-tetrazole Inhibit Aβ aggregation Image [37]
4 Benzofuran–Chalcone Hybrids inhibit Ab fibril formation, directly scavenge (ROS). Image [38]
5 Tacrine−Benzofuran Hybrids AChE and BChE Inhibitor Image [39]
6 Coumarin-Benzofuran Hybrids Inhibit Aβ aggregation and  AChE Image [40]
7 2-benzylidene-benzofuran-3 anti-acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) Image [41]
8 Benzofuran-Based Hybrid based on SKF-64346 Inhibition of Cholinesterase Activity, β-Amyloid Aggregation. Image [42]
9 MMBO Inhibit neurofibrillarytangles, tau phosphorylation. Image [43]
10 2-aryl Benzofuran Anti-acetylcholinesterase Image [44]

Table 3: List of Recently Marketed Drugs having Benzofuran Moiety

Biomarkers

Even at specialized centres, around 20 % of people are misdiagnosed with AD when the diagnosis is entirely clinical. As a result, the role of biomarkers in the diagnostic process is growing in importance, as positive biomarkers enhance diagnosis accuracy[45-47]. Structural imaging; Functional Brain Imaging (FBI); Cerebrospinal Fluid (CSF); amyloid beta Positron Emission Tomography (PET) were used.

General synthetic scheme for benzofuran analogues:

Since the medicinal significance of benzofurans is very broad, major efforts have been made to find novel synthetic techniques for their synthesis[48]. Some important syntheses of benzofurans are listed below.

Abu-Hashem et al.[49] reported salicylaldehyde(1a) interacts with chloroacetic acid, to form o-formylphenoxyacetic acid(1b). It yields benzofuran(1c) when glacial acetic acid is refluxed with acetic anhydride as shown in fig. 2a. Rangaswamy et al.[50] reported Salicylaldehyde(2a) was treated with 1chloropropan-2one(2b) in the occurrence of 1,8diazabicyclo-undec- 7ene which work as an activator to produce 2-acetylbenzofuran(2d) (fig. 2b). Zhou et al.[51] reported the synthesis of benzofurans derivatives is made possible by the ligand-free cyclization of closing alkynes2(3b) in the presence of CuBr catalyst with the N-tosylhydrazones produced from ortho hydroxybenzaldehyde(3a). The reaction conditions are tolerated by a wide spectrum of functional groups (fig. 2c).

IJPS-acetophenone

Fig. 2: Synthesis of benzofuran; (a): Benzofuran (1c); (b): 2-acetyl Benzofuran (2d); (c): Derivatives of benzofuran (3c); (d): Benzofuran derivative (4c and 4f) with one pot method; (e): Benzofuran by ionic liquid condition; (f): Substituted benzofuran via Buchwald condition (6c); (g): Microwave-assisted route of substituted benzofuran (7d); (h): Substituted benzofuran (8b); (i): Benzopyranones as a synthon for the synthesis of benzofuran (9c); (j): Benzofuran (10b) via cyclization of 2-alkoxy-acetophenone; (k): Aryl substituted benzofuran (11b) from 2-aryloxyl,2-di-arylethanol; (l): Aryl substituted benzofuran (12c) from 2-bromoethynyloxybenzene; (m): Benzofuran (13c) with benzyl ketones; (n): Benzofuran (14c) via perkin rearrangement and (o): Benzofuran (15c)

Wang et al.[52] reported an efficient ligand for Pd catalyzation with one-pot formation of benzofuran derivatives (4c and 4f), 2-chlorophenols(4a) combined with alkynes(4b) in the availability of hydroxyterphenylphosphine (fig. 2d). Xie et al.[53] reported the heck reaction with palladium (Pd) catalyzation is well-known in the formation of the benzofuran analogs (5b). The benefit of intramolecular heck reaction-Pd-catalyzed through ionic liquid catalysis is obvious (fig. 2e). Sheradsky et al.[54] reported a one-pot technique by treating acetophenone (6a) under modified Buchwald conditions, employing acetonitrile instead of dioxane (fig. 2f). This resulted in an excellent yield of benzofuran (6c) via hydrolysis and rearrangement[55].

de Luca et al.[56] reported an efficient and gentle microwave-assisted method for producing ortho-substituted benzofurans(7d) straight from acid derivatives (7a). Enables the synthesis of alkyl 2-benzofuran-methane amines from the 2,4,6-trichloro(1,3,5)triazine (7b), non-racemized N-protected amino acids (fig. 2g). Ghosh et al.[57] reported One-pot intermolecular attachment and cyclization which is driven by visible light was performed for 5-endodig in the water of orthohalophenol derivative(8a) with closing alkynes generated by Pd have already been established to provide elevated quantities of 2aryl or alkyl benzofurans (8b) with no as such accomplice of Ru or Ir complexes or any other possible component (fig. 2h). Zykov et al.[58], Kadieva et al.[59], and Brent et al.[60] reported benzopyranones(9a) or coumarins (LI) can be utilized as synthons for the Fittig-Ebert-Perkin reaction or pyrolysis to produce benzofurans(9c) as shown in fig. 2i.

A group of researchers reported several kinds of intramolecular cyclization of 2-alkoxyacetophenones (10a) have been described, resulting in 2-R-3-methylbenzofurans (10b). As condensing agents, Na and K alcoholates[61-63] or alkalis[64-68] in the polar solvent/environment are being utilized[69,70] as shown in fig. 2j. Montfort et al.[71] and Grinev et al.[72] reported by providing heat in the environment of a catalytic amount of poly-phosphoric acid, the cyclization of the 2-aryloxyl,2di-arylethanol(11a) or any possible available alkoxybenzenes may be exploited to produce benzofurans derivative(11b) with the aromatic substituents at ortho or meta position as shown in fig. 2k.

Inanaga et al.[73] and Tsukazaki et al.[74] reported benzofuran synthesis from the cyclization of 2bromoethynyloxybenzene(12a), 2bromovinyloxybenzene(12b), or benzoylmethyl- benzenes, a radical reaction which connects the alkyl and aryl carbon atoms as shown in fig. 2l. Pandey et al.[75] reported benzyl ketones(13a) when exposed to a mercury lamp in the presence of 1,4dicyanonaphthalene (DCN), undergo a transformation into the intermediate compound(13b), which is then later converted to the equivalent related benzofuran analog (13c). The carbonyl oxygen attacks the furan ring intramolecularly before it closes as shown in fig. 2m.

Blennow et al.[76] reported coumarone(14a) was used to create benzofuran from coumarin. By perkin rearrangement, the available intermediate 3,4-dibromo-3,4-dihydrocoumarin(14b) with the presence of KOH leads to benzofuran synthesis(14c) as shown in fig. 2n. Speicher et al.[77] reported benzofurans(15c) which are produced by reacting phenolates with halo ketones (15a) and then cyclo dehydrating them with H2SO4, polyphosphoric acid, or zeolites as shown in fig. 2o.

Anti-Alzheimer Activity of Benzofuran-Based Derivative and Their Synthetic Scheme

Ab fibril formation inhibitor:

Byun et al.[78], and Cheng et al.[79,80] offered many potential ways for developing ligands with specialized high binding affinity to Ab fibrils. They are designing via the novel series of amino-styryl benzofuran analogs and detailed their inhibitory effects for Ab fibril production. Thioflavin T (ThT) test is used to assess the activity of synthesized compounds against the fibrillization of Ab. Compounds (16a)as well as (16b) (fig. 3) 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.

IJPS-fibril

Fig. 3: Benzofuran analogs (16a-b) as Ab fibril formation inhibitor

Cholinesterase inhibitor:

Yun et al.[45] reported to study its anti-AD efficacy, 2-arylbenzofurans were synthesized. Benzofuran compounds have received a lot of attention due to their numerous biological and as well as therapeutical activities, such as anti-inflammatory[81], anti- bacterial[82], hypoglycaemic[83], anti-oxidant[84], anti-tumor[85], anti-cholinesterase[86], anti- fungal[87], anti-monoamine oxidase[88] and others. AD etiology is multifaceted, and multi-targeted therapies outperform single-targeted treatments in this illness[89]. Recently, many benzofuran-based compounds have been found as potent AChE inhibitors. the production and activity of 2aryl-benzofuran (17f) analogs as BACE1 and ChE inhibitors. 2-arylbenzofuran (17f) was synthesized from substituted 2hydroxy-benzaldehyde in 3 steps. The routes for the production of 2aryl- benzofuran analogs are represented in fig. 4a. It was synthesized by utilizing a slightly modified drozdzik approach.

IJPS-cholinesterase

Fig. 4: Chemical structure of compounds; (a): 2-arylbenzofuran (17f); (b): Benzofuran analog (19e); (c): Compound 20; (d): Compound 21; (e): Compounds 22a-i having anti-cholinesterase activity; (f): Compounds b having anti-cholinesterase activity; (g): Benzofuran derivatives 24f, 24h and 24j; (h): Compound 25 and (i): Compound 26

Benzofuran analogue with anti-aggregation activity:

Ha et al.[90] produced an orally active, Blood- Brain-Barrier (BBB) permeable benzofuran derivative with significant anti-aggregation action of compound 19e (MDR-1339). 2-(3,4-dimethoxyphenyl)-5-(3-methoxypropyl) benzofuran (fig. 4b) not only restored cellular survival after amyloid beta-induced cytotoxicity but also enhances adaptive learning ability and memory brain function in AD of the model mice by decreasing amyloid beta accumulation in the brains.

Kim et al.[91] studied by using thioflavin T tests, gel electrophoresis, and a variety of Aβ aggregation inhibition and aggregates' disaggregation assayed. Out of all of them, 20 (fig. 4c) were chosen as the final Aβ-disaggregator candidate, demonstrating that the Aβ-oligomers and plaques in the hippocampus had been lowered. Montanari et al.[92] reported 2-arylbenzofuran based derivatives and evaluated their anticholinesterase and neuroprotective activity. Among them, compound 21 (fig. 4d) showed multiple anti-AD effects, including cholinergic system restoration by inhibiting BChE, neuroprotective activity against Aβ oligomers, potent and selective cannabinoid receptor-2 ligand activity, and immunomodulatory effects that changed microglia from the pro- inflammatory M1 to the neuroprotective M2 phenotype.

Anticholinesterase inhibitory activity:

Abedinifar et al.[93] reported in 2018 that AChE and BChE architectures are remarkably similar, with 65 % amino acid sequence similarity. By restoring ACh levels, the inhibition of AChE and butyrylcholinesterase enzymes alleviated symptoms related to Alzheimer’s and including cognitive level and also includes short-term memory. Table 4 summarises the findings, which include target compounds with their IC50 values. None of the drugs inhibited AChE better than donepezil, however except 22j (fig. 4e), all of them had superior inhibitory activity of BChE and inhibited AchE the best of the target drugs, but 22h inhibited BChE more efficiently than donepezil, with an IC50 value of 0.054 M, which is about 100 times greater than the positive control. Mostofi et al.[94] reported 1,5-benzothiazepine-based derivatives and evaluated their anticholinesterase activity. Among them, compounds 23a, 23b, and 23c (fig. 4f) displayed the uppermost inhibition of BChE with IC50 values of 1.0, 1.0, and 1.8 µM respectively.

Compound R1 R2 X AChE Inhibitor IC50 value (μM) BChE Inhibitor IC50 value (μM)
22a H H Br 5.50±0.3 0.29±0.01
22b H 3-Me Br 13.8±0.5 0.11±0.01
22c H 4-Me Br 19.8±0.8 0.65±0.04
22d H 2-NO2 Br 3.5±0.3 0.15±0.01
22e H 4-NO2 Br 40.0±4.0 0.76+0.05
22f H 4-F Br 12.3±0.3 0.37±0.01
22g H 2,4-Cl2 Cl 4.4±0.3 0.37±0.01
22h H 2-F-6-NO2 Br 33.8±1.2 0.054±0.002
22i OCH3 H Cl 4.7±0.4 0.87±0.07
Donepezil - - - 0.031±0.005 5.4±0.1

Table 4: Inhibitory Activity of Synthesized Compounds 1A-N Cholinesterase Inhibitor

PET Imaging of beta-amyloid plaques:

Ono et al.[95] reported the synthesis of benzofuran derivatives for PET imaging of beta-amyloid plaques. A reaction called the intramolecular Wittig reaction between the compound triphenylphosphonium salt and 4-nitrobenzoyl chloride was used to efficiently synthesize the required Wittig reagent (fig. 4g). By treating derivatives 24e, 24g, and 24i with BBr3, the O-methyl groups were removed, yielded 24f, 24h, and 24j with yields of 47, 39, and 7%, respectively. Among all, the derivative 24h was found with the lowest Ki value 0.7 nM and highest brain penetration activity.

AChE/BuChE and β-/γ- secretase inhibitors:

The cholinergic neurotransmitter system’s significant variability, chronic cholinergic deficiency and synaptic alterations all play essential roles in the development of AD. AChE is the most important enzyme in the catalytic breakdown of ACh[95], as AD advances, the concentration of ACh in the brain decreases. It also binds to A, increasing A peptide aggregation[96].

Hasanvand et al.[96] reported 3-aminobenzofuran based derivatives and evaluated their potency against AChE and BuChE. Among them, compound 25 which has a 2-fluorobenzyl moiety (fig. 4h) displayed the excellent inhibitory activity. Furthermore, the kinetic study also revealed that it showed mixed-type inhibition on AChE.

AChE inhibitory activity:

Wu et al. reported N-glycosyl benzofuran based derivatives and evaluated their potency against AChE. Among them, compound 26 (fig. 4i) displayed the excellent inhibitory activity about 84 %[97].

Conclusion

AD is a neurodegenerative disease that impairs motor and cognitive function and is rapidly spreading in the current scenario with a male:female ratio of 1.2:1.5 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 AD is a huge issue due to the lack of an effective medicine. However, data suggests that the benzofuran derivative has strong bioactivity against AD.

Acknowledgments:

The authors would like to thank the Dean (Prof.) SK Abdul Rahaman, School of Medical and Allied Sciences, Galgotias University, Greater Noida-201310 for providing technical support and guidance.

Conflict of interests:

The authors confirm that this article's content has no conflict of interest.

References