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Review

Structure–Activity Relationship of Benzofuran Derivatives with Potential Anticancer Activity

by
Joviana Farhat
1,
Lara Alzyoud
2,3,
Mohammad Alwahsh
4,5,6 and
Basem Al-Omari
1,7,*
1
Department of Epidemiology and Population Health, College of Medicine and Health Sciences, Khalifa University, Abu Dhabi P.O. Box 127788, United Arab Emirates
2
College of Pharmacy, Al Ain University, Abu Dhabi P.O. Box 64141, United Arab Emirates
3
Health and Biomedical Research Center, Al Ain University, Abu Dhabi P.O. Box 64141, United Arab Emirates
4
Leibniz-Institut Für Analytische Wissenschaften-ISAS e.V., 44139 Dortmund, Germany
5
Institute of Pathology and Medical Research Center (ZMF), University Medical Center Mannheim, Heid Elberg University, 68167 Mannheim, Germany
6
Department of Pharmacy, Faculty of Pharmacy, AlZaytoonah University of Jordan, P.O. Box 130, Amman 11733, Jordan
7
KU Research and Data Intelligence Support Center (RDISC) AW 8474000331, Khalifa University of Science and Technology, Abu Dhabi P.O. Box 127788, United Arab Emirates
*
Author to whom correspondence should be addressed.
Cancers 2022, 14(9), 2196; https://doi.org/10.3390/cancers14092196
Submission received: 15 March 2022 / Revised: 17 April 2022 / Accepted: 25 April 2022 / Published: 28 April 2022
(This article belongs to the Section Cancer Therapy)
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Abstract

:

Simple Summary

Cancer is the leading cause of death worldwide and responsible for killing approximately 10 million people per year. Fused heterocyclic ring systems such as benzofuran have emerged as important scaffolds with many biological properties. Furthermore, derivatives of benzofurans demonstrate a wide range of biological and pharmacological activities, including anticancer properties. The main aim of this review is to highlight and discuss the contribution of benzofuran derivatives as anticancer agents by considering and discussing the chemical structure of 20 different compounds. Evaluating the chemical structure of these compounds will guide future medicinal chemists in designing new drugs for cancer therapy that might give excellent results in in vivo/in vitro applications.

Abstract

Benzofuran is a heterocyclic compound found naturally in plants and it can also be obtained through synthetic reactions. Multiple physicochemical characteristics and versatile features distinguish benzofuran, and its chemical structure is composed of fused benzene and furan rings. Benzofuran derivatives are essential compounds that hold vital biological activities to design novel therapies with enhanced efficacy compared to conventional treatments. Therefore, medicinal chemists used its core to synthesize new derivatives that can be applied to a variety of disorders. Benzofuran exhibited potential effectiveness in chronic diseases such as hypertension, neurodegenerative and oxidative conditions, and dyslipidemia. In acute infections, benzofuran revealed anti-infective properties against microorganisms like viruses, bacteria, and parasites. In recent years, the complex nature and the number of acquired or resistant cancer cases have been largely increasing. Benzofuran derivatives revealed potential anticancer activity with lower incidence or severity of adverse events normally encountered during chemotherapeutic treatments. This review discusses the structure–activity relationship (SAR) of several benzofuran derivatives in order to elucidate the possible substitution alternatives and structural requirements for a highly potent and selective anticancer activity.

1. Introduction

Several heterocyclic compounds are found in many medications and have formed an essential base for medicinal chemistry research. This is mainly due to heterocyclic compounds’ versatility and distinctive physicochemical features [1]. Among these discovered heterocyclic compounds is benzofuran [2], known as a natural compound originating from plants such as Asteraceae, Rutaceae, Liliaceae, and Cyperaceae [3]. Benzofurans can also emerge from non-natural sources through the dehydrogenation of 2-ethylphenol [4,5]. Structurally, benzofuran is characterized by a distinctive motif consisting of fused benzene and furan rings, as illustrated in Figure 1 [6].
It is suggested that introducing substituents at specified positions within the benzofuran’s core [2] results in new derivatives with unique structural characteristics that may possess an excellent therapeutic value [7]. Therefore, in recent years, derivatives of benzofurans have been frequently used in the development of new drugs [8]. These derivatives exhibited a promising anti-infective activity against bacteria, viruses, and parasites [9,10,11]. For example, in treating neurodegenerative disorders, derivatives of benzofurans revealed potential efficacy in slowing down the progression of Alzheimer’s [12] as well as minimizing Parkinson’s severity [13] and presented potential neuroprotective functions in brain disorders [14]. Furthermore, derivatives of benzofurans have the ability to achieve anti-dyslipidemic and antioxidative effects [15]. Some researchers extended the use of benzofurans’ derivatives to design an effective class of benzofuran-based vasodilators to treat some cardiovascular conditions [16]. In practice, the synthetic derivatives of benzofurans are represented by Amiodarone, which is used in the treatment of ventricular and supraventricular arrhythmias [17], and by Bufuralol as a non-specific β-adrenergic blocker with an affinity for β1- and β2-adrenergic receptors [18,19].
Despite the major progress that has been achieved in research, there are still barriers limiting the effective improvement of therapy, especially in cancer [20]. Nowadays, cancer is known to be the leading cause of death worldwide, accounting for approximately 10 million deaths in 2020 [20]. As cancer cases are constantly increasing, oncology research is investing significant efforts to identify novel, safe and effective therapies to minimize critical side effects caused by conventional treatments [19].
Fused heterocyclic ring systems have emerged as important scaffolds with many biological properties [1,21]. Accordingly, the peculiar structural motif of oxygen-containing heterocycles demonstrates a wide range of biological and pharmacological activities, including anticancer properties [2,18,22]. Earlier structure–activity relationship (SAR) studies of benzofurans’ derivatives found that ester or heterocyclic ring substitutions at the C-2 position were crucial for the compounds’ cytotoxic activity [18]. These modifications have a significant role in influencing the selectivity of these compounds toward cancer cells, which have significant importance given the damage to normal cells caused by the cytotoxic side effects of anticancer therapy. Therefore, this review will discuss the SAR of several anticancer derivatives of benzofurans to determine the critical substitution patterns and structural requirements useful to gain potent and selective anticancer activity.

2. Materials and Methods

The aim of this review is to highlight and discuss the contribution of benzofurans’ derivatives as anticancer agents. This review will discuss how the SAR of benzofuran can be used to predict their biological activity and better understand their applications in cancer treatment.
A comprehensive electronic literature search of PubMed (MEDLINE), EMBASE, and Web of Science without language or date restrictions was conducted. The keywords related to “benzofuran” OR “derivatives” OR “compounds” OR “agent” OR “class” OR “anti-proliferative” OR “anti-tumor” OR “anti-cancer” OR “anti-neoplastic” OR “novel” OR “new” OR “active” OR “activity” OR “efficacy” OR “agent” OR “potent” OR “cytotoxic” OR “scaffolds” OR “heterocyclic” OR “modeling” OR “experimental” OR “computational” OR “potent” OR “selective” OR “drug design” OR “docking” OR “synthesis” OR “in vitro” were used to search the literature.
All figures in this paper were produced by the authors using ACD/ChemSketch, which is a free molecular modeling software used to create images of chemical structures.

3. Benzofuran Derivatives as Anticancer Agents

3.1. Halogenated Derivatives of Benzofuran

Some halogen additions into the benzofuran ring, such as bromine, chlorine, or fluorine atoms, have consistently resulted in a significant increase in anticancer activities [23,24,25,26,27,28,29,30]. This is most likely due to the ability of halogens to form a “halogen bond”; an attractive interaction between the electrophilic halogen and a molecule’s nucleophilic sites, which substantially improves the binding affinity [31,32]. For example, a set of seven derivatives (1,1′-(5,6-dimethoxy-3-methyl-1-benzofuran-2,7-diyl) diethanone) were synthesized via standard bromination reaction and condensation with aryl/heteroarylpiperazine [28]. Consequently, those novel halogen derivatives underwent 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assays against three cancer cell lines (human chronic (K562), and acute (HL60) leukemia cells, human cervical cancer cells (HeLa)), and one normal endothelial cancer cell (HUVEC). Compound 1 (see Figure 2) has a bromine atom attached to the methyl group at the 3-position of the benzofuran ring; and was found to possess remarkable cytotoxic activity against K562, and HL60 leukemia cells with an inhibitory concentration (IC50) value of 5 μM and 0.1 μM (see Table 1), without cytotoxicity towards normal cells. This means that the position of the halogen in the benzofuran ring is a critical determinant of its biological activity [28].
In most cases, the halogen atom is attached to alkyl or acetyl chains rather than directly onto the benzofuran ring [28,33]. This placement does not deter the compound’s cytotoxic activity, as evidenced by electron-rich bromomethyl- or bromophenacyl-substituted benzofuran, which produced pronounced cytotoxic activity in both normal and cancer cells [34,35,36,37]. Selective Polo-like kinase 1 Polo-Box Domain (PLK1 PBD) inhibitor MCC1019 (compound 2) (see Figure 2) is a bromomethyl-substituted benzofuran developed by Abdelfatah and colleagues for the treatment of lung cancer and evaluated via in silico, in vitro, and in vivo models [33]. There are two key interactions between MCC1019 and PLK1 at residues Tryptophan 414 (Trp414) and Histidine 538 (His538), which must be maintained for optimum activity. In vitro testing against lung adenocarcinoma cells (A549) showed that MCC1019 successfully inactivated the serine-threonine kinase (AKT) signaling pathway and inhibited cancerous cell replication, causing a mitotic catastrophe [33,38]. This resulted in achieving selective inhibition of PLK1 PBD with an IC50 of 16.4 μM (see Table 1) [33]. Further in vivo testing using a murine lung cancer model demonstrated a significant anticancer activity by reducing the growth of metastatic lesions in the lung without affecting body weight or vital organ size [33].
The substitution of the N-phenyl ring of the benzofuran with halogen is considered beneficial due to their hydrophobic and electron-donating nature, which enhances benzofuran’ cytotoxic properties [27]. Several studies in the literature have emphasized the influence of the position of the halogen atom on the cytotoxic activity [39,40]. So far, the maximum activities have been recorded when a halogen atom is placed at the para position of the N-phenyl ring [41].
A series of fourteen apoptotic anticancer derivatives were developed using the Allosteric cannabinoid receptor type 1 (CB1) modulator 5-chlorobenzofuran-2-carboxamides [42]. Each compound was then tested to evaluate its antiproliferative activity against the human mammary gland epithelial cell line (MCF-10A) via cell viability assays [43]. Although multiple compounds exhibited excellent antiproliferative activity against tumor cells, compound 3 stood out as the most active derivative (see Figure 2). According to the SAR analysis, the presence of the N-phenethyl carboxamide significantly enhances its antiproliferative activity. This activity was further enhanced by morpholinyl substitution at the para position of the N-phenethyl ring [42]. This explains why compound 3 exhibits similar antiproliferative activity to oral anticancer drug doxorubicin (IC50 of 1.136 μM) [42], (see Figure 2 and Table 1). Interestingly, regardless of the halogen used (e.g., Cl, Br, F, etc.), all the aforementioned halogen-substituted compounds exhibit significant cytotoxicity [28,33,42]. This suggests that, while the nature of the halogen does not impact the cytotoxic activity of the compound, the position of the halogen is of great importance [28].

3.2. Hybrid Benzofuran as Anticancer Agents

Recent studies have highlighted novel classes of hybrid benzofurans’ derivatives like chalcone, triazole, piperazine, and imidazole substituted benzofuran, which have emerged as potent cytotoxic agents [44,45,46,47,48,49]. Utilizing the synergetic cytotoxic effect of heteroatom-substituted benzofuran presents a promising approach for the development of potent anticancer drugs with activities against malignant tumors.

3.2.1. Benzene-Sulfonamide-Based Benzofuran Derivatives

Benzene-sulfonamide has become a biologically significant scaffold, with several of its derivatives being used as anticancer and antitumor agents [50]. Benzene-sulfonamide-based benzofuran derivative (5-[benzyl-(4-chlorophenyl)sulfonylamino]-n-[2-(dimethylamino)ethyl]-3-methyl-1-benzofuran-2-carboxamide) represented in compound 4 (see Figure 3) was designed and synthesized to inhibit the hypoxia-inducible factor (HIF-1) pathway [51], which is involved in the carcinogenesis of tumor protein (p53)-independent malignant cancers [51,52,53]. In vitro testing of compound 4 against HCT116 and HCT116−/− p53-null cell lines showed the inhibition of both p53-null cells and p53-mutated cells (see Figure 3 and Table 2). Thus, the addition of a chlorine atom at the para position along with the replacement of the ester group by N containing alkyl chains were major determinants for the antiproliferative activity [51].

3.2.2. 6-Substituted Hexamethylene Amiloride (6-HMA)-Based Benzofuran Derivatives

The urokinase-type plasminogen activator (uPA) system mediates cancer invasion and metastasis through the uPA and its receptor (uPAR) [54]. Targeting uPA is one of the key strategies for combating metastasis in malignant cancers including triple-negative breast cancer [55,56]. In recent in vitro and in vivo studies, high doses of amiloride, a potassium channel blocker, have been found to inhibit uPA proteolytic activity, prompting the search for novel amiloride analogs as uPA inhibitors [57,58,59].
In order to investigate the potential of amiloride-benzofuran derivatives as uPA inhibitors, a series of 6-HMA, 6-N,N-(hexamethylene) amiloride derivatives were synthesized via the Suzuki–Miyaura coupling reactions as potential uPA inhibitors [60]. The addition of a benzofuran group to 6-HMA yields a compound with higher potency, and cytotoxicity (Ki = 183 nM) [61]. In compound 5, the addition of fluorine atom at position 4 of 2-benzofuranyl resulted in a 2-fold increase in potency and inhibitory activity (Ki = 88 nM; IC50 = 0.43 μM) [61] (see Figure 3 and Table 2). Such halogen substitutions at the para position of benzofuran are more likely to form favorable hydrophobic interactions, and therefore are more potent [62,63].

3.2.3. Quinazolinone- and Imidazolium-Based Benzofuran Derivatives

Quinazolinone is an aromatic heterocyclic ring that contains a quinazoline with a carbonyl group [64]. Quinazolinone, like imidazole, is regarded by many as a privileged scaffold with significant anticancer properties [65]. Two of its derivatives, gefitinib, and erlotinib, were introduced to the market as anticancer agents [66]. One study reported the synthesis of a small library of benzofuran derivatives fused to two prominent scaffolds, imidazole and quinazolinone, to create a molecule with a desirable drug-like profile and cytotoxicity [47]. Accordingly, the cell viability and proliferation rates of nine hybrid derivatives (1-[[(1-(benzofuran-2-yl)-2-(quinazolin-4(3H)-one-3-yl)]ethyl-1-yl]-3-methylimidazol-1-ium chloride) or (compounds 6a–i) were tested via MTT assays against human breast cancer (MCF-7) cells [47] (see Figure 3). All derivatives successfully inhibited the growth of cancer cells except compound 6e. Analysis of its structural features suggested that the presence of two halogen-substituted rings coupled with the lack of methoxy substituent on the heterocyclic ring was detrimental to its activity, resulting in no cytotoxicity, as shown in Table 2. This is expected, as the addition of halogen-substituted rings is usually resulting compounds with little to no cytotoxic activity [47].

3.2.4. Carbohydrazide- and Substituted Benzaldehydes-Based Benzofuran Derivatives

The condensation of 3-methyl-2-benzofuran carbohydrazide with various substituted benzaldehydes yielded a set of new benzofuran derivatives, compounds 7a–k (see Figure 3). The eleven benzofuran analogues were screened for potential anticancer activity using the triphenyl blue dye exclusion technique on Erlich ascites carcinoma (EAC) cells [67,68,69]. Out of these eleven benzofuran analogues, derivatives 7a, 7c, 7d, 7f, 7i, and 7j demonstrated the greatest anticancer activity, as evidenced by their high cytotoxic concentration scores (CTC50) shown in Table 3. The SAR results have shown that the presence of the CONH group is necessary for anticancer activity [70]. The addition of phenol and chlorine groups in compounds 7c, 7d, and 7i increased the number of binding interactions formed with the target, resulting in improved anticancer activity (see Figure 3). As for the nitro group in compound 7a, it significantly boosted activity by reducing the melting temperature of DNA in EAC cells [71] (see Figure 3). Interestingly, the phenolic hydroxy group of benzofuran was found to be crucial for modulating anticancer activity. The presence of a hydrogen donating group promotes the formation of favorable interactions with the target, hence inducing its cytotoxic properties [17,44,70,72].

3.2.5. Trimethoxyacetophenone-Based Benzofuran Derivatives

Combretastatin A-4 (CA-A4), which is a naturally occurring chemical, isolated from the roots of Combretum Caffrum, has recently attracted considerable attention for its antitumor and antimitotic activity [2,73]. The CA-A4 analogue (compound 8) consists of trimethoxy acetophenone and a benzofuran core, and it has an IC5O of 0.43 μM (see Figure 3). Subsequently, Flynn and colleagues used compound 8 as the lead compound for the SAR-guided design of novel tubulin polymerization inhibitors [74]. The results demonstrated that the introduction of C7-OH and a C2-substituent, as seen in compound 8a (BNC105), improved its anticancer activity with a tubulin inhibition IC50 of 0.8 μM [74] (see Figure 3 and Table 2). Notably, the observed antimitotic activity is approximately tenfold stronger than that of the lead compound. The presence of a hydrogen bond donor (hydroxyl) at C7 adds to the pharmacophore’s interactions; as for the C-2 substituent, it maintains conformational bias, ensuring that the compound remains in the cis-conformation. Further efforts to enhance the activity were made by formulating a prodrug, disoduimphosphase ester derivative compound 8b (BNC105P), which is rapidly cleaved in vivo to return to its active state compound 8a [74] (see Figure 3). When tested in vitro, the prodrug produced tenfold stronger antitumor activity, eightyfold better selectivity, and a fivefold longer half-life than the free drug [74]. This means that adjusting the formulation is equally important to modifying the substituents on the compound in terms of increasing antitumor activity.

3.2.6. N-Methylpiperidine-Based Benzofuran Derivatives

The hallmark of many cancers is the activation and dysregulation of the AKT/mammalian target of the rapamycin (mTOR) pathway, making it promising for drug discovery [75,76,77]. A series of mammalian targets of the rapamycin complex 1 (mTORC1) protein complex inhibitors were synthesized by performing different isosteric replacements on the lead compound ChemBridge 5219657, which was identified through high-throughput screening (HTS) [78,79]. Derivative 1-((2-(2-(benzyloxy) phenyl)-5-methoxybenzofuran-4-yl) methyl)-n, n-dimethylpiperidin-4-amine (compound 9) was found to exhibit the greatest cytotoxic activity against head and neck (SQ20B) cancer cell line with an IC50 value of 0.46 μM (see Figure 3 and Table 2). The replacement of the phenolic hydroxyl group with another H-bond donor like triflylamide conserved the cytotoxicity of the compound, whereas replacement with an H-bond acceptor altered its activity [78,79]. Whilst the introduction of triflate ester (a group that cannot donate or accept an H-bond) was well tolerated, the absolute removal of the phenolic hydroxy diminished the cytotoxicity of the compounds. Furthermore, substituting the dimethylamine and benzyl groups, with bulkier amine-containing groups such as 4-piperidino-piperidine, enhanced the cytotoxicity of the compounds [79].
Hypoxic microenvironments accelerate tumor metastasis and progression in solid tumor cancers, including pancreatic ductal adenocarcinoma (PADC) [80,81]. With the HIF-1 pathway being a target of interest, a small library of thirty-two benzofuran-derived HIF-1 inhibitors based on compound 10 were developed [82] (see Figure 3). MTT assays have found that derivatives 10a and 10b exhibit similar activity, but derivative 5-(4-bromo-N-(4-bromobenzyl) phenylsulfonamido)-3-methyl-N-(1-methylpiperidin-4-yl) benzofuran-2-carboxamide (compound 10b) emerged as the most promising candidate due to its significant antiproliferative activity and selective inhibition of HIF-1 pathway [83] (see Figure 3 and Table 2). The inclusion of hydrophilic heteroatom-containing groups, like piperidine, on the benzofuran ring significantly improved the compound’s physicochemical properties [82]. Additionally, the para-substituted halogen on the phenylsulfonyl- and N-containing alkyl chains contributed to the resultant antiproliferative activity [83].
Table
Table 2. In vitro cytotoxicity of hybrid benzofuran derivatives 4–20 against multiple cancer cell lines.
Table 2. In vitro cytotoxicity of hybrid benzofuran derivatives 4–20 against multiple cancer cell lines.
CompoundCell LineIC50 (μM)References
4HCT116 (p53-null)2.91[51]
MDA-MB-435s (p53-mutated)4.71
5uPA0.43[61]
6aMCF-77.70[47]
6bMCF-79.14
6cMCF-71.00
6dMCF-720.58
6eMCF-7inactive
6fMCF-773.26
6gMCF-71.00
6hMCF-7100
6iMCF-70.57
8Tubulin0.43[74]
8aTubulin0.76
8bTubulinND
9SQ20B0.46[79]
10NDND[82]
10aPANC-11.52
BxPC31.08
HCT1162.39
HCT116(p53−/−)1.66
MCF-72.84
A5492.98
MDA-MB-2313.73
10bPANC-11.07
BxPC30.65
HCT1161.81
HCT116(p53−/−)1.61
MCF-72.39
A5492.68
MDA-MB-2311.90
11aA5490.12[84]
Hela26.32
SGC79012.75
11bA5496.25
Hela18.71
SGC790136.23
11cA5498.11
Hela28.74
SGC7901>40
11dA54934.13
Hela12.68
SGC79017.45
12HT-10808.86[85]
13aHL602.34[86]
SMMC-77212.63
A5494.5
MCF-73.24
SW4803.61
13bHL600.64
SMMC-77212.10
A5493.34
MCF-74.78
SW4805.56
13cHL600.61[86]
SMMC-77212.30
A5495.35
MCF-73.03
SW4803.14
13dHL600.08
SMMC-77210.52
A5490.55
MCF-70.51
SW4800.47
14aNDND[87]
14bNDND
14cNDND
14dNDND
15aMCF-71.90[88]
A5492.38
Colo-2052.11
A27801.05
15bMCF-73.90
A5494.17
Colo-205ND
A2780ND
15cMCF-70.011
A5490.073
Colo-2050.10
A27800.034
15dMCF-77.23
A5496.91
Colo-2052.84
A278010.2
15eMCF-712.5
A5495.34
Colo-205ND
A27809.55
15fMCF-73.16
A549ND
Colo-2057.10
A27808.64
15gMCF-710.76
A54919.42
Colo-205ND
A2780ND
15hMCF-71.55
A5491.93
Colo-2051.28
A27802.13
15iMCF-70.21
A5490.43
Colo-2050.17
A27801.84
15jMCF-70.14
A5490.25
Colo-2050.12
A27800.33
16K562ND[89]
17aK562ND
17bK562ND
18A5499[90]
MCF-72
PC-310
19A5496.3[49]
20aA54910.9
20bA549Inactive
The definitions of all abbreviations are provided in a list at the end of the manuscript.
Table
Table 3. In vitro cytotoxicity inhibition of hybrid benzofuran derivatives 7a–k against EAC cancer cell lines.
Table 3. In vitro cytotoxicity inhibition of hybrid benzofuran derivatives 7a–k against EAC cancer cell lines.
CompoundCTC50 (μM/mL)Reference
7a35.5[71]
7b472
7c33.5
7d33.75
7e255
7f43
7g280
7h365
7i34
7j49
7k478
The definitions of all abbreviations are provided in a list at the end of the manuscript.

3.2.7. Piperazine-Based Benzofuran Derivatives

Piperazine is a six-membered ring containing two nitrogen atoms at opposite positions [91]. In vitro and/or in vivo studies have shown that several piperazine compounds revealed significant activities against a variety of cancers cell lines [92]. Given this, a hybrid of 2-benzoyl benzofuran with N-aryl piperazine linker is considered to be more biologically active than unsubstituted benzofuran [18,40,84]. Benzofuran piperazine hybrids were designed, synthesized, and tested via MTT assays against lung cancer (A549), human cervical carcinoma (Hela), and colonic cancer (SGC7901) cell lines [84]. Derivatives bearing keto-substituent on the piperazine ring (compounds 11a–d) exhibited the most cytotoxic activity against cancer cells [84] (see Figure 4). Similarly, the addition of an electron-withdrawing group or halide such as fluoro-, chloro-, and cyano- at the para position of benzene in compounds 11b, 11c, and 11d was beneficial for anticancer activity [84] (see Figure 4). Furthermore, compound 11a showed promising activity and selectivity to lung (A549) and colonic cancer (SGC7901) cell lines with IC50 values of 0.12 μM and 2.75 μM, respectively [84] (see Figure 4 and Table 2).

3.2.8. Neolignans-Based Benzofuran Derivatives

Naturally occurring dihydrobenzofuran neolignans are often found in high concentrations in aerial parts of plants like Mappianthus iodoies, Dorstenia kameruniana, and Aristolochia fordiana [45,93,94,95,96,97]. Many neolignans have shown considerable activity against a variety of cancers cell lines [98]. Neolignan-based benzofurans’ derivatives are expected to benefit from the synergistic cytotoxic effect of both molecules. Thus, eight dihydro benzofuran neolignans analogs were isolated from the seeds of crataegus pinnatifida [85]. In vitro testing recognized 7R,8S-balanophonin (compound 12) as the most potent analogue, with stronger inhibitory activity against HT-1080 cancer cells than positive control 5-fluorouracil (5FU) (IC50 = 35.62 μM) (see Figure 4 and Table 2). The SAR studies of hybrid dihydrobenzofuran neolignans revealed that the presence of a double bond at C-7′/C-8′ next to the aromatic ring is vital for cytotoxicity and that the reduction of the double bond can reduce the activity by tenfold or greater [85].

3.2.9. Imidazole-Based Benzofuran Derivatives

Imidazoles are five-membered, nitrogen-containing heterocycles with significant anticancer activity against a variety of biological targets [99]. However, there is no consensus surrounding the cytotoxic activity of benzofuran-imidazole derivatives [48,100,101]. It has been reported that the addition of an imidazole ring to the benzofuran produced compounds with weak cytotoxic properties [36]. Therefore, to yield optimal benzofuran imidazole hybrids, some modifications must be implemented. The 2-benzylbenzofuran ring is altered to 2-alkylbenzofuran to improve both the steric effect and charge distribution of the compound [100,101]. Then, electron-rich groups like 2-bromophenacyl, phenacyl, and napthylacyl- are substituted onto the imidazole ring, preferably into the 3-positon [102]. These alterations are crucial to ensure a maximal cytotoxic activity against cancer cells. Similar findings were observed in 2-phenyl-3-alkylbenzofuran imidazole/triazole hybrids (compounds 13a–d) (see Figure 4) [86]. These highly potent anticancer derivatives often include a 2-ethyl-imidazole or benzimidazole ring with a 2-bromobenzyl or napthylacyl substituent at the 3-position of the imidazole ring, all of which are important groups in modulating antitumor activity [103]. Among these compounds, compound 13d has shown the strongest inhibitory activity and selectivity towards breast cancer (MCF-7) and colon cancer (SW480) cells, with IC50 values ranging from 0.08 to 0.55 μM [86] (see Figure 4 and Table 2).

3.2.10. Pyrazole-Based Benzofuran Derivatives

The non-receptor tyrosine kinase (c-Src) has been identified as a promising target for cancer treatment, sparking the interest of researchers [104,105,106]. Pyrazole is a five-membered aromatic heterocyclic ring containing two neighboring nitrogen atoms [107]. Pyrazole derivatives have previously demonstrated antitumor activity against numerous types of cancer [108]. In an effort to discover novel potent c-Src inhibitors as anticancer agents, a set of benzofuran-pyrazoles hybrids containing chalcones, pyrazoline, isoxazole, and thiopyrimidine substituents were in vitro-synthesized and tested for their anticancer activity [87].
Compounds 14c and 14d, which consist of 3-furano-N-acetylpyrazoline and 3-furano-isoxazole rings, respectively, exhibited remarkable and broad-spectrum anticancer activity (see Figure 4). Incorporating acetyl, an electron-withdrawing group, into the N-1 of the pyrazoline ring appears to be essential for antiproliferative activity. Hence, the derivatives lacking the acetyl group such as compound 14a exhibited weak anticancer activity in-vitro [87] (see Figure 4). Increasing the size of the hetero-ring systems attached to the parent core resulted in weak-to-moderate antiproliferative potency [21]. Among all derivatives, compound 14b containing 3-pyrrolo-N-acetylpyrazoline demonstrated significant antiproliferative and anticancer activity against leukemia, lung cancer, colon cancer, central nervous system (CNS) cancer, melanoma, ovarian cancer, breast cancer, and renal cancer cells [87] (see Figure 4). Enzyme assays of compound 14c detected significant inhibition of Src and zeta-chain-associated protein (ZAP-70) kinases [87] (see Figure 4). Overall, the potent antitumor activity and favorable absorption, distribution, metabolism, and excretion (ADME) characteristics of compound 14b make it a viable candidate worthy of further investigation and modifications (Figure 4).

3.2.11. Imidazopyridine-Based Benzofuran Derivatives

Imidazopyridine is fused bicyclic heterocycles that are synthesized by several strategies such as condensation, oxidative coupling, tandem reaction, etc. [109]. A series of imidazopyridine-substituted benzofurans (compounds 15a–j) were derived from sulfonamides, and subsequently underwent MTT assays to evaluate their in vitro cytotoxicity against human cancer cells [110] (see Figure 4). Moreover, compounds 15a, 15c, 15h, 15i, and 15j were found to produce considerable anticancer activity against tested cell lines [88] (see Figure 4). Among these, derivative 15c, with the greatest cytotoxicity, significantly inhibited the growth of breast (MCF-7), lung (A549), colon (Colo-205), and ovarian (A2780) cancer cell lines with IC50 values of 0.011, 0.073, 0.10, and 0.034 μM [88], respectively (see Figure 4 and Table 2). The SAR has shown that the addition of electron-positive groups at the para position on the phenyl group significantly improved anticancer activity, regardless if it’s a strong group like 4-methoxy (compound 15c) or a weak group like 4-methyl (compound 15h). On the other hand, substitution with electron-withdrawing groups like chloro (15d), bromo (15e), nitro (15f), and cyano (15g) resulted in significant drop-in activity (Figure 4 and Table 2). Interestingly, compound 15a lacked any phenyl ring substituents but still maintained good anticancer activity [88] (see Figure 4). Furthermore, replacing the aryl ring with a hetero-aromatic ring such as 2,6-dimethylpyridine (compound 15i) or 4,5-dimethylthiophene (compound 15j) rings was more beneficial for anticancer activity than keeping the aryl ring (compound 15a and 15h) [88] (see Figure 4).

3.2.12. Aurones-Chromone- and -Coumarin-Based Benzofuran Derivatives

Flavonoids, aurones, chromones, and coumarins are abundantly found in plants, fungi, and bacteria [109]. These natural products are capable of modulating a wide range of biological pathways and achieving selective anticancer activity with few side effects [109,111,112]. Yet, only a limited number of hybrids with aurone-chromone, -coumarin fused heterocycles have been reported. Therefore, a series of 26 hybrid compounds between benzofuran core of aurones-chromone and -coumarin were designed [89]. This combination takes advantage of the potential synergistic anticancer effect of these flavonoids [113,114,115]. These derivatives were then evaluated for their anticancer activity against a panel of human leukemia cells (K562) at different concentrations. In particular, compounds 16, 17a, and 17b were able to induce around 24% apoptosis [89] (see Figure 4). Interestingly, the potency of the compounds is unaffected by different substitutions of the chromone [29]. Furthermore, it appears that exchanging the benzofuranone or methylbenzofuranone moieties with napthofuranone induces a stronger apoptotic effect [89]. In order to understand the pro-apoptotic properties of these benzofuran–coumarin derivatives, (Z)-7-methoxy-4-[(6-methyl-3-oxobenzofuran-2(3H)-ylidene) methyl]-2H-coumarine (compound 17a) was compared to 7-methoxy-coumarin-4-aldehyde and (Z)-2-(4-methoxybenzylidene)-6-methylbenzofuran-3(2H)-one by testing them in K526 cells at doses ranging from 5 to 100 μM [89]. The results demonstrated that compound 17a produced the strongest apoptosis induction at higher doses, outperforming both unsubstituted benzofuran and coumarins [89]. These findings imply that coupling aurone-like benzofuran with a chromone or coumarin can yield novel compounds with more potent pro-apoptotic properties compared to unconjugated benzofuran.

3.2.13. Chalcone-Based Benzofuran Derivatives

Many naturally occurring compounds are derived from plants, including the simple chalcone scaffold [116]. These structures are simple to synthesize, allowing for the chalcones to be incorporated into several derivatives with a wide range of biological activities [117]. Moreover, chalcones have been recognized as a valuable scaffold with potent anticancer activity [118]. Thus, a synergistic cytotoxic effect could be observed after the hybridization of chalcones and benzofuran, yielding compounds that are used to treat malignant tumors [18,29,44].
Encouraged by the anticancer potential of chalcones, a set of 1-(7-ethoxy-1-benzofuran-2-yl) substituted chalcone derivatives via the base-catalyzed Claisen-Schmidt reaction was synthesized [46,90]. All derivatives were then tested by sulforhodamine B (SRB) and adenosine 5′-triphosphate (ATP) cell viability assays, against breast (MCF-7), non-small-cell lung (A549), and prostate (PC-3) cancer cell lines [43]. The best cytotoxic activity was observed in chalcone derivative compound 18, with IC50 values ranging from 2 to 10 μM [90] (see Figure 4 and Table 2). Interestingly, compound 18 showed selective cytotoxicity toward human breast cancer cell line (MC-7), while being non-toxic towards normal breast cancer cells (MRC5). Furthermore, compound 18 was successful in inducing apoptosis in cancer cells while maintaining a promising safety profile, indicating that hybrid benzofuran chalcones have greater cytotoxic activity compared to unsubstituted benzofuran [90].

3.2.14. Oxadiazole- and Triazole-Based Benzofuran Derivatives

Oxadiazoles and triazoles are nitrogen-oxygen and nitrogen-containing five-membered heterocyclic aromatic rings commonly hybridized with other anticancer scaffolds, such as benzofuran [119,120,121]. These hybrid derivatives have shown substantial anticancer potential and play essential roles in cancer management [122,123]. Hence, ultrasound- and microwave-assisted green synthetic protocols were implemented for synthesizing a set of 15 benzofurans–oxadiazole and –triazole. Then, those compounds were evaluated for the anticancer activity against the lung cancer cell line (A549) [49]. Compound 19, benzofuran-oxadiazole hybrid, was reported as the most potent anticancer derivative, with cell viability of 27.49 μM and IC50 of 6.3 μM, outperforming reference drugs crizotinib and cisplatin, which had IC50 of 8.54 and 3.88 μM, respectively [49]. The enhanced anticancer activity is believed to be due to meta methoxy or para ethoxy substitutions on the phenyl ring of N-(substituted-phenyl)-acetamide (see Figure 4).
Although benzofuran triazole derivatives 20a and b exhibit excellent thrombolysis activity and minimal toxicity, they did not demonstrate strong anticancer activity against A549 cancer cells (see Figure 4 and Table 2). The presence of two adjacent electron-withdrawing chloro groups at the ortho and para positions of the phenyl ring in compound 20a was detrimental to its anticancer activity [49]. Similarly, in compound 20b, the addition of two adjacent methyl groups on the ortho and para positions of the phenyl ring yielded an inactive compound [49]. These SAR studies highlight the possible positive and negative impacts of structural modifications to oxadiazole- and triazole-benzofuran derivatives as anticancer drug candidates.

3.3. Cytotoxicity of Benzofurans’ Derivatives against Selected Cancer Cell Lines

Many of the compounds presented have been tested against the same cancer cell lines, and while they show high cytotoxicity, it is notable how different substitutions can influence the compound’s cytotoxicity against selected cancer cell lines. Imidazopyridine-benzofuran analogs bearing electron-positive groups at the 4-position on the phenyl group, for example, have significantly improved anticancer activity against various cancer cell lines (A549, MCF-7, HL-60, SW480, A2780, and Colo-205) [88]. The most effective modifications to the cytotoxicity of MCF-7 cell lines were quinazolinone and Imidazolium, Imidazole, and Chalcone-based benzofuran compounds [47,86,90]. A halogen atom attached to the methyl group at the 3-position of the benzofuran ring promotes cytotoxicity toward both A549 and HL60 cell lines [28,33]. More specifically, the presence of oxadiazole and triazole-benzofuran hybrids further boosts the anticancer activity of A549 cells [49]. The majority of the novel hybrids demonstrated potential anticancer agents against specific cancer cell lines, while maintaining a remarkable safety profile against normal cells. Most of the novel hybrids demonstrated potential anticancer agents against specific cancer cell lines while maintaining a remarkable safety profile against normal cells. Hence, benzofuran derivatives have the potential to be developed as novel therapeutic agents given their recent experimental findings and documented selectivity against cancer cells.

4. Conclusions

This review suggests benzofuran as a versatile scaffold with significant anticancer activity on various human cells such as breast, lung, and prostate cancer. Understanding the SAR of benzofurans’ derivatives facilitates the design and development of novel, safe, and potent in vitro therapeutic options in cancer. Therefore, this may provide a more robust assessment of anticancer activities before considering in vivo studies. The anticancer activity of benzofuran scaffolds is dependent on the type of substituent present and is frequently multifactorial. Furthermore, hybrid structures bearing benzofuran moiety stand out as highly potent anticancer agents. They utilize the functionalization or structural configuration of the conjugate molecule. This review recommends that studying the chemical structure of these compounds will result in anticancer agents that limit tumor progression with minimal adverse effects. Therefore, this could potentially have an impact on improving patients’ adherence to medication and subsequently disease prognosis.

Author Contributions

Conceptualization, J.F., L.A. and M.A.; methodology, J.F., L.A., M.A. and B.A.-O.; validation, J.F., L.A., M.A. and B.A.-O.; formal analysis, J.F., L.A. and M.A.; investigation, J.F., L.A., M.A. and B.A.-O.; resources, J.F., L.A. and M.A.; data curation, J.F., L.A. and M.A.; writing—original draft preparation, J.F., L.A. and M.A.; writing—review and editing, B.A.-O.; visualization, L.A.; supervision, B.A.-O.; project administration, J.F. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

5FU5-fluorouracil
6-HMA6-substituted hexamethylene amiloride
6-HMA6- N, N-hexamethylene
ADMEAbsorption, distribution, metabolism, and excretion
AKT signalingSerine–threonine kinase signaling
ATPAdenosine 5′-triphosphate
A549Hypotriploid alveolar basal epithelial cell lines
A2780Ovarian cancer cell line
BNC105PDisoduimphosphase ester derivative compound 8b
BxPC3Human pancreatic cancer cell lines
CB15-chlorobenzofuran-2-carboxamides
CNSCentral nervous system
CB1 modulatorCannabinoid receptor type 1 modulator
CA-A4Combretastatin A-4
CTC50cytotoxic concentration scores
Colo-205Colon cancer cell lines
EACErlich ascites carcinoma cells
HT-29Human colorectal adenocarcinoma cell lines
HCT116Human colorectal carcinoma cell lines
HIF pathwayHypoxia-inducible factor pathway
HUVECnormal endothelial cancer cell lines
HT-1080Fibrosarcoma cell lines
HL60Human acute leukemia cells
HeLahuman cervical cancer cells
HTSHigh-Throughput Screening
IC50half-maximal inhibitory concentration
KiDissociation constant
K562Human leukemia cell lines
MCF-7human breast cancer cells
MTT3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide
mTOR pathwaymammalian target of the rapamycin
mTORC1Mammalian target of rapamycin complex 1
MDA-MB-23Metastatic adenocarcinoma cell lines
MCF-10Ahuman mammary gland epithelial cell line
MRC5normal breast cancer cells
NANot Applicable
Panc-1Human pancreatic cancer cell lines
P53Tumor protein
PADCpancreatic ductal adenocarcinoma cell lines
PC-3Prostate cancer cell lines
PLK1 PBD inhibitorPolo-like kinase 1 Polo-Box Domain inhibitor
SARStructure–activity relationship
SRBsulforhodamine B
SQ20Bhead and neck cancer cell lines
SMMC-7721Hepatocellular carcinoma cell lines
SGC7901Colonic cancer cell lines
SrcNon-receptor tyrosine kinase protein
SW480Colon cancer cell lines
TNBCTriple-negative breast cancer cell lines
uPAurokinase-type plasminogen activator
uPARurokinase-type plasminogen activator receptor
ZAP-70 kinasesZeta-chain-associated protein kinase 70

References

  1. Chand, K.; Hiremathad, A.; Singh, M.; Santos, M.A.; Keri, R.S. A Review on Antioxidant Potential of Bioactive Heterocycle Benzofuran: Natural and Synthetic Derivatives. Pharmacol. Rep. 2017, 69, 281–295. [Google Scholar] [CrossRef]
  2. Radadiya, A.; Shah, A. Bioactive Benzofuran Derivatives: An Insight on Lead Developments, Radioligands and Advances of the Last Decade. Eur. J. Med. Chem. 2015, 97, 356–376. [Google Scholar] [CrossRef] [PubMed]
  3. Proksch, P.; Rodriguez, E. Chromenes and Benzofurans of the Asteraceae, Their Chemistry and Biological Significance. Phytochemistry 1983, 22, 2335–2348. [Google Scholar] [CrossRef]
  4. Heravi, M.M.; Zadsirjan, V.; Hamidi, H.; Tabar Amiri, P.H. Total Synthesis of Natural Products Containing Benzofuran Rings. RSC Adv. 2017, 7, 24470–24521. [Google Scholar] [CrossRef] [Green Version]
  5. Collin, G.; Höke, H. Benzofurans. In Ullmann’s Encyclopedia of Industrial Chemistry; Wiley: Hoboken, NJ, USA, 2007. [Google Scholar] [CrossRef]
  6. Jung, J.W.; Park, J.H.; Seo, K.H.; Oh, E.J.; Lee, D.Y.; Lim, D.W.; Han, D.; Song, M.C.; Baek, N.I. New Hydroxy Fatty Acid from the Root Bark of Morus alba L. J. Korean Soc. Appl. Biol. Chem. 2015, 58, 541–543. [Google Scholar] [CrossRef]
  7. Modell, A.E.; Blosser, S.L.; Arora, P.S. Systematic Targeting of Protein–Protein Interactions. Trends Pharmacol. Sci. 2016, 37, 702–713. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  8. Xu, Z.; Zhao, S.; Lv, Z.; Feng, L.; Wang, Y.; Zhang, F.; Bai, L.; Deng, J. Benzofuran Derivatives and Their Anti-Tubercular, Anti-Bacterial Activities. Eur. J. Med. Chem. 2019, 162, 266–276. [Google Scholar] [CrossRef] [PubMed]
  9. Nevagi, R.J.; Dighe, S.N.; Dighe, S.N. Biological and Medicinal Significance of Benzofuran. Eur. J. Med. Chem. 2015, 97, 561–581. [Google Scholar] [CrossRef]
  10. Hiremathad, A.; Patil, M.R.; Chethana, K.R.; Chand, K.; Santos, M.A.; Keri, R.S. Benzofuran: An Emerging Scaffold for Antimicrobial Agents. RSC Adv. 2015, 5, 96809–96828. [Google Scholar] [CrossRef]
  11. Zhong, M.; Peng, E.; Huang, N.; Huang, Q.; Huq, A.; Lau, M.; Colonno, R.; Li, L. Discovery of Novel Potent HCV NS5B Polymerase Non-Nucleoside Inhibitors Bearing a Fused Benzofuran Scaffold. Bioorg. Med. Chem. Lett. 2018, 28, 963–968. [Google Scholar] [CrossRef]
  12. Goyal, D.; Kaur, A.; Goyal, B. Benzofuran and Indole: Promising Scaffolds for Drug Development in Alzheimer’s Disease. ChemMedChem 2018, 13, 1275–1299. [Google Scholar] [CrossRef] [PubMed]
  13. Subair, T.I.; Soremekun, O.S.; Olotu, F.A.; Soliman, M.E.S. Therapeutic Path to Double Knockout: Investigating the Selective Dual-Inhibitory Mechanisms of Adenosine Receptors A1 and A2 by a Novel Methoxy-Substituted Benzofuran Derivative in the Treatment of Parkinson’s Disease. Cell Biochem. Biophys. 2021, 79, 25–36. [Google Scholar] [CrossRef] [PubMed]
  14. Wakabayashi, T.; Tokunaga, N.; Tokumaru, K.; Ohra, T.; Koyama, N.; Hayashi, S.; Yamada, R.; Shirasaki, M.; Inui, Y.; Tsukamoto, T. Discovery of Benzofuran Derivatives That Collaborate with Insulin-Like Growth Factor 1 (IGF-1) to Promote Neuroprotection. J. Med. Chem. 2016, 59, 5109–5114. [Google Scholar] [CrossRef]
  15. Sashidhara, K.V.; Modukuri, R.K.; Sonkar, R.; Rao, K.B.; Bhatia, G. Hybrid Benzofuran-Bisindole Derivatives: New Prototypes with Promising Anti-Hyperlipidemic Activities. Eur. J. Med. Chem. 2013, 68, 38–46. [Google Scholar] [CrossRef] [PubMed]
  16. Khalifa, N.M.; Srour, A.M.; El-Karim, S.S.A.; Saleh, D.O.; Al-Omar, M.A. Synthesis and 2D-QSAR Study of Active Benzofuran-Based Vasodilators. Molecules 2017, 22, 1820. [Google Scholar] [CrossRef] [Green Version]
  17. Dawood, K.M. An Update on Benzofuran Inhibitors: A Patent Review. Expert Opin. Ther. Pat. 2019, 29, 841–870. [Google Scholar] [CrossRef]
  18. Miao, Y.H.; Hu, Y.H.; Yang, J.; Liu, T.; Sun, J.; Wang, X.J. Natural Source, Bioactivity and Synthesis of Benzofuran Derivatives. RSC Adv. 2019, 9, 27510–27540. [Google Scholar] [CrossRef] [Green Version]
  19. Pucci, C.; Martinelli, C.; Ciofani, G. Innovative Approaches for Cancer Treatment: Current Perspectives and New Challenges. Ecancermedicalscience 2019, 13, 961. [Google Scholar] [CrossRef]
  20. Ferlay, J.; Ervik, M.; Lam, F.; Colombet, M.; Mery, L.; Piñeros, M.; Znaor, A.; Soerjomataram, I.; Bray, F. Global Cancer Observatory: Cancer Today. Available online: https://gco.iarc.fr/today (accessed on 11 December 2021).
  21. Martins, P.; Jesus, J.; Santos, S.; Raposo, L.R.; Roma-Rodrigues, C.; Baptista, P.V.; Fernandes, A.R. Heterocyclic Anticancer Compounds: Recent Advances and the Paradigm Shift towards the Use of Nanomedicine’s Tool Box. Molecules 2015, 20, 16852–16891. [Google Scholar] [CrossRef]
  22. Khodarahmi, G.; Asadi, P.; Hassanzadeh, F.; Khodarahmi, E. Benzofuran as a Promising Scaffold for the Synthesis of Antimicrobial and Antibreast Cancer Agents: A Review. J. Res. Med. Sci. 2015, 20, 1094–1104. [Google Scholar] [CrossRef]
  23. Gao, H.; Zhang, X.; Pu, X.J.; Zheng, X.; Liu, B.; Rao, G.X.; Wan, C.P.; Mao, Z.W. 2-Benzoylbenzofuran Derivatives Possessing Piperazine Linker as Anticancer Agents. Bioorg. Med. Chem. Lett. 2019, 29, 806–810. [Google Scholar] [CrossRef] [PubMed]
  24. Negalurmath, V.S.; Boda, S.K.; Kotresh, O.; Anantha Lakshmi, P.V.; Basanagouda, M. Benzofuran-Oxadiazole Hybrids: Design, Synthesis, Antitubercular Activity and Molecular Docking Studies. Chem. Data Collect. 2019, 19, 100178. [Google Scholar] [CrossRef]
  25. Li, W.; Yang, Z.H.; Hu, A.X.; Yan, X.W.; Ding, N.; Ye, J. Design, Synthesis, and Antitumor Activity of (E,Z)-1-(Dihydrobenzofuran-5-Yl)-3-Phenyl-2-(1,2,4-Triazol-1-Yl)-2-Propen-1-Ones. Chem. Biol. Drug Des. 2015, 86, 1339–1350. [Google Scholar] [CrossRef] [PubMed]
  26. Jin, L.P.; Xie, Q.; Huang, E.F.; Wang, L.; Zhang, B.Q.; Hu, J.S.; Wan, D.C.C.; Jin, Z.; Hu, C. Design, Synthesis, and Biological Activity of a Novel Series of Benzofuran Derivatives against Oestrogen Receptor-Dependent Breast Cancer Cell Lines. Bioorg. Chem. 2020, 95, 103566. [Google Scholar] [CrossRef] [PubMed]
  27. Lu, B.; Shen, X.; Zhang, L.; Liu, D.; Zhang, C.; Cao, J.; Shen, R.; Zhang, J.; Wang, D.; Wan, H.; et al. Discovery of EBI-2511: A Highly Potent and Orally Active EZH2 Inhibitor for the Treatment of Non-Hodgkin’s Lymphoma. ACS Med. Chem. Lett. 2018, 9, 98–102. [Google Scholar] [CrossRef]
  28. Krawiecka, M.; Kuran, B.; Kossakowski, J.; Cieslak, M.; Kazmierczak- Baranska, J.; Krolewska, K.; Nawrot, B. Synthesis and Cytotoxic Properties of Halogen and Aryl-/Heteroarylpiperazinyl Derivatives of Benzofurans. Anticancer Agents Med. Chem. 2014, 15, 115–121. [Google Scholar] [CrossRef]
  29. Amin, K.M.; Syam, Y.M.; Anwar, M.M.; Ali, H.I.; Abdel-Ghani, T.M.; Serry, A.M. Synthesis and Molecular Docking Study of New Benzofuran and Furo[3,2-g]Chromone-Based Cytotoxic Agents against Breast Cancer and P38α MAP Kinase Inhibitors. Bioorg. Chem. 2018, 76, 487–500. [Google Scholar] [CrossRef]
  30. Kang, T.S.; Wang, W.; Zhong, H.J.; Dong, Z.Z.; Huang, Q.; Mok, S.W.F.; Leung, C.H.; Wong, V.K.W.; Ma, D.L. An Anti-Prostate Cancer Benzofuran-Conjugated Iridium(III) Complex as a Dual Inhibitor of STAT3 and NF-ΚB. Cancer Lett. 2017, 396, 76–84. [Google Scholar] [CrossRef]
  31. Ford, M.C.; Ho, P.S. Computational Tools To Model Halogen Bonds in Medicinal Chemistry. J. Med. Chem. 2015, 59, 1655–1670. [Google Scholar] [CrossRef]
  32. Wilcken, R.; Zimmermann, M.O.; Lange, A.; Joerger, A.C.; Boeckler, F.M. Principles and Applications of Halogen Bonding in Medicinal Chemistry and Chemical Biology. J. Med. Chem. 2013, 56, 1363–1388. [Google Scholar] [CrossRef]
  33. Abdelfatah, S.; Berg, A.; Huang, Q.; Yang, L.J.; Hamdoun, S.; Klinger, A.; Greten, H.J.; Fleischer, E.; Berg, T.; Wong, V.K.W.; et al. MCC1019, a Selective Inhibitor of the Polo-Box Domain of Polo-like Kinase 1 as Novel, Potent Anticancer Candidate. Acta Pharm. Sin. B 2019, 9, 1021–1034. [Google Scholar] [CrossRef]
  34. Napiórkowska, M.; Cieślak, M.; Kaźmierczak-Barańska, J.; Królewska-Golińska, K.; Nawrot, B. Synthesis of New Derivatives of Benzofuran as Potential Anticancer Agents. Molecules 2019, 24, 1529. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Othman, D.I.; Abdelal, A.M.M.; El-Sayed, M.A.; El Bialy, S.A.A. Novel Benzofuran Derivatives: Synthesis and Antitumor Activity. Heterocycl. Commun. 2013, 19, 29–35. [Google Scholar] [CrossRef]
  36. Wan, W.C.; Chen, W.; Liu, L.X.; Li, Y.; Yang, L.J.; Deng, X.Y.; Zhang, H.B.; Yang, X.D. Synthesis and Cytotoxic Activity of Novel Hybrid Compounds between 2-Alkylbenzofuran and Imidazole. Med. Chem. Res. 2014, 23, 1599–1611. [Google Scholar] [CrossRef]
  37. Yang, X.D.; Wan, W.C.; Deng, X.Y.; Li, Y.; Yang, L.J.; Li, L.; Zhang, H.B. Design, Synthesis and Cytotoxic Activities of Novel Hybrid Compounds between 2-Phenylbenzofuran and Imidazole. Bioorg. Med. Chem. Lett. 2012, 22, 2726–2729. [Google Scholar] [CrossRef] [PubMed]
  38. Chen, Y.; Law, P.-Y.; Loh, H. Inhibition of PI3K/Akt Signaling: An Emerging Paradigm for Targeted Cancer Therapy. Curr. Med. Chem. Agents 2005, 5, 575–589. [Google Scholar] [CrossRef] [PubMed]
  39. Choi, M.; Jo, H.; Park, H.J.; Sateesh Kumar, A.; Lee, J.; Yun, J.; Kim, Y.; Han, S.B.; Jung, J.K.; Cho, J.; et al. Design, Synthesis, and Biological Evaluation of Benzofuran- and 2,3-Dihydrobenzofuran-2-Carboxylic Acid N-(Substituted)Phenylamide Derivatives as Anticancer Agents and Inhibitors of NF-ΚB. Bioorg. Med. Chem. Lett. 2015, 25, 2545–2549. [Google Scholar] [CrossRef] [PubMed]
  40. Mao, Z.W.; Zheng, X.; Lin, Y.P.; Hu, C.Y.; Wang, X.L.; Wan, C.P.; Rao, G.X. Design, Synthesis and Anticancer Activity of Novel Hybrid Compounds between Benzofuran and N-Aryl Piperazine. Bioorg. Med. Chem. Lett. 2016, 26, 3421–3424. [Google Scholar] [CrossRef]
  41. Wang, F.; Feng, K.R.; Zhao, J.Y.; Zhang, J.W.; Shi, X.W.; Zhou, J.; Gao, D.; Lin, G.Q.; Tian, P. Identification of Novel STAT3 Inhibitors Bearing 2-Acetyl-7-Phenylamino Benzofuran Scaffold for Antitumour Study. Bioorg. Med. Chem. 2020, 28, 115822. [Google Scholar] [CrossRef]
  42. Youssif, B.G.M.; Mohamed, A.M.; Osman, E.E.A.; Abou-Ghadir, O.F.; Elnaggar, D.H.; Abdelrahman, M.H.; Treamblu, L.; Gomaa, H.A.M. 5-Chlorobenzofuran-2-Carboxamides: From Allosteric CB1 Modulators to Potential Apoptotic Antitumor Agents. Eur. J. Med. Chem. 2019, 177, 1–11. [Google Scholar] [CrossRef]
  43. Riss, T.L.; Moravec, R.A.; Niles, A.L.; Duellman, S.; Benink, H.A.; Worzella, T.J.; Minor, L. Cell Viability Assays; Eli Lilly & Company and the National Center for Advancing Translational Sciences: Bethesda, MD, USA, 2004. [Google Scholar]
  44. Abdelhafez, O.M.; Amin, K.M.; Ali, H.I.; Abdalla, M.M.; Ahmed, E.Y. Design, Synthesis and Anticancer Activity of Benzofuran Derivatives Targeting VEGFR-2 Tyrosine Kinase. RSC Adv. 2014, 4, 11569–11579. [Google Scholar] [CrossRef]
  45. Adem, F.A.; Kuete, V.; Mbaveng, A.T.; Heydenreich, M.; Ndakala, A.; Irungu, B.; Efferth, T.; Yenesew, A. Cytotoxic Benzylbenzofuran Derivatives from Dorstenia Kameruniana. Fitoterapia 2018, 128, 26–30. [Google Scholar] [CrossRef]
  46. Coşkun, D.; Tekin, S.; Sandal, S.; Coşkun, M.F. Synthesis, Characterization, and Anticancer Activity of New Benzofuran Substituted Chalcones. J. Chem. 2016, 2016, 7678486. [Google Scholar] [CrossRef] [Green Version]
  47. Asadi, P.; Khodarahmi, G.; Jahanian-Najafabadi, A.; Saghaie, L.; Hassanzadeh, F. Biologically Active Heterocyclic Hybrids Based on Quinazolinone, Benzofuran and Imidazolium Moieties: Synthesis, Characterization, Cytotoxic and Antibacterial Evaluation. Chem. Biodivers. 2017, 14. [Google Scholar] [CrossRef] [PubMed]
  48. Etebari, M.; Khodarahmi, G.A.; Jafarian-Dehkordi, A.; Nokhodian, Z. Genotoxic Effects of Some L-[(Benzofuran-2-Yl)-Phenylmethyl]-Imidazoles on MCF-7 Cell Line. Res. Pharm. Sci. 2012, 7, 189–195. [Google Scholar]
  49. Irfan, A.; Faiz, S.; Rasul, A.; Zafar, R.; Zahoor, A.F.; Kotwica-Mojzych, K.; Mojzych, M. Exploring the Synergistic Anticancer Potential of Benzofuran–Oxadiazoles and Triazoles: Improved Ultrasound-and Microwave-Assisted Synthesis, Molecular Docking, Hemolytic, Thrombolytic and Anticancer Evaluation of Furan-Based Molecules. Molecules 2022, 27, 1023. [Google Scholar] [CrossRef]
  50. Jia, Y.; Li, M.; Cao, Y.; Feng, W.; Li, X.; Xue, W.; Shi, H. Discovery of a Novel Benzenesulfonamide Analogue That Inhibits Proliferation and Metastasis against Ovarian Cancer OVCAR-8 Cells. Drug Des. Devel. Ther. 2020, 14, 207–216. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  51. Yang, Y.R.; Wei, J.L.; Mo, X.F.; Yuan, Z.W.; Wang, J.L.; Zhang, C.; Xie, Y.Y.; You, Q.D.; Sun, H.P. Discovery and Optimization of New Benzofuran Derivatives against P53-Independent Malignant Cancer Cells through Inhibition of HIF-1 Pathway. Bioorg. Med. Chem. Lett. 2016, 26, 2713–2718. [Google Scholar] [CrossRef]
  52. Semenza, G.L. Defining the Role of Hypoxia-Inducible Factor 1 in Cancer Biology and Therapeutics. Oncogene 2010, 29, 625–634. [Google Scholar] [CrossRef] [Green Version]
  53. Nakamura, H.; Yasui, Y.; Maruyama, M.; Minegishi, H.; Ban, H.S.; Sato, S. Development of Hypoxia-Inducible Factor (HIF)-1α Inhibitors: Effect of Ortho-Carborane Substituents on HIF Transcriptional Activity under Hypoxia. Bioorg. Med. Chem. Lett. 2013, 23, 806–810. [Google Scholar] [CrossRef]
  54. Mahmood, N.; Mihalcioiu, C.; Rabbani, S.A. Multifaceted Role of the Urokinase-Type Plasminogen Activator (UPA) and Its Receptor (UPAR): Diagnostic, Prognostic, and Therapeutic Applications. Front. Oncol. 2018, 8, 24. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Ulisse, S.; Baldini, E.; Sorrenti, S.; D’Armiento, M. The Urokinase Plasminogen Activator System: A Target for Anti-Cancer Therapy. Curr. Cancer Drug Targets 2009, 9, 32–71. [Google Scholar] [CrossRef]
  56. Croucher, D.R.; Saunders, D.N.; Lobov, S.; Ranson, M. Revisiting the Biological Roles of PAI2 (SERPINB2) in Cancer. Nat. Rev. Cancer 2008, 8, 535–545. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Matthews, H.; Ranson, M.; Tyndall, J.D.A.; Kelso, M.J. Synthesis and Preliminary Evaluation of Amiloride Analogs as Inhibitors of the Urokinase-Type Plasminogen Activator (UPA). Bioorg. Med. Chem. Lett. 2011, 21, 6760–6766. [Google Scholar] [CrossRef] [Green Version]
  58. Song, C.W.; Lyons, J.C.; Makepeace, C.M.; Griffin, R.J.; Cragoe, E.J. Effect’s of Hma, an Analog of Amiloride, on the Thermosensitivity of Tumors in Vivo. Int. J. Radiat. Oncol. Biol. Phys. 1994, 30, 133–139. [Google Scholar] [CrossRef]
  59. Luo, J.; Tannock, I.F. Inhibition of the Regulation of Intracellular PH: Potential of 5-(N,N-Hexamethylene) Amiloride in Tumour-Selective Therapy. Br. J. Cancer 1994, 70, 617–624. [Google Scholar] [CrossRef] [Green Version]
  60. Chemler, S.R.; Trauner, D.; Danishefsky, S.J. The B -Alkyl Suzuki-Miyaura Cross-Coupling Reaction: A Versatile C-C Bond-Forming Tool REVIEWS The B -Alkyl Suzuki-Miyaura Cross-Coupling Reaction: Development, Mechanistic Study, and Applications in Natural Product Synthesis. Angew. Chem. Int. Ed. 2001, 40, 4544–4568. [Google Scholar] [CrossRef]
  61. Buckley, B.J.; Aboelela, A.; Minaei, E.; Jiang, L.X.; Xu, Z.; Ali, U.; Fildes, K.; Cheung, C.Y.; Cook, S.M.; Johnson, D.C.; et al. 6-Substituted Hexamethylene Amiloride (HMA) Derivatives as Potent and Selective Inhibitors of the Human Urokinase Plasminogen Activator for Use in Cancer. J. Med. Chem. 2018, 61, 8299–8320. [Google Scholar] [CrossRef]
  62. Gao, Y.; Ma, C.; Feng, X.; Liu, Y.; Haimiti, X. BF12, a Novel Benzofuran, Exhibits Antitumor Activity by Inhibiting Microtubules and the PI3K/Akt/MTOR Signaling Pathway in Human Cervical Cancer Cells. Chem. Biodivers. 2020, 17. [Google Scholar] [CrossRef]
  63. Soleimani, A.; Asadi, J.; Rostami-Charati, F.; Gharaei, R. High Cytotoxicity and Apoptotic Effects of Natural Bioactive Benzofuran Derivative on the MCF-7 Breast Cancer Cell Line. Comb. Chem. High Throughput Screen 2015, 18, 505–513. [Google Scholar] [CrossRef]
  64. Mishra, S. Quinazolinone and Quinazoline Derivatives: Synthesis and Biological Application; Intechopen: London, UK, 2019. [Google Scholar] [CrossRef]
  65. Radwan, A.A.; Alanazi, F.K. Biological Activity of Quinazolinones; Intechopen: London, UK, 2020. [Google Scholar] [CrossRef] [Green Version]
  66. Jafari, E.; Khajouei, M.R.; Hassanzadeh, F.; Hakimelahi, G.H.; Khodarahmi, G.A. Quinazolinone and Quinazoline Derivatives: Recent Structures with Potent Antimicrobial and Cytotoxic Activities. Res. Pharm. Sci. 2016, 11, 1–14. [Google Scholar]
  67. Kuttan, R.; Bhanumathy, P.; Nirmala, K.; George, M.C. Potential Anticancer Activity of Turmeric (Curcuma Longa). Cancer Lett. 1985, 29, 197–202. [Google Scholar] [CrossRef]
  68. Kumar, B.R.P.; Sharma, G.K.; Srinath, S.; Noor, M.; Suresh, B.; Srinivasa, B.R. Microwave-Assisted, Solvent-Free, Parallel Syntheses and Elucidation of Reaction Mechanism for the Formation of Some Novel Tetraaryl Imidazoles of Biological Interest. J. Heterocycl. Chem. 2009, 46, 278–284. [Google Scholar] [CrossRef]
  69. Sharma, G.K.; Pathak, D. Microwave-Assisted, Solvent-Free and Parallel Synthesis of Some Novel Substituted Imidazoles of Biological Interest. Chem. Pharm. Bull. 2010, 58, 375–380. [Google Scholar] [CrossRef] [Green Version]
  70. Shankar, B.; Jalapathi, P.; Saikrishna, B.; Perugu, S.; Manga, V. Synthesis, Anti-Microbial Activity, Cytotoxicity of Some Novel Substituted (5-(3-(1H-Benzo[d]Imidazol-2-Yl)-4-Hydroxybenzyl)Benzofuran-2-Yl)(Phenyl)Methanone Analogs. Chem. Cent. J. 2018, 12, 1. [Google Scholar] [CrossRef] [Green Version]
  71. Kumar Saxena, R.; Kumar, P.; Varshney, S. Synthesis and Biological Evaluation of Newer Benzofuran Derivatives as Potential Anticancer and Antithelmintic Agents. World J. Pharm. Res. 2015, 3, 821. [Google Scholar]
  72. Khanam, H.; Shamsuzzaman. Bioactive Benzofuran Derivatives: A Review. Eur. J. Med. Chem. 2015, 97, 483–504. [Google Scholar] [CrossRef]
  73. Nam, N.-H. Combretastatin A-4 Analogues as Antimitotic Antitumor Agents. Curr. Med. Chem. 2005, 10, 1697–1722. [Google Scholar] [CrossRef]
  74. Flynn, B.L.; Gill, G.S.; Grobelny, D.W.; Chaplin, J.H.; Paul, D.; Leske, A.F.; Lavranos, T.C.; Chalmers, D.K.; Charman, S.A.; Kostewicz, E.; et al. Discovery of 7-Hydroxy-6-Methoxy-2-Methyl-3-(3,4,5-Trimethoxybenzoyl)Benzo[ b ]Furan (BNC105), a Tubulin Polymerization Inhibitor with Potent Antiproliferative and Tumor Vascular Disrupting Properties. J. Med. Chem. 2011, 54, 6014–6027. [Google Scholar] [CrossRef] [Green Version]
  75. Vignot, S.; Faivre, S.; Aguirre, D.; Raymond, E. MTOR-Targeted Therapy of Cancer with Rapamycin Derivatives. Ann. Oncol. 2005, 16, 525–537. [Google Scholar] [CrossRef]
  76. Albert, S.; Serova, M.; Dreyer, C.; Sablin, M.P.; Faivre, S.; Raymond, E. New Inhibitors of the Mammalian Target of Rapamycin Signaling Pathway for Cancer. Expert Opin. Investig. Drugs 2010, 19, 919–930. [Google Scholar] [CrossRef] [PubMed]
  77. Faivre, S.; Kroemer, G.; Raymond, E. Current Development of MTOR Inhibitors as Anticancer Agents. Nat. Rev. Drug Discov. 2006, 5, 671–688. [Google Scholar] [CrossRef] [PubMed]
  78. Salomé, C.; Narbonne, V.; Ribeiro, N.; Thuaud, F.; Serova, M.; De Gramont, A.; Faivre, S.; Raymond, E.; Désaubry, L. Benzofuran Derivatives as a Novel Class of Inhibitors of MTOR Signaling. Eur. J. Med. Chem. 2014, 74, 41–49. [Google Scholar] [CrossRef] [PubMed]
  79. Salomé, C.; Ribeiro, N.; Chavagnan, T.; Thuaud, F.; Serova, M.; De Gramont, A.; Faivre, S.; Raymond, E.; Désaubry, L. Benzofuran Derivatives as Anticancer Inhibitors of MTOR Signaling. Eur. J. Med. Chem. 2014, 81, 181–191. [Google Scholar] [CrossRef]
  80. Garrido-Laguna, I.; Hidalgo, M. Pancreatic Cancer: From State-of-the-Art Treatments to Promising Novel Therapies. Nat. Rev. Clin. Oncol. 2015, 12, 319–334. [Google Scholar] [CrossRef]
  81. Spivak-Kroizman, T.R.; Hostetter, G.; Posner, R.; Aziz, M.; Hu, C.; Demeure, M.J.; Von Hoff, D.; Hingorani, S.R.; Palculict, T.B.; Izzo, J.; et al. Hypoxia Triggers Hedgehog-Mediated Tumor-Stromal Interactions in Pancreatic Cancer. Cancer Res. 2013, 73, 3235–3247. [Google Scholar] [CrossRef] [Green Version]
  82. Xu, X.-L.; Yang, Y.-R.; Mo, X.-F.; Wei, J.-L.; Zhang, X.-J.; You, Q.-D. Design, Synthesis, and Evaluation of Benzofuran Derivatives as Novel Anti-Pancreatic Carcinoma Agents via Interfering the Hypoxia Environment by Targeting HIF-1α Pathway. Eur. J. Med. Chem. 2017, 137, 45–62. [Google Scholar] [CrossRef]
  83. Naik, R.; Harmalkar, D.S.; Xu, X.; Jang, K.; Lee, K. Bioactive Benzofuran Derivatives: Moracins A-Z in Medicinal Chemistry. Eur. J. Med. Chem. 2015, 90, 379–393. [Google Scholar] [CrossRef] [PubMed]
  84. Ma, Y.; Zheng, X.; Gao, H.; Wan, C.; Rao, G.; Mao, Z. Design, Synthesis, and Biological Evaluation of Novel Benzofuran Derivatives Bearing N-Aryl Piperazine Moiety. Molecules 2016, 21, 1684. [Google Scholar] [CrossRef]
  85. Huang, X.X.; Zhou, C.C.; Li, L.Z.; Peng, Y.; Lou, L.L.; Liu, S.; Li, D.M.; Ikejima, T.; Song, S.J. Cytotoxic and Antioxidant Dihydrobenzofuran Neolignans from the Seeds of Crataegus Pinnatifida. Fitoterapia 2013, 91, 217–223. [Google Scholar] [CrossRef]
  86. Chen, W.; Deng, X.Y.; Li, Y.; Yang, L.J.; Wan, W.C.; Wang, X.Q.; Zhang, H.B.; Yang, X.D. Synthesis and Cytotoxic Activities of Novel Hybrid 2-Phenyl-3- Alkylbenzofuran and Imidazole/Triazole Compounds. Bioorg. Med. Chem. Lett. 2013, 23, 4297–4302. [Google Scholar] [CrossRef] [PubMed]
  87. Abd El-Karim, S.S.; Anwar, M.M.; Mohamed, N.A.; Nasr, T.; Elseginy, S.A. Design, Synthesis, Biological Evaluation and Molecular Docking Studies of Novel Benzofuran-Pyrazole Derivatives as Anticancer Agents. Bioorg. Chem. 2015, 63, 1–12. [Google Scholar] [CrossRef]
  88. Murthy, I.S.; Sireesha, R.; Deepti, K.; Srinivasa Rao, P.; Ramesh Raju, R. Design, Synthesis and Biological Evaluation of Sulphonamide Derivatives of Benzofuran-Imidazopyridines as Anticancer Agents. Chem. Data Collect. 2021, 31, 100608. [Google Scholar] [CrossRef]
  89. Zwergel, C.; Valente, S.; Salvato, A.; Xu, Z.; Talhi, O.; Mai, A.; Silva, A.; Altucci, L.; Kirsch, G. Novel Benzofuran-Chromone and -Coumarin Derivatives: Synthesis and Biological Activity in K562 Human Leukemia Cells. Med. Chem. Commun. 2013, 4, 1571–1579. [Google Scholar] [CrossRef]
  90. Coskun, D.; Erkisa, M.; Ulukaya, E.; Coskun, M.F.; Ari, F. Novel 1-(7-Ethoxy-1-Benzofuran-2-Yl) Substituted Chalcone Derivatives: Synthesis, Characterization and Anticancer Activity. Eur. J. Med. Chem. 2017, 136, 212–222. [Google Scholar] [CrossRef] [PubMed]
  91. Al-Ghorbani, M.; Begum, B.A.; Mamatha, S.V.; Ara Khanum, S. Piperazine and Morpholine: Synthetic Preview and Pharmaceutical Applications. J. Chem. Pharm. Res. 2015, 7, 281–301. Available online: www.jocpr.com (accessed on 17 November 2021). [CrossRef]
  92. Rathi, A.K.; Syed, R.; Shin, H.S.; Patel, R.V. Piperazine Derivatives for Therapeutic Use: A Patent Review (2010-Present). Expert Opin. Ther. Pat. 2016, 26, 777–797. [Google Scholar] [CrossRef]
  93. Cuca, L.E.; David Coy, E.; Alarcón, M.A.; Fernández, A.; Aristizábal, F.A. Cytotoxic Effect of Some Natural Compounds Isolated from Lauraceae Plants and Synthetic Derivatives. Biomédica 2011, 31, 335–378. [Google Scholar] [CrossRef] [Green Version]
  94. Jiang, Z.H.; Liu, Y.P.; Huang, Z.H.; Wang, T.T.; Feng, X.Y.; Yue, H.; Guo, W.; Fu, Y.H. Cytotoxic Dihydrobenzofuran Neolignans from Mappianthus Iodoies. Bioorg. Chem. 2017, 75, 260–264. [Google Scholar] [CrossRef]
  95. Mansoor, T.A.; Borralho, P.M.; Luo, X.; Mulhovo, S.; Rodrigues, C.M.P.; Ferreira, M.J.U. Apoptosis Inducing Activity of Benzophenanthridine-Type Alkaloids and 2-Arylbenzofuran Neolignans in HCT116 Colon Carcinoma Cells. Phytomedicine 2013, 20, 923–929. [Google Scholar] [CrossRef] [PubMed]
  96. Sivaraman, A.; Kim, J.S.; Harmalkar, D.S.; Min, K.H.; Park, J.W.; Choi, Y.; Kim, K.; Lee, K. Synthesis and Cytotoxicity Studies of Bioactive Benzofurans from Lavandula Agustifolia and Modified Synthesis of Ailanthoidol, Homoegonol, and Egonol. J. Nat. Prod. 2020, 83, 3354–3362. [Google Scholar] [CrossRef]
  97. Zhou, Z.B.; Luo, J.G.; Pan, K.; Shan, S.M.; Zhang, W.; Kong, L.Y. Bioactive Benzofuran Neolignans from Aristolochia Fordiana. Planta Med. 2013, 79, 1730–1735. [Google Scholar] [CrossRef]
  98. Zálešák, F.; Bon, D.J.Y.D.; Pospíšil, J. Lignans and Neolignans: Plant Secondary Metabolites as a Reservoir of Biologically Active Substances. Pharmacol. Res. 2019, 146, 104284. [Google Scholar] [CrossRef] [PubMed]
  99. Sharma, P.; Larosa, C.; Antwi, J.; Govindarajan, R.; Werbovetz, K.A. Imidazoles as Potential Anticancer Agents: An Update on Recent Studies. Molecules 2021, 26, 4213. [Google Scholar] [CrossRef] [PubMed]
  100. Hranjec, M.; Sović, I.; Ratkaj, I.; Pavlović, G.; Ilić, N.; Valjalo, L.; Pavelić, K.; Kraljević Pavelić, S.; Karminski-Zamola, G. Antiproliferative Potency of Novel Benzofuran-2-Carboxamides on Tumour Cell Lines: Cell Death Mechanisms and Determination of Crystal Structure. Eur. J. Med. Chem. 2013, 59, 111–119. [Google Scholar] [CrossRef] [PubMed]
  101. Song, W.J.; Yang, X.D.; Zeng, X.H.; Xu, X.L.; Zhang, G.L.; Zhang, H.B. Synthesis and Cytotoxic Activities of Novel Hybrid Compounds of Imidazole Scaffold-Based 2-Substituted Benzofurans. RSC Adv. 2012, 2, 4612–4615. [Google Scholar] [CrossRef]
  102. Chen, W.; Yang, X.D.; Li, Y.; Yang, L.J.; Wang, X.Q.; Zhang, G.L.; Zhang, H.B. Design, Synthesis and Cytotoxic Activities of Novel Hybrid Compounds between Dihydrobenzofuran and Imidazole. Org. Biomol. Chem. 2011, 9, 4250–4255. [Google Scholar] [CrossRef]
  103. Ali, I.; Lone, M.N.; Aboul-Enein, H.Y. Imidazoles as Potential Anticancer Agents. Medchemcomm 2017, 8, 1742–1773. [Google Scholar] [CrossRef]
  104. Berger, D.M.; Dutia, M.; Birnberg, G.; Powell, D.; Boschelli, D.H.; Wang, Y.D.; Ravi, M.; Yaczko, D.; Golas, J.; Lucas, J.; et al. 4-Anilino-7,8-Dialkoxybenzo[g]Quinoline-3-Carbonitriles as Potent Src Kinase Inhibitors. J. Med. Chem. 2005, 48, 5909–5920. [Google Scholar] [CrossRef]
  105. Tsao, A.S.; He, D.; Saigal, B.; Liu, S.; Lee, J.J.; Bakkannagari, S.; Ordonez, N.G.; Waun, K.H.; Wistuba, I.; Johnson, F.M. Inhibition of C-Src Expression and Activation in Malignant Pleural Mesothelioma Tissues Leads to Apoptosis, Cell Cycle Arrest, and Decreased Migration and Invasion. Mol. Cancer Ther. 2007, 6, 1962–1972. [Google Scholar] [CrossRef] [Green Version]
  106. Summy, J.M.; Gallick, G.E. Src Family Kinases in Tumor Progression and Metastasis. Cancer Metastasis Rev. 2003, 22, 337–358. [Google Scholar] [CrossRef]
  107. Li, M.; Zhao, B.X. Progress of the Synthesis of Condensed Pyrazole Derivatives (from 2010 to Mid-2013). Eur. J. Med. Chem. 2014, 85, 311–340. [Google Scholar] [CrossRef] [PubMed]
  108. Bennani, F.E.; Doudach, L.; Cherrah, Y.; Ramli, Y.; Karrouchi, K.; Ansar, M.; Faouzi, M.E.A. Overview of Recent Developments of Pyrazole Derivatives as an Anticancer Agent in Different Cell Line. Bioorg. Chem. 2020, 97. [Google Scholar] [CrossRef] [PubMed]
  109. Patil, V.M.; Masand, N.; Verma, S.; Masand, V. Chromones: Privileged Scaffold in Anticancer Drug Discovery. Chem. Biol. Drug Des. 2021, 98, 943–953. [Google Scholar] [CrossRef] [PubMed]
  110. Van Meerloo, J.; Kaspers, G.J.L.; Cloos, J. Cell Sensitivity Assays: The MTT Assay. Methods Mol. Biol. 2011, 731, 237–245. [Google Scholar] [CrossRef]
  111. Alsayari, A.; Muhsinah, A.B.; Hassan, M.Z.; Ahsan, M.J.; Alshehri, J.A.; Begum, N. Aurone: A Biologically Attractive Scaffold as Anticancer Agent. Eur. J. Med. Chem. 2019, 166, 417–431. [Google Scholar] [CrossRef]
  112. Thakur, A.; Singla, R.; Jaitak, V. Coumarins as Anticancer Agents: A Review on Synthetic Strategies, Mechanism of Action and SAR Studies. Eur. J. Med. Chem. 2015, 101, 476–495. [Google Scholar] [CrossRef]
  113. Boumendjel, A. Aurones: A Subclass of Flavones with Promising Biological Potential. Curr. Med. Chem. 2003, 10, 2621–2630. [Google Scholar] [CrossRef]
  114. Kontogiorgis, C.; Detsi, A.; Hadjipavlou-Litina, D. Coumarin-Based Drugs: A Patent Review (2008-Present). Expert Opin. Ther. Pat. 2012, 22, 437–454. [Google Scholar] [CrossRef]
  115. Zwergel, C.; Gaascht, F.; Valente, S.; Diederich, M.; Bagrel, D.; Kirsch, G. Aurones: Interesting Natural and Synthetic Compounds with Emerging Biological Potential. Nat. Prod. Commun. 2012, 7, 389–394. [Google Scholar] [CrossRef] [Green Version]
  116. Zhuang, C.; Zhang, W.; Sheng, C.; Zhang, W.; Xing, C.; Miao, Z. Chalcone: A Privileged Structure in Medicinal Chemistry. Chem. Rev. 2017, 117, 7762–7810. [Google Scholar] [CrossRef] [PubMed]
  117. Zhou, B.; Xing, C. Diverse Molecular Targets for Chalcones with Varied Bioactivities. Med. Chem. 2015, 5, 388–404. [Google Scholar] [CrossRef] [PubMed]
  118. Karthikeyan, C.; Narayana Moorthy, N.S.H.; Ramasamy, S.; Vanam, U.; Manivannan, E.; Karunagaran, D.; Trivedi, P. Advances in Chalcones with Anticancer Activities. Recent Pat. Anticancer Drug Discov. 2015, 10, 97–115. [Google Scholar] [CrossRef] [PubMed]
  119. Kumar, V.; Kaur, K. Triazole and Oxadiazole Containing Natural Products: A Review. Nat. Prod. J. 2014, 4, 115–130. [Google Scholar] [CrossRef]
  120. Nayak, S.; Gaonkar, S.L.; Musad, E.A.; Dawsar, A.M.A. 1,3,4-Oxadiazole-Containing Hybrids as Potential Anticancer Agents: Recent Developments, Mechanism of Action and Structure-Activity Relationships. J. Saudi Chem. Soc. 2021, 25, 101284. [Google Scholar] [CrossRef]
  121. Xu, Z.; Zhao, S.J.; Liu, Y. 1,2,3-Triazole-Containing Hybrids as Potential Anticancer Agents: Current Developments, Action Mechanisms and Structure-Activity Relationships. Eur. J. Med. Chem. 2019, 183, 111700. [Google Scholar] [CrossRef]
  122. Alam, M.M. 1,2,3-Triazole Hybrids as Anticancer Agents: A Review. Arch. Pharm. 2022, 355, e2100158. [Google Scholar] [CrossRef]
  123. Pervaram, S.; Ashok, D.; Sarasija, M.; Reddy, C.V.R.; Sridhar, G. Synthesis and Anticancer Activity of 1,2,4-Oxadiazole Fused Benzofuran Derivatives. Russ. J. Gen. Chem. 2018, 88, 1219–1223. [Google Scholar] [CrossRef]
Cancers 14 02196 g001 550
Figure 1. Chemical structure of benzofuran.
Figure 1. Chemical structure of benzofuran.
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Figure 2. Chemical structure of halogenated derivatives of benzofuran 1–3.
Figure 2. Chemical structure of halogenated derivatives of benzofuran 1–3.
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Figure 3. Chemical structures of anticancer hybrid benzofuran 4–10.
Figure 3. Chemical structures of anticancer hybrid benzofuran 4–10.
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Figure 4. Chemical structures of anticancer hybrid benzofuran 11–20.
Figure 4. Chemical structures of anticancer hybrid benzofuran 11–20.
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Table
Table 1. In vitro inhibitory activities of halogenated derivatives of benzofuran against multiple cancer cell lines.
Table 1. In vitro inhibitory activities of halogenated derivatives of benzofuran against multiple cancer cell lines.
CompoundCell LineIC50, μMGI50, μMReference
1K5625ND[28]
HL600.1ND
2PLK1 PBD16.4ND[33]
3A-549ND1.8[42]
MCF-7ND0.7
Panc-1ND1.3
HT-29ND1.6
The definitions of all abbreviations are provided in a list at the end of the manuscript.
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Farhat, J.; Alzyoud, L.; Alwahsh, M.; Al-Omari, B. Structure–Activity Relationship of Benzofuran Derivatives with Potential Anticancer Activity. Cancers 2022, 14, 2196. https://doi.org/10.3390/cancers14092196

AMA Style

Farhat J, Alzyoud L, Alwahsh M, Al-Omari B. Structure–Activity Relationship of Benzofuran Derivatives with Potential Anticancer Activity. Cancers. 2022; 14(9):2196. https://doi.org/10.3390/cancers14092196

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Farhat, Joviana, Lara Alzyoud, Mohammad Alwahsh, and Basem Al-Omari. 2022. "Structure–Activity Relationship of Benzofuran Derivatives with Potential Anticancer Activity" Cancers 14, no. 9: 2196. https://doi.org/10.3390/cancers14092196

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