Document Type : Review Article
Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, Iraq
Coumarins having an aryl phenol linked to the 3,4-, 5,6-, 6,7-, or 7,8-binding sites are referred to as benzocoumarins. Efforts have been made in recent years to separate new configurations of benzocoumarin analogues with notable biological activities and to devise novel production procedures to create such agents with unique or even improved bioactivities. The separation and characterization of natural benzocoumarin compounds are briefly described in the first section of this study. The innovative synthetic approaches for the production of benzocoumarin-related compounds and also the documented total pathways to synthesize naturally occurring benzocoumarin derivatives are presented in the second portion. The third part contains a comprehensive summary of the attempts conducted to investigate the pharmacological activities of benzocoumarin related compounds, as well as the additional make-up, methods of production, and bioactivity assessment of therapeutically appropriate analogues. The authors’ aim is to provide an overview of benzocoumarins, including their natural sources, chemical synthetic methodologies, and bio-medicinal activities that have been investigated over the last few decades.
Coumarin derivatives are heterocycle compounds that have been linked to a variety of health benefits when used in pharmaceutical, diet, and cosmetic applications. They have a large scale of pharmacological bioactivities, which makes them useful in a variety of medical statements. Laser dyes and fluorescence are examples of their industrial utility [1–9]. As a result of the investigations concerning coumarins and coumarin-related chemicals, there have been a significant number of reviews released in many pharmaceutical sciences, including chemistry of medicinal and natural products, pharmacology, and the pharmaceutical industry [10–17].
Benzocoumarin derivatives are coumarin related compounds which have a phenyl group attached to the 3,4- (class A), 5,6- (class B), 6,7- (class C), or 7,8- (class D) binding sites of the coumarin structure as shown in Figure 1. Alternariol (BC5) and its methyl ether (BC6), which are mycotoxins produced by Alternaria fungus, are the most well-known members of benzocoumarin chemicals .
Figure 1: Benzocoumarin class types
Benzocoumarins have antifungal, antimicrobial, and anticancer properties which have been found, prompting medicinal chemistry investigations into benzocoumarins. Many intriguing pharmacological properties (e.g., antidyslipidemic, anti-tumor, antibacterial, and immunomodulating bioactivities) have been discovered as a consequence of the screening of numerous benzocoumarin derivatives in recent years. Benzocoumarins have been evolved into crucial “scaffolds” in the creation of new drugs. However, there has not been a thorough examination of these chemicals. As a result, benzocoumarins were studied in this review in terms of medicinal chemistry [3,6].
Benzocoumarins’ Natural Sources
Only 51 benzocoumarin from natural origin have been identified, despite the enormous number of natural coumarins documented. 3,4-Benzocoumarins belong to class A (BC1-BC30) are shown in Figure as well as their dimers (BC49-BC51) in Figure 3, which constitute the majority of these 51 benzocoumarins, owing to the numerous studies of the lichen mycobiont of Graphis scripta and the fungal endophyte Alternaria species [18–22]. In addition, many higher plants, such as Acacia fasciculifera , Eucomis autumnalis , Itoa Orientalis , Eucalyptus Exserta , Herpetospermum Caudigerum , Lysimachia Clethroides , Tamarix Nilotica , Phyllanthus Niruri  are also been observed to have similar structures.
On the other hand, eight 5,6-benzocoumarins (BC31-BC38), as displayed in Figure 4, from class B were discovered. The majority of these compounds have been extracted from the Juncus acutus species. The 7,8-benzocoumarins, classified as class D (BC39-BC48) and displayed in Figure , make up the majority of the remaining natural benzocoumarins . Unfortunately, no natural sources of 6,7-benzocoumarin (class C) have been discovered. Information about the names of isolated natural benzocoumarins and their sources are summarized in Table 1.
Benzocoumarin’s Derivatives Synthesis
Traditional Approaches to Synthesize Benzocoumarins
Benzocoumarins are members of the coumarin family, and a number of benzocoumarin related compounds were synthesized by traditional coumarin’s production techniques, like Pechmann, Wittig, Perkin reactions, and other [46–48]. By employing the ortho- disseminated naphthalene derivatives as initial material for the generation of benzocoumarins [49–53].
In 2020, Ansary and his colleague addressed a variety of one-pot benzocoumarin’s derivatives synthesis techniques, as well as their benefits and drawbacks when compared to the other techniques. They concluded that the Kostanecki reaction procedure provides a significant enhancement in benzocoumarin's production reaction environment, as well as the benefit of its synthetic capabilities with a wide structural variety .
Novel Approaches to Synthesize Benzocoumarins
Organic chemists have been paying attention to the growing importance of benzocoumarins in the latest years. As a result, a number of extremely good synthetic approaches for these substances have been developed, some of which would be discussed below in detail.
Figure 6: Chemical structures of the benzocoumarins symbolized as BC52a-n
Cheng and his colleagues proposed a relatively convenient one-pot technique for the synthesis of benzocoumarin derivatives in 2001, utilizing new Ni-catalyzed cyclization of propiolates with tricyclic alkenes . In reasonable yields, this reaction can produce benzocoumarin derivatives, symbolized as BC52a-n and is depicted in Figure , with impressive stereoselectivity and regioselectivity.
Cheng and colleagues then refined the previously stated process by incorporating a novel Ni-catalysed cyclization of oxabicyclic alkenes with either 2-iodobenzoate or β-iodo-(Z)-propenoates to obtain annulated coumarins, symbolized here as BC53a-l and displayed in Figure 7, in excellent yield. Under the modest reaction conditions, this technique provided a facile and efficient one-pot production of a range of complex coumarin structures as BC53a-l .
Figure 7: Chemical backbones of the benzocoumarin symbolized as BC53a-i (BC53j=BC52a,BC53k=BC52j,BC53l=BC52n)
Nevertheless, the precise pathway of this synthesis is not perfectly understood, and the process for benzocoumarin generation is only explored in light of the previous findings and known Ni chemistry. Hon and colleagues in 2009 devised a novel and practical approach to produce benzocoumarin structures, symbolized as BC55a-e, via oxidizing the relative 2H-pyran ring derivative BC54 which was produced in situ by the cis-denials electrocyclization. 1-Tetralone used as a precursor for creating the aromatic rings of the benzocoumarins .
In 2010, Coelho and colleagues reported that the Reformatskii reaction of naphtha[2,1-b]pyran-1-one and bromoacetic acid ethyl ester resulted in the unexpected synthesis of the new benzocoumarin symbolised as BC56 .
The alcohol was produced by the Reformatskii reaction of the ethyl bromoacetate with a ketone in the presence of iodine and zinc. The conjugated ester (produced via removal of water) with the unpredicted new photochromic BC56 were obtained by refluxing alcohol and HOAc. Due to its fascinating photophysics, the photochromic properties of BC56 under continual irradiation by UV light were examined, too. According to the findings, the continual irradiation via UV rays at 20°C of the colorless BC56 and toluene solution resulted in the formation of lemon colouring with λmax spectrum at 432 nm. UV irradiation of BC56 leading mainly to the creation of photoproduct BC57 that is a heat-stable product, as well as a little amount of BC58, based on further investigation of 1H NMR spectra. Goel and colleagues published a novel generic approach to synthesize a variety of functional oxygen heterocycles, involving benzocoumarin BC59 & BC60, which are displayed in Figure 8 .
Figure 8: Chemical backbones of the benzocoumarins symbolized as BC59a-f and BC60a-b
Ray and colleagues reported a new efficient one-pot production method of class-A benzocoumarin derivatives and their improved models, symbolized as BC61a-h and depicted in Figure , by Suzuki-Miyaura cross-coupling of 2-bromonaphthalene carboxaldehyde derivatives or 2-bromobenzaldehyde with 2-hydroxyphenyl boronic acid, the subsequent oxidative lactonization of hydroxyl- and aldehyde-moiety was coming later .
Figure 9: The chemical backbones of benzocoumarins BC61a-h
To create the benzocoumarin structure’s biaryl lactones, Wang and colleagues devised a new and feasible C-H activation/C-O cyclization directed by carboxyl and was catalysed by Pd(II)/Pd(IV). Benzocoumarins, symbolized as BC62a-ab and displayed in Figure 10, were produced by the respective 2-aryl carboxylic acids cyclization in relatively high yields (more than 96%) under optimal operating conditions .
Figure 10: The chemical backbone of benzocoumarins BC62a-ab
Benzocoumarin’s Total Synthesis Efforts
Many efforts have been performed for the total synthesis of benzocoumarins in the last decades due to their unique structures and remarkable pharmacological bioactivities.
Alternariol Total Synthesis
The total synthesis of BC5 and its closely related compounds is an important issue in total benzocoumarins synthesis since they are famous mycotoxins. Sóti completed the first production of BC5 along with its methyl ether BC6 in 1977 . Subba Rao's research group published a straight forward technique for the 6-aryl-2,4- dimethoxybenzoic acid synthesis, which is the BC5 precursor , that made the production of BC5 derivatives easier. A highly efficacious technique for the total synthesis of BC5 was proposed by Koch in 2005, which involved 7 stages beginning with 3,5-dimethoxy-bromobenzene and orcinol. The main reaction is a Suzuki-type coupling of the orcinol-derived boronic acid along with a brominated resorcylic aldehyde catalysed by palladium. The final demethylation yielded 73% BC5, besides a little amount of BC6 in a yield about 20% .
Abe and colleagues reported another simple synthesis approach to BC5 in 2007, employing palladium reagent which catalysed the phenyl-benzoate derivatives intramolecular biaryl coupling reactions .
Away from BC5, Podlech's team produced BC12 in 10 stages utilizing protocatechuic aldehyde and phloroglucinol acid as original materials, in a yield of 23%. A Suzuki Miyaura reaction with subsequent lactone ring formation was the critical step. The 1H NMR of the synthesized BC12 showed that the NMR spectrum did not match that obtained from natural sources [66,67]. Mikula and colleagues published the procedure of synthesizing two Alternaria mycotoxins synthesis including alternariol sulphated methyl ether named BC10 and glucosylated alternariol methyl ether named BC27 .
Graphislactone Total Synthesis
From the Cephalosporium acremonium, which is a type of fungus in Trachelospermum jasminoides , or from the lichen mycobiont of Graphisscripta var. pulverulenta [20,22], BC19-BC25 were recovered. Nishioka and colleagues, via an intramolecular-biaryl coupling process of diphenylcarboxylate derivative mediated by Palladium, were chemically synthesized BC19-BC21 . Also, BC24 and BC25 were synthesized in a similar manner attributing to their structural similarities .
Podlech and colleagues created a novel synthesis technique for the configurationally similar benzocoumarin derivatives BC19, BC21-BC25 based on Suzuki coupling. This team work utilized the biaryl linkage formation to build the benzocoumarin backbone and dakin reaction to provide it with additional hydroxy moieties [69–71].
Neo-Tanshinlactone Total Synthesis
Lee and colleagues reported the discovery of a novel natural benzocoumarin, symbolized as BC48, using a bioassay-guided technique for isolation. Tandem alkylation/intramolecular aldol plus tandem esterification/intramolecular Friedel–Crafts acetylation reactions were used to complete the total synthesis of BC48. Six steps were required for this synthesis, which provided an overall 18% yield .
Mal and colleagues developed a convergent method to produce BC48 using benzannulation-lactonization as a crucial step. This procedure also allowed for the production of unexpected 6-alkoxy carbonyl-substituted BC48 as well as their analogues directly .
Juncus Benzocoumarin Total Synthesis
From the Juncus acutus plant’s rhizomes, Della-Greca and colleagues extracted several bioactive benzocoumarins which symbolized as BC 31-BC37 . Then, starting with β-tetralone and through two different pathways including a one-pot aromatization and rearrangement chain reactions, Hon’s research team reported the total synthesis of the BC33 for the first time .
Bioactivities of Benzocoumarins and Their Analogues
Because of their strong cytotoxic as well as anti-dyslipidemic properties, benzocoumarin-based structures have attracted a lot of interest. In laboratory trials, several natural benzocoumarins were investigated for their bioactivities from various species and their synthesized analogues [75–85].
This part of the review gives a bio-medical analysis of the natural and synthesized benzocoumarins, and also the development of structurally associated derivatives with better medicinal potentials.
BC6, BC19, BC24, and BC25 have been reported to be able to inhibit the SW1116 cells proliferation at half-maximal inhibitory concentrations (IC50) of 14, 8.5, 21, and 12 μg/mL, in sequence, as found by Tan and colleagues .
With IC50 of 6.87-8.85 μg/mL values, BC41 derived from the Salvia miltiorrhiza roots has demonstrated considerable antitumor activity towards cervical epithelioid carcinoma HeLa, hepatocellular carcinoma HepG2, and ovarian adenocarcinoma OVCAR-3 cell lines. In the same side, bioassay-directed fractionation was used to isolate BC46 and BC47 from the root of Vismia guianensis in 2000. The first product with dimethyl pyran ring exhibited extreme cytotoxicity towards KB cell line, while the second with pyran 1,4-diazaphenanthrenes ring and hydroxyl isopropyl moiety was inactive. This finding recommended that dimethyl pyran in the skeleton of BC46 seems to be necessary for cytotoxic action .
BC48, isolated by Lee and his colleagues from Salvia miltiorrhiza’s root in 2004, has revealed remarkable inhibitory activity towards two estrogenic receptors breast carcinoma cell lines. When analogized with tamoxifen citrate, this natural benzocoumarin exhibited 10 times greater potency and 20 times greater selectivity toward the test cell lines .
Compound BC63, which has an ethyl group at position 4, demonstrated high selectivity and excellent bioactivity, with a ED50 values of 0.45, 0.18, 13.5 & 10.0 μg/mL against MCF-7, ZR-75-1, MDA-MB-231, and HS-587–1, respectively. Additionally, with an ED50 of 0.10 μg/mL, BC63 displayed strong action against SKBR-3 cancerous cells line .
Other analogues were examined as antibreast-cancer candidates including BC64-BC68. Compound BC64 had a selectivity ratio of about 12 times for SK-BR-3 and MCF-7 cell lines, but compound BC65 had a selectivity ratio of 23 times for ZR–75-1 cell line and 23 folds greater activity toward MCF-7. BC66 had 2-3 times greater effectiveness towards SK-BR-3 and ZR-75-1 cell lines than compound BC48. Compared to BC48, BC67 and BC68 demonstrated wider anticancer activity. The anticancer efficacy of these two synthetic compounds, as indicated in preliminary SAR data, is dependent on the presence of nitrogen-related substitution [87-89].
In a follow-up data analysis, it was revealed that BC72 can couple with microtubules to induce tubulin depolymerisation. This process may result in ERK-mediated mitotic arrest and successive apoptosis through JNK excitation in human colorectal tumor tissue . Additional experiments suggested that adding the alicyclic ring to BC72 might drastically alter its antitumor bioactivity, especially in carcinoma cell lines other than breast cancer . For instance, BC75 demonstrated extremely high efficacy towards SKBR-3 and ZR-75-1 breast carcinoma cells, with ED50 values of 0.7 and 1.7 μM, in sequence. This synthetic benzocoumarin had also a wider cytotoxic activity than BC48 and BC63. A unique class of chemotherapeutics was discovered when the aromatic ring of BC48 was saturated, and the most potent compounds were BC76-BC79 [92,93].
For further structural engineering, a sequence of the insertion of alicyclic rings and secondary amines has been used to explore the potential pharmacologically active variants . As a result, the structurally similar BC48 and BC67 indicated dramatically weaker inhibitory effect against tumor cell development, and this was inferior to those demonstrated by BC80 and BC81. Lee and his colleagues investigated aqueous-soluble amine substituted analogues and discovered two novel active compounds, BC82 and BC83 in the cytotoxic activity experiment .
When compared to the previous compound BC67, compound BC82 had a 50 times higher aqueous solubility. Compounds BC82 and BC83 effectively led to decreasing the mammary cells account in genetically modified mice. In malignancy susceptible mammary glands, a single week of therapy with BC82 led to an approximately 80% decrease in BrdU-positive cells .
Sashidhara and colleagues have published a research paper dealing with the neo-tanshinlactone associated medical chemicals which included the library development of completely new benzocoumarin's related compounds depending on the chemical backbone of the natural BC48. Testing the antineoplastic bioactivity of the synthesized compounds towards breast carcinoma MCF-70 and MDA-MB-231 revealed that the benzocoumarins BC84-BC86 can suppress MCF-7 tumorigenesis with IC50 values of 3.8, 7.9, and 6.5 μM, respectively .
Very recently in 2021, Salmaan and colleagues synthesized new benzocoumarin- chalcone hybrids substituted with ester or arylamide moiety. The spectral and mass data corroborated the structures of the newly synthesized benzocoumarin compounds. The activity of the synthesized compounds against prostate carcinoma was tested, and the findings revealed that two of them were the most effective compounds among this group. As a result, these candidates appear to be the most attractive antiproliferative agents towards CYP450 dependent prostate carcinoma cells .
Sashidhara and colleagues conducted a comprehensive research to synthesize and evaluate the benzocoumarin derivatives’ antidyslipidemic efficacy in 2008. In the early stages, they prepared a series of new benzocoumarin-based compounds and found that products BC87-BC89 can reduce cholesterol, phospholipid, and triglyceride plasma levels by about 23%, in an experiment on rats’ model with significant hyperlipidemias.
In a non-enzymatic system, BC87 and BC88 exhibited scavenging ability towards superoxide and hydroxyl radicals’ formation. Furthermore, BC87-BC89 inhibited microsomal lipid peroxidation by 27 %, 24 %, and 31 %, for each. The benzocoumarin derivatives BC87 and BC88 were shown to have strong lipid-lowering and antioxidant characteristics .
Synthetic benzocoumarins BC90-BC92 were found to have excellent hypolipidemic activity with major cholesterol- and triglyceride-lowering activities. These synthetic candidates appeared to be great choices for creating a new lead with anti-atherosclerotic benefits and hypolipidemic bioactivity, in follow-up studies [99–101].
During the last years, Sashidhara and colleagues created a variety of new benzocoumarins functionalized with an amide group to afford effective anti-thrombotic candidates. BC93 demonstrated the most promising antithrombotic activity among the compounds examined, which was equivalent to currently used acetylsalicylic acid or warfarin. However, BC93 differs from these conventional medications in that it did not cause an increase in bleed time, indicating its great potential as a new anti-thrombotic agent . In an experiment on an animal model, BC94-BC96 showed potential anti-thrombotic property owing to their capacity to drop the platelets coagulation and aggregation. Furthermore, these two compounds may enhance the thrombin time considerably. From these findings, Sashidhara and colleagues proposed that these amidebenzocoumarin derivatives can be considered as anti-thrombotic candidates owing to their antiplatelet and anticoagulant properties . Figure 11 displays the skeletal formulas of the synthetic benzocoumarins with a potential to act as anti-thrombotic applicants.
Estrogenic and Anti-estrogenic Activities
Benzocoumarins were discovered to have steroid-like properties in 1956 . The potential of these agents as agonists or antagonists towards estrogen receptor phenotype was studied by Jha and colleagues. The synthetic compounds BC97 and BC98, which are depicted in Figure , displayed estrogenic activity at 10 mg/kg, resulting in a 21% and 25% increase in uterine weight above the control. When these benzocoumarins transformed to their dibenzopyrans BC99-BC101 by adding 6,6-dimethyl group, as illustrated in Figure , the authors concluded that BC101 had an antagonistic effect since the weight of uterus has dropped by 20%. The effect of the agents symbolized as BC99 and BC100 can be considered to be more estrogenic than anti-estrogenic .
The planer structure of the ring system and the small core structure compared with estradiol might explain the weaker antagonistic properties of these compounds, BC97-BC101. Based on this finding, Sun and colleagues have synthesized a number of class-A benzocoumarin’s derivatives as well as their pyranonated products in order to assess their capability to modulate estrogen receptor selectively. An estrogen receptor ligand binding experiment was used to determine the affinity and selectivity of these analogues over the alpha subtype of the estrogen receptor. As a result, several of these analogues have been discovered to be effective and selective agonists towards the beta estrogen receptor. Small lipophilic groups like methyl group were shown to be necessary at multiple sites for good interaction, as shown in SAR assay .
Research investigating benzocoumarin backbone synthesis and its medicinal potential has attracted a large mass of intention during the past decades by many researchers involving medicinal chemists. Due to the presence of a phenyl ring, benzocoumarins have a longer π conjugation backbone than typical coumarins. This structural feature has attracted investigators’ desire to study the natural sources of benzocoumarins, their synthetic methods, and possible medical effects. As a result, both natural and synthetic benzocoumarins have been examined for a variety of biomedical activities, including anticancer, anti-estrogenic, and anti-dyslipidemic properties. Furthermore, the intriguing biological activities of benzocoumarins stimulate the development of a variety of synthetic techniques to meet the demand for synthesizing superior analogues with improved activities.
The successful progress of benzocoumarins with respect to separation, synthesis, biological activity investigation, and SAR analyses has been observed throughout the last several decades. Regardless of the reality that surveys on benzocoumarins have become more coherent and detailed, reviews on their pharmacological properties were in the early stages until now, as so many of them are focused on the synthesis of benzocoumarins, and there are few research findings on comprehensive activity mechanisms for this family of coumarins. Upcoming research should focus on investigating more about the biochemical pathways through which these benzocoumarins can react with their various molecular targets inside the body. As a result, the authors concluded that the benzocoumarin chemical nucleus is a promising scaffold for developing new drugs in the near future.
The authors are very grateful to the University of Mosul/College of Pharmacy for their provided facilities, which helped to improve the quality of this work.
This research did not receive any specific grant from fundig agencies in the public, commercial, or not-for-profit sectors.
All authors contributed toward data analysis, drafting and revising the paper and agreed to responsible for all the aspects of this work.
Conflict of Interest
We have no conflicts of interest to disclose.
Sarah Ahmed Waheed
Yasser Fakri Mustafa
HOW TO CITE THIS ARTICLE
Sarah Ahmed Waheeda, Yasser Fakri Mustafa. Benzocoumarin Backbone Is a Multifunctional and Affordable Scaffold with a Vast Scope of Biological Activities, J. Med. Chem. Sci., 2022, 5(5) 703-721
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