Iraqi Journal of Pharmacy

A narrative review of benzo-fused coumarins, shedding light on their medicinal activities

ABSTRACT

Background: Coumarins and their derivatives excel in chemical diversity, coupled with a wide variety of biological potentials, and tend to be beneficial to the health of the human body. One of these derivatives that has sparked the attention of medicinal chemistry specialists in recent decades is benzo-fused coumarins, which have demonstrated their potential as antioxidants, antimicrobials, antidiabetics, antithrombotics, and many more. Objective: This paper discusses the medicinal importance of benzo-fused coumarins derived from natural or synthetic sources. Conclusion: The researchers documented that benzo-fused coumarin's basic structure is a promising framework that opens up the chance of discovering innovative applicants with advanced therapeutic potentials.

Keywords: Benzo-fused coumarins, Antimicrobials, Anticancer, Antidiabetic, Antioxidant.

1. INTRODUCTION

Coumarou is the French word that indicates coumarin (Y), which is an oxygen-containing heterocyclic product that includes a sizable number of naturally occurring or synthetic chemicals with various biological effects (1). Some examples of these effects include cancer curative (2–7), anti-inflammatory (8–10), oxidative harm preventer (11–14), antimicrobial (15–19), anti-diabetogenic (20), and others.

In addition, coumarou has a wide range of uses in chemistry, including fluorescent dyes (21), optical brighteners (22), and lasers (21), as well as uses as an additive in pharmaceuticals, food, and perfumes (23). Newly developed synthetic methods have been used to create a large number of compounds with the coumarou scaffold as their basis (24).

According to where the benzene ring is located, there are four different types of benzo-fused coumarins, also known as benzocoumarins, which are coumarins that have been fused with a benzene ring and belong to the family of "π-extended coumarin-based compounds". Benzocoumarin derivatives are divided into four groups according to the location of the fused aromatic ring in Y (parent coumarin scaffold): benzo[h]coumarin Y1 (7,8-benzocoumarin), benzo[g]coumarin Y2 (6,7-benzocoumarin), benzo[f]coumarin Y3 (5,6-benzocoumarin), and benzo[c]coumarin Y4 (3,4-benzocoumarin), as shown in Figure 1(25).

Numerous benzo-fused coumarins have been extensively developed in recent years, as a result, attempts to investigate novel therapeutic compounds have been motivated by these coumarins' bioactivities (26). The study team was inspired by these findings to write a review of the medicinal potentials of both synthetic and naturally derived benzo-fused coumarins, with a focus on the most notable examples.

Figure 1: The structural foundations of coumarin and benzo-fused coumarins.

Benzo-fused coumarins' medicinal activities

Benzocoumarins have been of considerable importance because of their diverse range of medicinal potentials, which include antimicrobial (27), antidyslipidemic (28), antioxidant (29), as well as enzyme-inhibitory effects (30) and others (31). So many compounds of benzocoumarin-based structure, whether natural or synthetic, were assessed in chemical laboratories for their bioactivities (26). The following part will review the biological potentials of numerous natural or synthetic benzocoumarin derivatives, along with the upgrade of structurally linked compounds with unprecedented or improved biological activities, and specifically focus on the most significant structural and molecular variables that modify their potentials (26). Figure 2 shows the comprehensive medicinal activities detected for benzocoumarins.

Figure 2: An illustration depicting the medicinal potentials of benzocoumarins.

1.1 Anticancer activity

Zhang and coworkers isolated four benzo[c]coumarin derivatives from Cephalosporium acremonium IFB-E007 in 2005, which included the new graphislactones G (Y5) and H (Y6), as well as the previously identified graphislactone A (Y7) and alternariol monomethylether (Y8), as displayed in Figure 3. The SW1116 cell line's susceptibility to these natural products' anticancer effect was studied. The findings showed that they exhibited a significant anticancer effect against the tested human colon carcinoma cell-line, with IC₅₀ levels varying between 8.50 and 21.0 μg/mL (32).

Also, from the Salvia miltiorrhiza root, Sun and coworkers isolated a new product of benzo[h]coumarin in 2006, known as tanshinlactone A (Y9), as demonstrated in Figure 3. The HepG2 (human hepatoma), OVCAR-3 (human ovarian carcinoma), and HeLa (human cervical carcinoma) cell lines were used to test this natural product's anticancer effect. According to the findings, the natural product Y9 displayed notable cytotoxicity against the investigated cell lines, with IC₅₀ levels varying between 6.8 and 8.8 μg/mL (33).

Figure 3:Benzo[c]coumarins with cytotoxic potential occur naturally, as demonstrated by Zhang and colleagues (Y5-Y8) and Sun and colleagues (Y9). 

In 2021, Abdul-Ridha and coworkers prepared a new benzo[f]coumarin-derived series that was linked with functionalized arylamides or chalcone-esters. The PC-3 cell line (prostatic adenocarcinoma) was used to evaluate these compounds' anticancer effect. From this series, two compounds, herein termed Y10 and Y11, as displayed in Figure 4, exhibited the best cytotoxic activity against the investigated cells, with IC₅₀ values of 71.3 μg/mL for Y10 and 78.2 μg/mL for Y11 (34).

Recently, Jasim and Mustafa reported the syntheses of a novel series of benzo[g]coumarins (Y12-Y17), as shown in Figure 4. The cytotoxicity of this series was assessed against several cell lines, including MCF-7 (breast adenocarcinoma), SKG (cervical carcinoma), SK-OV-3 (ovary adenocarcinoma), AMN3 (mammary adenocarcinoma), Hela (epithelioid cervix carcinoma), and KYSE-30 (esophageal carcinoma). The results revealed that these benzo[g]coumarins exhibited cytotoxic activity against the tested cell lines with IC₅₀ levels between 13.080 and 100.020 μM, with compound Y14 being the most promising as an anticancer candidate (35).

Figure 4:Abdul-Ridha and colleagues (Y10 and Y11) developed benzo[f]coumarin-related conjugates with anticancer potential. Also, Jasim and Mustafa's (Y12-Y17) benzo[g]coumarins with cytotoxic potential.

1.2 Antioxidant activity

In 2005, from the resident fungal endophyte population cultivated in Trachelospermum jasminoides, Song and coworkers isolated graphislactone A (Y7), as presented in Figure 3. Against free radicals known as 2,2-diphenyl-1-picrylhydrazyl (DPPH), this natural product demonstrated significant quenching properties, with an IC₅₀ level of 2.90 μg/mL. Additionally, it showed greater activity in the removal of hydroxy moieties in a dose-dependent pattern than the reference used. Also, product Y7 suppressed the generation of reactive species throughout the oxidation of low-density lipoprotein, utilizing cupric ions as an inducer, and showed superior activity than the reference used in the antioxidative test (36).

Sashidhara and coworkers developed new Schiff-base compounds based on a benzo[h]coumarin core in 2008 and then assessed the antioxidative properties of these bases. Two of these synthetic benzo[h]coumarin-related compounds, Y18 and Y19, as shown in Figure 5, showed the highest inhibition levels among the others against the free moieties used, hydroxyl and superoxide (37).

A new benzo[f]coumarins series (Y20-Y30) was synthesized by Salem and coworkers in 2016, as shown in Figure 5. The ABTS assay was used to assess these compounds' ability to prevent oxidation in homogenized tissues obtained from rats' kidneys and brains. The outcomes of this assessment showed that benzo[f]coumarins Y21, Y22, Y23, Y25, and Y27 possessed a significant ability to prevent oxidation, ranging from 84.40% to 84.60%, while Y20, Y26, and Y29 had good antioxidant activity ranging between 69.30 and 75.50%. In addition, the antioxidant activity of Y24, Y28, and Y30 was rather moderate and ranged from 43.10% to 56.20% (38).

Waheed and Mustafa recently prepared and evaluated the antioxidative potential of a new series of benzo[g]coumarin-related compounds (Y31-Y36), as shown in Figure 5. The authors found that these benzo[g]coumarins have a good ability to quench the tested free moieties, with compound Y33 being the most promising, which had IC₅₀ levels of 56.12 μM against DPPH and 59.41 μM against hydroxide free moieties (39).

Figure 5:As oxidative inhibitors, Sashidhara and colleagues created benzo[h]coumarins (Y18 and Y19). Salem and colleagues synthesized benzo[f]coumarins (Y20-Y30) as free radical quenchers. Furthermore, Waheed and Mustafa's benzo[g]coumarin-related compounds (Y31-Y36) have antioxidant properties. 

1.3 Antidiabetic activity

Wieseand coworkers isolated three benzocoumarin derivatives in 2016, namely pannorin (Y37), alternariol (Y38), and alternariol monomethylether (Y39), from Botryotinia fuckeliana and Aspergillus isolates, and tested their activity on the GSK-3β enzyme. The team found that these derivatives had strong inhibitory activity on the tested enzyme. This good activity may be attributed to the benzocoumarin structure, which has a highly oxygenated core. The chemical structures of these benzocoumarins are illustrated in Figure 6 (40).

Figure 6: Benzocoumarin derivatives with antidiabetic potentialisolated by Wiese and coworkers.

Moreover, Mumijo is a famous and distinctive substance that is frequently utilized in traditional medicine systems. It contains a dibenzo-α-pyrone core (Y4), as shown in Figure 1, which is responsible for most of its bioactivities. Barouji and coworkersfound that it could reduce glucose levels and enhance the activities of superoxide dismutase in the β-cells of the pancreas in diabetic rat models, thus being a promising antidiabetic agent  (41).

As mentioned previously, Jasim and Mustafacreated a novel series of benzo[g]coumarin compounds (Y12-Y17) in 2022, as depicted in Figure 4, and tested their glucose-lowering capacity against two enzymes, namely, yeast α-glucosidase and porcine α-amylase. The team discovered that Y12 and Y13 had the most effective glucose-lowering potential among other prepared benzo[g]coumarins  (42). Also, in the same year, Waheed and Mustafasynthesized a number of benzo[g]coumarins (Y31-Y36) and evaluated their antidiabetic activity. According to the results, Y33 and Y34, as illustrated above in Figure 5, possessed the strongest suppressive activity on both yeast α-glucosidase and porcine α-amylase enzymes (43).

1.4 Antimicrobial activity

In 2020, Mohamed and coworkers found that urolithin A (Y40) and urolithin B (Y41), benzo[c]coumarin-derived products produced by the gut microbiome, as shown in Figure 7, were able to suppress the Q-S system, which is the communication platform that is crucial for the infectivity of bacteria; therefore, they were effective against carbapenem-resistant A. baumannii, MRSA, Campylobacter species, S. dysenteriae, and V. cholera. As a result, these urolithins are considered promising candidates for the development of modern antibacterial drugs (44).

In 2022, Megha and coworkers prepared and investigated the antimicrobial activity of new benzo[g]coumarin compounds. They discovered that all of the newly synthesized compounds had varying levels of activity against the tested bacterial strains. Four of these benzo[g]coumarins (Y42-Y45), as shown in Figure 7, possessed strong activity against the B. subtilis bacterial strain (45).

Also, in 2022, Waheed and Mustafacreated a novel set of benzo[g]coumarin compounds (Y31-Y36) and checked their antimicrobial activities. The team discovered that two of the synthesized benzo[g]coumarins, Y33 and Y34, as shown in Figure 5, had the most potent activity against all of the bacterial and fungal strains used. This promising activity could be attributed to the chloride and fluoride moieties at position 4 ̋  (46).

Similarly, Jasim and Mustafa prepared another set of benzo[g]coumarin compounds (Y12-Y17) and tested their antimicrobial activities, as presented in Figure 4. As with Waheed and Mustafa, the researchers found that the benzo[g]coumarins Y14 and Y15, with chloride and fluoride at position 4 ̋, exhibited the strongest activity against the gram-negative bacteria and fungi strains used. In addition, the intermediate benzo[g]coumarin-related compound obtained during the synthesis had promising antifungal activity, while Y12 possessed good antibacterial activity (47).

Figure 7: Antimicrobial activity of benzo[c]coumarin-related urolithins (Y40 and Y41) reported by Mohamed and colleagues. Megha and colleagues also prepared benzo[g]coumarins (Y42-Y45) with antibacterial potential. 

1.5 Antithrombotic activity

In 2011, Sashidhara and coworkers reported the synthesis of a novel series of 3-carboxamide-benzo[h]coumarins. These compounds were scanned for their antithrombotic effect in-vivo. The study’s results displayed that compound Y46, as depicted in Figure 8, exhibited the most potent antithrombotic effect among the tested compounds, even better than the reference. Interestingly, compound Y46 did not cause an increase in bleeding time. Therefore, it seems to be an attractive candidate for the development of new antithrombotic agents (48).

In 2012, Sashidhara and coworkers prepared and evaluated the antithrombotic effect of a new series of benzo[h]coumarin-amides. The authors concluded that some of these prepared compounds (Y47-Y49), as demonstrated in Figure 8, had a promising antithrombotic effect in-vivo when compared to the reference (49). Further tests were conducted on compounds Y47, Y48, and Y49, leading to the conclusion that these active molecules significantly reduced collagen- and adenosine diphosphate-induced platelet aggregation. Besides, they resulted in a significant increase in thrombin time. Thus, they possessed antithrombotic activity via both antiplatelet and anticoagulant activity (49).

Figure 8: Sashidhara and colleagues synthesized a benzo[h]coumarin-derived compound (Y46) with antithrombotic activity. Sashidhara and colleagues developed antithrombotic benzo[h]coumarins (Y47-Y49). 

1.6 Anti-inflammatory activity

In 2015, Lv and coworkers isolated two novel benzo[h]coumarins, muralatins A (Y50) and B (Y51), from Murraya alata leaves, as shown in Figure 9. The anti-inflammatory activity of these natural products was screened by measuring their suppressing effect on nitric oxide generation in lipopolysaccharide-stimulated RAW 264.7 macrophage cells. The results revealed that these muralatins exhibited a remarkable suppressing effect on nitric oxide generation as compared to the reference, with IC₅₀ values of 12.40 and 9.10 μM, respectively (50).

Recently, Liang and coworkers documented the isolation of two new benzo[h]coumarins, murratins C (Y52) and D (Y53), from Murraya exotica twigs and leaves, as illustrated in Figure 9 (51). The activity of these natural products as anti-inflammatory agents was evaluated by estimating their suppressing effect on nitric oxide generation in lipopolysaccharide-stimulated RAW 264.7 macrophage cells. Based on the results, when compared to the reference, the natural product Y53 possessed a moderate suppressing effect on nitric oxide generation with an IC₅₀ value of 39.0 μM, while Y52 did not show suppression (51).

Figure 9: Naturally occurring benzo[h]coumarins (Y50 and Y51) with anti-inflammatory potential as reported by Lv and colleagues, as well as those (Y52 and Y53) studied by Liang and colleagues. 

1.7 Estrogenic and antiestrogenic activities

In 2006, Larrosa and coworkers studied the estrogenic and anti-estrogenic activity of urolithins A (Y40) and B (Y41), benzo[c]coumarin-derived products produced by the gut microbiome, as displayed in Figure 7. The study results revealed that both urolithins possessed an affinity for α- and β-estrogenic receptors. The binding of Y40 to the estrogenic receptors was more effective than that of Y41. Also, Y40 affinity for the α-estrogenic receptors was higher than that for the β-estrogenic receptors. In addition, these urolithins demonstrated dose-dependent estrogenic effect (when estradiol is not present) and anti-estrogenic effect (when estradiol is present) (52).

In 2004, Pandey and coworkers prepared a series of substituted benzo[c]coumarins and screened their activity as estrogenic receptor agonists and antagonists in-vivo. According to the study findings, two of the tested compounds, Y54 and Y55, as demonstrated in Figure 10, displayed moderate estrogenic activity with uterine weight gains of 25.0 percent and 21.0 percent greater than the control, respectively (26).

In 2006, Sun and coworkers synthesized a series of functionalized benzo[c]coumarins and studied their affinity and selectivity for α- and β-estrogenic receptor subtypes. Based on the findings, the majority of the tested compounds were potent and selective β-estrogenic receptor agonists (53). Compounds Y56, Y57, Y58, and Y59, as shown in Figure 10, performed the best, with IC₅₀ values ranging between 4.1 and 7.8 nM and selectivity over α-estrogenic receptors ranging from 29 to 124-fold. The authors concluded that, for optimum binding and selectivity, small hydrophobic moieties like ethyl and methyl were required in different locations in the molecule (53).

Figure 10: Benzo[c]coumarins with estrogenic activity (Y54 and Y55) synthesized by Pandey and colleagues, and those (Y56-Y59) synthesized by Sun and colleagues. 

1.8 Enzyme inhibitory activity

In 1991, Ogawa and coworkers reported the isolation of pannorin (Y37), a benzo[h]coumarin-derived product, as indicated in Figure 6, from the culture media of the Chrysosporium pannorum M10539 fungus. The activity of this natural product was screened towards the rate-limiting enzyme in cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl co-enzyme A reductase. The results revealed that at 160 μM, Y37 inhibited 50% of the tested enzyme activity (54).

In 2005, Hormazabal and coworkers isolated graphislactone A (Y7), an identified benzo[c]coumarin-derived product, as illustrated in Figure 3, from the endophytic fungus Microsphaeropsis olivacea. The effect of this natural product on the acetylcholinesterase enzyme was assessed. The authors found that Y7 inhibited acetylcholinesterase moderately, with an IC₅₀ value of 8.10 µg/mL (55).

In the same year, 2005, Garino and coworkers prepared four new benzo[c]coumarins (Y60-Y63), as shown in Figure 11. These compounds were subjected to enzymatic inhibitory activity evaluation against nitric oxide synthase, HIV aspartyl protease, serine proteases (trypsin and α-chymotrypsin), and a panel of protein kinases. The results of this evaluation indicated that compounds Y60, Y61, Y62, and Y63 exhibited modest inhibitory activity on some of the tested enzyme models. Therefore, they are promising starting templates for a drug discovery program (56).

In 2020, Nabeel and coworkersdeveloped a new series of benzo[f]coumarins conjugated with anti-inflammatory agents via alkyl-amide linkers (Y64–Y70), as depicted in Figure 11. The enzymatic inhibitory activity of these compounds was determined in-vitro against the acetylcholinesterase enzyme. The authors concluded that compounds Y65, Y66, Y67, and Y69 possessed good inhibitory activity versus the tested enzyme, with IC₅₀ values ranging between 1.8 and 8.2 µM, while the other compounds were inactive (57).

Figure 11: Garino and colleagues created benzo[c]coumarins (Y60-Y63) that inhibit enzymes. Nabeel and colleagues also created benzo[f]coumarins (Y64-Y70) with the same activity type. 

1.9 Immunomodulatory activity

In 2007, Wu and coworkers studied the effect of tanshinlactone A (Y9), a natural benzo[h]coumarin-derived product, on the proliferation of human peripheral blood mononuclear cells (PBMCs) induced by phytohemagglutinin. The outcomes of this study showed that Y9, which was identified from Salvia miltiorrhiza as shown in Figure 3, had a significant suppressing effect on the proliferation of PBMCs with an IC₅₀ value of 15.60 μM. The authors concluded that Y9 reduced the production of interferon-γ and interleukin-2 as well as the activation of mitogen-activated protein kinases in PBMCs. Therefore, this natural product was most likely a PBMC immunomodulator (58).

1.10 Antidyslipidemic activity

As stated above, new Schiff-base compounds based on a benzo[h]coumarin core have been synthesized by Sashidhara and coworkers. Rats with hyperlipidemia caused by triton were used to test these compounds' antidyslipidemic effectiveness. According to the findings, two of these synthetic benzo[h]coumarin-related compounds, Y18 and Y19, as depicted in Figure 5, demonstrated superior ability in lowering levels of tested lipids in plasma. These levels were decreased by 24.0%, 20.0%; 20.0%, 21.0%; and 23.0%, 25.0% for phospholipids, triglycerides, and total cholesterol, respectively (37).

Further, three new series of benzo[h]coumarin-related compounds were prepared, and their in vivo antidyslipidemic effect was tested in ongoing investigations by Sashidhara and coworkers. Three of these new benzo[h]coumarins (Y71-Y73), as shown in Figure 12, had a remarkable ability to reduce levels of triglycerides and total cholesterol in plasma. They might therefore be good candidates for the creation of new drugs used in the treatment of hyperlipidemia (59,60).

Figure 12: Benzo[h]coumarin-related compounds that exhibited antidyslipidemic properties developed by Sashidhara and coworkers.

2. CONCLUSION

The findings of the preceding study afforded three clear-cut conclusions. First, the growing focus on benzo-fused coumarins in pharmaceutical chemistry is due chiefly to their extended pi-conjugated arrangement in comparison to coumarins. Such a feature has sparked the interest of specialists in investigating their bioactive facets. Second, numerous natural and synthetic benzo-fused coumarin derivatives have been proven to have a plethora of therapeutic potentials, including antioxidant, anticancer, antimicrobial, antidiabetic, and many more. Third and finally, the pharmacological potential of the benzo-fused coumarin derivatives succeeds in making them promising therapeutic scaffolds. So, researchers and developers should focus more on creating and developing new benzo-fused coumarins with unique or advanced potentials, in addition to understanding how these derivatives bind to and affect their targets.

3. ACKNOWLEDGEMENTS

The University of Mosul/College of Pharmacy provided resources that enhanced the level of talent of this work, for which the authors are extremely grateful.

4. CONFLICT OF INTEREST

The authors declare that there is no conflict of interest.

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مراجعة سردیة للکومارین الملتحمةبالبنزو، تسلیط الضوء على أنشطتها الطبیة

المعلومات الاساسیة: تتمیز الکومارینات ومشتقاتها بالتنوع الکیمیائی، إلى جانب مجموعة متنوعة من الإمکانیات البیولوجیة، وتمیل إلى أن تکون مفیدة لصحة جسم الإنسان. أحد هذه المشتقات التی أثارت اهتمام المتخصصین فی الکیمیاء الطبیة فی العقود الأخیرة هی الکومارینات الملتحمة مع البنزین، والتی أظهرت إمکانیاتها کمضادات للأکسدة، ومضادات للبکتیریا، ومضادات للسکر، ومضادات للتخثر، وغیرها الکثیر. الهدف من الدراسة: تناقش هذه المقالة الأهمیة الطبیة للکومارینات الملتحمة مع البنزین و المشتقة من مصادر طبیعیة أو صناعیة. الاستنتاج: وثق الباحثون أن الترکیب الأساسی للکومارینات الملتحمة مع البنزین هو ﺑؙﻧﻳﺔ واعدة یمکن أن تفتح الفرصة لاکتشاف عوامل مبتکرة ذات قدرات علاجیة متقدمة.

 الکلمات المفتاحیة: البنزوکومارینات، مضاد للمیکروبات، مضاد للسرطان، مضاد لمرض السکر، مضاد للأکسدة.

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