Review
Natural biflavonoids as potential therapeutic agents against microbial diseases

https://doi.org/10.1016/j.scitotenv.2021.145168Get rights and content

Highlights

  • Natural biflavonoids like amentoflavone, ginkgetin, morelloflavone, agathisflavone, hinokiflavone, robustaflavone, and many others are known.

  • These biflavonoids have activity against Influenza, SARS, Dengue, HIV, HBV, HSV, EBV, protozoal (Leishmania, Malaria), bacterial and fungal infections.

  • Structurally these dimeric flavonoids have more effectiveness over the monomeric flavonoids.

  • Natural biflavonoids have the potential to undergo medicinal chemistry manipulation and become source of new anti-microbial drugs.

Abstract

Microbes broadly constitute several organisms like viruses, protozoa, bacteria, and fungi present in our biosphere. Fast-paced environmental changes have influenced contact of human populations with newly identified microbes resulting in diseases that can spread quickly. These microbes can cause infections like HIV, SARS-CoV2, malaria, nosocomial Escherichia coli, methicillin-resistant Staphylococcus aureus (MRSA), or Candida infection for which there are no available vaccines/drugs or are less efficient to prevent or treat these infections. In the pursuit to find potential safe agents for therapy of microbial infections, natural biflavonoids like amentoflavone, tetrahydroamentoflavone, ginkgetin, bilobetin, morelloflavone, agathisflavone, hinokiflavone, Garcinia biflavones 1 (GB1), Garcinia biflavones 2 (GB2), robustaflavone, strychnobiflavone, ochnaflavone, dulcisbiflavonoid C, tetramethoxy-6,6″-bigenkwanin and other derivatives isolated from several species of plants can provide effective starting points and become a source of future drugs. These biflavonoids show activity against influenza, severe acute respiratory syndrome (SARS), dengue, HIV-AIDS, coxsackieviral, hepatitis, HSV, Epstein-Barr virus (EBV), protozoal (Leishmaniasis, Malaria) infections, bacterial and fungal infections. Some of the biflavonoids can provide antiviral and protozoal activity by inhibition of neuraminidase, chymotrypsin-like protease, DV-NS5 RNA dependant RNA polymerase, reverse transcriptase (RT), fatty acid synthase, DNA polymerase, UL54 gene expression, Epstein−Barr virus early antigen activation, recombinant cysteine protease type 2.8 (r-CPB2.8), Plasmodium falciparum enoyl-acyl carrier protein (ACP) reductase or cause depolarization of parasitic mitochondrial membranes. They may also provide anti-inflammatory therapeutic activity against the infection-induced cytokine storm. Considering the varied bioactivity of these biflavonoids against these organisms, their structure-activity relationships are derived and wherever possible compared with monoflavones. Overall, this review aims to highlight these natural biflavonoids and briefly discuss their sources, reported mechanism of action, pharmacological uses, and comment on resistance mechanism, flavopiridol repurposing and the bioavailability aspects to provide a starting point for anti-microbial research in this area.

Introduction

Microbes are classified into four major groups consisting of organisms like viruses, protozoa, bacteria, and fungi. These microbial infections can manifest in various ways in their hosts (animals or humans). They may infect the epithelial surface of the skin, or the internal mucosal surfaces of the respiratory, gastrointestinal, and urogenital tracts. Some are transmitted by air as droplets (influenza, common flu, or SARS), water and foods (hepatitis A, pathogenic Escherichia coli strains), physical or contaminated surface contact (Herpes simplex virus, bacteria, and fungi), exchange of bodily fluids during intercourse or sharing of infected needles, or mother to child during pregnancy (HIV, Hepatitis B, and HSV) and by insect vectors (malaria, protozoal infections). After the first contact, these organisms will strive to establish infection by epithelial colony formation or tissue penetration for replication. A full-fledged disease state requires steps like replication and transmission of infection which generally happens within the host (Janeway et al., 2001). These stages can be blocked by the host immune defense mechanisms (pathogen recognition, phagocytosis, inflammatory response, macrophage activation, and natural killer cell recruitment). Along with the initial host immune system response and the adaptive immune response, prophylactic support of drugs can result in the effective removal of infection and prevent the disease.

Nature and the plant kingdom have provided medicines to man for centuries and many drugs are derived from natural products (Cary and Peterlin, 2017; Newman and Cragg, 2016). Traditional forms of treatments like Ayurveda, traditional Chinese medicines (TCM), or other forms of indigenous folk therapy (African traditional medicine, Brazilian traditional medicine) existing in each country or region points to the usage of plant species for various ailments based on the synergistic effect of extracts or decoctions (Baskaran et al., 2018; Chinsembu, 2019; Gu et al., 2014; Lin et al., 2014; Ricardo et al., 2017). Secondary metabolites like flavonoids, coumarins, saponins or tannins from plant sources help us to combat various ailments (Hostetler et al., 2017; Menezes and Diederich, 2019a; Menezes et al., 2016; Zakaryan et al., 2017). Many of them like cinnamyl esters (phenylpropanoids), coumarins, and flavonoids are end products originally derived from the shikimic acid pathway via several biogenetic cascades and have shown antiviral, antibacterial, anticancer, and other bioactivities (Cary and Peterlin, 2017; Guzman, 2014; Hassan et al., 2016; Menezes et al., 2016; Mishra et al., 2020; Zakaryan et al., 2017). Natural flavonoids isolated from herbs and plants are used as medicines and have shown therapeutic effects against several types of viruses and microbes (Lalani and Poh, 2020; Lin et al., 2014; Zakaryan et al., 2017).

Biflavonoids are polyphenolics belonging to the class of flavonoids. Their structure consists of two similar or non-similar flavonoid units connected by Csingle bondC or C-O-C bonds forming dimeric molecules (Gontijo et al., 2017). Amentoflavone 1 and robustaflavone 3 are examples of biflavonoids connected by the Csingle bondC bond, while hinokiflavone 8, ochnaflavone 15b are connected via the C-O-C bond. The majority of the biflavonoids discussed belong to the combination of flavones (apigenin, luteolin), flavanones (e.g. eriodictyol, naringenin), flavonols (quercetin, kaempferol, and derivatives), or flavanonols (taxifolin). The nomenclature, classification, and biological activities for this upcoming class of flavonoids have been recently compiled (Gontijo et al., 2017). Amentoflavone 1 and other derivatives (Fig. 1) were isolated from several plant families (~120) and have shown different biological activities (Yu et al., 2017). While ginkgetin 5 isolated from Ginkgo biloba and other plants, has shown anti-viral, antifungal, anti-obesity, anti-cancer, and anti-inflammatory activities (Adnan et al., 2020). Amentoflavone 1 and other derivatives have anticancer activity and induce mechanisms like apoptosis, activation of caspases, angiogenesis inhibition, and topoisomerase inhibition (Mercader and Pomilio, 2013).

Similarly, sumaflavone (an amentoflavone derivative) has shown binding with beneficial low molecular weight, non-structured, and non-toxic soluble amyloid β-oligomers (Uddin et al., 2020). Natural and synthetic biflavonoids have shown potential for anti-Alzheimer's therapy by inhibition of amyloid β (1–42) aggregation and other mechanisms (Sum et al., 2017; Uddin et al., 2020). Both 1 and sumaflavone have shown inhibition of nitric oxide (NO) production in macrophages via nuclear factor-κB (NF-κB) and activator protein 1 (AP-1) inactivation (Woo et al., 2005; Yang et al., 2006). Robustaflavone 3 isolated from Nandina domestica fruits effectively reduces the production of nitric oxide (NO), pro-inflammatory cytokine interleukin-1 beta (IL-1β), and IL-6 having potential application for inflammatory bowel disease (IBD) therapy (Jo et al., 2019). Biflavonoids from medicinal herbs or plants such as Selaginella tamariscina, Ginkgo biloba, Cephalotaxus koreana, Nandina domestica and Lonicera japonica were effective for improving procollagen growth and inhibition of MMP-I leading to safe topical anti-wrinkle formulation (Lee et al., 2008). 1 isolated from Cycas rumphii led to oxidative DNA cleavage in presence of copper (II) ions. The reduction of Cu(II) to Cu(I) in presence of 1 generated hydroxyl radicals and the rate was twice that observed for apigenin (Uddin et al., 2004). Similarly, isoginkgetin 6 (3′,8″-dimer of acacetin) was found to have better antioxidant activity compared to acacetin (Li et al., 2019b).

The synthetic 6-methyl-4′-hydroxy flavone dimers (MW-707) having polyethylene glycol (PEG) chains from 4 to 5 function as potent killers of multidrug-resistant cancer cells overexpressing MRP1 (multidrug resistance protein 1; see Fig. 1) (Dury et al., 2017). Similarly, synthetic apigenin dimeric forms had multi-drug reversal (MDR) effects in cancer cells and were independent of the PEG chain used as a linker. The dimeric molecule connected by the PEGs linker (n = 4) was the most potent in reversing taxol resistance while similar results were seen with 2 and 3 PEGs (Wong et al., 2009). From these examples, it becomes clear that natural or synthetic dimeric flavonoids could exert better therapeutic outcomes. The search for safe and efficient antiviral and antimicrobial drugs/therapies available during pandemics for treatment and therapy in economically lagging countries is an urgent need. Naturally derived biflavonoids offer low toxicity to human cells and therefore may provide novel routes for the discovery of new drugs against infectious pathogens (Antia et al., 2010; Coulerie et al., 2012; Konziase, 2015; Lopes Andrade et al., 2019; Makhafola et al., 2012). Therefore, in this review paper, we discuss the bioactivity potential of natural biflavones as anti-viral, anti-protozoal, antibacterial and antifungal agents. The review is divided into sections dealing with natural and synthetic sources of biflavonoids followed by the antiviral activity based on the different types of RNA and DNA viruses. Then we discuss the bioactivity of biflavonoids in antiprotozoal infections like Leishmania, Chagas disease, and malaria. Biflavonoids also possess inherent anti-bacterial and antifungal activity which is discussed in the latter sections. Overall, we compare their structure and activity with monoflavonoids having similar substitutions on the flavonoid core. Finally, we present a brief perspective with respect to the resistance mechanism, repurposing of known drugs focussed on flavone, and propose bioavailability strategies with biflavonoids. In most cases isolation and preliminary bioactivity studies are reported, and wherever possible comparison with monomeric flavonoids have been provided.

The Selaginella genus is known to be a rich source of biflavonoids (Almeida et al., 2013). The most commonly encountered biflavones are amentoflavone (3′,8-biflavone) 1, agathisflavone (6,8-biflavone) 2, robustaflavone (3′,6-biflavone) 3, hinokiflavone ([I-6-O-II-4′]-biapigenin) 8 and the amentoflavone methyl ethers bilobetin 4, ginkgetin 5, isoginkgetin 6, and sciadopitysin 7 (Fig. 1) which are mostly isolated from TCM sources like Selaginella tamariscina, and Ginkgo biloba leaves (Gontijo et al., 2017; Yu et al., 2017). The above-mentioned biflavones consist of two apigenin (4′,5,7-trihydroxy flavone) which possesses anti-viral, anti-cancer, anti-bacterial activity, and so-on (Hostetler et al., 2017; Salehi et al., 2019). Additionally strychnobiflavone (SBF) 9 was isolated from Strychnos pseudoquina (Boff et al., 2016). The amentoflavone derivatives like sotetsuflavone 10a and podocarpusflavone A 10b were isolated from Dacrydium balansae (Coulerie et al., 2012). While the prenylated amentoflavone derivatives dulcisbiflavonoid A, B, and C 12a-12c were isolated from Garcinia dulcis (Abdullah et al., 2018). Morelloflavone 11 (luteolin-naringenin) and its derivatives (11a-11c) were isolated from Calophyllum panciflorum A C Smith (Guttiferae) and other Garcinia biflavonoids like GB1 (dihydrokaempferol-naringenin), GB2 (eriodictyol-naringenin), GB3 (dimer of taxifolin-eriodictyol) 13a-e from Garcinia kola seeds (Ito et al., 1999). The garcinia flavones GB2 13b and manniflavanone GB3 13d were also isolated (in large amounts 15-20 g) from the stem bark of Symphonia globulifera (Mkounga et al., 2009). Hinokiflavone 8 was isolated from Dacrydium balansae, Metasequoia glyptostroboides, Rhus succedanea, and Garcinia multiflora (Coulerie et al., 2012; Lin et al., 1997a; Miki et al., 2008). While lanaroflavone 14 was isolated from Campnosperma panamense and ochnaflavone and its derivatives 15a-c were isolated from Ochna species (Fig. 4) (Makhafola et al., 2012; Weniger et al., 2006). Similarly, isoprenylated (C5 isoprene) amentoflavone and morelloflavone derivatives called garciniaflavones A-F (see Fig. S1 in supplementary information) were isolated from Garcinia subelliptica leaves (Fukugi in Japanese) along with a major quantity of morelloflavone 11 and podocarpusflavone A 10b (Ito et al., 2013). The biomimetic synthesis of biflavones occurs via peroxidase adjacent to the 4′-OH group in flavones (Yan et al., 2019). While other biflavones can be formed by apigenin phenolic coupling (Gontijo et al., 2017). Table 1 provides the natural source, bioactivity, and isolated quantity details of relevant biflavonoids. The process of isolation from plant sources is time consuming, costly and in many cases, the natural isolation of these biflavonoids has provided low yields suitable only for in vitro studies (see Table 1). Considering the availability from plant sources, conservation, and environmental issues, their synthetic availability in the pure form will greatly benefit in vivo studies and the drug discovery process. Therefore synthetic efforts for producing these natural/synthetic biflavonoids are essential for biological evaluation (Rahman et al., 2007; Sum et al., 2017; Xu et al., 2020; Yan et al., 2019). We have denoted the name and structure of biflavonoids shown in Fig. 1, Fig. 2, Fig. 3, Fig. 4 with the use of bold number in the content of our manuscript. The A, B and C-rings of flavonoids are indicated in Fig. 1.

Section snippets

Antiviral activity of biflavonoids

Natural flavonoids are effective against RNA and DNA viruses by blocking their attachment and entry into cells; interference with viral replication stages, translation and polyprotein processing, and final release of the new viral particles into healthy un-infected cells (Zakaryan et al., 2017). Flavonoids can function as prophylactic or therapeutic and indirect inhibitors by interaction with the immune system (Zakaryan et al., 2017). The continued usage of antiviral drugs can lead to viral

Anti-leishmanial activity

Leishmaniasis is a chronic disease caused by protozoa of the distinct Leishmania genus transmitted by sandflies of the genus Phlebotomus and Lutzomyia (The WHO reports that >90 species of sandflies have been identified to probably function as vectors). The Leishmania parasites consist of two life forms, amastigotes, and promastigotes depending on the stage in their life cycle. Promastigotes multiply in the midgut of the sand fly vector, whereas amastigotes are intracellular forms that are

Antimicrobial biflavonoids

Antibiotic resistance by pathogenic microbes resulting in an increased morbidity and mortality rate due to infectious diseases has become a concern worldwide. Soon we will be faced with the post-antibiotic era with pandemics caused by drug-resistant bacterial strains. To combat such infections, natural products are useful, considering their role as secondary metabolites in plants have similar functions (Wink, 2008). Moreover, new metabolites and their mixtures are constantly being synthesized

Antifungal activity of biflavonoids

The mechanism of antifungal activity of 1 isolated from S. tamariscina was investigated against several pathogenic fungal strains, including Candida albicans, Saccharomyces cerevisiae, and Trichosporon beigelii. The application of 1 stimulated the accumulation of intracellular trehalose in C. albicans and lead to disruption of the dimorphic transition from mycelial to filamentous form, indicating a stress response (Jung et al., 2006). Safety profile on tested human erythrocytes indicated a low

Comparing the structure-activity relationship (SAR) between monomeric flavonoids and biflavonoids: function of lipophilicity

SAR analysis of flavonoids on influenza viral NAs revealed that for inhibitory effect, the 4′-OH, 7-OH, carbonyl group at C4, and C2double bondC3 double bond were essential features, and the presence of a glycosylation group greatly reduced NA inhibition (Liu et al., 2008). The natural flavonoids quercetin, catechin, naringenin, luteolin, hispidulin, vitexin, chrysin, and kaempferol could target the NA active site as seen by molecular docking providing an antiviral effect. The molecular docking, binding

Future perspectives concerning resistance mechanism, repurposing and bioavailability aspects of biflavonoids

Microbes can easily adapt to new environments and are constantly evolving new mechanisms to resist previously effective drug treatments. Rather than using single molecules which could give rise to resistant strains, plants have evolved to produce a mixture of secondary metabolites that are varied in their composition and concentrations depending on the requirement (Wink, 2008). This may be the key factor to prevent the development of resistance and adaptation of pathogens against their chemical

Conclusions

Biflavonoids could function as prophylactic agents since a majority of the studies have shown the effectiveness of dimeric forms over the monomeric forms (hinokiflavone, podocarpusflavone A over apigenin against Dengue virus, strychnobiflavone (9) and its monomer 3MQ against HSV and anti-leishmanial). Amentoflavone and its derivatives have shown anti-influenza, anti-SARS CoV while hinokiflavone [(I-6-O-II-4′)-biflavone] or its derivatives have shown anti-influenza, anti-dengue and

Abbreviations

    3′-dGTP

    3′-Deoxyguanosine-5′-triphosphate

    CPA

    cysteine protease A

    DNA

    deoxy ribonucleic acid

    EBV

    Epstein-Barr virus

    EC50

    Half maximal effective concentration

    HIV

    Human immunodeficiency virus

    HSV

    Herpes simplex virus

    HBV

    Hepatitis B virus

    IAV

    Influenza A virus

    IC50

    half maximal inhibitory concentration

    ID50

    half maximal inhibitory dose

    RNA

    ribonucleic acid

    SARS-CoV

    Severe acute respiratory syndrome-Corona virus

    FAS

    Fatty Acid Synthase

    MDCK

    Madin-Darby Canine Kidney

    MRP1

    Multidrug Resistance Protein 1

    RT

    reverse transcriptase

    RDDP

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

CRediT authorship contribution statement

JM: Conceptualization, Data curation, Writing- Original draft preparation, Reviewing and Editing, Figures- visualization, and drawing. VC: Data curation, Writing- Reviewing, and Editing. JM and VC: Final editing, and approval of the draft for submission.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

JM was supported @ Nagasaki International University (NIU) by the Tokyo Biochemical Research Foundation (TBRF), Japan post-doctoral fellowship for Asian researchers (TBRF-RF-16-99), and is thankful to Prof. Hideaki Fujita and the Faculty of Pharmaceutical Sciences (NIU) for the research facilities. VRC acknowledges FAPERJ (APQ1 E-26/010.002205/2016), CNPq, CAPES, and UFF for financial support and research fellowships.

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