Lignans and Their Derivatives from Plants As Antivirals

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Review Lignans and Their Derivatives from Plants as Antivirals

Qinghua Cui 1,2,3,*, Ruikun Du 1,2,3 , Miaomiao Liu 1 and Lijun Rong 4,*

1 College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China; [email protected] (R.D.); [email protected] (M.L.) 2 Qingdao Academy of Chinese Medicinal Sciences, Shandong University of Traditional Chinese Medicine, Qingdao 266122, China 3 Research Center, Shandong University of Traditional Chinese Medicine, Jinan 250355, China 4 Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA * Correspondence: [email protected] (Q.C.); [email protected] (L.R.); Tel.: +86-186-6017-1818 (Q.C.); +1-312-996-0110 (L.R.) Academic Editor: David Barker Received: 8 November 2019; Accepted: 23 December 2019; Published: 1 January 2020

Abstract: Lignans are widely produced by various plant species; they are a class of natural products that share structural similarity. They usually contain a core scaﬀold that is formed by two or more phenylpropanoid units. Lignans possess diverse pharmacological properties, including their antiviral activities that have been reported in recent years. This review discusses the distribution of lignans in nature according to their structural classiﬁcation, and it provides a comprehensive summary of their antiviral activities. Among them, two types of antiviral lignans—podophyllotoxin and bicyclol, which are used to treat venereal warts and chronic hepatitis B (CHB) in clinical, serve as examples of using lignans for antivirals—are discussed in some detail. Prospects of lignans in antiviral drug discovery are also discussed.

Keywords: lignans; antivirals; mechanism; drug development

1. Introduction Lignans are a large group of naturally occurring compounds that are derived from the shikimic acid biosynthetic pathway [1]. Structurally, Lignans contain a basic scaffold of two or more phenylpropanoid units [2], and the monomers forming lignans are cinnamic acid, cinnamyl alcohol, propenyl benzene, and allyl benzene. When the molecular linkage of monomers occurs between positions β-β0 (also referred to as an 8-80), these compounds are designated as “classical lignans”. In contrast, the compounds are grouped into “neolignans” if the main structural units are coupled in any other way (non β-β0 linkage). Figure1 shows the monomers and the classification. Neolignans have more varied structures than classical lignans. Lignans are widely distributed in the plant kingdom, and they exist in plant roots, rhizomes, stems, leaves, flowers, fruits, seeds, xylem, and resins. Plants, such as the Lauraceae family, especially the genera of Machilus, Ocotea, and Nectandra are rich sources of lignans. Additionally, Annonaceae, Orchidaceae, Berberidaceae, and Schisandraceae family contain a large number of constituents of lignans and neolignans [3–5]. Up to date, lignans are found in over 70 families in plant kingdom, and more than 200 classical lignans and 100 neolignans have been characterized [6]. They are usually present as dimers, but some of them are trimers or tetramers. Most of the lignans in plants are in a free state, while some of them can combine with glycon and form glycosides and other derivatives.

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FigureFigure 1. The 1. The monomers monomers and and thisthis classification classification of lignans. of lignans. With such structural diversity of lignans being discovered, it is not surprising that many attractive Withpharmacological such structural activities diversity of the lignan of lignans family, such being as antitumor discovered, [7], antioxidant it is not [5], surprising antibacterial [that8], many attractiveimmunosuppressive pharmacological [9 ],activities and antiasthmatic of the propertieslignan family, [10] were such reported. as antitumor Pertinent to[7], this antioxidant review, [5], antibacterialmany [8], lignans immunosuppressive have been identified with [9], antiviral and antias activitiesthmatic [11]. Tubulinproperties binding, [10] reverse were transcriptasereported. Pertinent to this review,inhibition, many integrase lignans inhibition, have and been topoisomerase identified inhibition with areantiviral included activities as the reported [11]. mechanisms Tubulin binding, of antiviral activities [12]. Here, we will highlight the antiviral activities and mechanisms of action reverse transcriptase inhibition, integrase inhibition, and topoisomerase inhibition are included as (MOA) of different lignans and their derivatives. the reported mechanisms of antiviral activities [12]. Here, we will highlight the antiviral activities and mechanisms2. Antiviral of E ffactionect and (MOA) MOA of different lignans and their derivatives. Lignans display a vast structural diversity due to the numerous potential coupling modes of the 2. Antiviralphenoxy Effect radicals and [ 13MOA]. As mentioned above, they can be grouped into two subclasses: classical lignans and neolignans. Next, we will discuss the antiviral lignans and possible MOA, according to different Lignanssubclasses, display and thena vast summarize structural them diversity in Table1 dueat the to end the of numerous this section. potential coupling modes of the phenoxy radicals [13]. As mentioned above, they can be grouped into two subclasses: classical lignans 2.1. Classical Lignans and neolignans. Next, we will discuss the antiviral lignans and possible MOA, according to different subclasses, andThe then classical summarize lignans contain them dimeric in Table structures 1 at the that end are of formedthis section. by a β -β0-linkage between two phenyl propane units, some of them with a different degree of oxidation in the side-chain and a different substitution pattern in the aromatic moieties. They can be classified into six 2.1. Classical Lignans major subtypes—dibenzylbutanes, dibenzylbutyrolactones, arylnaphthalenes/aryltetralins, substituted Thetetrahydro-furans, classical lignans 2,6-diarylfurofurans, contain dimeric andstructures dibenzocyclooctadienes that are formed [6,14 by]. Figurea β-β′2-linkage illustrates between the two phenyl propanestructures andunits, relationships some of amongthem them.with a different degree of oxidation in the side-chain and a different substitution pattern in the aromatic moieties. They can be classified into six major subtypes—dibenzylbutanes, dibenzylbutyrolactones, arylnaphthalenes/aryltetralins, substituted tetrahydro-furans, 2,6-diarylfurofurans, and dibenzocyclooctadienes [6,14]. Figure 2 illustrates the structures and relationships among them.

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TMP is the shorter title of tetra-O-methyl nordihydroguaiaretic acid. It is a methylated derivative of NDGAFigure and 2.2. Relationships Relationshipswas also initially between between founded di ffdifferenterent classicalin theclassical resin lignans. lignans.of the It depicts creosote It depicts the basicbush the mother [26].basic As nucleusmother the derivative structurenucleus of NDGA,ofstructure di itff erentwas of subtypestested different the of subtypes antiviral classical of lignans, effectsclassical the agains lignans, maint structuralWNV the main and feature structural ZIKV of simultaneously this feature subclass of this is the subclass withβ-β0 NDGA;linkage. is the the resultsDibenzylbutaneβ- β′showed linkage. both Dibenzylbutane (central compounds position) (central inhibited is theposition) basic the structure isinfe thection basic of ofstructure classical WNV lignan,ofand classical ZIKA, other lignan, with subtypes othergood of subtypes and lignans similar derive from this structure with different chemical reactions. IC50 values,of lignans and derive MOA from was this likely structur by impairinge with different viral chemical replication reactions. [24]. Meanwhile, Pollara showed that TMP2.1.1. inhibits Dibenzylbutanes poxvirus growth in vitro by preventing the efficient spread of virus particles from cell to2.1.1. cell Dibenzylbutanes [27]. Additionally, there were some reports regarding the antiviral activity of TMP against herpesDibenzylbutanes, simplex virus (HSV)which andare alsohuman known immunodeficiency as simple lignans, virus are (HIV) the simplest [28,29]. Moreover,classical lignans, it was whichmade intoare are the thevaginal only only lignanointment lignan subtype subtype for women without without with being being HPV-linked cyclized. cyclized. They cervical They are phenylpropane areintraepithelial phenylpropane dimersneoplasia dimers that and have that it β β showedhavea β-β′ alinkage. an- excellent0 linkage. Dibenzylbutane safety Dibenzylbutane profile lignans in Phase lignansalso I/II show trials also an [30]. show increased an increased diversity diversity due to multiple due to multiplepossible possibleoxidationBesides, oxidation states Xu isolatedalong states the alongfour butane new the butanelignanschain [15]. chainfrom Niranthin, [the15]. aerial Niranthin, partsnordihydroguaiaretic of nordihydroguaiaretic Justicia procumbens acid (Acanthaceae)(NDGA), acid (NDGA), and andterameprocol terameprocoltested their (TMP), activity (TMP), are againstthe are representative the HIV-1. representative One compound of compoundsthe news with secoisolariciresinol withantiviral antiviral activity activity dimethylether in this in subclass, this subclass, acetate and and Figure3 shows their structures. exhibitedFigure 3 shows anti-HIV-1 their structures.activity with an IC50 of 5.27 µM in vitro [31]. Niranthin. This compound was first isolated from Phyllanthus niruri Linn. (family Euphorbiaceae) [16], which has long been used in folk medicine for liver protection and anti-hepatitis B virus (HBV) in many Asian countries. Ray-L screened 25 compounds from Phyllanthus Species in vitro and niranthin showed the best anti-HBsAg activity among them [12]. When evaluated for the anti-HBV activity in vitro, niranthin was found to significantly decrease the secretion of HBsAg and HBeAg with IC50 values of 15.6 and 25.1 µM in the human HBV-transfected cell line HepG2.2.15, respectively. In vivo, niranthin treatment of the DHBV-infected ducklings significantly reduced the serum DHBV DNA, HBsAg, HBeAg, ALT, and AST. Mechanistic studies showed that niranthin inhibited not only Figure 3. StructuresStructures of dibenzylbutanes and corresponding compounds. DHBV DNA replication, but also HBV antigen expression, which suggests that niranthin acts as an anti-HBV agent through at least two or more targets [16]. 2.1.2.Niranthin. Dibenzylbutyrolactones This compound was first isolated from Phyllanthus niruri Linn. (family Euphorbiaceae) [16], whichNDGA has long was been isolated used from in folk the medicineleaves of Larrea for liver tridentat protectiona (Zygophyllaceae); and anti-hepatitis the plant B virus was (HBV) known in manyas creosoteDibenzylbutyrolactones, Asian bush, countries. which Ray-L has been screenedwhich traditionally are 25 also compounds known used as in from lignans- folkPhyllanthus medicineβ-β′-lactones(lignanolides), acrossSpecies differentin vitro countriesand are niranthin based and onshowedregions dibenzylbutanes, for the more best anti-HBsAgthan with 50 different9-9′epoxy activity diseases and among C9 carbonyl.[17]. them It was [ 12Lignanolides ].reported When evaluatedthat are NDGA often for found exerts the anti-HBVin beneficial the same activity effectsplants ason theirmonode-diverse diseases, hydrogenated like cancer, or renal didehydrogen damage, Alzheimer’sated compounds disease, and and corresponding other neurodegenerative derivatives. in vitro, niranthin was found to significantly decrease the secretion of HBsAg and HBeAg with IC50 valuesThepathologies representative of 15.6 [18–20]. and 25.1compounds Atµ theM inmolecular the with human antiviral level, HBV-transfected NDGA activiti ises a inpotent this cell linesubclass scavenger HepG2.2.15, are of arctigenin reactive respectively. oxygen (ATG), Inspeciesyatein, vivo, andniranthin[21]. hinokininNDGA treatment has (Figure been of identified4). the DHBV-infected to inhibit the ducklings replication significantly of the related reduced dengue the virus serum (DENV); DHBV DNA,MOA HBsAg,showedATG HBeAg,that was it initiallyinhibits ALT, and isolated DENV AST. Mechanisticinfectionfrom Arctium by studiestargeting lappa L showed. (Compositae).genome that replication niranthin So far, inhibited andthe researchviral notassembly onlyof antiviral DHBV [22]. activityDNAMoreover, replication, has NDGA been butmainly showed also focused HBV the antigeneffect on IAVagainst expression, and hepati HIV. which tisThe C erythrocytevirus suggests (HCV), that agglutination West niranthin Nile actsVirus test as showed(WNV), an anti-HBV thatand ATGagentZika Viruscan through inhibit (ZIKV) at the least in replication vitro two [23,24]. or more of Forthe targets influenzaIAV [in16 ].vitro, A viruses and the (IAV), inhibition NDGA was can shown suppress to be the 100% replication with a concentrationof IAV and the of induction 26.8 mM ofbased cytokines, on hemagglutination trypsin, and MMP-9, titer [32]. with In improved vivo, ATG animal can reduce survival lung [25]. index, See increaseTable 1 for the more survival details. rate of the infected mice, and induce the interferon levels of normal mice, which suggested that mechanistically ATG can induce the production of interferon [33]. ATG and its glycoside arctiin were also shown to be orally effective, but less than oseltamivir, the results suggested that it is a good choice of the combined arctiin with oseltamivir for IAV in immunocompromised mice that were infected with IAV [34]. Additionally, ATG strongly inhibited the expression of protein P17 and P24 of the HIV-1 in vitro. MOA showed that it targets reverse transcription [35]. Studies on the structure-activity relationship (SAR) showed that: (1) the structure of lactones is necessary; and, (2) the number and arrangement of phenolic hydroxyl groups are very important for the activity of lignanolides [36]. Yatein was isolated from Chamaecyparis obtuse (Cupressaceae). It could significantly suppress HSV-1 replication in HeLa cells without apparent cytotoxicity [37]. MOA showed that yatein can inhibit HSV-1 alpha gene expression, including the expression of the ICP0 and ICP4 genes, by arresting HSV-1 DNA synthesis and structural protein expression in HeLa cells [38]. Hinokinin was first isolated from the ether extract of Chamecyparis obtusa in 1933, and it was also found in different species of Phyllanthus (Euphobiaceae) [39], Aristolochia (Aristolochiaceae) [40], Piper (Piperaceae) [41], Virola (Myristicaceae) [42], Linum (Linaceae) [43], and so on. The anti-inflammatory, antimicrobial activities, and cytotoxicity of this compound have been extensively studied [44]. Meanwhile, it showed good antiviral activities against human HBV [12], HIV [45], SARS-virus (SARS-

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NDGA was isolated from the leaves of Larrea tridentata (Zygophyllaceae); the plant was known as creosote bush, which has been traditionally used in folk medicine across different countries and regions for more than 50 different diseases [17]. It was reported that NDGA exerts beneficial effects on diverse diseases, like cancer, renal damage, Alzheimer’s disease, and other neurodegenerative pathologies [18–20]. At the molecular level, NDGA is a potent scavenger of reactive oxygen species [21]. NDGA has been identified to inhibit the replication of the related dengue virus (DENV); MOA showed that it inhibits DENV infection by targeting genome replication and viral assembly [22]. Moreover, NDGA showed the effect against hepatitis C virus (HCV), West Nile Virus (WNV), and Zika Virus (ZIKV) in vitro [23,24]. For influenza A viruses (IAV), NDGA can suppress the replication of IAV and the induction of cytokines, trypsin, and MMP-9, with improved animal survival [25]. See Table1 for more details. TMP is the shorter title of tetra-O-methyl nordihydroguaiaretic acid. It is a methylated derivative of NDGA and was also initially founded in the resin of the creosote bush [26]. As the derivative of NDGA, it was tested the antiviral effects against WNV and ZIKV simultaneously with NDGA; the results showed both compounds inhibited the infection of WNV and ZIKA, with good and similar IC50 values, and MOA was likely by impairing viral replication [24]. Meanwhile, Pollara showed that TMP inhibits poxvirus growth in vitro by preventing the efficient spread of virus particles from cell to cell [27]. Additionally, there were some reports regarding the antiviral activity of TMP against herpes simplex virus (HSV) and human immunodeficiency virus (HIV) [28,29]. Moreover, it was made into vaginal ointment for women with HPV-linked cervical intraepithelial neoplasia and it showed an excellent safety profile in Phase I/II trials [30]. Besides, Xu isolated four new lignans from the aerial parts of Justicia procumbens (Acanthaceae) and tested their activity against HIV-1. One of the new secoisolariciresinol dimethylether acetate exhibited anti-HIV-1 activity with an IC50 of 5.27 µM in vitro [31].

2.1.2. Dibenzylbutyrolactones

Dibenzylbutyrolactones, which are also known as lignans-β-β0-lactones(lignanolides), are based Moleculeson dibenzylbutanes,2019, 24, x with 9-90epoxy and C9 carbonyl. Lignanolides are often found in the same5 of 19 plants as theirmonode- hydrogenated or didehydrogenated compounds and corresponding derivatives. CoV)The [46], representative and human compounds cytomegalovirus with antiviral (HCMV) activities [47]. The in this defects subclass are are all arctigenin data from (ATG), in vitro yatein, and no in-depthand hinokininresearch (Figureon MOA.4).

FigureFigure 4. Structures 4. Structures of ofdibenzylbutyrolactone dibenzylbutyrolactone andand corresponding corresponding compounds. compounds.

ATG was initially isolated from Arctium lappa L. (Compositae). So far, the research of antiviral 2.1.3. Arylnaphthalenes/Aryltetralins activity has been mainly focused on IAV and HIV. The erythrocyte agglutination test showed that ATGThe relationship can inhibit the between replication the of arylnaphthalene the IAV in vitro, andand thearyltetralin inhibition subclasses was shown is to of be interest 100% with due to theira deceptive concentration structural of 26.8 similarities. mM based on Both hemagglutination of these compounds titer [32 are]. In based vivo, ATGon dibenzylbutanes can reduce lung and formedindex, by increasecyclization the survivalof six sites rate in of one the C6-C3 infected unit mice, and and seven induce sites the in interferon another levelsC6-C3 of unit. normal Their mice, subtle which suggested that mechanistically ATG can induce the production of interferon [33]. ATG and its structural difference lies in whether the B ring consists of a benzene ring or a six-membered ring. glycoside arctiin were also shown to be orally eﬀective, but less than oseltamivir, the results suggested Arylnaphthalenes are also named benzene tetrahydronaphthalene, which means that the B-ring that it is a good choice of the combined arctiin with oseltamivir for IAV in immunocompromised structure consists of six-membered rings. Aryltetralins are named benzene naphthalene, because the B-ring structure consists of benzene. The representative compounds of arylnaphthalene are diphyllin and 6-deoxyglucose-diphyllin (DGP), and podophyllotoxin represents aryltetralin (Figure 5). Diphyllin is a natural component of plants with a naphthalene and one hydroxyl lignans [48]. It exists in Haplophyllum alberti-regelii, H. bucharicum, and H. perforatum (Rutaceae) [49]. It showed broad- spectrum antiviral activity as a potent vacuolar ATPase (V-ATPase) inhibitor [50]. For example, it blocked ZIKV infection in HT1080 cells with an IC50 of ~0.06 µM [51]; it also altered the cellular susceptibility to IAV through the inhibition of endosomal acidification, thus interfering with downstream virus replication [52]. There are more reports regarding the antiviral effect of glycosylated diphyllin. DGP, which is also known as patentiflorin A, was first isolated from plant of Justicia gendarussa (Acanthaceae) [53]. As the glycosylated diphyllin, it exhibited anti-ZIKV activity both in vitro and in vivo, and it displayed broad-spectrum antiviral activity against other flaviviruses. MOA showed that DGP inhibits ZIKV fusion with cellular membranes and infection by preventing the acidification of endosomal/lysosomal compartments in the target cells [51]. Besides, it also displays potent activity against a broad spectrum of HIV strains with IC50 values in the range of 15–21 nM [54]; MOA showed that it acts as a potential inhibitor of HIV-1 reverse transcription [55]. Podophyllotoxin is one of the best-characterized lignans which is a type of aryletralin lignan lactone, and it was initially found in Dysosmae Verspiellis Rhixoma Et Radix or American mandrake or mayapple (all belong to family Berberidaceae) [3]. One of the research interests of podophyllotoxin is focused on anti-cancer activities [56,57]. Furthermore, it was first cited in 1942 as a topical treatment for venereal warts (Condyloma acuminatum), which is an ailment that is caused by papillomavirus [11]. The clinical randomized controlled trial data with 45 cases showed that podophyllotoxin 0.5% solution has a beneficial effect on anoenital warts and it is effective and safe for untreated anogenital warts in immunocompetent individuals [58].

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mice that were infected with IAV [34]. Additionally, ATG strongly inhibited the expression of protein P17 and P24 of the HIV-1 in vitro. MOA showed that it targets reverse transcription [35]. Studies on the structure-activity relationship (SAR) showed that: (1) the structure of lactones is necessary; and, (2) the number and arrangement of phenolic hydroxyl groups are very important for the activity of lignanolides [36]. Yatein was isolated from Chamaecyparis obtuse (Cupressaceae). It could signiﬁcantly suppress HSV-1 replication in HeLa cells without apparent cytotoxicity [37]. MOA showed that yatein can inhibit HSV-1 alpha gene expression, including the expression of the ICP0 and ICP4 genes, by arresting HSV-1 DNA synthesis and structural protein expression in HeLa cells [38]. Hinokinin was first isolated from the ether extract of Chamecyparis obtusa in 1933, and it was also found in different species of Phyllanthus (Euphobiaceae) [39], Aristolochia (Aristolochiaceae) [40], Piper (Piperaceae) [41], Virola (Myristicaceae) [42], Linum (Linaceae) [43], and so on. The anti-inﬂammatory, antimicrobial activities, and cytotoxicity of this compound have been extensively studied [44]. Meanwhile, it showed good antiviral activities against human HBV [12], HIV [45], SARS-virus (SARS-CoV) [46], and human cytomegalovirus (HCMV) [47]. The defects are all data from in vitro and no in-depth research on MOA.

2.1.3. Arylnaphthalenes/Aryltetralins The relationship between the arylnaphthalene and aryltetralin subclasses is of interest due to their deceptive structural similarities. Both of these compounds are based on dibenzylbutanes and formed by cyclization of six sites in one C6-C3 unit and seven sites in another C6-C3 unit. Their subtle structural diﬀerence lies in whether the B ring consists of a benzene ring or a six-membered ring. Arylnaphthalenes are also named benzene tetrahydronaphthalene, which means that the B-ring structure consists of six-membered rings. Aryltetralins are named benzene naphthalene, because the B-ring structure consists of benzene. The representative compounds of arylnaphthalene are diphyllin Moleculesand 2019 6-deoxyglucose-diphyllin, 24, x (DGP), and podophyllotoxin represents aryltetralin (Figure5). 6 of 19

FigureFigure 5. Structures 5. Structures of arylnaphthalene/arylte of arylnaphthalene/aryltetralintralin and and corresponding corresponding compounds.compounds.

2.1.4. SubstitutedDiphyllin Tetrahydrofurans is a natural component of plants with a naphthalene and one hydroxyl lignans [48]. It exists in Haplophyllum alberti-regelii, H. bucharicum, and H. perforatum (Rutaceae) [49]. It showed broad-spectrumSubstituted tetrahydrofurans antiviral activity as ar ae potent also vacuolardesignated ATPase as (V-ATPase) monoepoxylignans. inhibitor [50]. It For refers example, to the formationit blocked of ZIKVfuran infectionor tetrahydrofuran in HT1080 cells structures with an ICthat50 of are ~0.06 basedµM[ 51on]; itdibenzylbutanes; also altered the the representativecellular susceptibility compounds to are IAV lariciresinol through the (LA) inhibition and the of endosomalderivatives. acidiﬁcation, Figure 6 shows thus interferingthe structures’ details. There are lots of traditional medicinal plants, such as Patrinia scabra Bunge (Caprifoliaceae) [59], Stelleropsis tianschanica (Rutaceae) [60], and Rubia philippinensis (Rubiaceae) [61] with ingredients of LA and the derivatives. Among them, the plant of Isatis indigotica Fort (Cruciferae) was the most studied because of the root. The root of Isatis indigotica Fort is a very famous antiviral traditional medicine in China and is called Radix Isatidis (Banlangen in Chinese); during the prevalence of SARS in 2003, the traditional Chinese medicine products containing Radix Isatidis were once out of stock in China. So far, lots of derivatives with LA structure were isolated from Radix Isatidis and antiviral activities were demonstrated. For example, lariciresinol-4-O-β-D-glucopyranoside was shown to inhibit the IAV- induced pro-inflammatory response [62]; the underlying defense mechanism against IAV infection is from pharmacological actions on the immune system, signal transduction, cell cycle, and metabolism [63]; (7′R,8S)-9′-lariciresinol-(alpha-methyl)-butanoate showed a low amount of activity to anti-HIV-1 [64]; Isatindolignanoside A was shown to have antiviral activity against Coxsackievirus B3 (CVB3), with IC50 and SI values of 25.9 µM and >3.9, respectively [65]; Clemastanin B (7S,8R,8′R- (−)-lariciresinol-4,4′-bis-O-β-D-glucopyranoside), as the active ingredient of Radix Isatidis, it showed to inhibit different subtypes of human IAVs (H1N1, H3N2, and influenza B) [66].

H3CO O O Oglc NH HO OCH3 OH O H CO 3 OH OCH 3 OH OH Oglc

Substituted tetrahydrofuran Lariciresinol Isatindolignanoside A

MeO GlcO MeO O O O GlcO H3CO HO OH OBuMe OCH OH 3 OMe OMe OGlc OH OH

Clemastanin B lariciresinol-4-O- - (7ʹR, 8S)-9ʹ-lariciresinol- D-glucopyranoside ( -methyl)-butanoate Figure 6. Structures of substituted tetrahydrofurans and corresponding compounds.

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Molecules 2020, 25, 183 6 of 17 Figure 5. Structures of arylnaphthalene/aryltetralin and corresponding compounds. with downstream virus replication [52]. There are more reports regarding the antiviral effect of 2.1.4. Substitutedglycosylated Tetrahydrofurans diphyllin. DGP, which is also known as patentiflorin A, was first isolated from plant of Justicia gendarussa Substituted(Acanthaceae) tetrahydrofurans [53]. As the glycosylated are also diphyllin, designated it exhibited as anti-ZIKVmonoepoxylignans. activity both in It vitro refersand to the formationin vivoof, andfuran it displayed or tetrahydrofuran broad-spectrum antiviralstructures activity that against are other based flaviviruses. on dibenzylbutanes; MOA showed the representativethat DGP compounds inhibits ZIKV are fusion lariciresinol with cellular (LA) membranes and the and derivatives. infection by preventing Figure 6 theshows acidification the structures’ details. Thereof endosomal are lots/lysosomal of traditional compartments medicinal in the targetplants, cells such [51]. as Besides, Patrinia it also scabra displays Bunge potent (Caprifoliaceae) activity [59], Stelleropsisagainst a tianschanica broad spectrum (Rutaceae) of HIV strains [60], with and IC50 Rubiavalues philippinensis in the range of (Rubiaceae) 15–21 nM [54]; [61] MOA with showed ingredients that it acts as a potential inhibitor of HIV-1 reverse transcription [55]. of LA and thePodophyllotoxin derivatives. isAmong one of thethem, best-characterized the plant of Isatis lignans indigotica which is aFort type (Cruciferae) of aryletralin lignanwas the most studied lactone,because and of itthe was root. initially found in Dysosmae Verspiellis Rhixoma Et Radix or American mandrake or Themayapple root of Isatis (all belong indigotica to family Fort Berberidaceae) is a very famous [3]. One ofantiviral the research traditional interests of medicine podophyllotoxin in China is and is called Radixfocused Isatidis on anti-cancer (Banlangen activities in [Chinese);56,57]. Furthermore, during itthe was prevalence first cited in 1942of SARS as a topical in 2003, treatment the fortraditional Chinesevenereal medicine warts products (Condyloma containing acuminatum), Radix which Isatidis is an were ailment once that out is caused of stock by papillomavirus in China. So [11 far,]. lots of The clinical randomized controlled trial data with 45 cases showed that podophyllotoxin 0.5% solution derivativeshas awith beneficial LA e ffstructureect on anoenital were warts isolated and it isfrom effective Radix and safe Isatidis for untreated and antiviral anogenital wartsactivities in were demonstrated.immunocompetent For example, individuals lariciresinol-4- [58]. O-β-D-glucopyranoside was shown to inhibit the IAV- induced pro-inflammatory response [62]; the underlying defense mechanism against IAV infection 2.1.4. Substituted Tetrahydrofurans is from pharmacological actions on the immune system, signal transduction, cell cycle, and metabolism Substituted[63]; (7′R, tetrahydrofurans8S)-9′-lariciresinol-(alpha-methyl)-butanoate are also designated as monoepoxylignans. showed It refers a low to the amount formation of activity to anti-HIV-1of furan [64]; or tetrahydrofuran Isatindolignanoside structures thatA was are basedshown on to dibenzylbutanes; have antiviral the activity representative against compounds Coxsackievirus are lariciresinol (LA) and the derivatives. Figure6 shows the structures’ details. There are lots of B3 (CVB3),traditional with IC medicinal50 and SI plants, values such of as 25.9Patrinia µM scabra andBunge >3.9, (Caprifoliaceae)respectively [65]; [59], Stelleropsis Clemastanin tianschanica B (7S,8R,8′R- (−)-lariciresinol-4,4(Rutaceae) [60′-bis-], andORubia-β-D-glucopyranoside), philippinensis (Rubiaceae) as [the61] withactive ingredients ingredient of LA of and Radix the derivatives.Isatidis, it showed to inhibitAmong different them, subtypes the plantof ofIsatis human indigotica IAVsFort (H1N1, (Cruciferae) H3N2, was and the mostinfluenza studied B) because [66]. of the root.

H3CO O O Oglc NH HO OCH3 OH O H CO 3 OH OCH 3 OH OH Oglc

Substituted tetrahydrofuran Lariciresinol Isatindolignanoside A

MeO GlcO MeO O O O GlcO H3CO HO OH OBuMe OCH OH 3 OMe OMe OGlc OH OH

Clemastanin B lariciresinol-4-O- - (7ʹR, 8S)-9ʹ-lariciresinol- D-glucopyranoside ( -methyl)-butanoate Figure Figure6. Structures 6. Structures of substituted of substituted tetrahydrofurans tetrahydrofurans and and corresponding corresponding compounds. compounds.

The root of Isatis indigotica Fort is a very famous antiviral traditional medicine in China and is called Radix Isatidis (Banlangen in Chinese); during the prevalence of SARS in 2003, the traditional Chinese medicine products containing Radix Isatidis were once out of stock in China. So far, lots of derivatives with LA structure were isolated from Radix Isatidis and antiviral activities were demonstrated. For example, lariciresinol-4-O-β-d-glucopyranoside was shown to inhibit the IAV-induced pro-inﬂammatory response [62]; the underlying defense mechanism against IAV Molecules 2019, 24, x 7 of 19

2.1.5. 2,6-Diarylfurofurans 2,6-diarylfurofuran, which is also known as bisepoxylignan, is a lignan with a double Molecules 2020, 25, 183 7 of 17 tetrahydrofuran ring structure, which is formed by two side chains of phenylpropanoid interlinked to form two epoxy structures. There are a few reports of these compounds on antiviral activities Molecules 2019infection, 24, x is from pharmacological actions on the immune system, signal transduction, cell cycle, 7 of 19 (Figure 7). and metabolism [63]; (70R,8S)-90-lariciresinol-(alpha-methyl)-butanoate showed a low amount of 2.1.5.Phillygenin 2,6-Diarylfurofuransactivity to is anti-HIV-1 the major [64 active]; Isatindolignanoside constituent of Fructus A was shownForsythiae to have (Oleaceae). antiviral It activity can suppresses against high glucose-inducedCoxsackievirus lipid B3 accumulation (CVB3), with IC50 andand SIit valueshas antibacterial of 25.9 µM and and>3.9, antioxidant respectively [65 activities]; Clemastanin [56], and is 2,6-diarylfurofuran,B(7S,8R,8 R-( )-lariciresinol-4,4 which is-bis- alsoO- β-knownd-glucopyranoside), as bisepoxylignan, as the active ingredientis a lignan of Radix with Isatidis a, double could also be a potential0 − therapeutic0 agent for alleviating inflammation [57]. Antiviral studies show tetrahydrofuranthat phillygeninit showed hasring to inhibit good structure, di protectiveﬀerent which subtypes effects is offormed human against by IAVs infectionstwo (H1N1, side H3N2, chainsthat andare of inﬂuenzacaused phenylpropanoid by B) [IAV;66]. it could interlinked reduce toinflammation form 2.1.5.two 2,6-Diarylfurofuransepoxy that is structures. caused by IAVThere in arevivo a infew the repo meanwhilerts of these [58]. compounds on antiviral activities (Figure 7). Sesamin2,6-diarylfurofuran, was isolated from which the seeds is also of known Sesamum as bisepoxylignan,indicum (Pedaliaceae). is a lignan It has with anti-inflammatory a double cytokinesPhillygenintetrahydrofuran in human is the ringmajorPBMCs structure, active that which constituent are is formedinduced of by Fructus twoby side H1N1 Forsythiae chains [67]. of phenylpropanoid (Oleaceae). However, It canthere interlinked suppresses is no to report high glucose-induceddemonstratingform two its epoxy lipid direct structures. accumulation anti-influenza There are and aactivity. few it reportshas antibacterial of these compounds and onantioxidant antiviral activities activities (Figure [56],7). and is could also be a potential therapeutic agent for alleviating inflammation [57]. Antiviral studies show that phillygenin has good protective effects against infections that are caused by IAV; it could reduce inflammation that is caused by IAV in vivo in the meanwhile [58]. Sesamin was isolated from the seeds of Sesamum indicum (Pedaliaceae). It has anti-inflammatory cytokines in human PBMCs that are induced by H1N1 [67]. However, there is no report demonstrating its direct anti-influenza activity.

FigureFigure 7. Structures 7. Structures of 2,6-diarylfurofurans of 2,6-diarylfurofurans and and corresponding corresponding compounds. compounds.

Phillygenin is the major active constituent of Fructus Forsythiae (Oleaceae). It can suppresses 2.1.6. Dibenzocycloocteneshigh glucose-induced lipid accumulation and it has antibacterial and antioxidant activities [56], and is Thecould structure also be of a potential this subclass therapeutic of agentlignans for alleviatinghas not only inflammation biphenyl [57 ].structure, Antiviral studies but also show an eight- that phillygenin has good protective effects against infections that are caused by IAV; it could reduce memberedinflammation ring structure that is causedsynthesized by IAV inby vivo biphenyl in the meanwhile and side [ 58chainring.]. Figure 8 shows the structures of dibenzocyclooctadiene and the corresponding compounds. So far, more than 150 lignans have SesaminFigure was 7. isolated Structures from of the 2,6-diarylfurofurans seeds of Sesamum indicum and corresponding(Pedaliaceae). It compounds. has anti-inflammatory been isolatedcytokines and in humanidentified PBMCs from that more are induced than by 60 H1N1 species [67]. of However, Schisandraceae there is no family report demonstrating [68]. The reason of its direct anti-influenza activity. 2.1.6.dibenzocyclooctene Dibenzocyclooctenes lignans are called ‘Schisandra chinensis lignans’, even in the professional scientific2.1.6. literature Dibenzocyclooctenes [69]. The structure of this subclass of lignans has not only biphenyl structure, but also an eight- membered ringThe structurestructure of thissynthesized subclass of lignans by biphenyl has not only and biphenyl side chainring. structure, but Figure also an 8 eight-membered shows the structures ring structure synthesized by biphenyl and side chainring. Figure8 shows the structures of of dibenzocyclooctadienedibenzocyclooctadiene and and the the corresponding corresponding compounds. compounds. So far,So morefar, more than 150than lignans 150 lignans have have been isolatedbeen isolated and identified and identified from from more more than than 60 60 species of ofSchisandraceae Schisandraceaefamily family [68]. The [68]. reason The ofreason of dibenzocyclooctenedibenzocyclooctene lignans lignans are are called called ‘Schisandra ‘Schisandra chinensis chinensis lignans’, lignans’, even in the professionaleven in the scientific professional scientificliterature literature [69 ].[69].

Figure 8. Structures of dibenzocyclooctene and corresponding compounds.

Molecules 2020, 25, 183 8 of 17

Schisandra Chinensis (Turcz.) Baill. is the most famous plant in Schisandraceae family, and the fruits (called Fructus Schizandrae) were widely used as a traditional Chinese medicine for treating hepatitis, myocardial disorders, and hyperlipidemia and neurodegenerative diseases in the countries of East Asia and others [70–72]. In this plant, nine major bioactive lignans were identified as dibenzocyclooctenes, they are schisandrol A, schisandrol B, angeloylgomisin H, gomisin G, schisantherin A, schisanhenol, schisandrin A, schisandrin B, and schisandrin C [73]. In terms of antiviral activities, we have found that schisandrin A inhibits DENV replication via upregulating the antiviral interferon responses through theMolecules STAT 2019 signaling, 24, x pathway [74]. Schisandrin A and schisandrin B exhibited antiviral activity against8 of 19 HIV [75], and schizandrin C was shown to be the most active compound in protection against liver injuryBicyclol, in mice.has been A derivative approved of as schizandrin a hepatoprotectant C, Bicyclol, by has the been Chines approvede Food as and a hepatoprotectant Drug Administration by the Chinese(CFDA) Foodfor the and treatment Drug Administration of liver injury in (CFDA) 2004 [76]. for the treatment of liver injury in 2004 [76]. Bicyclol(4,4′0-dimethoxy-5,6,5-dimethoxy-5,6,5′,60,6′-bis(methylenedioxy)-2-hydroxymethyl-20-bis(methylenedioxy)-2-hydroxymethyl-2′-methoxycarbonyl0-methoxycarbonyl biphenyl) isis an an analog analog of theof activethe active component component schizandrin schizandrin C from CFructus from SchiznadraeFructus Schiznadrae[77], as illustrated [77], as inillustrated Figure9 .in Bicyclol Figure 9. was Bicyclol shown was to shown have activities to have activitiesin vitro inand vitroin and vivo in. Clinicalvivo. Clinical data showeddata showed that itthat could it could inhibit inhibit virus virus replication replication in patients in patients that that were were infected infected with with HBV, HBV, and and the ditheff erencedifference of the of responsethe response to bicyclol to bicyclol therapy therapy between between HBV HBV genotypes genotypes B B and and C C was was not not statisticallystatistically significantsignificant [78]. [78]. Other results showed that that bicyclol bicyclol significantly significantly inhibited inhibited HCV HCV replication replication inin vitro vitro andand in inhepatitis hepatitis C Cpatients patients [79]. [79 ].Mechanistic Mechanistic studies studies suggest suggest that that anti anti-hepatitis-hepatitis activity activity of of bicyclol bicyclol is is through thethe modulation ofof cytotoxiccytotoxic T T lymphocytes lymphocytes [ 76[76],], and and by by up-regulating up-regulating the the host host restrictive restrictive factor factor (GLTP) (GLTP) for HCVfor HCV replication replication and and causing causing the spontaneousthe spontaneous restriction restriction of HCV of HCV replication replication [79]. Bicyclol[79]. Bicyclol is now is usednow toused treat to thetreat patients the patients with chronicwith chronic hepatitis hepatitis B in China B in China [80]. [80].

Figure 9.9. BicyclolBicyclol as as an an anti-HBV anti-HBV drug drug [76 ].[76]. Schizandrin Schizandrin C was C isolatedwas isolated from F.from Schizandrae F. Schizandraeand veriﬁed and asverified the most as activethe most compound active compound in protection in againstprotection liver against injury inliver mice. injury DDB in (Dimethyl mice. DDB dicarboxylate (Dimethyl biphenyl)dicarboxylate as an biphenyl) analog of as schizandrin an analog of C schizandrin has been widely C has used been for wide thely improvement used for the improvement of the abnormal of liverthe abnormal function ofliver CHB function hepatitis of inCH China.B hepatitis Bicyclol in asChina. a novel Bicyclol substitute as a fornovel DDB substitute was found for toDDB be more was efoundﬀective to inbe protectionmore effective against in protection liver injury against and was liver also injury showed and was to inhibit also sh hepatitisowed to virus inhibit replication hepatitis invirus vitro replication and in vivo. in vitro and in vivo.

RubrifloralignanRubrifloralignan AA was was isolated isolated from from another another species species of Schisandraceae of Schisandraceaefamily— Schisandrafamily—Schisandra rubriflora. Itrubriflora can not. It only can inhibitsnot only the inhibits formation the format of syncytiumion of syncytium induced byinduced HIV-1IIIB by HIV-1 and cellШB deathand cell induced death byinduced HIV-1, by but HIV-1, it also but inhibits it also theinhibits replication the replication of HIV. Mechanistically,of HIV. Mechanistically, rubrifloralignan rubrifloralignan A was shownA was toshown inhibit to inhibit the early the early stage stage in HIV-1 in HIV-1 replication replication [81]. [81]. The The derivative, derivative, (+/ (+/)-Gomisin−)-Gomisin M1, M1, exhibitedexhibited − the mostmost potentpotent anti-HIVanti-HIV activity,activity, withwith ECEC5050 and SI values of <<0.650.65 µMµM and >>68,68, respectively [82]. [82]. Halogenated gomisin J derivatives were shown to be a nonnucleoside inhibitorinhibitor of HIV type 1 reverse transcriptase [[83].83].

2.2. Neolignans β β Neolignans are are a a class class of of lignans lignans that that do donot notcontain contain the β the-β′ (also- 0 referred(also referred to as an to 8-8 as′) anphenyl- 8-80) phenyl-propanepropane linkage linkagethat are thatcharacteristic are characteristic of classical of classicallignans. lignans.They can They be further can be grouped further groupedinto different into disubtypesﬀerent subtypesbased on based the nature on the natureand position and position of the oflinkage the linkage between between the phenylpropane the phenylpropane units. units. In Incontrast contrast to toclassical classical lignans, lignans, there there are are only only a afew few reports reports on on the the antiviral antiviral activities activities of of neolignans. Figure 10 shows the structuresstructures ofof somesome neolignanneolignan compounds.compounds. 1,4-Benzodioxane lignans. This subtype of neolignans has received significant attention through the years due to their good biological activities. One representative is Silymarin flavonolignans, which were isolated from the seeds of Silybum marianum [84] and they are the most commonly consumed herbal products among the HCV-infected patients in western countries [85]. Besides, they were showed to possess antioxidative, anti-inflammatory, and hepatoprotective activities [86]. Recent studies have also documented the antiviral activities of silymarin and its derivatives against HCV and other viruses [87]. Its derivative intravenous silibinin, which was named Legalon® SIL, and has been shown to block HCV production and increase anti-inflammatory and anti-proliferative gene expressions without affecting serum albumin levels in the clinical phase [88]. In addition, it was showed that silymarin inhibited the replication of IAV [89]. MOA showed that silymarin inhibited

Molecules 2019, 24, x 9 of 19

Molecules 2020, 25, 183 9 of 17 the late mRNA synthesis during IAV replication. It was also reported that silymarin inhibited other viruses, such as DENV, Chikungunya virus, Mayaro virus, HIV, and HBV [86]. (7′R,81,4-Benzodioxane′S,7′′R,8′′S)-erythro-strebluslignanol lignans. This subtype of neolignansG, a neolignan has received and also significant a dimer attentionof strebluslignanols, through the years due to their good biological activities. One representative is Silymarin flavonolignans, was isolated from the root of Streblus asper. It exhibits significant anti-HBV activities in the secretion which were isolated from the seeds of Silybum marianum [84] and they are the most commonly of HBsAg and HBeAg, with IC50 values of 3.67 and 14.67 µM, respectively [90]. consumed herbal products among the HCV-infected patients in western countries [85]. Besides, theySecolignans were showed or Cleavage to possess lignans. antioxidative, These neolignans anti-inflammatory, are presumed and hepatoprotective to be obtained activities by the pyrolysis, [86]. oxidation,Recent and studies cyclization have also of documented arylnaphthalenes the antiviral [91]. activities Most of of the silymarin reported and compounds its derivatives were against isolated fromHCV the andplants other of viruses genus [ 87Peperomia]. Its derivative (Piperaceae) intravenous [92], silibinin, Urtica which(Urticaceae) was named [93], Legalon and ®SelaginellaSIL, (Selaginellaceae)and has been shown[94]. toThey block exhibited HCV production anti-tumor and increase [95], anti-inflammatory anti-inflammatory and [96], anti-proliferative anti-HIV, insect antifeedantgene expressions [97], and without other pharmacological affecting serum albumin activities. levels Two in the compounds, clinical phase Peperomins [88]. In addition, A and it B, was which wereshowed isolated that from silymarin Peperomia inhibited pellucida the replication(Piperaceae) of IAV[98], [ 89showed]. MOA modera showedte that inhibitory silymarin effects inhibited on HIV- 1 IIIBthe growth late mRNA in C8166 synthesis cells, duringwith EC IAV50 values replication. of around It was 5 also µM. reported However, that it silymarin appears inhibited that the otherobserved bioactivityviruses, was such due as DENV, to cytotoxicity Chikungunya [99]. virus, Mayaro virus, HIV, and HBV [86].

FigureFigure 10. 10. StructuresStructures of of some some neolignanneolignan compounds. compounds.

(7 R,8 S,7”R,8”S)-erythro-strebluslignanol G, a neolignan and also a dimer of strebluslignanols, 0 0 was isolated from the root of Streblus asper. It exhibits significant anti-HBV activities in the secretion of HBsAg and HBeAg, with IC50 values of 3.67 and 14.67 µM, respectively [90]. Secolignans or Cleavage lignans. These neolignans are presumed to be obtained by the pyrolysis, oxidation, and cyclization of arylnaphthalenes [91]. Most of the reported compounds were isolated from the plants of genus Peperomia (Piperaceae) [92], Urtica (Urticaceae) [93], and Selaginella (Selaginellaceae) [94]. They exhibited anti-tumor [95], anti-inflammatory [96], anti-HIV, insect antifeedant [97], and other pharmacological activities. Two compounds, Peperomins A and B, which were isolated from Peperomia pellucida (Piperaceae) [98], showed moderate inhibitory effects on HIV-1 IIIB growth in C8166 cells, with EC50 values of around 5 µM. However, it appears that the observed bioactivity was due to cytotoxicity [99].

Molecules 2020, 25, 183 10 of 17

Table 1. The antiviral activities of lignans and their derivatives from plants.

Subclass Cpd From Plants Organs Virus(es) IC50 (µM) CC50 (µM) Status MOA/Targets Refs Phyllanthus niruri L. 369.9 In HepG In Vitro inhibits DHBV DNA replication and HBV antigen Niranthin Whole plants HBV 15.6~25.1 [12,16] (Euphorbiaceae) 2.2.15 In Vivo expression. DENV No data No data targets genome replication and viral assembly NDGA-mediated alterations of host lipid HCV 30 70 in Huh7 metabolism, LD morphology, and VLDL transport aﬀect HCV proliferation Larrea tridentate In Vitro NDGA Leaves (resin) (Zygophyllaceae) WNV: disturb the lipid metabolism probably by [22–25] WNV/ZIKV 7.9/9.1 162.1 in Vero interfering with the sterol regulatory element binding proteins (SREBP) pathway suppresses replication of IAV and induction of IAV In Vivo cytokines, trypsin, and MMP-9, with improved Dibenzylbutanes animal survival WNV/ZIKV 9.3/5.7 1071.0 in Vero In Vitro impaires viral replication prevents the eﬃcient spread of virus particles poxvirus No data No data In Vitro from cell to cell Larrea tridentata HSV 43.5 160 in Vero In Vitro TMP inhibits both these viruses replication by TMP Leaves (resin) blocking the binding of the host cell transcription (Zygophyllaceae) HIV 25 No data In Vitro [24,26–30] factor, Sp1, to viral promoters. selectively interferes with HPV viral genes E6/E7 with Sp1dependent promoters, and induces HPV In Clinical apoptosis by inactivation of the CDC2/cyclin B complex (maturation promoting factor) and production and phosphorylation of survivin Secoisolariciresinol Justicia procumbens Air-dried HIV-1 5.27 11.6 In Vitro waiting for the deeper research [31] dimethyleTher acetate (Acanthaceae) aerial parts In Vitro Arctium lappa L. IAV No data No data induce the production of interferon ATG Whole plants In Vivo (Compositae) [32–36] inhibit the expression of protein P17 and P24 of HIV-1 No data No data In Vitro the HIV-1 virus inhibiting HSV-1 alpha gene expression, Dibenzyltyrolactones Chamaecyparis obtuse including expression of the ICP0 and ICP4 genes, Yatein Dried leaves HSV-1 30.6 5.5 >100 In Vitro [37,38] (Cupressaceae) ± and by arresting HSV-1 DNA synthesis and structural protein expression in HeLa cells HBV No data No data In Vitro Chamecyparis obtusa HIV <28 527 in H9 Hinokinin Woods waiting for the deeper research [12,45–47] (Cupressaceae) SARS-CoV >10 >750 in Vero HCMV No data 115 in A549 Molecules 2020, 25, 183 11 of 17

Table 1. Cont.

Subclass Cpd From Plants Organs Virus(es) IC50 (µM) CC50 (µM) Status MOA/Targets Refs genus Haplophyllum ZIKV 0.06 3.48 in MDCK vacuolar ATPase (V-ATPase) inhibitors Epigeal part In Vitro (Rutaceae) Diphyllin 0.1–0.6 in [48–52] inhibit endosomal acidification, thus interfering IAV different 24.1 in A549 with downstream virus replication strains Arylnaphthalenes prevented the acidification of In Vitro endosomal/lysosomal compartments in target Justicia gendarussa Stems and ZIKV 0.01–0.07 15–32 DGP In Vivo cells, thus inhibiting ZIKV fusion with cellular (Acanthaceae) leaves [51,53–55] membranes and infection. HIV-1 15–21 nM No data In Vitro HIV-1 reverse transcription Dysosmae Verspiellis & Roots and Papilloma Aryltetralins Podophyllum peltatum Launched in China waiting for the deeper research [3,11,56–58] stems virus (Berberidaceae) lariciresinol-4-O- pharmacological actions on the immune system, IAV 50 µg/mL >200 µg/mL In Vitro [62,63] β-d-glucopyranoside signal transduction, cell cycle, and metabolism (7 R, 8S)-9 -lariciresinol- 0.67mM in Substituted 0 0 Isatis indigotica Fort HIV-1 0.66 mM In Vitro No report [64] (α-methyl)-butanoate Roots C8166 tetrahydrofurans (Cruciferae) Isatindolignanoside A CVB3 25.9 >100 In Vitro waiting for the deeper research [65] 0.087–0.72 targets viral endocytosis, uncoating or RNP Clemastanin B IAV 6.2–7.5 mg/mL In Vitro [66] mg/mL export from the nucleus Fructus Forsythiae Phillygenin Fruits IAV In Vivo reduce inflammation caused by IAV. [57,58] (Oleaceae) 2,6-diarylfurofurans inflammatory Sesamum indicum cytokines Sesamin Seeds No data No data In Vitro anti-inflammatory cytokines in human PBMCs [67] (Pedaliaceae) induced by H1N1 Analogue of schizandrin C from inhibit virus replication in patients Dibenzocyclooctene Bicyclol HBV Launched in China [76–80] Fructus Schiznadrae infected with HBV modulation of cytotoxic T lymphocytes In vitro/Vivo/ up-regulating the host restrictive factor (GLTP) HCV 30 No data Clinical for HCV replication, and causing spontaneous restriction of HCV replication Schisandra rubriflora Rubrifloralignan A Fruits HIV-1 40.46 123.35 In Vitro inhibit the early stage of HIV-1 replication [81–83] (Schisandraceae) blocked HCV production, increased anti-inflammatory, anti-proliferative gene 1,4-Benzodioxane Silybum marianum HCV In Clinical Silymarin Seeds expressions without affecting serum [84–89] lignans (Compositae) albumin levels IAV No data No data In Vitro inhibition of late viral RNA synthesis Dimer of (7 R,8 S,7”R,8”S)-erythro- Streblus asper 3.67/HBsAg 0 0 Roots HBV No data In Vitro inhibit the secretion of HBsAg and HBeAg [90] strebluslignanols strebluslignanolG (Moraceae) 14.67/HBeAg Peperomia pellucida related to the cytotoxicity expressed as Secolignans Peperomins A&B Whole plants HIV-1 IIIB 5 No data In Vitro [98,99] (Piperaceae) CC50 of compounds

IC50, inhibitory concentration of compound that produces 50% inhibition of virus-induced cytopathic eﬀects; CC50, concentration that reduces the growth of target cells by 50%. Molecules 2020, 25, 183 12 of 17

3. Prospects of Lignans and Their Derivatives in Antiviral Development Lignans are traditionally defined as a class of secondary metabolites that are derived from the oxidative dimerization of two or more phenylpropanoid units. They boast a vast structural diversity, despite their common biosynthetic origins. It is also well-established that this class of compounds exhibit a range of potent biological activities. Owing to these factors, lignans have proven to be a challenging and desirable synthetic target that have instigated the development of some different synthetic methods, advancing our collective knowledge towards the synthesis of complex and unique structures. Virus-related diseases are becoming a more challenging public health concern with increased global travel and emergence of viral resistance to the clinical antiviral drugs. There is an urgent need to develop novel antiviral drugs targeting different viral and host proteins. Lignans, as discussed in this review, have large structural diversity and pharmacological activities, including antivirals. Two types of antiviral lignans—podophyllotoxin and bicyclol, which show high potency in the treatment of venereal warts and chronic hepatitis B, respectively—serve as good examples of developing lignans for antivirals. However, we believe that the potential of lignans in antivirals needs further exploration in the research and development. As noted above, although many of the classical lignans have been showed to display wide-range antiviral activities, little is known regarding the neolignans, which have more varied structures than classical lignans, with regards to their antiviral activities. These neolignans should be carefully evaluated to assess their activities against different viruses, and it is highly likely that many new antiviral activities will be discovered. Furthermore, action of mechanism studies should be investigated for facilitating the development of lead lignans in antiviral drug discovery.

Author Contributions: Writing—Original Draft preparation, Q.C. and M.L.; Writing—Review and Editing, L.R., R.D., and Q.C. All authors have read and agreed to the published version of the manuscript. Funding: This work was supported by (1) The Drug Innovation Major Project (Grant No. 2018ZX09711001); (2) the Key Research and Development Projects of Science and Technology Department of Shandong Province (Grant No. 2017CXGC1309); (3) Shandong Provincial Natural Science Foundation, China (Grant No. ZR2019MH078). Conﬂicts of Interest: The authors declare no conﬂict of interest.

References

1. Teponno, R.B.; Kusari, S.; Spiteller, M. Recent advances in research on lignans and neolignans. Nat. Prod. Rep. 2016, 33, 1044–1092. [CrossRef][PubMed] 2. Ayres, D.C.; Loike, J.D. Lignans. Chemical, Biological and Clinical Properties. Lignans Chem. Biol. Clin. Prop. 1991, 100, 1. 3. Kaplan, I.W. Condylomata acuminate. New Orleans Med. Surg. J. 1942, 94, 388–390. 4. Wu, X.Q.; Li, W.; Chen, J.X.; Zhai, J.W.; Xu, H.Y.; Ni, L.; Wu, S.S. Chemical Constituents and Biological Activity Proﬁles on Pleione (Orchidaceae). Molecules 2019, 24, 3195. [CrossRef][PubMed] 5. Lu, H.L.; Liu, G.T. Antioxidant activity of dibenzocyclooctene lignans isolated from Schisandraceae. Planta Med. 1992, 58, 4. [CrossRef][PubMed] 6. Pan, J.Y.; Chen, S.L.; Yang, M.H.; Wu, J.; Sinkkonen, J.; Zou, K. An update on lignans: Natural products and synthesis. Nat. Prod. Rep. 2009, 26, 1251–1292. [CrossRef] 7. Capilla, A.S.; Sánchez, I.; Caignard, D.H.; Renard, P.; Pujol, M.D. Antitumor agents. Synthesis and biological evaluation of new compounds related to podophyllotoxin, containing the 2,3-dihydro-1,4-benzodioxin system. Eur. J. Med. Chem. 2001, 36, 11. [CrossRef] 8. Kawazoe, K.; Yutani, A.; Tamemoto, K.; Yuasa, S.; Shibata, H.; Higuti, T.; Takaishi, Y. Phenylnaphthalene Compounds from the Subterranean Part of Vitex rotundifolia and Their Antibacterial Activity Against Methicillin-Resistant Staphylococcus aureus. J. Nat. Prod. 2001, 64, 588–591. [CrossRef] 9. Hirano, T.; Wakasugi, A.; Oohara, M.; Oka, K.; Sashida, Y. Suppression of mitogen-induced proliferation of human peripheral blood lymphocytes by plant lignans. Planta Med. 1991, 57, 4. [CrossRef] 10. Iwasaki, T.; Kondo, K.; Kuroda, T.; Moritani, Y.; Yamagata, S.; Sugiura, M.; Kikkawa, H.; Kaminuma, O.; Ikezawa, K. Novel selective PDE IV inhibitors as antiasthmatic agents. synthesis and biological activities of a series of 1-aryl-2,3-bis(hydroxymethyl)naphthalene lignans. J. Med. Chem. 1996, 39, 9. [CrossRef] Molecules 2020, 25, 183 13 of 17

11. Charlton James, L. Antiviral Activity of Lignans. J. Nat. Prod. 1998, 61, 1447–1451. [CrossRef][PubMed] 12. Huang, R.L.; Huang, Y.L.; Ou, J.C.; Chen, C.C.; Hsu, F.L.; Chang, C. Screening of 25 compounds isolated from Phyllanthus species for anti-human hepatitis B virus in vitro. Phytother Res. 2003, 17, 449–453. [CrossRef] [PubMed] 13. Pilkington, L.I. Lignans: A Chemometric Analysis. Molecules 2018, 23, 1666. [CrossRef][PubMed] 14. Kirkman, L.M.; Lampe, J.W.; Campbell, D.R.; Martini, M.C.; Slavin, J.L. Urinary Lignan and isoflavonoid excretion in men and women consuming vegetable and soy diets. Nutr. Cancer 1995, 24, 12. [CrossRef] [PubMed] 15. Jeffries, D.E.; Lindsley, C.W. Asymmetric Synthesis of Natural and Unnatural Dibenzylbutane Lignans from a Common Intermediate. J. Org. Chem. 2019, 84, 5974–5979. [CrossRef][PubMed] 16. Liu, S.; Wei, W.; Shi, K.; Cao, X.; Zhou, M.; Liu, Z. In Vitro and in vivo anti-hepatitis B virus activities of the lignan niranthin isolated from Phyllanthus niruri L. J. Ethnopharmacol. 2014, 155, 1061–1067. [CrossRef] 17. Hernandez, D.J.; Anderica, R.A.C.; Pedraza, C.J. Paradoxical cellular effects and biological role of the multifaceted compound nordihydroguaiaretic acid. Arch. Pharm. 2014, 347, 685–697. [CrossRef] 18. Zúñiga-Toalá, A.; Zatarain-Barrón, Z.L.; Hernández-Pando, R.; Negrette-Guzmán, M.; Huerta-Yepez, S.; Torres, I.; Pinzón, E.; Tapia, E.; Pedraza-Chaverri, J. Nordihydroguaiaretic acid induces Nrf2 nuclear translocation in vivo and attenuates renal damage and apoptosis in the ischemia and reperfusion model. Phytomedicine 2013, 20, 775–779. [CrossRef] 19. Tong, W.; Ding, X.; Adrian, T. The mechanisms of lipoxygenase inhibitor-induced apoptosis in human breast cancer cells. Biochem. Biophys. Res. Commun. 2002, 296, 942–948. [CrossRef] 20. Manzanero, S.; Santro, T.; Arumugam, T.V. Neuronal oxidative stress in acute ischemic stroke: Sources and contribution to cell injury. Neurochem. Int. 2013, 62, 712–718. [CrossRef] 21. Floriano-Sanchez, E.; Villanueva, C.; Medina-Campos, O.N.; Rocha, D.; Sánchez-González, D.J.; Cárdenas-Rodríguez, N.; Pedraza-Chaverrí, J. Nordihydroguaiaretic acid is a potent in vitro scavenger of peroxynitrite, singlet oxygen, hydroxyl radical, superoxide anion and hypochlorous acid and prevents in vivo ozone-induced tyrosine nitration in lungs. Free Radic Res. 2006, 40, 523–533. [CrossRef][PubMed] 22. Soto, A.R.; Bautista, C.P.; Syed, G.H.; Siddiqui, A.; Del Angel, R.M. Nordihydroguaiaretic acid (NDGA) inhibits replication and viral morphogenesis of dengue virus. Antivir. Res. 2014, 109, 132–140. [CrossRef] [PubMed] 23. Syed, G.H.; Siddiqui, A. Effects of hypolipidemic agent nordihydroguaiaretic acid on lipid droplets and hepatitis C virus. Hepatology 2011, 54, 1936–1946. [CrossRef][PubMed] 24. Merino-Ramos, T.; de Oya, N.J.; Saiz, J.-C.; Martín-Acebes, M.A. Antiviral Activity of Nordihydroguaiaretic Acid and Its Derivative Tetra-O-Methyl Nordihydroguaiaretic Acid against West Nile Virus and Zika Virus. Antimicrob. Agents Chemother. 2017, 61. [CrossRef] 25. Wang, S.; Le, T.Q.; Kurihara, N.; Chida, J.; Cisse, Y.; Yano, M.; Kido, H. Influenza virus-cytokine-protease cycle in the pathogenesis of vascular hyperpermeability in severe influenza. J. Infect. Dis. 2010, 202, 991–1001. [CrossRef] 26. Oyegunwa, A.O.; Sikes, M.L.; Wilson, J.R.; Scholle, F.; Laster, S.M. Tetra-O-methyl nordihydroguaiaretic acid (Terameprocol) inhibits the NF-kappaB-dependent transcription of TNF-alpha and MCP-1/CCL2 genes by preventing RelA from binding its cognate sites on DNA. J. Inflamm. 2010, 7, 59. [CrossRef] 27. Pollara, J.J.; Laster, S.M.; Petty, I.T. Inhibition of poxvirus growth by Terameprocol, a methylated derivative of nordihydroguaiaretic acid. Antivir. Res. 2010, 88, 287–295. [CrossRef] 28. Chen, H.; Teng, L.; Li, J.N.; Park, R.; Mold, D.E.; Gnabre, J.; Hwu, J.R.; Tseng, W.N.; Huang, R.C.C. Antiviral Activities of Methylated Nordihydroguaiaretic Acids. 2. Targeting Herpes Simplex Virus Replication by the Mutation Insensitive Transcription Inhibitor Tetra-O-methyl-NDGA. J. Med. Chem. 1998, 41, 3001–3007. [CrossRef] 29. Gnabre, J.N.; Brady, J.N.; Clanton, D.J.; Ito, Y.; Dittmer, J.; Bates, R.B.; Huang, R.C. Inhibition of human immunodeficiency virus type 1 transcription and replication by DNA sequence-selective plant lignans. Proc. Natl. Acad. Sci. USA 1995, 92, 11239–11243. [CrossRef] 30. Khanna, N.; Dalby, R.; Tan, M.; Arnold, S.; Stern, J.; Frazer, N. Phase I/II clinical safety studies of terameprocol vaginal ointment. Gynecol. Oncol. 2007, 107, 554–562. [CrossRef] 31. Xu, X.; Wang, D.; Ku, C.; Zhao, Y.; Cheng, H.; Liu, K.-L.; Rong, L.-J.; Zhang, H.-J. Anti-HIV lignans from Justicia procumbens. Chin. J. Nat. Med. 2019, 17, 945–952. [CrossRef] Molecules 2020, 25, 183 14 of 17

32. Gao, Y.; Dong, X.; Kang, T.G. Activity of in vitro anti-influenza virus of arctigenin. Chin. Herb. Med. 2002, 33, 724–725. 33. Fu, L.; Xu, P.; Liu, N.; Yang, Z.; Zhang, F.; Hu, Y. Antiviral effect of Arctigenin Compound on Influenza Virus. Tradit. Chin. Drug Res. Clin. Pharmacol. 2008, 19, 4. 34. Hayashi, K.; Narutaki, K.; Nagaoka, Y.; Hayashi, T.; Uesato, S. Therapeutic Effect of Arctiin and Arctigenin in Immunocompetent and Immunocompromised Mice Infected with Influenza A Virus. Biol. Pharm. Bull. 2010, 33, 1199–1205. [CrossRef] 35. Schröder, H.C.; Merz, H.; Steffen, R.; Müller, W.E.; Sarin, P.S.; Trumm, S.; Schulz, J.; Eich, E. Differential in vitro anti-HIV activity of natural lignans. Zeitschrift für Naturforschung C 1990, 45, 1215–1221. 36. Eich, E.; Pertz, H.; Kaloga, M.; Schulz, J.; Pertz, H.; Eich, E.; Pommier, Y. ( )-Arctigenin as a Lead Structure − for Inhibitors of Human Immunodeficiency Virus Type-1 Integrase. J. Med. Chem. 1996, 39, 86–95. [CrossRef] 37. Kuo, Y.C.; Kuo, Y.H.; Lin, Y.L.; Tsai, W.J. Yatein from Chamaecyparis obtusa suppresses herpes simplex virus type 1 replication in HeLa cells by interruption the immediate-early gene expression. Antivir. Res. 2006, 70, 112–120. [CrossRef] 38. Wang, Y.; Wang, X.; Xiong, Y.; Kaushik, A.C.; Muhammad, J.; Khan, A.; Dai, H.; Wei, D.-Q. New strategy for identifying potential natural HIV-1 non-nucleoside reverse transcriptase inhibitors against drug-resistance: An in silico study. J. Biomol. Struct. Dyn. 2019, 1–15. [CrossRef] 39. Chang, C.; Lien, Y.; Liu, K.C.S.C.; Li, S.-S. Lignans from Phyllanthus urinaria. Phytochemistry 2003, 63, 825–833. [CrossRef] 40. Kuo, P.; Li, Y.; Wu, T. Chemical Constituents and Pharmacology of the Aristolochia species. J. Tradit. Complement. Med. 2012, 2, 249–266. [CrossRef] 41. Gangan, V.; Hussain, S.S. Alkaloids from Piper hookeri: Revision of NMR assignments by the application of 2D NMR spectroscopy. J. Pharm. Res. 2011, 4, 3. 42. Nunomura, S.; Yoshida, M. Lignans and benzoic acid derivatives from pericarps of Virola multinervia (Myristicaceae). Biochem. Syst. Ecol. 2002, 30, 3. [CrossRef] 43. Schmidt, T.J.; Hemmati, S.; Klaes, M.; Konuklugil, B.; Mohagheghzadeh, A.; Ionkova, I.; Fuss, E.; Alfermann, A.W. Lignans in flowering aerial parts of Linum species—chemodiversity in the light of systematics and phylogeny. Phytochemistry 2010, 71, 1714–1728. [CrossRef][PubMed] 44. Marcotullio, M.C.; Pelosi, A.; Curini, M. Hinokinin, an emerging bioactive lignan. Molecules 2014, 19, 14862–14878. [CrossRef] 45. Cheng, M.-J.; Lee, K.-H.; Tsai, I.-L.; Chen, I.-S. Two new sesquiterpenoids and anti-HIV principles from the root bark of Zanthoxylum ailanthoides. Bioorg. Med. Chem. 2005, 13, 5915–5920. [CrossRef] 46. Wen, C.-C.; Kuo, Y.-H.; Jan, J.-T.; Liang, P.-H.; Wang, S.-Y.; Liu, H.-G.; Li, C.-K.; Chang, S.-T.; Kuo, C.-J.; Lee, S.-S.; et al. Specific Plant Terpenoids and Lignoids Possess Potent Antiviral Activities against Severe Acute Respiratory Syndrome Coronavirus. J. Med. Chem. 2007, 50, 4087–4095. [CrossRef] 47. Rozália, P.; Abrantes, M.; Serly, J.; Duarte, N.; Molnar, J.; Ferreira, M.-J.U. Antitumor-promoting Activity of Lignans: Inhibition of Human Cytomegalovirus IE Gene Expression. Anticancer Res. 2010, 30, 451–454. 48. Chen, H.; Liu, P.; Zhang, T.; Gao, Y.; Zhang, Y.; Shen, X.; Li, X.; Shen, W. Effects of diphyllin as a novel V-ATPase inhibitor on TE-1 and ECA-109 cells. Oncol. Rep. 2018, 39, 921–928. [CrossRef] 49. Nesmelova, E.F.; Razakova, D.M.; Akhmedzhanova, V.I.; Bessonova, I.A. Diphyllin from Haplophyllum alberti-regelii, H. bucharicum, and H. perforatum. Chem. Nat. Compd. 1983, 19, 608. [CrossRef] 50. Sørensen, M.G.; Henriksen, K.; Neutzsky-Wulff, A.V.; Dziegiel, M.H.; Karsdal, M.A. Diphyllin, a Novel and Naturally Potent V-ATPase Inhibitor, Abrogates Acidification of the Osteoclastic Resorption Lacunae and Bone Resorption. J. Bone Miner. Res. Off. J. Am. Soc. Bone Miner. Res. 2007, 22, 9. [CrossRef] 51. Martinez-Lopez, A.; Persaud, M.; Chavez, M.P.; Zhang, H.; Rong, L.; Liu, S.; Wang, T.T.; Sarafianos, S.G.; Diaz-Griffero, F. Glycosylated diphyllin as a broad-spectrum antiviral agent against Zika virus. EBioMedicine 2019, 47, 269–283. [CrossRef][PubMed] 52. Chen, H.-W.; Cheng, J.X.; Liu, M.-T.; King, K.; Peng, J.Y.; Zhang, X.-Q.; Wang, C.-H.; Shresta, S.; Schooley, R.T.; Liu, Y.-T. Inhibitory and combinatorial effect of diphyllin, a v-ATPase blocker, on influenza viruses. Antivir. Res. 2013, 99, 371–382. [CrossRef][PubMed] 53. Susplugas, S.; Hung, N.; Bignon, J.; Thoison, O.; Kruczynski, A.; Sévenet, T.; Guéritte, F. Cytotoxic Arylnaphthalene Lignans from a Vietnamese Acanthaceae. Justicia patentiflora. J. Nat. Prod. 2005, 68, 734–738. [CrossRef][PubMed] Molecules 2020, 25, 183 15 of 17

54. Zhang, H.-J.; Rumschlag-Booms, E.; Guan, Y.-F.; Liu, K.-L.; Wang, D.-Y.; Li, W.-F.; Nguyen, V.H.; Cuong, N.M.; Soejarto, D.D.; Fong, H.H.S. Anti-HIV diphyllin glycosides from Justicia gendarussa. Phytochemistry 2017, 136, 94–100. [CrossRef] 55. Zhang, H.-J.; Rumschlag-Booms, E.; Guan, Y.-F.; Wang, D.-Y.; Liu, K.-L.; Li, W.-F.; Nguyen, V.H.; Cuong, N.M.; Soejarto, D.D.; Fong, H.H.S. Potent Inhibitor of Drug-Resistant HIV-1 Strains Identified from the Medicinal Plant Justicia gendarussa. J. Nat. Prod. 2017, 80, 1798–1807. [CrossRef] 56. Zalesak, F.; Bon, D.J.D.; Pospisil, J. Lignans and Neolignans: Plant secondary metabolites as a reservoir of biologically active substances. Pharm. Res. 2019, 146, 104284. [CrossRef] 57. Alsdorf, W.; Seidel, C.; Bokemeyer, C.; Oing, C. Current pharmacotherapy for testicular germ cell cancer. Expert Opin. Pharm. 2019, 20, 837–850. [CrossRef] 58. Komericki, P.; Akkilic-Materna, M.; Strimitzer, T.; Aberer, W. Efficacy and Safety of Imiquimod Versus Podophyllotoxin in the Treatment of Anogenital Warts. Sex. Transm. Dis. 2011, 38, 3. [CrossRef] 59. Ma, Z.-J.; Lu, L.; Yang, J.-J.; Wang, X.-X.; Su, G.; Wang, Z.; Chen, G.; Sun, H.; Wang, M.; Yang, Y. Lariciresinol induces apoptosis in HepG2 cells via mitochondrial-mediated apoptosis pathway. Eur. J. Pharm. 2018, 821, 1–10. [CrossRef] 60. Zhao, D.; Wu, T.Y.; Guan, Y.Q.; Ma, G.X.; Zhang, J.; Shi, L.L. Chemical constituents from roots of Stelleropsis tianschanica. China J. Chin. Mater. Med. 2017, 42, 3379–3384. 61. Bajpai, V.K.; Shukla, S.; Paek, W.K.; Lim, J.; Kumar, P.; Kumar, P.; Na, M.K. Efficacy of (+)-Lariciresinol to Control Bacterial Growth of Staphylococcus aureus and Escherichia coli O157:H7. Front. Microbiol. 2017, 8, 804. [CrossRef][PubMed] 62. Li, J.; Zhou, B.; Li, C.; Chen, Q.Y.; Wang, Y.; Li, Z.; Chen, T.; Yang, C.; Jiang, B.; Zhong, Z. Lariciresinol-4-O-beta-d-glucopyranoside from the root of Isatis indigotica inhibits influenza A virus-induced pro-inflammatory response. J. Ethnopharmacol. 2015, 174, 379–386. [CrossRef][PubMed] 63. Zhou, B.; Li, J.; Liang, X.; Yang, Z.; Jiang, Z. Transcriptome profiling of influenza A virus-infected lung epithelial (A549) cells with lariciresinol-4-beta-D-glucopyranoside treatment. PLoS ONE 2017, 12, e0173058. 64. Liu, Z.L.; Liu, Y.Q.; Zhao, L.; Xu, J.; Tian, X. The phenylpropanoids of Aster flaccidus. Fitoterapia 2010, 81, 140–144. [CrossRef][PubMed] 65. Meng, L.; Guo, Q.; Chen, M.; Jiang, J.; Li, Y.; Shi, J. Isatindolignanoside A, a glucosidic indole-lignan conjugate from an aqueous extract of the Isatis indigotica roots. Chin. Chem. Lett. 2018, 29, 1257–1260. [CrossRef] 66. Yang, Z.; Wang, Y.; Zheng, Z.; Zhao, S.; Zhao, J.; Lin, Q.; Li, C.; Zhu, Q.; Zhong, N. Antiviral activity of Isatis indigotica root-derived clemastanin B against human and avian influenza A and B viruses in vitro. Int. J. Mol. Med. 2013, 31, 867–873. [CrossRef] 67. Fanhchaksai, K.; Kodchakorn, K.; Pothacharoen, P.; Kongtawelert, P. Effect of sesamin against cytokine production from influenza type A H1N1-induced peripheral blood mononuclear cells: Computational and experimental studies. Vitr. Cell Dev. Biol. Anim. 2016, 52, 107–119. [CrossRef] 68. Ren, R.; Ci, X.-X.; Li, H.-Z.; Luo, G.-J.; Li, R.-T.; Deng, X.-M. New Dibenzocyclooctadiene Lignans from Schisandra sphenanthera and Their Proinflammatory Cytokine Inhibitory Activities. Z. Für Nat. B 2014, 65, 8. [CrossRef] 69. Szopa, A.; Barna´s,M.; Ekiert, H. Phytochemical studies and biological activity of three Chinese Schisandra species (Schisandra sphenanthera, Schisandra henryi and Schisandra rubriflora): Current findings and future applications. Phytochem. Rev. 2018, 18, 109–128. [CrossRef] 70. Checker, R.; Patwardhan, R.; Sharma, D.; Menon, J.; Thoh, M.; Bhilwade, H.N.; Konishi, T.; Sandur, S.K. Schisandrin B exhibits anti-inflammatory activity through modulation of the redox-sensitive transcription factors Nrf2 and NF-kappaB. Free Radic. Biol. Med. 2012, 53, 1421–1430. [CrossRef] 71. Park, S.Y.; Park, S.J.; Park, T.G.; Rajasekar, S.; Lee, S.-J.; Choi, Y.W. Schizandrin C exerts anti-neuroinflammatory effects by upregulating phase II detoxifying/antioxidant enzymes in microglia. Int. Immunopharmacol. 2013, 17, 12. [CrossRef][PubMed] 72. Szopa, A.; Ekiert, R.; Ekiert, H. Current knowledge of Schisandra chinensis (Turcz.) Baill. (Chinese magnolia vine) as a medicinal plant species: A review on the bioactive components, pharmacological properties, analytical and biotechnological studies. Phytochem. Rev. 2017, 16, 195–218. [CrossRef][PubMed] 73. Liu, H.; Lai, H.; Jia, X.; Liu, J.; Zhang, Z.; Qi, Y.; Zhang, J.; Song, J.; Wu, C.; Zhang, B.; et al. Comprehensive chemical analysis of Schisandra chinensis by HPLC-DAD-MS combined with chemometrics. Phytomed. Int. J. Phytother. Phytopharm. 2013, 20, 9. [CrossRef][PubMed] Molecules 2020, 25, 183 16 of 17

74. Yu, J.-S.; Wu, Y.-H.; Tseng, C.-K.; Lin, C.-K.; Hsu, Y.-C.; Chen, Y.-H.; Lee, J.-C. Schisandrin A inhibits dengue viral replication via upregulating antiviral interferon responses through STAT signaling pathway. Sci. Rep. 2017, 7, 45171. [CrossRef][PubMed] 75. Xu, L.; Grandi, N.; Del Vecchio, C.; Mandas, D.; Corona, A.; Piano, D.; Esposito, F.; Parolin, C.; Tramontano, E. From the traditional Chinese medicine plant Schisandra chinensis new scaffolds effective on HIV-1 reverse transcriptase resistant to non-nucleoside inhibitors. J. Microbiol. 2015, 53, 6. [CrossRef][PubMed] 76. Liu, G. Bicyclol: A Novel Drug for Treating Chronic Viral Hepatitis B and C. Med. Chem. 2009, 5, 29–43. [CrossRef] 77. Zhang, T. New drugs derived from medicinal plants. Thérapie 2016, 57, 14. 78. Ruan, B.; Wang, J.; Bai, X. Comparison of bicyclol therapy for patients with genotype B and C of hepatitis B virus. Chin. J. Exp. Clin. Virol. 2007, 21, 3. 79. Huang, M.-H.; Li, H.; Xue, R.; Li, J.; Wang, L.; Cheng, J.; Wu, Z.; Li, W.; Chen, J.; Lv, X.; et al. Up-regulation of glycolipid transfer protein by bicyclol causes spontaneous restriction of hepatitis C virus replication. Acta Pharm. Sin. B 2019, 9, 769–781. [CrossRef] 80. Zhou, Y.; Chai, X. Protective effect of bicyclol against pulmonary fibrosis via regulation of microRNA5 in rats. J. Cell. Biochem. 2019, 121, 651–660. [CrossRef] 81. Tian, R.R.; Xiao, W.L.; Yang,L.M.; Wang,R.R.; Sun, H.D.; Liu, N.F.; Zheng, Y.T. The Isolation of Rubrifloralignan A and Its Anti-HIV-1 Activities. Chin. J. Nat. Med. 2006, 4, 40–44. 82. Chen, M.; Kilgore, N.; Lee, K.-H.; Chen, D.-F. Rubrisandrins A and B, Lignans and Related Anti-HIV Compounds from Schisandra rubriflora. J. Nat. Prod. 2006, 69, 1697–1701. [CrossRef][PubMed] 83. Fujihashi, T.; Hara, H.; Sakata, T.; Mori, K.; Higuchi, H.; Tanaka, A.; Kaji, H.; Kaji, A. Anti-human immunodeficiency virus (HIV) activities of halogenated gomisin J derivatives, new nonnucleoside inhibitors of HIV type 1 reverse transcriptase. Antimicrob. Agents Chemother. 1995, 39, 2000–2007. [CrossRef][PubMed] 84. Federico, A.; Dallio, M.; Loguercio, C. Silymarin/Silybin and Chronic Liver Disease: A Marriage of Many Years. Molecules 2017, 22, 191. [CrossRef][PubMed] 85. Strader, D.B.; Bacon, B.R.; Lindsay, K.L.; La Brecque, D.R.; Morgan, T.; Wright, E.C.; Seeffff, L.B. Use of complementary and alternative medicine in patients with liver disease. Am. J. Gastroenterol. 2002, 97, 7. [CrossRef][PubMed] 86. Liu, C.-H.; Jassey, A.; Hsu, H.-Y.; Lin, L.-Z. Antiviral Activities of Silymarin and Derivatives. Molecules 2019, 24, 1552. [CrossRef] 87. Wagoner, J.; Negash, A.; Kane, O.J.; Martinez, L.E.; Nahmias, Y.; Bourne, N.; Owen, D.M.; Grove, J.; Brimacombe, C.; McKeating, J.A.; et al. Multiple effects of silymarin on the hepatitis C virus lifecycle. Hepatology 2010, 51, 1912–1921. [CrossRef] 88. DebRoy, S.; Hiraga, N.; Imamura, M.; Hayes, C.N.; Akamatsu, S.; Canini, L.; Perelson, A.S.; Pohl, R.T.; Persiani, S.; Uprichard, S.L. Hepatitis C virus dynamics and cellular gene expression in uPA-SCID chimeric mice with humanized livers during intravenous silibinin monotherapy. J. Viral Hepat. 2016, 23, 708–717. [CrossRef] 89. Song, J.H.; Choi, H.J. Silymarin efficacy against influenza a virus replication. Phytomedicine 2011, 18, 832–835. [CrossRef] 90. Li, J.; Meng, A.-P.; Guan, X.-L.; Li, J.; Wu, Q.; Deng, S.-P.; Su, X.-J.; Yang, R.-Y. Anti-hepatitis B virus lignans from the root of Streblus asper. Bioorg. Med. Chem. Lett. 2013, 23, 2238–2244. [CrossRef] 91. Lu, X.; Zhang, W.; Cheng, X.-H.; Wang, H.-G.; Yu, D.-Y.; Feng, B.-M. Advances on the secolignans compounds in natural products. J. Shenyang Pharm. Univ. 2014, 11, 922. Available online: http://en.cnki.com.cn/Article_ en/CJFDTotal-SYYD201411019.htm. 92. Su, X.; Na, L.; Ning, M.-M.; Zhou, C.-H.; Yang, Q.-R.; Wang, M.W. Bioactive Compounds from Peperomia pellucida. J. Nat. Prod. 2006, 69, 247–250. 93. Feng, B.M.; Qin, H.H.; Wang, H.G.; Shi, L.Y.; Yu, D.Y.; Ji, B.Q.; Zhao, Q.; Wang, Y.Q. Three new secolignan glycosides from Urtica fissa E. Pritz. J. Nat. Med. 2012, 66, 562–565. [CrossRef][PubMed] 94. Feng, W.-S.; Chen, H.; Zheng, X.-K.; Wang, Y.-Z.; Chen, H.; Li, Z. Two new secolignans from Selaginella sinensis (Desv.) Spring. J. Asian Nat. Prod. Res. 2009, 11, 658–662. [CrossRef][PubMed] 95. Cheng, M.-J.; Lee, S.-J.; Chang, Y.-Y.; Wu, S.-H.; Tsai, I.-L.; Jayaprakasam, B.; Chen, I.-S. Chemical and cytotoxic constituents from Peperomia sui. Phytochemistry 2003, 63, 603–608. [CrossRef] Molecules 2020, 25, 183 17 of 17

96. Tsutsui, C.; Yamada, Y.; Ando, M.; Toyama, D.; Wu, J.L.; Wang, L.; Taketani, S.; Kataoka, T. Peperomins as anti-inﬂammatory agents that inhibit the NF-kappaB signaling pathway. Bioorg. Med. Chem. Lett. 2009, 19, 4084–4087. [CrossRef][PubMed] 97. Govindachari, T.R.; Kumari, G.N.K.; Partho, P.D. Two secolignans from Peperomia dindigulensis. Phytochemistry 1998, 49, 2129–2131. [CrossRef] 98. Lin, M.; Yu, D.; Wang, Q. Secolignans with Antiangiogenic Activities from Peperomia dindygulensis. Chem. Biodivers. 2011, 8, 862–870. [CrossRef] 99. Zhang, G.-L.; Li, N.; Wang, Y.-H.; Zheng, Y.-T.; Zhang, Z.; Wang, M.-W. Bioactive lignans from Peperomia heyneana. J. Nat. Prod. 2007, 70, 662–664. [CrossRef]

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