The Current Landscape of Bioactive Molecules against DENV: A Systematic Review

With a 30-fold increase in incidence over the previous 50 years, dengue fever is now the most widespread viral disease transmitted by mosquitoes in the world. The intricate interaction of the human defense system, hereditary predisposition, and specific bitterness elements is more likely to be the pathogenesis of dengue. There are presently no viable treatments for dengue. Synthetic drugs which are used against this ailment also show major side effects. There must be a deeper understanding of the underlying mechanism generating severe symptoms to develop auguring markers, cutting-edge diagnostics, and treatments and finally a well-rounded and secure antiserum. Hence, the aim is to search for safer and more potent drugs derived from plants. Plants or herbs are mainly targeting replication or its enzyme or specific stereotypes, though an exact mechanism of phytoconstituents interfering with the viral replication is still undiscovered. The present attempt provided the update with the objective to bringing up forward pathophysiological eventualities involved in dengue virus along with the naturally derived treatment relevant to provide the impregnable therapy by evading the noxious symptoms for dengue fever. Governor's plum, Cryptocarya chartacea, magnolia berry, and Chinese ginger are such plants exhibiting many effective phytoconstituents against DENV and can be further explored for novel drug discovery by medicinal scientists.


Introduction
Te Flaviviridae class of virus that causes dengue fever, disseminated by mosquitoes, recently becomes widespread throughout all WHO zones. Over the past 20 years, dengue fever cases have doubled since 2000, when there were only 505,430 cases; by 2020 there were 5 million cases. Between 2000 and 2015, the reported death toll rose from 960 to 4032, with young people carrying most of the burden [1]. Any serotype of the dengue virus might result in dengue fever (DENV-1, DENV-2, DENV-3, and DENV-4), and future defense response against these virus types is typically brought on by infection with one type but not against others. In addition, if exposed to alternative type a second time, a more severe illness could manifest. Tis is brought on by a phenomenon called "immune subordinate upgrading" in which antibodies to one serotype enhance the contamination with a diferent serotype [2]. Te four dengue virus serotypes DENV (1)(2)(3)(4) are related to one another and have gene sequence similarities of 65 to 70 percent [3]. Virus dwells of lipid and polysaccharide envelope and 11 KB plusstrand RNA genome, three structural proteins-Glycoprotein, protein coat (C), membrane (M), and casing as well as seven nonstructural proteins:NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5 [4]. Individual functions of these nonstructural proteins include NS1, responsible for viral infection. On the other side, RNA replication is aided by the lipophilic integral biological membrane peptide NS2A, while NS2B is a protease coenzyme. In viral RNA production, NS3 regulates the nucleoside triphosphate and helicase enzymes. NS4A aids in the formation of replication vesicles, while NS4B inhibits interferon beta and gamma signaling [5]. NS5 (105 KDa), the biggest and most widespread polypeptide, is necessary for RNA production and successfully inhibits the interferon (IFN) system [6]. Female mosquitoes exposed to the virus, generally the Aedes aegypti mosquito, bite people and spread the infection. Although other Aedes species can act as bearing, their importance is far inferior to that of Aedes aegypti. When a mosquito bites a person with DENV infection, the virus frst multiplies in the mosquito's gut before moving on to subordinate tissues such as the acinus. Te hallmarks of dengue infection appear in a roughly logical order, commencing with viremia and moving on to systemic infammation and hematological changes [7,8]. Te duration between ingesting the virus and passing it on to a noninfected person is known as the extrinsic incubation period (EIP). Te EIP takes about 8 to 12 days at an ambient temperature of 25°C to 28°C. A mosquito bite might cause symptoms to appear 4-7 days later in an afected host. Te dengue virus can be transmitted to mosquitos by an infected (asymptomatic) host [4]. In brief, DENV initially infects the mammalian host cells at the periphery, following infection of draining lymph nodes. Virus titers rise in the bloodstream and lymphatics, spreading DENV infection to organs such as the liver and the spleen. Viremia is controlled by the host after a few days, when signs of systemic infammation are observed. Patients present "cytokine storm," a term used to describe the high levels of circulating proinfammatory cytokines, which is believed to increase endothelial activation and cause the hemorrhagic manifestations of dengue [8].
For a variety of viral diseases, there are several antiviral medications available in the market such as acetaminophen, aspirin, ibuprofen, and naproxen sodium that are categorized according to their site of action and method of preventing viral reproduction in the host cell. Te safety, efectiveness, and cytotoxicity of these antiviral drugs have considerable drawbacks and have a signifcant difculty or challenge occurs from the development of resistance, which opens the door for viral genome evolution. Tis draws away focus from synthetic antiretroviral drugs and towards conventional or alternative medicines, frequently thought to have less ramifcation and pernicious issues. Natural remedies, also known as phytomedicines, ofer a number of advantages over synthetic molecules since they are efective against a variety of host receptors, which enable the treatment of alignment at the ground level through a variety of mechanisms with little or no side efects. Tis manuscript highlights pathophysiology of the DENV virus, scopes, and potential pharmaceutical targets to treat the dengue with natural medicine including herbs.

Pathogenesis of Dengue
2.1. Viral Entry. Te method that pathogens utilize to enter their host cells has attracted increased attention in current years. It is thought that keratinocytes and young Langerhans cells in the dermis are the main cells that get infected after a tainted mosquito bite [9]. For last ten years, there have been a lot of research and discussion about the target cell and the DENV section cycle in both vertebrate and invertebrate cells. In any case, the interaction between the sections has not been explained well enough. Tere has been evidence for a long time that viruses have receptors that change depending on the type of cell they infect [10][11][12][13][14][15][16][17]. DENV is attracted to mononuclear phagocytes, such as leukocyte macrophages, accessory cells, and Langerhans cells in the skin. Tese cells are thought to be the main targets when DENV is present, even though DENV also afects hepatocytes and endothelial cells [18][19][20]. Tese viral receptors connect to carbs in DENV E glycoprotein. In hepatocytes and endothelial cells, DENV also binds to proteins called lectins, vital part-hub unique ICAM-3-getting integrin (L-SIGN), and heparin sulfate-containing proteins [18,21]. Te precise function of the virus and host cell in pathogenesis of dengue fever is illustrated in Figure 1.
van der Schaar et al. [23] showed the beginning stages of DENV in a magnifcent way. First, the molecule that causes the infection binds to a cell receptor. In this way, DENV/ receptor edifces spread along the surface of the cell until they reach a clathrin-covered pit, where the complex loses its ability to change, as shown in Figure 2. Ten, the clathrincovered pit squeezes into the cytoplasm of the cell, sending the particles to early endosomes that have Rab5 (receptor) on them. Rab-5 and Rab-7 proteins play important roles in the development of endosomes [24]. In general, the early endosome that carries DENV changes into a postendosome by collecting Rab7 over and over again, followed by a gradual lack of Rab5. Lastly, DENV particles can only be found in late endosomes that are Rab7-positive and are prone to pH fermentation. Tis is needed for DENV to join with the cell layer and spread infection. Cholesterol was found to be a big part of a useful DENV disease in cell and virus flms. Cholesterol is thought to be an important part of the viral envelope because treating DENV virions with cholesteroldepleting mixtures, such as methyl-cyclodextrin (MCD), stopped them from spreading. Hence, the need for cholesterol in the virion is a limited part of the four DENV serotypes [25]. Cell cholesterol is usually thought to be related to lipid-pontoons, which act as stages for infection receptors during the passage cycle at the cell surface. On the other hand, DENV replication depends on cholesterol in the intracellular layer to hold the infection's NS (nonstructural) proteins in place [14,26]. Recent inquisition has revealed a connection between cholesterol and the transmission of viruses as statins impede the transport of DENV E protein in infected cells [27].

Virion
Assembly. Te nucleocapsid of the dengue virus is made up of viral membrane proteins and envelope glycoproteins E that are buried inside a lipid layer that surrounds genomic RNA and basic capsid C protein ( Figure 3). Te viral determinant E mediates infection restriction to specifc receptors located on the outer layer of Dandy virustolerant host cells such as accessory cells (ACs), WBCs, and neural building blocks of life [29]. Only a few of the DENV receptors have been discovered this far, including anticoagulant sulfate, CD14 (cluster of diferentiation 14), human laminin receptor, GRP78/BiP, and the adeptly known DCexplicit intercell bond atom three snatching nonintegrin (DC-SIGN) [14][15][16][30][31][32][33]. After limitation, the infection is taken by the body of receptor-interceded endocytosis. Te E protein becomes permanently trimerized as the pH of the endocytosis pathway drops, preventing that capsid from fusing with the cell. When the nucleocapsid is released, the provirus is carried into the protoplasm of infected cells, where it is translated at the unpleasant ER to produce a polyprotein with around 3,400 proteins [34]. Combining cell proteolytic enzymes with the viral nonstructural (NS) 2B-3 proteolytic enzymes results in the co-and posttransformation of this polyprotein into three and seven NS proteins. After interpretation and processing, a polypeptide combination containing the NS5 ribonucleotide bases-subordinate DNA-directed/dependent RNA polymerase, auxiliary NS enzymes, virus (+) genetic material, and perhaps cellular components is collected. Viral RNA copying takes place inside this alleged replication complex (RC), which is linked to infection-induced internal layer formations. Copying starts with a long mixture of genetic (negative) ribonucleic acid, which is used as a blueprint for the creation of (+) ribonucleic acid ofspring. Te newly blended (−) RNA undergoes base matching with the (positive) ribonucleic acid template during record consummation, resulting in the formation of a long RNA pair known as homologous replication form (RF) [35]. It serves as a replication and hilter-kilter blueprint for the generation of new (+) RNA via a homologous recombination (HR). It can bind to RNA to begin a new interpretation cycle or aggregate to create virions, which are thought to create at the ER (endoplasmic reticulum) when the newly produced (+) RNA  Evidence-Based Complementary and Alternative Medicine ribonucleic acid strands are freed by the RI (replicative intermediate). Te golgi bodies are believed to be required for virion maturation and are where the glycosylation of protein molecules as well as the proteolytic cleavage of proteins such as prM (precursor of mature M) into the components pr and M by the golgi resident protease or a similar enzyme occurred [36]. Te uncleaved premembrane inhibits E from undergoing a corrosive catalyzed transition into a fusogenic structure during its travel in the secretion route by establishing a prM-E (premembrane and envelop) heterodimeric complex. Te prfragment is given after cleavage, E creates homodimeric structures, and the experienced viral particles exit the contaminated cell. Te Flavivirus life cycle is displayed in Figure 3.

Role of Plant Derived Bioactive Compounds for the Management of DENV
Commonly prescribed symptomatic medications, or socalled current drugs, are highly regarded for their efectiveness and speed of action. On the other side, continuous use might lead to the patient building an immunity to it. Te popularity of natural treatments for treating dengue fever, which are signifcantly less expensive and have no side efects, is a result of the widespread knowledge that these pharmaceuticals, although being too expensive, have certain undesirable side efects. Elucidation of compounds separated from bioactive plants have shown promising results [37]. Organic products from many sources show promise impediment to dengue, either by averting the virus from infltrating the genome or by pared down the procreate structural and nonstructural proteins. Te organic bioactive compounds from plants and a few ocean sources, which inhibit several targets of the dengue virus, are highlighted in this review.

Mimosa Catechu.
Mimosa catechu (Mimosaceae) is a native plant of South and Southeast Asia, Indian subcontinent, as well as Myanmar, Tailand, and China (Yunnan) [38]. It is a moderate tree with shadowy greyishbrown to dark brown trunk, straight and grey stem, pinnately and alternate leaves, and 5 to 10 cm-long axillary jumps with snowy to light yellow blooms [39].  2-ethyl-3-methylbut-1-ene, tetra decanoic, epicatechin, 4hydroxybenzoic acid, afzelechin, aromadendrin, kaempferol, and baicalein [40]. Crude extracts from several portions of this plant had been reported to treat diarrhea, diabetes, microbial disease, and in building body immunity. It also has anti-infammatory, antipyretic, antioxidant, antiulcer, hepatoprotective, and immunomodulatory activity [41]. Acacia's extracts also had antiviral properties against the dengue virus. Reduced peptides found in the DENV outer coating in various DENV types had an infuence on the proteins extracted from catechu. According to an analysis, DENV foci formation was persuasively stopped at a half maximal inhibitory dosage of 0.18 g/mL, peptides from Acacia catechu extract shown the highest antidengue efcacy. Te viral production was reduced by less than 100 times by administrating 1.25 g/L crude peptide extract [38].

3.2.
Pawpaw. Pawpaw (family: Caricaceae) might be a hybrid of two or more Carica species endemic to Mexico and Central America [42]. It is a fast-growing, unbranched, tall, annual herb with no branches. Te phytochemical profle of immature pawpaw leaves revealed the presence of scopolamine, hydroxybenzene, favonoids, and amino acids [43,44]. Quercetin ( Figure 4) was one of the Carica papaya (CP) bioactive molecules that revealed an antidengue efect. Infections such as dengue could be treated using this method, according to studies at both the transmission and host levels [45]. Within 24 hours, participants in a diferent trial who routinely consumed 2 tablespoons of pawpaw leaf juice daily noticed a rise in their granulocyte count [46]. Seven days of pawpaw administration to dengue patients with thrombopenia resulted in a signifcant but variable increase in platelet counts [47]. Similarly in nine clinical studies (6 from India, 1 from Pakistan, 1 from Indonesia, and 1 from Malaysia) matched the criteria for inclusion; CP extract may shorten hospital stays, and the average platelet count from the frst to the ffth day of therapy increases [48].

Evidence-Based Complementary and Alternative Medicine
After scrutinized papaya leaf juice for three days following a 24-hour viral infusion elicited a jump in CCL2/MCP-1 levels during the peak of viremia in dengue-infected AG129 mice. Another study revealed that both the methanolic crude and methanolic silver synthesized nanoparticles from C. papaya leaf extracts had high antiviral activities against dengue virus type 2 with IC50 values of 13.09 μg/mL and 09.20 μg/mL, respectively [49].

Punarnava Red.
Punarnava red is also called as Boerhavia difusa (family: Nyctaginaceae). It is widely dispersed throughout India, the Pacifc, and the Southern United States [50]. Ethanolic B. difusa extract (EBD) and aqueous B. difusa extract (ABD) were, respectively, appraised for their phytochemical constituents and antioxidant properties. It consists of tannins, total phenols, favonoids, alkaloids, oxalates, saponins, and phytates [51]. It has been employed as antidiuretic, antibacterial, antiproliferative, antidiabetic, and antifbrinolytic and used as neuro protective [52]. Bharati and Sinha assessed the antidengue cogency of shoots of and Punarnava Linn (10 gm) in patients with dengue infection, and by administering them this extract, the quantity of platelets was raised [53].

Malancha.
Malancha is also known as Alternanthera philoxeroides belonging to the family: Amaranthaceae. It was famous as "alligator weed" in its native places or areas, such as S. Africa, Brazil, Uruguay, and Argentina, and "Malancha" in Bengal. It is an inhabitant of both aquatic and marsh areas, having whitish, papery fowers with hollow, hairy, cylindrical stem, and leaves simple and opposite venation. Out of many constituents found in the plant, coumarin showed antidengue efects [55]. It was investigated for the antiviral activity of four extracts (light petroleum, acetoxy ethane, diethyl ether, and cyclopropyl alcohol). While all of the aforementioned extracts exhibited a noticeable inhibitory impact, A. philoxeroides' light petroleum extract had the strongest inhibitory efcacy against DENV [56].
3.6. Neem. Neem, scientifcally known as Azadirachta indica, is a member of the Meliaceae family. It was discovered in Africa and Indian subcontinental countries.
Terapeutic applications for neem included pain relief, infammation reduction, fever reduction, infection prevention, and tumor suppression [57]. In vitro research demonstrated that Azadirachta indica inhibited viral multiplication. Te aqueous extract of neem leaves totally suppressed 100-10,000 TCID (tissue culture infectious dose) of the virus at its maximal nontoxic dose of 1.897 mg/ml [58]. Its phytochemistry profle includes Nimbin, 6-deacetylnimbin, desacetylsalannin, and 3-tigloyl azadirachtol. In a computer simulation, nimbin was proven to be efcacious against the protein of all dengue virus types [59]. Te verdicts of this study revealed that the triterpenoids nimbin, desacetyl nimbin, and desacetyl salannin, which were widely found in neem plants, have a strong closeness for DENV attachment NS2B-NS3 protein and might be used to generate highly trenchant and propitious medications to treat dengue virus infection [60].  [67]. In many nations, curcumin has been used as a nutraceuticals since ancient times. It has the capability to be used simultaneously as a direct combatant against dengue infections and as a great building block for very efective nonlinear antagonists. Examining the toxicity of C. longa (0.147 mg/mL) extract in the liver and kidney of DDY (Deutschland, Denken, and Yoken strain) mice, its antiviral efects on DENV-2 were evaluated in preclinical and clinical studies.

Bignonia pulchra
To assess the antidengue activity, researchers conducted an assay and an MTT test, respectively, in Huh7it-1 cells. To measure viral load, blood samples from infected subjects were obtained 6 and 12 hours after exposure [68]. In plaque tests, curcumin was more efcacious than other drugs at preventing DENV infection, indicating that these drugs target the biochemical reactions required for the virus to mature and reproduce. Anti-DENV activity in Huh7it-1 cells (IC50 17.91 μg/mL) [69,70]. Te NS2B/NS3 protein, which encodes the DENV protease enzyme, was shown to be strongly inhibited in another study. Studying animals in their natural habitat, or in vivo, C. longa extract at 0.147 mg/mL inhibited DENV-2 replication and shortened the time period during which viremia was present [71].
3.10. Licorice. Licorice, as Glycyrrhiza glabra, is a member of the Fabaceae family and is native to the southern and northern hemisphere [72]. Memory improvement, antipsychotic efects, microbe and cancer protection, free radical scavenger, and healing an ulcer relief were only a few of the therapeutic activities demonstrated by Glycyrrhiza glabra root extract. Te roots may include a variety of chemical compounds or phytochemicals with a wide range of pharmacological efects [73]. Furthermore, Licorice showed excellent docking characteristics to the protein of dengue [45,74]. It was shown that glycyrrhizin can inhibit Flavivirus procreation at a high nonlethal cytotoxic dose [75]. A study of antiviral phytochemicals identifes three compounds such as Cyanidin 3-O-glucoside chloride, Nigellone, and (R)-Glabridinas potent inhibitors of the dengue virus NS3 protease, which was a key step in the development of an efective vaccine for the mosquito-borne tropical disease dengue fever [76].

Nutmeg. Te
Myristicaceae category contained nutmeg, also known as Myristica fatua. It is a fragrant tree that grows in Bangladesh, India, and Indonesia and produces yellow organic fruits that resemble apricots or peaches. It was once used in herbal medicine as an antioxidant, analgesic, amenorrheal, aphrodisiac, and digestive specialist [81]. Te results of the study indicated that nutmeg methanolic extract magnifcently reduced DENV infection up to 21.61 percent devoid of the cytostatic efect. Furthermore, the antidengue efect against DENV with EC50 was 25.33 μg ml −1 [82].
3.13. Webera corymbosa. Chomelia asiatica, also recognized as Webera corymbose (family: Rubiaceae), is typically grown in India. In the past, Webera corymbosa leaf, barks, and underlying structures were employed in ancient Ayurvedic medicine to cure a wide range of illnesses [83]. DENV-infected C6/C36 cells that were treated with acetone extracts of Webera corymbosa reported a CC50 value of 34.35 percent at a concentration of 500 micrograms per milliliter [84].
3.14. Mangosteen. Te mangosteen, known as Garcinia mangostana (MG), belongs to the family Guttiferae, also Evidence-Based Complementary and Alternative Medicine recognized as "the sovereign of natural goods." Tis tropical evergreen tree is found in India, Sri Lanka, Myanmar, Malaysia, the Philippines, and Tailand [50,85]. It contains signifcant phytoconstituents mangosteen, acetoside, and various potent xanthene derivatives [86]. Te IC50 values were 5.47 μM 24 h treatments, inhibiting virus replication. Te infection rates of four diferent dengue virus types were lowered by 40-60 percent when DENV-infected cells were treated with MG (20 M). It diminishes the production of dengue virus type 2, 3 by 100 folds, whereas in dengue 1, 3 type, additionally, it could drastically reduce the body's production of mediators and infammatory markers. Te efects of -MG were superior to those of the anti-infammatory drug and the antiretroviral ribavirin [87].

Euphorbia hirta (Asthma-Plant). Asthma plant (family:
Euphorbiaceae), develops in open felds in India, Ceylon, British Malaya, Java, and Socialist Republic of Vietnam, is well known for its folklore medicinal applications [88]. Asthma plant is a small, hairy, annual herb with branches that reach a height of 60 cm, is scarlet or purple, and generates large amounts of latex. Te herb was reportedly used as a spasmolytic, alpha-glucosidase inhibitor, antiinfammatory, antitumor, and antidengue agent [89]. Patients were able to recover more rapidly because to Euphorbia hirta's promotion of platelet formation, which decreased further bleeding. Te natives of the Philippines also took Euphorbia hirta-made capsules to treat dengue. Euphorbia inhibited DENV-1, DENV-2, DENV-3, and DENV4 (IC50 � 33.84, 33.55, 58.35, and 119 μg/mL), respectively [88].

Hauili.
Hauili, also known as Ficus septica (family: Moraceae), is a fg that is indigenous to Malasia, Australia Terra Australis, South China, Republic of China, and Land of Seven Sisters [90]. Te majority of the world's tropical wet forests contain more than 750 varieties of woody plants of the genus Ficus, described by Morceau. A deciduous shrub or small tree with aerial roots that resemble a bush, Ficus deltoidea frequently starts of as an epiphyte. With branches that were around 15-22 feet high and 3-10 feet wide, it frequently reached a height of 22 feet. Te bark and trunk were commonly grey and thin, respectively [91]. In conventional medicine, they had been used as a carminative, stomachic, microbicide, in postural hypotension, and as an antidysentery medication. Gardens were planted with a wide variety of plants for decoration and shade. [92]. WS1 human foetal skins typical fbroblasts cells, HepG2 human hepatoma, Huh7.5 human hematoma, and A549 human lung epithelial carcinoma cells were only a few of the cell types that Hauili in the Philippines leaf methanol shielded from DENV contamination [53,93]. Te immunofuorescence experiment demonstrated that the methanol extracts of Ficus septica's fruit, heartwood, leaves, and stem exhibited a potential anti-DENV-1 and DENV-2 impact. DENV-1 (IC50 � 17.44.6 g/ml) and DENV2 (IC50 � 15.82.5 g/ml) were strongly suppressed by FS-(L)-M [94].

Red
Fire. Hemigraphis reptans, often known as red fame (Family: Acanthaceae), are native Malaysian green plants and are once used to treat wounds, infammation, diabetes mellitus, iron-defciency anemia, heavy menstruation, and gallstones [95]. Evidence suggested that Hemigraphis leaf extracts assessed positive results against DENV-2 and NS2B-NS3 protease with IC50 values of 100 g ml for the management of dengue fever [96].
3.18. Ocimum sanctum. Ocimum tenuiforum, also identifed as Ocimum sanctum (family: Lamiaceae), believed to have hepatoprotective, calming, and antiviral properties [97]. It prevented hiccups, fever, and ulcers. Ocimum sanctum L. (Labiatae) is a tiny, highly perfumed annual plant that grows to a height of eighteen feet and is often called holy basil, Tulsi. Ocimum sanctum L. contains vitamin C and A; minerals such as calcium, zinc, and iron; as well as chlorophyll and other favonoids [98]. It had been shown to have qualities that were antidiabetic, bruise-healing, tocopherol, actinotherapy, antiangiogenic, oral contraceptives, anti-infammatory, antibacterial, antistress, and antitumor [99]. In addition, O. sanctum methanolic extract displayed antiviral activity against DENV-1 by inhibiting CPE development and viral replication. Te methanol extract of A. paniculata at its MNTD only inhibits CPE formation, not viral replication, which is how the antidengue-1 cytotoxic activity is achieved. Te efectiveness of methanolic extracts of Andrographis paniculata and Ocimum sanctum against DENV1 was examined using HepG2 cells. Prior to the antiviral experiment, the maximum nontoxic dose (MNTD) of the extract and the median tissue culture infective dose (TCID50) of DENV-1 against HepG2 cells were determined. Te antiviral activity was assessed by measuring the degree of inhibition based on cytopathic efects (CPE), cell survival using the MTT test, and plaque inhibition assay [100].

Magnolia berry. Typically growing in northeastern
China, magnolia-vine also known as Magnolia berry (family: Schisandraceae) is a fora whose natural products had been used to treat alimentary tract and digestive tract problems, respiratory difculties, blood-vascular issues, body exhaustion, excessive sweating, and sleeplessness to show nonsteroidal anti-infammatory drugs, antiviral, and neuroprotective characteristics [101]. Tree days of schisandrin derivatives (active constituent) treatment were given to Huh-7 cells that had DENV infection. Using RT-PCR and western blotting, respectively, DENV RNA and protein levels were assessed; the amount of NS2B represented the level of DENV protein production. On comparing treated cells with crude cells, schisandrin A efectively reduced DENV RNA and protein levels. Te supression of DENV RNA and protein content in cells treated with schisandrin B and C is lesser than cells treated with schisandrin A. EC50 values for schizandrol A, schizandrol B, and schizandrol C were discovered to be 28.1 0.42 M, 34.0 0.95 M, and 42.6 3.48 M, respectively. As the cells were treated to either schisandrin analogue at possible antibacterial dosages, no obvious cytotoxicity was seen. Consequently, schisandrin A was chosen as a promising inhibitor [102]. 8 Evidence-Based Complementary and Alternative Medicine 3.20. Governor's plum. Governor's plum or Flacoutia ramontchi (family: Salicaceae) is a conifer tree native to Madagasikara and Indochinese Peninsula [103]. Potential actions include infammation inhibiting, antimalarial, antiviral, and snake venom phosphodiesterase inhibiting. Active constituents of Flacourtia ramontchi embraces daucosterol; sitosterol; phenolic glycoside favonoids such as robigenin, three rutinoside, and quercetin; facosides including facoside A, B, and C polioithrysoside; and salirepin [103,104]. In another study, Betulinic acid 3-cafeate, ramontchi, A, and E, as well as scolochinenoside D, severely hindered RNA polymerase action in the dengue virus RNA polymerase experiment. However, in the experiment, betulinic acid 3-cafeate and facourtia sides A and E along with scolochinenoside D dramatically reduced RNA polymerase activity (IC50 = 0.85 μM, 0.1 μM, 1 μM, and 5 μM, respectively). For both tests, Flacourtia ramontchi's stem bark extract was shown to be the most efective. Tis was the frst-timebioassay-guided isolation, yielded six novel phenolic glycosides, together with poliothrysoside, facourtosides (A-F), xylosmin, scolochinenoside D, betulinic acid 3cafeate, and itoside H [104].

Cryptocarya chartacea.
Tere were a variety of secondary compounds found in Cryptocarya chartacea (Family: Lauraceae), favonoids, such as pyrones, that had demonstrated biological actions such as antiviral and cytostatic activity [105]. Selecting new caledonian plants with considerable dengue virus RDRP (RNA dependent RNA polymerase) inhibitory activity was made possible by an in vitro screening of the plants. chartaceones A-F, together with pinocembrin were isolated from Cryptocarya chartacea during a chemical examination of the plant. Racemic mixtures were used to extract them, and one-and twodimensional NMR spectroscopy was used to describe them. By comparing their experimental and predicted spectra with chiral HPLC, the four diastereomers of chartaceone A were identifed and their absolute confgurations were identifed. Te strongest NS5 RDRP inhibitors have IC50 values in the range from 1.8 to 4.2 M and are dialkylated favanones such as chartaceones CF. Tis family of non-nucleoside DENV RDRP inhibitors was called Chartaceones [105].

Chinese Lizard
Tail. Chinese lizard tail, also known as fsh mint (family: Saururaceae), primarily found in Eastern Asia, mainly China, is a plant that experienced seasonal regrowth and springtime regrowth. It had counteracted the efects of leukemia having anticarcinogenic, antiinfammatory, and anti-anaphylaxis properties [106]. To minimize side efects of clinically used medications, fsh mint, an edible vegetable in China, was notifed to be an efective supplement. Phytochemicals found in H. cordata include favonoids, alkaloids, fatty acids, sterols, polyphenolic acids, sterol esters, and quercetin, out of which quercetin showed antidengue efects along with antiproliferative, antioxidant, antidiabetic, antihypertension, and antimutagenic potential [107]. According to the study's fndings, pre-and postbreeding with H. cordata extract dramatically decreased the synthesis of internal DEN-2 RNA, which related to a decrease in zika protein production. At an efective dose (EC50) of 0.8 mg/mL, the extract was bound to DEN-2 and dramatically reduced intracellular RNA synthesis when used in the straight block mode of action. Furthermore, the aqueous extract of Houttuynia cordata's showed inhibitory efects on dengue virus and cells with dengue infection in another study [108]. In addition, quercetin or isoquercetin, two signifcant water extractable favonoids, were present in H. cordata hot water extracts at 10 M, they inhibited HSV-2 infection by blocking NF-B activation [109,110].

Baikal skullcap.
Baikal was a type of fower plant of the Lamiaceae family, native to both Russia and East Asia. Scutellaria baicalensis had roughly 360 diferent species worldwide. Scutevulin and carthamidin and baicalin were included in the list of ingredients for their medicinal characteristics, as well as kaempferol 3-O-D-glucoside for its antioxidant capabilities [111,112]. Baicalin was demonstrated to target nonstructural viral proteins of DENV-2 internal replicon [113]. Baicalin, a bioactive metabolite from Baikal, indicated potent antidengue activity [114,115]. Delving further revealed that the S. Baicalensis extract particularly earmarked certain DENV infection and proliferation phases. Studies also showed that S. baicalensis extract had a strong direct virucidal activity that could neutralize exogenous DENVs that were circulating in patients with viremic disease. Tis activity served as a crucial criterion for the creation of antidengue drugs. Te presence of baicalein, a favonoid renowned for its ability to inhibit the reproduction of the dengue virus, may be one of the naturally occurring antiviral components, according to fndings that also highlighted the potential of S. baicalensis aqueous extract for use against the dengue virus [116].

Distictella elongata. Distictella elongata (family:
Bignoniaceae) was originated in Minas Gerais, Brazil. It has been claimed to have antimicrobial efects versus DENV-2 in addition to its antioxidant and anticancer activities. It might be useful as a source of pectolinarin due to its previously documented antiviral, anti-infammatory, and collageninducing activities. Distictella elongata fruit ethyl alcohol extracts were used to extract acacetin-7-O-rutinoside and pectolinarin, both of which had anti-DENV-2 activity (EC50 � 9.8 μg/ml) [117,118].

Red Rea
Weed. Gymnogongrus grifthsiae, a polysiphonia, a native to Brazil, belongs to the Phyllophoraceae family contains unrefned polysiphonia extract sulfated with galactan. Two identical sulfated starches from red seaweeds, carrageenan, and rhamnan were tested for their antiviral activity against the four dengue virus subtypes (DENV) in various host cell types. Red seaweed has been shown to be resistant to Herpes simplex types I and II [121]. Red seaweed revealed a selective antagonist of dengue virus type-2 multiplication in Vero cells but had a less potent antiviral efect against dengue virus types 3 and 4 [122].

Moreton Bay Chestnut.
Black bean or Moreton Bay chestnut, Castanospermum australe, is a native to Australia and could also be noticed in Asia. Te seeds of this plant, which contained active constituent castanospermine, were poisonous to horses and could make people sick and after being carefully converted to fne powder, they could be consumed [123]. DENV-1, 2, 3, and 4 subtype cellular exudation and dissemination were reported to be inhibited by castanospermine both in vitro and in vivo [124].

Cissampelos pareira.
In India, traditional uses for velvet leaf (family: Menispermaceae) included purifcation of blood and pain relief. Cissampelo favone that worked well against all four types of dengue virus. Te root of this plant could help wounds heal and was also known to relieve pain and ease joint pain. C. pareira inhibited DENV-2in vivo and prevented mouse mortality with IC50 � 85.7 μM [125,126].
A summary of all the plant products including part of the plant used, targets, and their uses as antidengue agents and their IC50/EC50 values is provided in Tables 1 and 2, respectively.

Conclusion and Future Perspectives
Notwithstanding tremendous progress, attempts being made to develop dengue vaccines or treatment regimens have not yet shown satisfactory results. Many research organizations are working towards the development of antivirals to treat DENV infection, which will indeed assist in the creation of this vital resource for the treatment of severe sickness. Natural products are a great source of biodiversity for the development of novel antivirals, with new structureactivity interactions, and efcient preventative and therapeutic approaches to viral diseases. It has been further concluded that plants such as Governor's plum, Cryptocarya chartacea, Magnolia berry, and Chinese ginger revealed many active pharmaceutical constituents against DENV and could be a promising target for drug discovery. In addition, more investigation is required to pinpoint the most suitable stages to stop the spread of virus infection and by concentrating on each stage of the viral life cycle, newfangled molecules may be developed to stop the infection of host cells, viral maturation, viral RNA synthesis, and viral particle spread. To aid in the development of efective antiviral treatments, further exploration in defning the underlying mechanisms, describing the bioactive ingredients, as well as assessing the efcacy and potential application in vivo is encouraged since many studies in this feld are still in the preliminary stages. A multitargeted therapy may also help to lower the likelihood of creating drug resistant viruses. Subsequent research should also investigate the possibilities of combination therapies with other natural agents or with conventional pharmaceuticals. Hence, the development of antiviral medications will beneft greatly from natural items in the future.

Data Availability
Te data that support the fndings of the study are available from the corresponding authors upon request.

Conflicts of Interest
Te authors declare that there are no conficts of interest in the submission of the manuscript.