The year 2020 observed one of the deadliest pandemics that has threatened the global health, security and economy [1]. It was rapidly shown to be caused by a novel coronavirus, causing severe acute respiratory syndrome [2]. The number of people infected with the severe Acute Respiratory Syndrome (ARD) associated with COVID-19 is rapidly increasing worldwide [3]. The WHO Emergency Committee declared a global health emergency based on growing case notification rates at Chinese and international locations on January 30^th, 2020 [4]. The pandemic started in December 2019 in Wuhan, China, and till date, it has covered almost the entire globe. Approximately 210 countries and territories worldwide have been affected by COVID-19 disease (Source:www.stat stica.com). According to the current records of WHO reported on August 23^rd, 2020, globally there are 23,057,288 confirmed cases of COVID-19, including a high death toll of 800,906. The country-wise COVID-19 data has been provided in Table 1. In India, the pandemic broke around January 2020, increasing leaps and bounds in the following months. The official website of the government of India reported 710,771 active cases and 57,542 deaths. The data also showed that the cured/discharged individuals accounted for a good 2338035 number, finally surpassing the number of active cases and giving a tiny hope for a brighter and healthier future. Most patients with COVID-19 exhibit mild to moderate symptoms, but approximately 15% progress to severe pneumonia, and about 5% eventually develop ARDS, septic shock and/or multiple organ failure [5]. A number of antiviral drugs, including the nucleotide analogue remdesivir, are being actively tested, but none of them has been approved for the treatment of COVID-19 [5]. Besides the vaccine development, there is also a need for approaches involving natural plant products which can directly target the virus or block viral entry. The present review highlights the efficacy of flavonoids as a treatment strategy either alone or in combination with other drugs against COVID-19.

Coronaviruses belong to the order Nidovirales, suborder Cornidovirineae and family Coronaviridae [6]. Coronaviruses are a group of RNA viruses that cause diseases in birds and mammals. These viruses lead to respiratory tract infections in humans which may range from mild to lethal. At present, there are seven confirmed human Coronaviruses which are mentio-ned in Table 2. The SARS-CoV-2 (Severe Acute Respiratory Syndrome Related Coronavirus-2) or COVID-19 belongs to the genus Sarbecovirus and is zoonotic in nature. It infects few animal species and also humans [7]. These viruses share around 96.20% homology with bat coronavirus sequences [8].

The human coronavirus mainly causes upper respiratory tract problems, including the common cold. The study by Killerby et al. [9] states that these viruses infect most of the people, atleast once or more in the lifetime. Before the present COVID-19 pandemic, two other viruses of the same group, i.e. SARS-CoV and MERS-CoV, also caused a large number of deaths in 2002-03 and 2012, respectively. The COVID-19 has an incubation period of 2 weeks, and the symptoms appear slowly during this period. The virus is known to replicate in the upper and lower respiratory tracts of the patients [10].

Flavonoids form the largest group of secondary metabolites that are produced by plants. These naturally occurring polyphenols are found universally in all fruits, vegetables and medicinal plants [36]. Recent years have seen an impetus in exploring the potential of flavonoids. From time to time, different studies have shown that flavonoids exhibit an array of health-promoting properties, like antioxidant properties, antiviral properties, anticancer properties, anti-inflammatory properties, and neuroprotective properties [37]. Flavonoids are further divided into 6 subclasses on the basis of the level of oxidation and substitution pattern of the C ring [37]. Different subclasses of flavonoids and their properties are provided in Fig. (1).

The current pandemic has made it very clear that we can never win against the nature. The panic of having no cure against the disease forced the scientists to look up to nature itself to find some remedy against this peril. According to the WHO report, around 80% of the world’s population is dependent on medicinal plants in order to meet their health requirements.

Owing to their abundant health-promoting properties, many plant molecules have been studied and modulated into drugs for a number of diseases [38]. Many plant products have shown promising antiviral properties. A study by Cragg et al. [39] showed that many plants derived formulations can exert their effects on different stages of viral infections. Due to their positive effects and low side effects, many synthetic drugs against viral diseases have been replaced by medicinal plants [40]. Studies have shown that many plants show high anti-viral, anti-inflammatory and antioxidant properties. It may be a very helpful approach to consider plant products for the treatment of COVID-19. Since ancient times, Indian herbs have been used for the treatment of various diseases, including viral infections. The Indian traditional medicinal system is one of the oldest treatment systems in history and plays a vital role in curbing global health problems [41]. A study by Pundari-kakshudh and Kanaki [42] showed that around 25,000 plants have been used in different medicines. A single herb can contain a number of constituents which in combination with the other compounds may produce desirable pharmacological outcomes [43]. The advantage of using herbal medicine for viral infection is that it builds up the immunity by modulating the immune system of the body. The herbal antiviral drugs have also been used in the previous two coronavirus outbreaks, viz. SARS CoV and MERS-CoV. These drugs have also been found to be effective against influenza and the dengue virus. The ministry of AYUSH has listed different medicines under three broad categories, viz. a) preventive and prophylactic b) symptom management of COVID-19 like illnesses, and c) add-on interventions to the conventional care. The complete list of recommended medicinal plants is given in Table 3.

Fig. (1). Structure, sources and properties of common flavonoids.

Table 3. List of recommended medicinal plant extracts by AYUSH for the treatment of COVID-19.

A. Preventive and Prophylactic: 1. Samshamani Vati 500 mg: Twice a day with warm water for 15 days. The medicine contains aqueous extract of Tinospora cordifolia. 2. Nilavembu Kudineer decoction 60 ml: Twice a day for 14 days. The medicine contains aqueous extract of Andrograhis paniculata & others. 3. Preparation of decoction by boiling Behidana (Cydonia oblonga) 3 gm, Unnab (Zizyphus jujube) 5 in number. Sapistan (Cordia myxa) 9 in number in water. 4. Arsenicum album 30: Daily once in empty stomach for three days.	Effective Against Chronic Fever Effective against cold and fever Have antioxidant, immune-modulatory, anti-allergic and anti-influenza activity Immune-modulator. Effective against SARS-CoV-2	Ayurveda Siddha Unani Homeopathy
B. Symptom Management of COVID-19 like Illnesses 1. AYUSH-64 : 02 tablets twice a day 2. Agasthya Hareetaki : 05 gm twice a day with warm water 3. Anuthaila/Sesame oil 02 drops in each nostril daily in the morning 4. Nilavembu Kudineer/Kaba Sura Kudineer— decoction 60 m1 twice a day 5. Adathodai Manapagu — Syrup 10 ml twice a day 6. Arsenicum album, Bryonia alba, Rhus toxico dendron, Belladonna Gelsemium Eupatorium perfoliatum.	For respiratory infections For respiratory infections For respiratory infections For fever Effective against lung inflammation, viral infections, asthma and lung diseases
C. Add on Interventions to the Conventional Care 1. AYUSH-64 : 02 tablets twice a day 2. Agastya Hareetaki: 05 gm twice a day with warm water. 3. Vishasura Kudineer: Decoction 60 m1 twice a day 4. Kaba Sura Kudineer — decoction 60 m1 twice a day	Effective against fever, cough, sore throat and shortness of breath

Viral infections are difficult to be controlled as the virus is made up of a few building blocks that too are common in all living organisms [44]. This level of similarity between the building blocks of the virus and biological cells makes it difficult to formulate antiviral drugs, as it may hamper the uninfected cells also [45]. Flavonoids act on the virus in a number of ways, as pointed below:

(1) Certain flavonoids inhibit the production of prostaglandins which are needed for the fusion of cell membranes [46].

(2) A number of known viruses, like HIV and poliovirus, rupture lysosome which results in cell damage. The acidification and activation of lysosomes can only be done by their own proton pumps. Flavonoids are known to inhibit these proton pumps, and thus, prevent their rupture and cell death [47].

(3) Flavonoids like quercetin have been proven to inhibit the functioning of the reverse transcriptase of RNA viruses [48].

Pollansky and Lori [49] showed that the use of herbal broad-spectrum antiviral treatment Gene-Eden-VIR/Novirin had a variety of antiviral effects on beta coronaviruses and also on the SARS-CoV. This drug is a combination of various plant products, like quercetin, the extract of cardamom, green tea, cinnamon, licorice and selenium. This herbal concoction was found to be effective against several other viruses also, such as Epstein Bars Virus (EBV), Human Papillomavirus (HPV), Human Cytomegalovirus (hcMV) and also Herpes Simplex Virus (HSV). The individual properties of each component and its possible effect against SARS-CoV are given in Table 4. The above study of Gene Eden Virus/Novirin concluded that the ingredients had a range of antiviral effects, especially on SARS-CoV, which included the inhibition of viral cell entry and infection, prevention of replication, inhibition of viral proteases, amplification of immune response, and decreased production of quasi-species. The study holds importance due to the large-scale similarity of SARS-CoV and SARS-CoV-2. Moreover, to fill in the gap of producing new drugs, these existing drugs can form a potential candidate in the drug development against COVID-19. Citrus flavonoids have also emerged as the promising drug candidate against COVID-19. Utomo and Meiyanto [50], by performing molecular docking, showed the efficacy of compounds present in curcuma species, citrus species, Alpinia galangal and Caesalpinia sappan against SARS-CoV-2. The study used three target proteins, viz. the receptor binding domain of spike protein (RBD-S), ACE-2 (Angiotensin Converting Enzyme 2) of the host and SARS-CoV-2 protease. The study showed that Citrus and galangal compounds showed a higher binding affinity to the receptor proteins. The higher affinity may be the reason for the higher inhibitory effect of these citrus and galangal compounds on viral infections. Out of all the compounds, the citrus flavonoid, hesperidin, was found to be a promising candidate for SARS-CoV-2 drugs as the docking score of hesperidin was observed to be lower than the lopinavir (a presently used drug against SARS-CoV-2). Thus, the present plant products could be suitable prophylactic agents as these are generally consumed through the diet. The study also proves that citrus sp. is the best herb to combat beta coronavirus, including SARS-CoV-2. This study also pointed out that other than hesperidin, other flavonoids in citrus sp. have shown a reduced binding energy for spike glycoprotein and ACE-2 in comparison to lopinavir and nafamostat, respectively. The affinity for these citrus flavonoids of these two proteins will help in inhibiting the attachment of the virus to the host, thus reducing the infection rate. Liu et al. [51] were also successful in crystallizing the main protease (Mpro)/chymotrypsin-like protease (3CL pro) from COVID-19. Using this protease as the main target, a molecular docking study was performed which showed that flavonoids, such as kaempferol, quercitin, luteolin-7-glucoside, naringenin, apigenin-7-glucoside and epicatechin gallate, are the most recommended ones to act as potential inhibitors of COVID-19 main protease (Mpro) [52]. Many earlier studies have also shown the antiviral properties of citrus flavonoids [53-55]. The major advantage of these citrus flavonoids is that they can be either taken as food or mixed with other herbal medicines. Moreover, the peels of the citrus fruits also contain a high content of flavonoids and can also be used to extract these components.

COVID-19 has emerged as the most frightening viral infection to be handled by mankind to date. Due to the lack of drug against this infection, the governments all over the world have exercised practices, such as social distancing, oral hygiene and quarantine, so as to minimize the human contact. This will hopefully stop the spread of COVID-19 and will also break the transmission chain and prevent the surge in COVID cases. To date, a number of vaccines are available, such as Covishield, AstraZeneca, Moderna, Sinopharm and Covaxin, and it is advised that people should get themselves vaccinated as soon as possible. Most of the vaccines have passed the clinical trials, but there are also reports of several side effects associated with the vaccines. The first mass vaccination program was started in early December 2020. To establish the efficacy and safety of the vaccines, studies with randomized standard controlled design (as well as follow-up) on large samples are required in order to generate confidence among people.

Our review is an attempt to showcase the importance of various plant components that have been used for decades as dietary supplements or as a part of herbal medicines. The undiscovered world of herbal medicine may prove to be a silver lining in these gloomy hours of COVID-19. These plant components, owing to their high antiviral properties, have already been used for treating some viral infections. Some of these components have already shown promising results against SARS-CoV, and owing to the similarity between SARS-CoV and SARS-CoV-2, these components may act against COVID-19 also. Thus, apart from working on potential drugs and vaccinations against COVID-19, due attention should also be given to these natural products that may act together with drugs for positive results.