**1. Introduction**

Treatment of Covid-19 (SARS-CoV-2) disease which is characterized by acute respiratory syndrome and continues widely in the world and causes a serious number of deaths, is among the discussed topics [1]. The clinical symptoms of this disease, such as fatigue, headache, diarrhea, cough, fever, and dyspnea, occur after an incubation period (about 5–7 days) [2]. In some patients, respiratory failure, acute

respiratory distress syndrome (ARDS), or multiple organ failure may take shape. In most patients, it can be asymptomatic or mild [1–3]. However, some conditions such as old age cardiovascular diseases, chronic kidney disease, diabetes, hypertension, and chronic obstructive pulmonary disease (COPD) predispose to severe Covid-19 disease. The covid-19 disease can cause several complications such as COPD, coagulation dysfunction, septic shock, metabolic acidosis, cardiac arrhythmia, heart failure, liver dysfunction, kidney damage, or secondary infections [2]. Many studies have noted that inflammation is a natural defense mechanism against various pathogens and its association with oxidative stress in various pathological conditions [4–12]. There is a great deal of evidence that systemic hyper-inflammation plays a role in the occurrence of lung and multi-organ failure in Covid-19 patients [1]. High levels of ferritin, fibrinogen, D-dimer, interleukin-6 (IL-6), C-reactive protein, and procalcitonin were found in the sera of Covid-19 patients. It has been determined that these laboratory and clinical signs are associated with macrophage activation syndrome and hyper inflammation [3]. Macrophages and monocytes play an important role in the inflammatory reactions that accompany severe Covid-19 infection [13]. These immune cells secrete large amounts of proinflammatory cytokines (Tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8)) typical for critically ill patients with Covid-19 [14–17]. Cytokine excessive release in Covid-19 disease causes acute heart damage, acute respiratory failure, or the development of multi-organ failure and worsening of the situation [2]. For this reason, the use of anti-inflammatory agents in the treatment of Covid-19 disease plays a very important role in preventing the severity of the disease. Identifying new agents in addition to existing agents will contribute to developing new strategies to overcome the pandemic [1].

Apigenin is a yellow-colored flavone with a closed formula of C15H10O5 and a molecular weight of 270.24 g/mol. It is chemically known as 4′,5,7-trihydroxyflavone or 5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyren-4-one (**Figure 1A**). Apigenin is mostly found in the flowers of *Matricaria chamomilla* (German chamomile) from the Asteraceae family, but it is also abundant in *Apium graveolens* (celery) leaves, *Allium sativum L*. (garlic) and *Petroselinum crispum L.* (parsley) species [18– 20]. It was determined that it was found at a higher rate in the leaf part of the plants [21]. Resveratrol is in the structure of 3,4′,5 trihydroxystilbene and has two isomers as trans and cis isomers (**Figure 1B**). Trans isomers have higher biological activities than cis isomers. The chemical structure of resveratrol is similar to the synthetic estrogen, diethylstilbestrol. It is also the main component of a molecular family that includes glucosides and polymers, and has been shown to be found in grapevines, peanuts, and mulberries [22, 23]. Morine has been named a natural polyphenol (3, 5, 7, 20, 40-pentahydroxyflavone). The hydroxyl groups at the 3 and 4′ positions in morin can be electrochemically oxidized to form the corresponding quinones (**Figure 1C**) [24, 25]. The chemical formula of Silymarin is C25H22O10 (**Figure 1D**). The main ingredient of silymarin is silybin. Flavolignans constitute 70–80% of silymarin. 20–30% consists of polyphenolic components. Silydiadin, silychristin and isosilybin make up the remaining 40% of the compound [26, 27].

Polyphenols are plant-derived phenolic compounds. Polyphenols have been characterized by extensive biological activities in a variety of mammalian systems. These compounds act as free radical scavengers and exhibiting anti-mutagenic, antiinflammatory, antioxidants, and antiviral effects [28]. In various studies conducted recently, the use of phenolic compounds as anti-inflammatory and antioxidant has become widespread [29–37]. Some factors such as the cheapness of flavonoids and the *Can Polyphenols be Used as Anti-Inflammatory Agents against Covid-19… DOI: http://dx.doi.org/10.5772/intechopen.98684*

#### **Figure 1.**

*Chemical structures and anti-inflammatory effects of related phenolic compounds. A (Apigenin), B (Resveratrol), C (Morin), and D (Silymarin).*

absence of side effects also increase their usability [38]. As such, the use of flavonoids as an anti-inflammatory will be effective in suppressing hyper-inflammation caused by Covid-19 disease, which is quite common and quite deadly worldwide and thus decreases the mortality rates by reducing the severity of the disease. Therefore, in this study, it will be emphasized that Apigenin, Resveratrol, Morin, and Silymarin, which are natural flavonoids, can be potential agents that can suppress hyper-inflammation in Covid-19 patients.

### **2. Virus morphology and way of attachment to the cell**

When you look at the morphological structure of the Coronavirus, the Virus is a member of a single-stranded (+) RNA enveloped virus family. This virus was identified by scientists in the United States and the United Kingdom in the sixties as a causative agent of the common cold in humans [39]. Coronaviruses are pleomorphic or spherical and are 80–120 nm in diameter. As a result of research conducted in 1968, electron microscope images determined that this family has virus crown-like structures resembling "solar corona", whose name is derived from the Latin word "coronavirus" [40]. It has been determined that there are four main structural proteins in the structure of the coronavirus. These proteins: The first is the trimeric Spike glycoprotein, localized on the surface of the virus envelope and required for virus entry into cells, and this protein is named S. The second is called matrix or membrane protein, and is named M. The third is the small envelope protein required for the collection and release of virions and is named E. The fourth is called the nucleocapsid protein and is named N, which helically binds to the RNA genome forming the symmetrical nucleocapsid (**Figure 2**) [41]. However, homology modeling revealed that the new virus has a similar receptor binding domain structure (RBD) to that of SARS-CoV, despite amino acid variation at several key residues. It was hypothesized that the virus entered cells using the Angiotensin Receptor Enzyme-2 (ACE2) protein, which is widely expressed in the kidney, heart, lung, testis, and gastrointestinal tract [42]. ACE2 is a membranebound protein responsible for the reduction of Ang II to Ang 1–7 [43]. Several steps are required to initiate and complete the Covid-19 infection cycle: These steps 1. Recognize and bind to the cellular receptor (s). The second is that changes occur in the structure

#### **Figure 2.**

*The structure of the coronavirus and its entryway into the cell. ssRNA: Single-stranded RNA, N: Nucleocapsid proteins. S: The trimeric spike glycoprotein. It recognizes the ACE2 receptor on the cell membrane after cleavage and activation by two serine proteases: FURIN and TMPRSS2. M: Membrane or matrix protein, E: Small envelope protein.*

and proteolysis of the S protein. The third is fusion to the cellular membrane. The fourth is the entry of the virus into host cells by endocytosis [44]. In host cells, the virus uses an endogenous cellular mechanism to replicate viral RNA. It is well known that the spiky glycoprotein S located on the surface of the viral phospholipidic membrane is very important for coronavirus pathogenesis and infection. The life cycle of SARS-CoV-2 begins with the RBD of the S protein in contact with the ACE2 receptor in cells [45, 46]. It was determined that two host serine proteases, TMPRSS2 and the endo-protease Furin, were involved in this event (**Figure 2**).
