Coronaviridae is a family of enveloped RNA viruses known as Coronaviruses (CoVs) that provoke infections in animals and humans [1,2,3,4,5,6]. Presently, seven human coronaviruses (HCoVs), commonly considered of zoonotic origin, are described in the scientific literature [7] that cause infections mainly associated with respiratory symptoms [8,9,10]. More in detail, HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1 are “common cold” coronaviruses causing seasonal, usually mild, respiratory diseases [11,12]. Although, in most cases, these HCoVs do not lead to severe clinical symptoms, HCoV-NL63 and HCoV-HKU1 infections can provoke bronchiolitis and croup [13,14], whilst CoV 229E and OC43 can provoke pneumonia [15,16]. Nonetheless, three highly pathogenic HCoVs have emerged in the last two decades, i.e., Middle East Respiratory Syndrome (MERS)-CoV, Severe Acute Respiratory Syndrome (SARS)-CoV-1, and SARS-CoV-2 [17,18,19], which can lead to life-threatening pathologic events associated with the recent MERS, SARS, and the current COronaVIrus Disease 19 (COVID-19), which is causing enormous problems globally in both sanitary and socioeconomic terms [20]. SARS-CoV-1 and MERS-CoV are more lethal than SARS-CoV-2, but this latter is more transmissible, explaining the current pandemic status of COVID-19 [21]. In the first step of coronavirus infection, a specific molecular recognition between the virus particle, through the virus spike (S) protein, and the host cell takes place, involving different HCoV-specific receptors [22,23,24,25,26] that were identified for several CoVs and are considered one of the primary targets for anti-CoV biomedical strategies together with the SARS-CoV-2 main protease (M^pro) [27,28]. The receptors for the “common cold” HCoVs are human aminopeptidase N (APN), associated with the infection from HCoV-229E, and 9-O-acetylated sialic acid (9-O-Ac-Sia), used by HCoV-OC43 and HCoV-HKU1. On the other hand, the receptor for HCoV-NL63, i.e., angiotensin-converting enzyme 2 (ACE2), is also common to the more pathogenic SARS-CoV-1 and SARS-CoV-2, whilst dipeptidyl peptidase 4 (DPP4) was associated with MERS-CoV [29,30]. Once intracellular, all HCoVs replicate their RNA with the consequent expression of the viral proteins needed for the production of new viral particles inside the infected cell [31]. As anticipated, four out of the seven HCoVs are associated with usually mild upper respiratory infections, whilst MERS-CoV and SARS-CoV-1 and -2 can cause lethal events [32]. This latter, first emerging in China at the end of 2019 [32], can lead to severe pneumonia and, being easily transmissible, has spread worldwide rapidly, leading the World Health Organization (WHO) to declare COVID-19 a pandemic [33]. Currently, there are more than two million deaths (2,566,793, as found in Worldometers.info [34] accessed on 3 March 2021) worldwide due to COVID-19, with enormous consequences for the public health and the economy worldwide [35,36,37]. While the whole world is fighting against COVID19 and awaits an effective mass immunization, the scientific community is devoting immense efforts toward developing specific therapies for the treatment of SARS-CoV-2 infection. Moreover, since inflammatory cytokine storms together with immune system impairment are commonly observed in patients with severe COVID-19, several research studies have highlighted the advantages of dual therapies with antiviral and anti-inflammatory benefits [38,39]. Due to the urgent need for such a pharmacological treatment, drug repurposing [40,41,42] and herbal medicine are two of the most considered anti-COVID-19 approaches [43,44,45,46,47]. In fact, several plants such as mulberry, tea, and Dragon’s Blood tree are known as remedies to treat respiratory ailments and for their anti-inflammatory and antithrombotic properties, which are useful aspects in the fight against COVID-19 [48,49,50,51,52].

Syzygium aromaticum L., also known as Eugenia caryophyllata L. [53], is an evergreen tree with sanguine flowers belonging to the family Myrtaceae that grows in tropical climates and has been widely used in Ayurveda and Chinese traditional medicines for over 2000 years. Arabic traders brought it to the Western world in the fourth century A.D., and in medieval Europe, it became very popular as a medicinal spice [54].

Indigenous to the Moluccas, this tree is cultivated in several countries of Asia and Africa, including India, Indonesia, Madagascar, Malaysia, Sri Lanka, and Zanzibar [55]. The dried flower bud of this plant is indicated by the English name “clove”, derived from the Latin word “clavus” (nail), as the shape resembles that of a small-sized nail. Cloves are currently used in three different forms, as whole dried buds (commonly referred to as “cloves”), ground spice, and essential oil. Though all forms share similar biomedically-relevant properties, they differ in the degree of potency, with the oil showing the highest potency and, thus, often being diluted with almond oil. Whole cloves, containing a good amount of oil in their interiors, are still endowed with a medium potency, whilst ground cloves are the least potent form, as, in this form, the spice generally loses most of the essential oil [54].

Cloves have long been used in both traditional medicine and for culinary purposes and serve to produce an essential oil known since ancient times in food flavorings, traditional medicine, and perfume production [53]. Even though cloves are mostly used as a nutritional spice for food in the Western world, in the past, they have constituted a remedy for a variety of health concerns, with the clove anesthetic (due to eugenol), stimulating, antimicrobial, antifungal, antiviral, and antiseptic properties having been known for centuries [54].

On the other hand, the clove essential oil finds applications in dental care, including the treatment of gum infections [56], burns [57], and respiratory and digestive disorders [56,58]. The previous literature studies also evidenced other remarkable properties, such as antiangiogenic [53,59], anticancer [53,56,58], antioxidant [60], anti-inflammatory [61], and antimutagenic activities [62].

The American Food and Drug Administration (FDA) agency has confirmed the safety of clove buds, clove oil, and some clove ingredients as a food supplement [63], while the WHO has established the acceptable daily uptake of cloves in humans at 2.5 mg/kg body weight [64].

The spice contains a good amount of minerals like magnesium, manganese, potassium, iron, and selenium [54]. Among the others, potassium as an important electrolyte of the cell and body fluids has a key role in the heart rate and blood pressure control [65], while manganese is used by the body as a cofactor for the antioxidant enzyme superoxide dismutase [66,67]. Additionally, cloves are a good source of beta carotene vitamin B1, vitamin B6, vitamin C, vitamin K, riboflavin, and vitamin A, used by the body for maintaining healthy mucus membranes and skin [68]. Noteworthy, vitamin C sustains a resistance against infectious agents [69] and is used by cells to scavenge harmful oxygen-free radicals [70].

Several research studies have been carried out to identify the main clove phytochemicals [71,72,73,74,75,76,77]. Dried clove buds contain ~20% essential oil, which is rich in eugenol, accounting for 70–90%. The other main phytochemicals isolated from clove essential oil include eugenyl acetate, β-caryophyllene, and several sesquiterpenes [53,78], including α-cubebene, α-copaene, and γ- and δ-cadinene [79]. Crategolic acid, vanillin, gallotannic acid, methyl salicylate, eugeniin, rhamnetin, kaempferol, eugenitin, oleanolic acid, methyl amyl ketone, methyl salicylate, α- and β-humulene, benzaldehyde, chavicol, and β-ylangene are present in lesser amounts [74]. In particular, eugenol and minor constituents like methyl salicylate and methyl amyl ketone are responsible for the characteristic pleasant aroma of cloves. The extraction of phytochemicals, achievable with high efficiency by presoaking and the liquid ammonia treatment of plant materials [80], in the case of cloves was realized with different operating conditions, including using supercritical CO₂ [81]_.