The structural stability of resveratrol at its interface binding pose was confirmed by molecular dynamic simulations . druggable targets. Among the clinical trials actually recruited, some natural compounds are ongoing to examine their potential role to prevent and to treat the COVID-19 infection. Many natural scaffolds, including alkaloids, terpenes, flavonoids, and benzoquinones, were investigated by in-silico, in-vitro, and in-vivo approaches. Despite the large data set obtained by a computational approach, experimental evidences in most cases are not available. To fill this gap, further efforts to validate these results are required. We believe that an accurate investigation of naturally occurring compounds may provide insights for the potential treatment of COVID-19 patients. antiviral therapies generally takes from 10 to 17 years, while for particular vaccine production HDAC inhibitor it should be necessary to wait for a timeframe of approximately 12C18 months. In December 2020, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for the Pfizer-BioNTech COVID-19 (BNT162b2) vaccine (Pfizer, Inc; Philadelphia, Pennsylvania). This vaccine is a lipid nanoparticle-formulated nucleoside-modified mRNA vaccine encoding HDAC inhibitor the prefusion Spike glycoprotein of SARS-CoV-2. Despite the ultracold-chain storage and requirements for handling and administration, HDAC inhibitor this vaccine will be feasible to implement. Still, these requirements could limit its availability to some populations, thereby negatively impacting health equity. In this perspective, scientific efforts should be made to overcome these challenges and advance health equity . An issue to emphasize is the importance of the network between experts in complementary disciplines involved in COVID-19 investigation. In this connection, a trans-European Cooperation in Science and Technology (COST) action network is currently promoting scientific collaborations to speed up the achievements against COVID-19 . Another main point is represented by the evolution and the adaptive mutations of the virus . Indeed, the presence of SARS-CoV-2 Spike mutations can affect the interaction with the human epithelial cell receptors Angiotensin Converting Enzyme 2 (ACE2). The question of whether this would correspond to a novel and more potent COVID-19 specificities eventually requiring the development of wider-spectrum anti-SARS-CoV-2 strategies, such as vaccines or antiviral drugs, remains open [7,8,9]. Hence, the repurposing of clinically evaluated drugs is one of the most promising strategies to address the immense landscape of diseases, including infectious ones such as COVID-19. Remarkably, while most drug repurposing occurrences are based on synthetic compounds, naturally occurring molecules may offer significant opportunities. In fact, nature itself may be considered a magic bullet providing molecules with promising or still unexplored pharmacological properties [10,11]. It was reported that around 80% of the human population draws on traditional plants in the developing world for health quality and requirements [12,13]. Moreover, natural products are considered an essential source of successful drug leads and provide unique structural diversity with respect to standard combinatorial chemistry. Since more than 95% of the worlds biodiversity has not been evaluated for potential biological activity, the main challenge involves how to efficiently access and enhance this natural chemical diversity [14,15,16]. Therefore, the different chemical space structural, affordability, lack of substantial toxic effects and inherent biologic properties of natural products allow to consider them good candidates for new therapeutics [17,18]. As a result of the current COVID-19 outbreak, the repurposing of natural products could be an effective strategy to handle the SARS-CoV-2 infection. Currently, several studies have highlighted the antiviral properties of several natural compounds [12,19,20]. Therefore, naturally occurring molecules with broad antiviral spectrum may offer a safe, effective, and inexpensive platform for identifying novel treatment of SARS-CoV-2. To prepare this review article, the PubMed database (www.ncbi.nlm.nih.gov/pubmed) was used to analyze scientific manuscripts matching the queries SARS-CoV-2 and natural products. After analyzing the compelling articles dealing with the antiviral activity of natural compounds against SARS-CoV-2, we dedicated our attention to natural compounds recognizing SARS-CoV-2 druggable HDAC inhibitor targets. Particularly, natural compounds currently under clinical trials were extensively herein discussed. Due to the amount of data from scientific literature, in our opinion sometimes inaccurate and superficial, our main goal is to give a vision on the possible role of the natural compounds against SARS-CoV-2. In this regard, based on the MGC33310 recent analysis gathered on SARS-CoV-2 targets , we focused on natural compounds HDAC inhibitor under clinical trials in the first section. Meanwhile, in the second section, we provided in-vitro, in-vivo and in-silico results of the natural derivatives against SARS-CoV-2. This analysis may help to figure out the most promising natural products which lead to the development of drugs for the treatment or prophylaxis of the emergent pandemic. Since the drug repurposing is a time-saving medicinal chemistry strategy, it could offer an excellent opportunity to obtain useful and non-toxic drugs to fight COVID-19. 2. Results 2.1. Natural Occurring Compounds Undergoing Clinical Trials The clinical severity of COVID-19 varies.