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Berberine is a well-known phytochemical with significant antiviral activity against a wide range of viruses. Due to having a unique backbone consisting of four interconnected rings, it can be used as a platform for the design and development of novel semisynthetic antiviral agents. The question here is whether novel broad-spectrum antiviral drugs with enhanced activity and toxicity potential can be obtained by attempting to modify the structure of this privileged lead compound. The present study aims to review the results of recent studies in which berberine and its close analogues (protoberberine alkaloids) have been used as starting materials for the production of new semisynthetic antiviral structures. For this purpose, relevant studies published in high-quality journals indexed in databases such as Scopus, Web of Science, PubMed, etc. in the time frame of 2017 to 2023 were collected. Our selection criterion in the current review focuses on the studies in which protoberberines were used as starting materials for the production of semisynthetic agents with antiviral activity during the indicated time period. Correspondingly, studies were identified in which semisynthetic derivatives with significant inhibitory activity against a wide range of viruses including human immunodeficiency virus (HIV), enterovirus 71 (EV71), zika virus (ZIKV), influenza A/B, cytomegalovirus (CMV), respiratory syncytial virus (RSV), and coxsackieviruses were designed and synthesized. Our conclusion is that, despite the introduction of diverse semisynthetic derivatives of berberine with improved activity profiles compared to the parent natural leads, sufficient derivatization has not been done yet and more studies are needed., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)

The appearance of several coronavirus pandemics/epidemics during the last two decades (SARS-CoV-1 in 2002, MERS-CoV in 2012, and SARS-CoV-2 in 2019) indicates that humanity will face increasing challenges from coronaviruses in the future. The emergence of new strains with similar transmission characteristics as SARS-CoV-2 and mortality rates similar to SARS-CoV-1 (∼10% mortality) or MERS-CoV (∼35% mortality) in the future is a terrifying possibility. Therefore, getting enough preparations to face such risks is an inevitable necessity. The present study aims to review the drug achievements and challenges in the fight against SARS-CoV-2 with a combined perspective derived from pharmacology, pharmacotherapy, and medicinal chemistry insights. Appreciating all the efforts made during the past few years, there is strong evidence that the desired results have not yet been achieved and research in this area should still be pursued seriously. By expressing some pessimistic possibilities and concluding that the drug discovery and pharmacotherapy of COVID-19 have not been successful so far, this short essay tries to draw the attention of responsible authorities to be more prepared against future coronavirus epidemics/pandemics., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)

In the global movement to find the appropriate agents to fight the coronavirus disease of 2019 (COVID-19), emetine is one of the strongest anti-SARS-CoV-2 compounds with sub-micromolar EC 50 values, identified in several studies and high-throughput screening efforts. The reported anti-SARS-CoV-2 mechanisms indicate the effect of this compound on both virus-based and host-based targets. In addition to having excellent antiviral effects, emetine can relieve COVID-19 patients by reducing inflammation through inhibitory activity against NF-κB by the mechanism of IκBα phosphorylation inhibition; it can also limit the lipopolysaccharide-induced expression of pro-inflammatory cytokines TNFα, IL-1β, and IL-6. Emetine also can well reduce pulmonary arterial hypertension as an important COVID-19 complication by modulating a variety of cellular processes such as the Rho-kinase/CyPA/Bsg signaling pathway. The therapeutic value of emetine for combating COVID-19 was highlighted when in vivo pharmacokinetic studies showed that the concentration of this compound in the lungs increases significantly higher than the EC 50 of the drug. Despite its valuable therapeutic effects, emetine has some cardiotoxic effects that limit its use in high doses. However, high therapeutic capabilities make emetine a valuable lead compound that can be used for the design and development of less toxic anti-COVID-19 agents in the future. This Review provides a collection of information on the capabilities of emetine and its potential for the treatment of COVID-19, along with structural analysis which could be used for further research in the future., Competing Interests: The author declares no competing financial interest., (© 2022 American Chemical Society.)