The Trimeric Artesunate Analog TF27, a Broadly Acting Anti-Infective Model Drug, Exerts Pronounced Anti-SARS-CoV-2 Activity Spanning Variants and Host Cell Types.

Starting in 2019, the spread of respiratory syndrome coronavirus 2 (SARS-CoV-2) and the associated pandemic of the corona virus disease (COVID-19) has led to enormous efforts in the development of medical countermeasures. Although innovative vaccines have scaled back the number of severe COVID cases, the emergence of the omicron variant (B.1.1.529) illustrates how vaccine development struggles to keep pace with viral evolution. On the other hand, while the recently approved antiviral drugs remdesivir, molnupiravir, and Paxlovid are considered as broadly acting anti-coronavirus therapeutics, only molnupiravir and Paxlovid are orally available and none of these drugs are recommended for prophylactic use. Thus, so far unexploited small molecules, targeting strategies, and antiviral mechanisms are urgently needed to address issues in the current pandemic and in putative future outbreaks of newly emerging variants of concern. Recently, we and others have described the anti-infective potential and particularly the pronounced antiviral activity of artesunate and related compounds of the trioxane/sesquiterpene class. In particular, the trimeric derivative TF27 demonstrated strong anti-cytomegalovirus activity at nanomolar concentrations in vitro as well as in vivo efficacy after oral administration in therapeutic and even prophylactic treatment settings. Here, we extended this analysis by evaluating TF27 for its anti-SARS-CoV-2 potential. Our main findings are as follows: (i) compound TF27 exerted strong anti-SARS-CoV-2 activity in vitro (EC50 = 0.46 ± 0.20 µM), (ii) antiviral activity was clearly distinct from the induction of cytotoxicity, (iii) pretreatment with TF27 prevented virus replication in cultured cells, (iv) antiviral activity has likewise been demonstrated in Calu-3 human lung and Caco-2 human colon cells infected with wild-type, delta, or omicron SARS-CoV-2, respectively, and (v) analysis of TF27 combination treatments has revealed synergistic interaction with GC376, but antagonistic interaction with EIDD-1931. Combined, the data demonstrated the pronounced anti-SARS-CoV-2 activity of TF27 and thus highlight the potential of trioxane compounds for further pharmacologic development towards improved options for COVID-specific medication.

Light‐Driven Catalyst‐Free Access to Phthalazines: Entry to Antiviral Model Drugs by Merging Domino Reactions**

We report the development of a metal-free four-step one-pot synthetic strategy to access high-value functionalized phthalazines using o-methyl benzophenones as starting compounds. Combining a light-mediated enolization of o-methyl benzophenones/Diels-Alder reaction domino process with a subsequent deprotection/aromatization domino reaction in one-pot leads to sustainable and efficient organic synthesis. The tangible advantages, i. e., absence of catalysts or additives, utilization of commercially available and/or easily accessible substrates, mild reaction conditions, simplicity, and single work-up procedure, make this combined process highly appealing for the direct construction of various 1-aryl-phthalazines. Importantly, in vitro bioactivity evaluation of these newly prepared heterocyclic compounds demonstrated a strong antiviral efficacy against major human pathogens like HCMV and SARS-CoV-2.

Light‐Driven Catalyst‐Free Access to Phthalazines: Entry to Antiviral Model Drugs by Merging Domino Reactions****A previous version of this manuscript has been deposited on a preprint server (https://doi.org/10.26434/chemrxiv‐2022‐j4xvz)

We report the development of a metal‐free four‐step one‐pot synthetic strategy to access high‐value functionalized phthalazines using o‐methyl benzophenones as starting compounds. Combining a light‐mediated enolization of o‐methyl benzophenones/Diels‐Alder reaction domino process with a subsequent deprotection/aromatization domino reaction in one‐pot leads to sustainable and efficient organic synthesis. The tangible advantages, i. e., absence of catalysts or additives, utilization of commercially available and/or easily accessible substrates, mild reaction conditions, simplicity, and single work‐up procedure, make this combined process highly appealing for the direct construction of various 1‐aryl‐phthalazines. Importantly, in vitro bioactivity evaluation of these newly prepared heterocyclic compounds demonstrated a strong antiviral efficacy against major human pathogens like HCMV and SARS‐CoV‐2.

Synthesis and in vitro Study of Artemisinin/Synthetic Peroxide-Based Hybrid Compounds against SARS-CoV-2 and Cancer.

The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause life-threatening diseases in millions of people worldwide, in particular, in patients with cancer, and there is an urgent need for antiviral agents against this infection. While in vitro activities of artemisinins against SARS-CoV-2 and cancer have recently been demonstrated, no study of artemisinin and/or synthetic peroxide-based hybrid compounds active against both cancer and SARS-CoV-2 has been reported yet. However, the hybrid drug's properties (e. g., activity and/or selectivity) can be improved compared to its parent compounds and effective new agents can be obtained by modification/hybridization of existing drugs or bioactive natural products. In this study, a series of new artesunic acid and synthetic peroxide based new hybrids were synthesized and analyzed in vitro for the first time for their inhibitory activity against SARS-CoV-2 and leukemia cell lines. Several artesunic acid-derived hybrids exerted a similar or stronger potency against K562 leukemia cells (81-83 % inhibition values) than the reference drug doxorubicin (78 % inhibition value) and they were also more efficient than their parent compounds artesunic acid (49.2 % inhibition value) and quinoline derivative (5.5 % inhibition value). Interestingly, the same artesunic acid-quinoline hybrids also show inhibitory activity against SARS-CoV-2 in vitro (EC50 13-19 µm) and no cytotoxic effects on Vero E6 cells (CC50 up to 110 µM). These results provide a valuable basis for design of further artemisinin-derived hybrids to treat both cancer and SARS-CoV-2 infections.

Anti-SARS-CoV-2 Inhibitory Profile of New Quinoline Compounds in Cell Culture-Based Infection Models.

Invited for the cover of this issue are Manfred Marschall, Svetlana B. Tsogoeva and co-workers at Friedrich-Alexander University of Erlangen-Nürnberg. The image depicts a new anti-SARS-CoV-2 compound in front of SARS-CoV-2 viruses. Read the full text of the article at 10.1002/chem.202103861.

Front Cover: Anti-SARS-CoV-2 Inhibitory Profile of New Quinoline Compounds in Cell Culture-Based Infection Models (Chem. Eur. J. 4/2022)

A new anti-SARS-CoV-2 compound, developed in this joint study, is shown in front of SARS-CoV-2 viruses. The ongoing pandemic of human SARS-CoV-2 infections (COVID-19) creates a high demand for antiviral drug development. The shown quinoline?morpholine hybrid and other new quinoline-based compounds were synthesized and investigated for their in vitro activity against SARS-CoV-2. They exerted an anti-SARS-CoV-2 activity similar to or stronger than that of the reference drug. More information can be found in the Research Article by M. Marschall, S.?B. Tsogoeva et?al. (DOI: 10.1002/chem.202103861).

Anti-SARS-CoV-2 Inhibitory Profile of New Quinoline Compounds in Cell Culture-Based Infection Models

A new anti-SARS-CoV-2 compound, developed in this joint study, is shown in front of SARS-CoV-2 viruses. The ongoing pandemic of human SARS-CoV-2 infections (COVID-19) creates a high demand for antiviral drug development. The shown quinoline?morpholine hybrid and other new quinoline-based compounds were synthesized and investigated for their in vitro activity against SARS-CoV-2. They exerted an anti-SARS-CoV-2 activity similar to or stronger than that of the reference drug. More information can be found in the Research Article by M. Marschall, S.?B. Tsogoeva et?al. (DOI: 10.1002/chem.202103861).

Anti-SARS-CoV-2 Inhibitory Profile of New Quinoline Compounds in Cell Culture-Based Infection Models.

The presently ongoing pandemic of human SARS-CoV-2 infections (COVID-19) presents an enormous challenge in surveillance, vaccine and antiviral drug development. Here we report the synthesis of new bioactive quinoline-morpholine hybrid compounds and their virological evaluation, which proves pronounced cell culture-based inhibitory profile against SARS-CoV-2. Thus, selected quinoline compounds may suggest specific hit-to-lead development.

Development of a PROTAC-Based Targeting Strategy Provides a Mechanistically Unique Mode of Anti-Cytomegalovirus Activity.

Human cytomegalovirus (HCMV) is a major pathogenic herpesvirus that is prevalent worldwide and it is associated with a variety of clinical symptoms. Current antiviral therapy options do not fully satisfy the medical needs; thus, improved drug classes and drug-targeting strategies are required. In particular, host-directed antivirals, including pharmaceutical kinase inhibitors, might help improve the drug qualities. Here, we focused on utilizing PROteolysis TArgeting Chimeras (PROTACs), i.e., hetero-bifunctional molecules containing two elements, namely a target-binding molecule and a proteolysis-inducing element. Specifically, a PROTAC that was based on a cyclin-dependent kinase (CDK) inhibitor, i.e., CDK9-directed PROTAC THAL-SNS032, was analyzed and proved to possess strong anti-HCMV AD169-GFP activity, with values of EC50 of 0.030 µM and CC50 of 0.175 µM (SI of 5.8). Comparing the effect of THAL-SNS032 with its non-PROTAC counterpart SNS032, data indicated a 3.7-fold stronger anti-HCMV efficacy. This antiviral activity, as illustrated for further clinically relevant strains of human and murine CMVs, coincided with the mid-nanomolar concentration range necessary for a drug-induced degradation of the primary (CDK9) and secondary targets (CDK1, CDK2, CDK7). In addition, further antiviral activities were demonstrated, such as the inhibition of SARS-CoV-2 replication, whereas other investigated human viruses (i.e., varicella zoster virus, adenovirus type 2, and Zika virus) were found insensitive. Combined, the antiviral quality of this approach is seen in its (i) mechanistic uniqueness; (ii) future options of combinatorial drug treatment; (iii) potential broad-spectrum activity; and (iv) applicability in clinically relevant antiviral models. These novel data are discussed in light of the current achievements of anti-HCMV drug development.