Easy access to α-ketoamides as SARS-CoV-2 and MERS Mpro inhibitors via the PADAM oxidation route.

SARS-CoV-2 caused worldwide the current outbreak called COVID-19. Despite multiple countermeasures implemented, there is an urgent global need for new potent and efficient antiviral drugs against this pathogen. In this context, the main protease (Mpro) of SARS-CoV-2 is an essential viral enzyme and plays a pivotal role in viral replication and transcription. Its specific cleavage of polypeptides after a glutamine residue has been considered as a key element to design novel antiviral drugs. Herein, we reported the design, synthesis and structure-activity relationships of novel α-ketoamides as covalent reversible inhibitors of Mpro, exploiting the PADAM oxidation route. The reported compounds showed µM to nM activities in enzymatic and in the antiviral cell-based assays against SARS-CoV-2 Mpro. In order to assess inhibitors' binding mode, two co-crystal structures of SARS-CoV-2 Mpro in complex with our inhibitors were solved, which confirmed the covalent binding of the keto amide moiety to the catalytic Cys145 residue of Mpro. Finally, in order to interrogate potential broad-spectrum properties, we assessed a selection of compounds against MERS Mpro where they showed nM inhibitory potency, thus highlighting their potential as broad-spectrum coronavirus inhibitors.

Extending the Library of 4-Hydroxycoumarin Derivatives with Potential Pharmacological Activity by a Catalyst-Free and Purification-Free Method

Constant mutations of SARS-CoV-2 from 2019 to the present commences potential dilemma to the efficacy of developed COVID-19 antiviral drugs. In this current report, series of 3-phenyl(alkylamino)methyl-4-hydroxycoumarin was identified as compounds of drug-likeliness that, through molecular docking simulations, also demonstrated favourable binding to different sites of the SARS-CoV-2 RBD/hACE2 complex. This was achieved by varying the chain of the alkyl length and the substituent of the phenyl moiety. The subjected 3-phenyl(alkylamino)methyl-4-hydroxycoumarin compounds were successfully synthesized by a catalyst-free multicomponent condensation reaction of 4-hydroxycoumarin, p-substituted benzaldehyde, and linear alkyl amines in dichloromethane (DCM) at 22 °C. The crude products were achieved in a moderate (40–50 %) to a very good (80–90 %) yield with excellent purity without the need for chemical purification verified by nuclear magnetic resonance (NMR) spectroscopy. The simple method to produce 3-phenyl(alkylamino)methyl-4-hydroxycoumarin and the preliminary docking results present an opportunity for advancement in drug discovery. © 2023 The Authors. ChemistrySelect published by Wiley-VCH GmbH.

Computational Design, Synthesis, and Biophysical Evaluation of ß-Amido Boronic Acids as SARS-CoV-2 Mpro Inhibitors.

The COVID-19 pandemic has given a strong impetus to the search for antivirals active on SARS-associated coronaviruses. Over these years, numerous vaccines have been developed and many of these are effective and clinically available. Similarly, small molecules and monoclonal antibodies have also been approved by the FDA and EMA for the treatment of SARS-CoV-2 infection in patients who could develop the severe form of COVID-19. Among the available therapeutic tools, the small molecule nirmatrelvir was approved in 2021. It is a drug capable of binding to the Mpro protease, an enzyme encoded by the viral genome and essential for viral intracellular replication. In this work, by virtual screening of a focused library of ß-amido boronic acids, we have designed and synthesized a focused library of compounds. All of them were biophysically tested by microscale thermophoresis, attaining encouraging results. Moreover, they also displayed Mpro protease inhibitory activity, as demonstrated by performing enzymatic assays. We are confident that this study will pave the way for the design of new drugs potentially useful for the treatment of SARS-CoV-2 viral infection.

Green methodologies for the synthesis of 2-aminothiophene.

Pollution and the rising energy demand have prompted the design of new synthetic reactions that meet the principles of green chemistry. In particular, alternative synthesis of 2-aminothiophene have recently focused interest because 2-aminothiophene is a unique 5-membered S-heterocycle and a pharmacophore providing antiprotozoal, antiproliferative, antiviral, antibacterial or antifungal properties. Here, we review new synthetic routes to 2-aminothiophenes, including multicomponent reactions, homogeneously- or heterogeneously-catalyzed reactions, with focus on green pathways.

Multicomponent Reactions in the Synthesis of Antiviral Compounds.

BACKGROUND: Multicomponent reactions are one-pot processes for the synthesis of highly functionalized hetero-cyclic and hetero-acyclic compounds, often endowed with biological activity. OBJECTIVE: Multicomponent reactions are considered green processes with a high atom economy. In addition, they present advantages compared to the classic synthetic methods, such as high efficiency and low waste production. METHODS: In these reactions, two or more reagents are combined together in the same flask to yield a product containing almost all the atoms of the starting materials. RESULTS: The scope of this review is to present an overview of the application of multicomponent reactions in the synthesis of compounds endowed with antiviral activity. The syntheses are classified depending on the viral target. CONCLUSION: Multicomponent reactions can be applied to all the stages of the drug discovery and development process, making them very useful in the search for new agents active against emerging (viral) pathogens.

Design, synthesis and biological evaluation of 1,5-disubstituted α-amino tetrazole derivatives as non-covalent inflammasome-caspase-1 complex inhibitors with potential application against immune and inflammatory disorders.

Compounds targeting the inflammasome-caspase-1 pathway could be of use for the treatment of inflammation and inflammatory diseases. Previous caspase-1 inhibitors were in great majority covalent inhibitors and failed in clinical trials. Using a mixed modelling, computational screening, synthesis and in vitro testing approach, we identified a novel class of non-covalent caspase-1 non cytotoxic inhibitors which are able to inhibit IL-1ß release in activated macrophages in the low µM range, in line with the best activities observed for the known covalent inhibitors. Our compounds could form the basis of further optimization towards potent drugs for the treatment of inflammation and inflammatory disorders including also dysregulated inflammation in Covid 19.

Combining High-Throughput Synthesis and High-Throughput Protein Crystallography for Accelerated Hit Identification.

Protein crystallography (PX) is widely used to drive advanced stages of drug optimization or to discover medicinal chemistry starting points by fragment soaking. However, recent progress in PX could allow for a more integrated role into early drug discovery. Here, we demonstrate for the first time the interplay of high throughput synthesis and high throughput PX. We describe a practical multicomponent reaction approach to acrylamides and -esters from diverse building blocks suitable for mmol scale synthesis on 96-well format and on a high-throughput nanoscale format in a highly automated fashion. High-throughput PX of our libraries efficiently yielded potent covalent inhibitors of the main protease of the COVID-19 causing agent, SARS-CoV-2. Our results demonstrate, that the marriage of in situ HT synthesis of (covalent) libraires and HT PX has the potential to accelerate hit finding and to provide meaningful strategies for medicinal chemistry projects.