Synthesis and antiviral activity of novel spirocyclic nucleosides

Cobb, Alexander J. A.; Dell'Isola, Antonio; Abdulsattar, Ban O.; McLachlan, Matthew M. W.; Neuman, Benjamin W.; Müller, Christin; Shankland, Kenneth; Al-Mulla, Hawaa M. N.; Binks, Alexander W. D.; Elvidge, Warren

doi:10.1039/c8nj02777c

Cited by 14 publications

(9 citation statements)

References 26 publications

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“…with several known antiviral compounds. [25,[28][29][30][31] Epoxide 17 can be also used for generating simple diolebased fragments like 32 (rotatable bonds 0, MW 198, HBA 3, HBD 2 and TPSA 49) absolutely conform to Ro3 criteria and ideal for FBDD projects. [32] While, the presence of the double bond in 17 is certainly interesting because allows an extra point of diversity (synthetic handle) and represent an interesting site for chemical optimizations and follow up, conversely this moiety may act as a site of metabolic liability and therefore not always suitable for medicinal chemistry purposes.…”

Section: Resultsmentioning

confidence: 99%

Design and Synthesis of Fsp3‐Enriched Spirocyclic‐Based Biological Screening Compound Arrays via DOS Strategies and Their NNMT Inhibition Profiling

et al. 2022

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Medicinal chemists are keen to explore tridimensional compounds, especially when it comes to small molecules. It has already been stressed that the majority of known drugs tend to be flat, whereas natural products tend to be more tridimensional and represent a good source of active compounds. 3D metrics have been implemented and computational descriptors are available to evaluate and prioritize compounds based on their 3D geometry. This is usually done by comparing the saturated carbon atoms in a molecule with the total number of its non‐hydrogen atoms (the Fsp3 value). While this aspect is clear, still there are not enough synthetic tools that support the realization of novel chemotypes that conform to these criteria. Herein we describe a diversity oriented synthesis (DOS) synthetic cascade technology that starts from two simple reagents, and generates highly enriched Fsp3 novel and diverse spiro‐scaffolds with pragmatic synthetic handles (points of diversity). The spiro nature of these scaffolds not only ensures high Fsp3 values but renders the compounds more rigid and therefore more effective in forming precise stereo‐interactions with their potential biological targets. These compounds were also profiled for their drug‐like properties and as potential modulators of the NNMT enzyme.

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Section: Resultsmentioning

confidence: 99%

Design and Synthesis of Fsp3‐Enriched Spirocyclic‐Based Biological Screening Compound Arrays via DOS Strategies and Their NNMT Inhibition Profiling

et al. 2022

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“…Cobb et al [ 39 ] reported the synthesis of a library of spirocyclic nucleoside analogs tested for antivirial activity. A series of azido-alkyne 53 were treated under thermal conditions in toluene for 24 hto obtain the corresponding spirocyclic nucleoside analogs 54 via intramolecular 1,3-dipolar cycloaddition ( Scheme 11 ).…”

Section: Clicked Nucleosides and Nucleotidesmentioning

confidence: 99%

Modified Nucleosides, Nucleotides and Nucleic Acids via Click Azide-Alkyne Cycloaddition for Pharmacological Applications

et al. 2021

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The click azide = alkyne 1,3-dipolar cycloaddition (click chemistry) has become the approach of choice for bioconjugations in medicinal chemistry, providing facile reaction conditions amenable to both small and biological molecules. Many nucleoside analogs are known for their marked impact in cancer therapy and for the treatment of virus diseases and new targeted oligonucleotides have been developed for different purposes. The click chemistry allowing the tolerated union between units with a wide diversity of functional groups represents a robust means of designing new hybrid compounds with an extraordinary diversity of applications. This review provides an overview of the most recent works related to the use of click chemistry methodology in the field of nucleosides, nucleotides and nucleic acids for pharmacological applications.

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“…The capping process is an essential post-transcriptional step for viral RNA translation by host ribosomes an addition to it is role in distinguishing between self mRNA and host mRNA (63). The 2′-O methyltransferase (2′-O MTase) enzyme that is located in non-structural protein 16 (nsp16) is one of the multiple enzymes required for cap structure formation, this enzyme is usually conserved (64). Several studies indicated that small molecules such as S-adenosyl-l-homocysteine, sinefungin, and aurintricarboxylic acid (ATA) (65-67) can inhibit nsp16 activity for CoV by interfering the interaction between nsp16/ nsp10 and nsp16/ nsp14.…”

Section: Journal Of University Of Anbar For Pure Science (Juaps)mentioning

confidence: 99%

Coronavirus Current and New Potential Therapeutic Targets: A Review

Abdulsattar¹,

Mutlk²,

Abdulsattar³

2021

JUAPS

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The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emergence in late 2019 marked the introduction of a highly spread viral pathogen threatening human population globally. The new virus is closely related genetically and clinically to severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). There are no specific antiviral drugs approved against human coronavirus infection and all treatments are supportive. The genome of coronavirus contains several open reading frames (ORFs) that encode both non-structural proteins (nsp) and structural proteins. Most of the encoded proteins have been reported as multifunctional proteins and plays a specific role in coronavirus (CoV) replication and assembly. This review focuses on the potential vaccine and antiviral targets for coronavirus, including different proteins and genes. Understanding the current targets and discovering new possible therapeutic targets will help toward developing effective vaccines and antiviral drug against current SARS-CoV-2 outbreak and possible future outbreak.

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Synthesis and antiviral activity of novel spirocyclic nucleosides

Abstract: A diverse range of spirocyclic nucleosides have been prepared from a common precursor and tested for their antiviral activity.

Cited by 14 publications

References 26 publications

Design and Synthesis of Fsp3‐Enriched Spirocyclic‐Based Biological Screening Compound Arrays via DOS Strategies and Their NNMT Inhibition Profiling

Design and Synthesis of Fsp3‐Enriched Spirocyclic‐Based Biological Screening Compound Arrays via DOS Strategies and Their NNMT Inhibition Profiling

Modified Nucleosides, Nucleotides and Nucleic Acids via Click Azide-Alkyne Cycloaddition for Pharmacological Applications

Coronavirus Current and New Potential Therapeutic Targets: A Review

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