Synthesis and Antiviral Evaluation of 5-(4-Aryl-1,3-butadiyn-1-yl)-uridines and Their Phosphoramidate Pronucleotides.

The emergence of RNA viruses driven by global population growth and international trade highlights the urgent need for effective antiviral agents that can inhibit viral replication. Nucleoside analogs, which mimic natural nucleotides, have shown promise in targeting RNA-dependent RNA polymerases (RdRps). Starting from protected 5-iodouridine, we report the synthesis of -substituted-(1,3-diyne)-uridines nucleosides and their phosphoramidate prodrugs.

Lyotropic liquid crystal emulsions of LAVR-289: Influence of internal mesophase structure on cytotoxicity and in-vitro antiviral activity.

Emerging and reemerging viruses pose significant public health threats, underscoring the urgent need for new antiviral drugs. Recently, a novel family of antiviral acyclic nucleoside phosphonates (ANP) composed of a 4-(2,4-diaminopyrimidin-6-yl)oxy-but-2-enyl phosphonic acid skeleton (O-DAPy nucleobase) has shown promise. Among these, LAVR-289 stands out for its potent inhibitory effects against various DNA viruses.

Molecularly Imprinted Polymeric Nanoparticles as Drug Delivery System for Tenofovir, an Acyclic Nucleoside Phosphonate Antiviral.

A molecularly imprinted polymer of Tenofovir (1), an FDA-approved acyclic nucleoside phosphonate with antiviral activity, was synthesized using a non-covalent approach. A pre-polymerization complex was formed between (1) and DMAEMA and in-house synthetic -[(2-methacryloyloxy)ethyl] thymine, with EGDMA as a cross-linker in an MeCN/HO (9:1, 1:1) mixture as a porogen, giving an imprinting factor (IF) of 5.5 at 2.

Antibiotics and Antibiotic Resistance-Mur Ligases as an Antibacterial Target.

The emergence of Multidrug Resistance (MDR) strains of bacteria has accelerated the search for new antibacterials. The specific bacterial peptidoglycan biosynthetic pathway represents opportunities for the development of novel antibacterial agents. Among the enzymes involved, Mur ligases, described herein, and especially the amide ligases MurC-F are key targets for the discovery of multi-inhibitors, as they share common active sites and structural features.

Cobalt-assisted route to rare carbocyclic -ribonucleosides.

(Re)emerging RNA viruses have been major threats to public health in the past years, and from the few drugs available, nucleoside analogues are still at the cornerstone of the antiviral therapy. Among them, the synthesis of carbocyclic -nucleosides is suffering from long syntheses and poor yields. Herein we report a concise stereoselective synthesis of rare carbocyclic -nucleosides (11a-l) bearing non-canonical nucleobases through a cobalt-assisted-route as key step starting from the optically pure (-)-cyclopentenone 1.

Synthesis and Structure-Activity Relationship Studies of Pyrido [1,2-]Purine-2,4()-Dione Derivatives Targeting in .

In 2002, a new class of thymidylate synthase (TS) involved in the de novo synthesis of dTMP named Flavin-Dependent Thymidylate Synthase (FDTS) encoded by the thyX gene was discovered; FDTS is present only in 30% of prokaryote pathogens and not in human pathogens, which makes it an attractive target for the development of new antibacterial agents, especially against multi-resistant pathogens. We report herein the synthesis and structure-activity relationship of a novel series of hitherto unknown pyrido[1,2-e]purine-2,4(1H,3H)-dione analogues. Several synthetics efforts were done to optimize regioselective N1-alkylation through organopalladium cross-coupling.

Tunable Approach to C-Linked Analogs of Glycosamines.

The synthesis of (1)-2-amino-2-deoxy-β-l-gulopyranosyl benzene and the α and β forms of 2-amino-2-deoxy-l-idopyranosyl benzene derivatives was accomplished through stereospecific addition of tributylstannyllithium to readily available ()- or ()--butanesulfinyl-arabinofuranosylamine building blocks, followed by stereoretentive Pd-catalyzed Migita-Kosugi-Stille cross-coupling, stereoselective reduction, and an activation-cyclization strategy. Application of this methodology paves the way to new three-dimensional chemical space and preparation of unknown (non-natural) and complex 2-amino-2-deoxy sugars of biological interest.

Nucleosides and emerging viruses: A new story.

With several US Food and Drug Administration (FDA)-approved drugs and high barriers to resistance, nucleoside and nucleotide analogs remain the cornerstone of antiviral therapies for not only herpesviruses, but also HIV and hepatitis viruses (B and C); however, with the exception of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), for which vaccines have been developed at unprecedented speed, there are no vaccines or small antivirals yet available for (re)emerging viruses, which are primarily RNA viruses. Thus, herein, we present an overview of ribonucleoside analogs recently developed and acting as inhibitors of the viral RNA-dependent RNA polymerase (RdRp). They are new lead structures that will be exploited for the discovery of new antiviral nucleosides.

Chemical Approaches to Carbocyclic Nucleosides.

Nucleoside analogues are at the forefront of antiviral therapy for last decades. To circumvent some of their limitations, based on their metabolism, and in order to improve their anti-viral potency and selectivity, several families of nucleoside analogues have been described through structural modifications at the sugar and heterocycles. The replacement of the oxygen of the nucleoside by a methylene has led to the family of carbocyclic (or cyclopentane) nucleoside analogues.

Circadian and chemotherapy-related changes in urinary modified nucleosides excretion in patients with metastatic colorectal cancer.

Urinary levels of modified nucleosides reflect nucleic acids turnover and can serve as non-invasive biomarkers for monitoring tumour circadian dynamics, and treatment responses in patients with metastatic colorectal cancer. In 39 patients, median overnight urinary excretion of LC-HRMS determinations of pseudouridine, was ~ tenfold as large as those of 1-methylguanosine, 1-methyladenosine, or 4-acetylcytidine, and ~ 100-fold as large as those of adenosine and cytidine. An increase in any nucleoside excretion after chemotherapy anticipated plasma carcinoembryonic antigen progression 1-2 months later and was associated with poor survival.

Molecularly Imprinted Hydrogels Selective to Ribavirin as New Drug Delivery Systems to Improve Efficiency of Antiviral Nucleoside Analogue: A Proof-of-Concept Study with Influenza A Virus.

This study describes the synthesis and evaluation of different imprinted hydrogels using ribavirin as template molecule. Ribavirin serves as a model molecule because it possesses a broad-spectrum antiviral effect against RNA viruses, which are expected as emerging viruses. The choice of monomers enables to stabilize the pre-polymerization complex and to synthesize biocompatible polymers.

Synthesis of acyclic nucleoside phosphonates targeting flavin-dependent thymidylate synthase in Mycobacterium tuberculosis.

Flavin-Dependent Thymidylate Synthase (FDTS) encoded by ThyX gene was discovered as a new class of thymidylate synthase involved in the de novo synthesis of dTMP named only in 30 % of human pathogenic bacteria. This target was pursed for the development of new antibacterial agents against multiresistant pathogens. We have developed a new class of ANPs based on the mimic of two natural's cofactors (dUMP and FAD) as inhibitors against Mycobacterium tuberculosis ThyX.

Synthesis and Antiviral Evaluation of (1,4-Disubstituted-1,2,3-Triazol)-()-2-Methyl-but-2-Enyl Nucleoside Phosphonate Prodrugs.

A series of hitherto unknown (1,4-disubstituted-1,2,3-triazol)-()-2-methyl-but-2-enyl nucleosides phosphonate prodrugs bearing 4-substituted-1,2,3-triazoles were prepared in a straight approach through an olefin acyclic cross metathesis as the key synthetic step. All novel compounds were evaluated for their antiviral activities against HBV, HIV and SARS-CoV-2. Among these molecules, only compound , a hexadecyloxypropyl (HDP)/(-oxymethyl)-ester (POC) prodrug, showed activity against HBV in Huh7 cell cultures with 62% inhibition at 10 μM, without significant cytotoxicity (IC = 66.

Design, synthesis and biological evaluation of 2-substituted-6-[(4-substituted-1-piperidyl)methyl]-1H-benzimidazoles as inhibitors of ebola virus infection.

Novel 2-substituted-6-[(4-substituted-1-piperidyl)methyl]-1H-benzimidazoles were designed and synthesized as Ebola virus inhibitors. The proposed structures of the new prepared benzimidazole-piperidine hybrids were confirmed based on their spectral data and CHN analyses. The target compounds were screened in vitro for their anti-Ebola activity.

Design and Synthesis of Various 5'-Deoxy-5'-(4-Substituted-1,2,3-Triazol-1-yl)-Uridine Analogues as Inhibitors of Mur Ligases.

The synthesis of hitherto unknown 5'-deoxy-5'-(4-substituted-1,2,3-triazol-1-yl)-uridine and its evaluation, through an one-pot screening assay, against MurA-F enzymes involved in (Mtb), are described. Starting from UDP--acetylmuramic acid (UDP-MurNAc), the natural substrate involved in the peptidoglycan biosynthesis, our strategy was to substitute the diphosphate group of UDP-MurNAc by a 1,2,3-triazolo spacer under copper-catalyzed azide-alkyne cycloaddition conditions. The structure-activity relationship was discussed and among the 23 novel compounds developed, -acetylglucosamine analogues and emerged as the best inhibitors against the Mtb MurA-F enzymes reconstruction pathway with an inhibitory effect of 56% and 50%, respectively, at 100 μM.

Thiopurine Derivative-Induced Fpg/Nei DNA Glycosylase Inhibition: Structural, Dynamic and Functional Insights.

DNA glycosylases are emerging as relevant pharmacological targets in inflammation, cancer and neurodegenerative diseases. Consequently, the search for inhibitors of these enzymes has become a very active research field. As a continuation of previous work that showed that 2-thioxanthine (2TX) is an irreversible inhibitor of zinc finger (ZnF)-containing Fpg/Nei DNA glycosylases, we designed and synthesized a mini-library of 2TX-derivatives (TXn) and evaluated their ability to inhibit Fpg/Nei enzymes.

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes-6.

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of Editorials that is published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal [...

Monitoring of phosphorylation using immobilized kinases by on-line enzyme bioreactors hyphenated with High-Resolution Mass Spectrometry.

Nucleosides analogues are the cornerstone of the treatment of several human diseases. They are especially at the forefront of antiviral therapy. Their therapeutic efficiency depends on their capacity to be converted to the active nucleoside triphosphate form through successive phosphorylation steps catalyzed by nucleoside/nucleotide kinases.

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes-5.

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of Editorials which is published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal [...

Synthesis of imprinted hydrogel microbeads by inverse Pickering emulsion to controlled release of adenosine 5'‑monophosphate.

Herein, we propose the synthesis of a microspherical imprinted hydrogel meant for the controlled release of a nucleotide, adenosine 5'-monophosphate (5'-AMP). Indeed, molecularly imprinted polymers-based (MIPs) materials possess remarkable selective molecular recognition ability that mimicks biological systems. MIPs have been used in numerous applications and hold great promise for the vectorization and/or controlled release of therapeutics and cosmetics.

Monitoring of successive phosphorylations of thymidine using free and immobilized human nucleoside/nucleotide kinases by Flow Injection Analysis with High-Resolution Mass Spectrometry.

Nucleosides and their analogues play a crucial role in the treatment of several diseases including cancers and viral infections. Their therapeutic efficiency depends on their capacity to be converted to the active nucleoside triphosphates form through successive phosphorylation steps catalyzed by nucleoside/nucleotide kinases. It is thus mandatory to develop an easy, rapid, reliable and sensitive enzyme activity tests.

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes⁻4.

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of Editorials, which is published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal . [..

Synthesis and characterization of various 5'-dye-labeled ribonucleosides.

Hitherto unknown chromophoric nucleosides are reported. This novel set of visibly coloured dye-labeled 5'-nucleosides, including 1,2,4,5-tetrazine, dicyanomethylene-4H-pyran, benzophenoxazinone, 9,10-anthraquinone and azobenzene chromophores, were prepared mainly under Cu-catalyzed azide-alkyne cycloaddition (CuAAC). The design criteria are outlined.

Selective inhibition of human cathepsin S by 2,4,6-trisubstituted 1,3,5-triazine analogs.

We report herein the synthesis and biological evaluation of a new series of 2,4,6-trisubstituted 1,3,5-triazines as reversible inhibitors of human cysteine cathepsins. The desired products bearing morpholine and N-Boc piperidine, respectively, were obtained in three to four steps from commercially available trichlorotriazine. Seventeen hitherto unknown compounds were evaluated in vitro against various cathepsins for their inhibitory properties.