Optimization of SARS-CoV-2 M Inhibitors by a Structure-Based Multilevel Virtual Screening Method.

With the aim of developing novel anti-SARS-CoV-2 drugs to address the ongoing evolution and emergence of drug-resistant strains, the reported SARS-CoV-2 M inhibitor was selected as a lead to find novel, highly potent, and broad-spectrum inhibitors. Using a fragment-based multilevel virtual screening strategy, 15 hit compounds were identified and subsequently synthesized. Among them, (IC = 1.

Synthesis and functional screening of novel inhibitors targeting the HDAC6 zinc finger ubiquitin-binding domain.

Histone deacetylase 6 (HDAC6) is a promising target for treating neurodegenerative disorders, several cancer types and viral infections. Unique among HDACs, the HDAC6 isoform possesses a zinc finger ubiquitin-binding domain (UBD) crucial for managing misfolded protein aggregates and facilitating viral infection. HDAC6 binds aggregated polyubiquitinated proteins through its UBD, mediating their transport to the aggresome and subsequent removal via autophagy.

Discovery of (3-Phenylcarbamoyl-3,4-dihydro-2-pyrrol-2-yl)phosphonates as Imidazoline Receptor Ligands with Anti-Alzheimer and Analgesic Properties.

Imidazoline receptors (I-IRs) are altered in Alzheimer's disease (AD) patients and are associated with analgesia. I-IRs are not structurally described, and their pharmacological characterization relies on their modulation by highly affine ligands. Herein, we describe the synthesis of (3-phenylcarbamoyl-3,4-dihydro-2-pyrrol-2-yl)phosphonates endowed with relevant affinities for I-IRs in human brain tissues.

Exploring 4,7-Disubstituted Pyrimido[4,5-]pyrimidines as Antiviral and Anticancer Agents.

Thirteen new 4,7-disubstituted pyrimido[4,5-]pyrimidines were synthesized via a straightforward methodology starting from thiourea. The anti-proliferative activity of these compounds was evaluated across a diverse panel of eight cancer cell lines, with derivatives and showing efficacy against several hematological cancer types. Furthermore, all compounds were assessed for their antiviral potency against a panel of viruses.

Protecting Group Control of Hydroxyketone-Hemiketal Tautomeric Equilibrium Enables the Stereoselective Synthesis of a 1-Azido -Nucleoside.

The synthesis of 1-azido -nucleosides is described to expand the set of azide-functionalized nucleosides for bioorthogonal applications and as potential antiviral drugs. Lewis acid-promoted azidation of a nucleoside hemiketal resulted in the formation of a tetrazole through a Schmidt reaction manifold. Conformational control to prevent ring-chain tautomerism enabled efficient 1-azidation with complete β-diastereoselectivity.