Organic & Biomolecular Chemistry最新文献

The development of potent K⁺-competitive acid blockers (P-CABs) as inhibitors of acid gastric secretion attracts much research attention. In this study, the structure-guided design and enantioselective synthesis of P-CABs yielded a diaza-tricyclic compound with moderate inhibitory activity against the gastric proton pump. The eutomer was experimentally confirmed, consistent with pharmacophore predictions, and its binding mode to the gastric proton pump was elucidated via cryo-electron microscopy.

Herein, we report a mild and highly atom-economical synthesis of pentasubstituted 2-aminopyrroles from ynehydrazides and dialkyl acetylenedicarboxylates under ambient conditions. This transformation proceeds through a tandem sequence that combines conjugate addition, 3,4-diaza Cope rearrangement and 5-exo-dig cyclization, providing a rapid and modular route to the target scaffolds in moderate to high yields. Furthermore, an integrated approach for the direct conversion of simple terminal alkynes into the target pyrroles was devised, facilitating efficient access to these complex structures.

A novel and efficient method for the C(3)–H alkenylation of quinoxalin-2(1H)-ones has been developed using trifluoroacetic acid (TFA) as a Brønsted acid catalyst and Hantzsch esters (HEs) as the alkenylating agent. This metal-free protocol provides direct access to structurally diverse quinoxalinone–pyridine hybrid scaffolds under mild conditions, offering excellent functional group tolerance with yields ranging from good to high. The scope of the reaction was demonstrated by synthesizing 36 examples of quinoxalinone–pyridines in yields ranging from 61% to 82%. Quinoxalinone ring-containing drugs are well known for different pharmaceutical activities and, therefore, in the present case, we conducted a thorough in silico screening of the synthesized molecules (3a–3e′) to elucidate their potent biological activities. We have adopted standard computational protocols, including DFT calculations, ADMET analysis, pharmacophore mapping, and molecular docking with proteins, to study the optimized geometries of the synthesized ligands. Protein scaffolds associated with cancer, diabetes, inflammation, and antimicrobial activity were targeted to investigate the drug likeness. The method revealed that compounds 3h–3m, among the 31 molecules, show high potential as viable drugs. Specifically, 3l yielded the best docking result, and the MD simulation indicated that 3l has potential as a drug candidate.

Cathepsin A (CatA) is a human serine type carboxypeptidase enzyme which functions optimally around pH 4–5 and displays deamidase/esterase activity at elevated pH levels around 7–8. The activity of CatA is associated with key biological processes and CatA has emerged as a potential drug target. The pH-dependent activity of CatA was attributed to the pH regulator Glu149-Glu69 amino acid pair in the active site. In the literature, the kinetics of CatA have been investigated and pH-dependent enzyme mechanisms have been proposed. In this study, a quantum cluster approach with DFT calculations was employed to investigate the geometries and energetics of the enzymatic reaction and gain insight into the pH-dependent carboxypeptidase mechanism of CatA. To mimic different pH conditions, the critical residues and the model substrate were modelled at various protonation states. Under high pH conditions, the reaction mechanisms had the highest barriers, and this was attributed to deactivation of the C-end binding site of the enzyme leading to unorthodox substrate binding modes. The experimental low pH deactivation was accounted for by the low enzyme–substrate binding when the substrate C-end was protonated. It was determined that optimal pH conditions were achieved when three of the Glu69, Glu149, Asp64 and substrate C-end were protonated. It is hypothesised that two adjacent low-barrier hydrogen bonds are formed between the substrate/Glu149 and Glu149/Glu69 pairs at the carboxylate binding site when the substrate's anionic C-end is bonded to CatA's C-end binding site, under optimum pH conditions.

Benzoxazine-based compounds, a class of heterocycles with diverse biological properties, hold strong potential in therapeutic areas such as anti-inflammatory, anti-cancer, anti-tuberculosis and anti-microbial treatments. In the pharmaceutical field, many drugs are administered in racemic form, although in most cases, only one enantiomer is responsible for the desired therapeutic effect. The aim of this review is to summarize the various enantioselective synthetic strategies developed to obtain dihydro-1,4-benzoxazine derivatives, with particular emphasis on approaches such as catalytic hydrogenation, intramolecular cyclization and cycloaddition. Additionally, alongside enantioselective synthetic approaches, racemic mixtures can be separated into their individual enantiomers, most notably by chiral high-performance liquid chromatography (HPLC). All of these strategies aim to optimize access to enantiomerically pure compounds with well-defined absolute configurations, thereby paving the way for more targeted and effective therapeutic developments.

Reduced peptide bonds of the methyleneamino Ψ[CH₂–NH] type are widely recognized as peptide bond isosteres with significant value in drug discovery and development. Solid-Phase Synthesis (SPS) enables Solid-Phase Fragment Condensation (SPFC), a key strategy for the construction of complex peptides. In this study, we report the SPS of peptides containing selectively side-chain deprotected homoserine (Hse) residues, followed by solution-phase oxidation of the liberated Hse side-chain hydroxyl group to the corresponding γ-aldehydes. The intrinsic instability of these intermediates, primarily due to intramolecular cyclization to γ-hydroxy lactam or lactone products, is systematically examined, and stabilization strategies to overcome these limitations are developed. The resulting stabilized homoserinyl γ-aldehyde peptides were subsequently employed, as proof of concept, in solid-phase reductive amination with the N-terminus of resin-bound peptides. Overall, this approach enables the efficient formation of Hse-β-Ψ[CH₂–NH] reduced peptide bonds and establishes a versatile platform for broader peptide ligation and modification strategies.

We report a metal-free strategy for the efficient synthesis of polysubstituted quinolines via Brønsted acid-promoted cyclization of readily accessible ene-ynamides. Promoted by stoichiometric TfOH under mild conditions (30 °C), this method transforms simple, modular substrates into a wide range of quinoline derivatives in a single step, eliminating the need for precious-metal catalysts or prefunctionalized reagents. Its broad functional group tolerance and successful gram-scale operation underscore the method's practical utility and potential for broader application.

Sialyltransferases catalyze regioselective glycosidic bond formation between sialic acid and a glycan acceptor. Pasteurella multocida α2-3-sialyltransferase 1 (PmST1) is a widely used enzyme in chemoenzymatic synthesis. In particular, the PmST1 M144D mutant is routinely employed as an α2-3-sialyltransferase, although only low levels of α2-6-sialyltransferase activity have been reported. Here, we discover that for certain acceptors, the formation of the undesired α2-6-sialoside can reach up to 20% of the product. To elucidate the factors that influence this regioselectivity, we systematically examined the effects of (i) sulfation of the acceptor, (ii) the chemical nature of the aglycone, (iii) pH, and (iv) the extent of reaction completion. The results indicate that sulfation at the 6-position of GlcNAc or a β-ethyl-NHCbz aglycone is a factor that can increase the amount of α2-6 sialoside product. Surprisingly, pH had only a small impact, and the amount of α2-6 sialoside product did not differ over the course of the reaction. These findings provide insights into the enzymatic specificity of PmST1 M144D and inform its optimized use in chemo-enzymatic synthesis of defined sialosides.

Divergent synthesis has emerged as a powerful and economical approach in synthetic chemistry. Herein, we show a base-dependent divergent photochemical C–C coupling reaction of tertiary amines with cyanoaromatics. Remarkably, by simply adjusting the type of base, we can selectively carry out α-cyanation and pyridylation of tertiary amines.

Nitro-functionalized compounds and their derivatives have attracted considerable attention because of their synthetic value/special biological activities. Direct cascade cyclization reactions of unsaturated hydrocarbons with nitro-reagents are of particular interest to the chemical community because these strategies provide opportunities for the introduction of important nitro groups onto target frameworks with high step and atom economy. In recent years, tert-butyl nitrite (TBN) has shown considerable promise in cascade cyclization reactions due to its distinctive chemical properties, offering a novel platform for the efficient and diverse synthesis of heterocyclic compounds. This review highlights recent advances in this field, categorizing the discussion by reaction substrates and featuring representative examples and mechanisms. It also addresses the current challenges and future research directions.