Organic & Biomolecular Chemistry最新文献

A base-promoted [2 + 1] annulation reaction between iminoindoline-derived alkenes and 4-bromo-pyrazolones has been disclosed, affording a series of novel, pharmaceutically interesting spiro-cyclopropyl pyrazolones containing indolines in good to excellent yields with moderate to good diastereoselectivities. This protocol features broad functional group compatibility, simple operation, and mild reaction conditions.

A PyBroP/base-promoted three-component sequential decarboxylative nucleophilic addition protocol has been developed. Under the optimized conditions, a wide array of β-keto acids, isatylidene malononitriles and pyridine N-oxides couple efficiently to deliver the desired 3,3-disubstituted oxindole-fused pyridine derivatives in moderate to excellent yields. This method features good functional group tolerance, high positional selectivity, mild reaction conditions, and a one-pot procedure. The methodology can be scaled up to the gram scale, and the synthetic utility of the product was further validated. Control experiments have also been carried out to elucidate the plausible mechanistic pathway.

An efficient iodine-promoted four-component reaction has been developed for the synthesis of diverse polysubstituted pyrimidines from simple and readily available starting materials under metal-free conditions. The multicomponent strategy innovatively utilizes primary aliphatic amines as C–C–N synthons, aromatic aldehydes as C1 synthons and ammonium iodide as an environmentally benign nitrogen source, achieving α-C(sp³)–H and β-C(sp³)–H bond functionalization of primary aliphatic amines in one pot. This method offers a valuable alternative for synthesizing structurally diverse pyrimidines.

Electronic structure calculations were performed to assess how a β-boryl substituent modulates barriers for the classical Ei elimination of sulfoxides. Four main boron substituents were investigated: H, Me, F and OMe. Across the series, methanesulfenic-acid elimination exhibits reduced activation free energies and enthalpies as the boron functionality accepts electron density from the C_β–H bond, promoting a more asynchronous transition state with advanced C_β–H cleavage and O–H formation and correspondingly less S–C_α bond rupture relative to the benchmark ethyl methyl sulfoxide transition state. Nevertheless, β-boryl substrates of the 1B family access lower-energy minima that lead preferentially to boryl sulfenate elimination: the corresponding ΔG^‡ values are 9.5–15.5 kcal mol⁻¹ lower than for the competing proton-transfer (sulfenic-acid) pathway. Replacing methyl with vinyl or phenyl lowers ΔG^‡ by 1.9–4.9 kcal mol⁻¹ through enhanced stabilization of developing electron density at sulfur. A comparison of common boronic esters (catechol, pinacol, BMIDA) for both proton-transfer and boronic-ester-transfer pathways shows catechol (Bcat) gives the lowest barriers, whereas BMIDA is distinctive in that its methanesulfenic acid elimination resembles that of methyl ethyl sulfoxide, and boryl-sulfenate elimination is disfavoured owing to loss of intramolecular N → B coordination. Collectively, β-boryl substitution lowers Ei barriers via electron-acceptor stabilization and biases reaction manifolds toward boryl sulfenate elimination, with the extent governed by conjugation patterns and ester identity.

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.