Bioorganic Chemistry最新文献

Methylxanthines, particularly theophylline, have long served as effective bronchodilators for severe asthma. Emerging evidence links bacterial infection to asthma pathogenesis, motivating the search for multifunctional therapeutic agents. In this study, a series of 8-substituted 1,3-dimethylxanthines bearing aryl and heteroaryl groups were synthesized and structurally characterized by NMR, elemental analysis, and HR-ESI-MS. Most compounds exhibited significant bronchodilator activity in an acetylcholine-induced guinea pig model, surpassing theophylline. The compounds demonstrated potent in vitro PDE-4B inhibition relevant to asthma-related inflammation. Several derivatives also showed antibacterial activity against susceptible Gram-positive and Gram-negative strains in asthmatic patients. Molecular docking and 200 ns molecular dynamics simulations revealed strong and stable binding of the most active compounds, 14d and 17 k, within the PDE-4B active site, correlating with their in vivo efficacy. Notably, 17 k displayed superior oral pharmacokinetic properties, high lipophilicity, moderate solubility, and optimal molecular size, comparable to theophylline and roflumilast (standard PDE-4B inhibitor). These findings identify 17 k as a promising lead for the development of orally active dual-acting agents for asthma management.

Neuroinflammation and oxidative stress are recognized as key drivers of neuronal death and the progression of neurodegenerative diseases. At the same time, they serve as central hubs linking the major pathological hallmarks of Alzheimer's disease (AD), including Aβ aggregation, tau protein hyperphosphorylation, neurofibrillary tangle formation, and neuronal injury. In this study, we screened natural active molecules of cannabidiol (CBD) and its derivatives, and conducted molecular docking simulations. A class of CBD aminoquinone scaffolds with potential anti-AD activity was identified, and 32 CBD aminoquinone derivatives were synthesized for comprehensive in vitro and in vivo evaluation. Among them, compound G-12 with p-F-aniline moiety exhibited potent anti-inflammatory activity (IC₅₀ = 1.39 μM), outstanding neuroprotective effects (IC₅₀ = 1.29 μM), and prominent behavioral manifestations. In addition, G-12 displayed acceptable in vivo pharmacokinetic (PK) properties. The superior performance of G-12 indicated that through the Nrf2/HO-1 oxidative stress pathway, it affected the TLR4/NF-κB inflammatory pathway, inhibited neuroinflammation, and thereby influenced Aβ aggregation, protecting neurons. This strategy that links several major pathological features of AD is effective in combating AD. G-12 is also a lead compound with the potential to be developed into a multifunctional drug for AD.

Ischemic stroke, a leading cause of disability, lacks effective therapeutics for delayed intervention. This study characterized three compounds (JK-1, TXY-1, and R11-6) isolated from endophytic fungi metabolites of the medicinal plant Rhodiola tibetica and evaluated their efficacy in post-stroke recovery. Delayed oral administration of JK-1, TXY-1, and R11-6, initiated 3 days after stroke, significantly improved neurological behaviors following a two-week treatment in photothrombotic stroke mice, as evidenced by significantly reduced foot-fault rates and shorter adhesive-removal latencies. Notably, robust efficacy was also observed after only one week of treatment. The compounds mitigated neuronal injury in the peri-infarct cortex of stroke mice, as indicated by increased neuron density and preservation of synaptic proteins PSD-95 and p-CaMKII. Mechanistically, all three compounds suppressed pro-inflammatory NF-κB/NLRP3 axis activation, thereby attenuating microglial M1 polarization and astrocytic reactivity. Moreover, they enhanced endogenous defenses through IL-10 and HO-1 induction, jointly modulating the neuroinflammatory cascade in stroke mice. TXY-1 and R11-6 induced stronger HO-1 expression than the JK-1 group, consistent with their greater suppression of NF-κB activity. Taken together, these findings demonstrate that delayed administration of these compounds promotes post-stroke neurological recovery through multi-target modulation of neuroinflammation and highlight Rhodiola-fungal symbionts as sustainable sources of neuroprotective agents.

Over the past two decades, transaminases or aminotransferases have been involved in the chemoenzymatic synthesis of active pharmaceutical ingredients by highly efficient and straightforward catalysis of prochiral ketones to chiral amines. These enzymes are promising targets used in the pharmaceutical sector since they are relatively easy to clone and express from a variety of bacteria and other species, where they play key catalytic roles in amino acid metabolic pathways. Also, their high thermal and solvent stability makes them very suitable candidates for use in industry. These enzymes are selected based on their substrate specificity and catalytic efficiency, and are further evolved into industrial enzymes using protein engineering and enzyme recyclability methods. Their key catalytic role in APIs and pharmaceutical-relevant molecules synthesis involves asymmetric synthesis, kinetic resolution, and deracemization. Although these enzymes are now regularly used in industry for the synthesis of Sitagliptin, Mexiletine, Dolutegravir, etc., there is still scope for improvement involving challenges such as equilibrium thermodynamics, co-product removal, limited substrate tolerance, and scope. This review focuses on the detailed use of these enzymes in the pharmaceutical industry over the past 20 years and comprehensive approaches encompassing protein and equilibrium engineering, immobilization, continuous-flow biocatalysis, smart donors, and multi-enzymatic cascades, which have been and are being used for their evolution into the pharmaceutical industry.

SHP2 is a key oncoprotein and a promising target in various types of blood cancers and solid tumors. Here, we report the discovery of a novel series of dimeric pyrazolo[3,4-d]pyrimidin-4-one derivatives as potent SHP2 inhibitors. Among them, compound A4 exhibited potent inhibitory activity against both SHP2^WT and SHP2^E76K, and it demonstrated dose-dependent activity against the SHP2 protein tyrosine phosphatase (PTP) domain. At the cellular level, A4 significantly suppressed the proliferation of MV-4-11, KYSE520, HCT116, MDA-MB-231 and HepG2 cell lines. Further mechanistic studies revealed that A4 downregulated SHP2-mediated phosphorylation of AKT and ERK, and induced apoptosis in MV-4-11 cells. Molecular docking revealed a comprehensive network of interactions between A4 and the SHP2-PTP domain, providing a structural basis for its potent inhibitory activity. Collectively, this work identifies compound A4 as a promising selective SHP2 orthosteric inhibitor with a distinct chemical scaffold.