Bioorganic Chemistry最新文献

Dodecyl- and tetradecyl-substituted triphenylphosphonium (TPP) derivatives (1d and 1e) were previously identified by our group as potent antimicrobials, although their mammalian cytotoxicity and hemolytic activity limited their therapeutic potential. To mitigate these drawbacks, six novel para-substituted TPP derivatives bearing dodecyl or tetradecyl chains were synthesized by introducing electron-donating (8d, 8e) or electron-withdrawing (9d, 9e, 10d, 10e) substituents on the phenyl rings. The 4-CF₃ derivatives (10d and 10e) retained potent activity against the tested Staphylococcus aureus strains (MICs of 1-2 μg/mL) while exhibiting substantially reduced mammalian cytotoxicity compared with the parent compounds. Their biological profiles also revealed differences between mammalian cytotoxicity, hemolytic activity, and antibacterial activity across bacterial species. Mechanistic studies revealed preferential accumulation in bacterial membrane fractions, alongside effects on membrane potential and bacterial respiratory and metabolic activity. Notably, the potent anti-S. aureus activity of 10d and 10e, despite their weaker effects on membrane depolarization and bioenergetics, points to a more complex relationship between these effects and antibacterial potency. Overall, these findings highlight electronic modification of the TPP moiety as a promising strategy for modulating the biological properties of TPP-based antimicrobials and reducing mammalian cytotoxicity while retaining activity against selected bacterial pathogens.

Inflammation underlies numerous chronic diseases, and plant-derived clerodane diterpenoids have emerged as promising anti-inflammatory agents. Phytochemical investigation of the bark of Croton laui, an ethnomedicinally significant plant, afforded thirty-six previously undescribed neoclerodane diterpenoids, crolatinoids D-Z and AA-AM (1-36), together with twenty-four known analogues (37-60). Structurally, these metabolites feature a rich assortment of five- and/or six-membered oxacyclic ring systems formed through eight distinct oxygen-bridging patterns (12,20-, 17,20-, 15,16-, 19,20-, 18,19-, 6,18-, 3,19-, and 2,20-), encompassing ether, lactone, furan, hemiacetal, and acetal functionalities. Notably, compounds 1-4 possess an unprecedented 17,20-ether bridge, giving rise to a distinctive 6/6/5/5 fused heterocyclic framework. In anti-inflammatory assays, seven compounds inhibited NO production by over 50% at 20 μM, with compound 59 exhibiting the most potent activity (IC₅₀ = 2.98 ± 0.06 μM). Mechanistic studies revealed that 59 exerts its effects through dual inhibition of the NF-κB and MAPK pathways, and its in vivo efficacy was validated in a zebrafish inflammation model. These findings substantially expand the chemical diversity of neoclerodane diterpenoids and identify 59 as a promising lead for anti-inflammatory drug development.

Small-molecule modulators may complement antibody therapy, offering potential advantages such as optimizable chemical structures, improved tumor accessibility, and better flexibility in pharmacokinetic control. Lymphocyte activation gene-3 (LAG-3) is an inhibitory immune checkpoint receptor that suppresses T-cell function by interacting with MHC-II molecules; however, systematic research on small-molecule modulators targeting LAG-3 remains lacking. In this study, a multi-stage structure-guided screening process was employed to identify candidate compounds targeting a predicted binding pocket adjacent to the LAG-3/MHC-II interface. Starting with approximately 3.9 million compounds database, the study employed a sequential screening and prioritization process involving AutoDock-GPU docking, Glide hierarchical docking, physicochemical and ADMET screening, 500 ns molecular dynamics simulations, and MM/PBSA binding free energy analysis. Based on predicted binding conformations, interface stability, estimated binding energies, and drug-like properties, ligand160490 and ligand223516, hereafter termed Z21 and Z28, were ultimately prioritized for functional evaluation. In activated human peripheral blood mononuclear cells, Z28 increased the frequency of CD4⁺IFN-γ⁺ and CD8⁺IFN-γ⁺ T cells, whereas Z21 did not exhibit a similar effect. In the MC38 syngeneic tumor model, both Z21 and Z28, when used in combination with anti-PD-1, reduced tumor growth, accompanied by increased frequency of tumor-infiltrating CD8⁺ T cells. Together, the in vitro and in vivo results support Z21 and Z28 as prioritized small-molecule candidates for further investigations. Subsequent studies should focus on determining whether Z21 and Z28 exert their biological effects by directly binding to LAG-3 and interfering with LAG-3/MHC-II interaction. Our findings support further mechanistic and pharmacological evaluation of Z21 and Z28.

A phytochemical investigation of the aerial parts of Ligularia platyglossa (Franch.) Hand-Mazz led to the isolation of 19 undescribed eremophilane sesquiterpenoids, ligulaplenolides A-S (1-19), together with 26 sesquiterpenoids (20-45), representing five sesquiterpenoid skeletons. Notably, compounds 1 and 2 feature rare eremophilane frameworks that have seldom been reported in the genus Ligularia. Their structures were established through comprehensive spectroscopic data, including HRESIMS, IR, 1D, and 2D NMR. The absolute configurations were unambiguously determined by single-crystal X-ray diffraction. The anti-inflammatory activities of all isolates were evaluated using LPS-induced RAW264.7 macrophage models. Nine isolates (2, 9, 21, 24, 26, 29, 33, 36, and 42) exhibited pronounced inhibitory effects on LPS-induced nitric oxide (NO) overproduction. Among them, compounds 2 and 9 showed remarkable anti-inflammatory activity with IC₅₀ values of 4.50 μM and 14.09 μM, respectively, outperforming the positive control L-NMMA (IC₅₀ = 18.28 μM). Furthermore, 2 and 9 significantly suppressed the production of key inflammatory cytokines, including tumor necrosis factor alpha (TNF-α), (interleukin-6) IL-6, and interleukin-1β (IL-1β). These two compounds exert their anti-inflammatory activities by inhibiting inducible nitric oxide synthase (iNOS) expression to reduce NO production and by suppressing IκB phosphorylation to block NF-κB nuclear translocation and subsequent pro-inflammatory cytokine expression. This study clarifies the anti-inflammatory pharmacodynamic material basis of L. platyglossa and elucidates its underlying mechanism through regulating the NF-κB signaling pathway.

Here, we report the discovery and optimization of 1-cinnamylpiperazine derivatives as antibiotic-potentiating agents inspired by the known RND efflux pump inhibitor 1-(1-naphthylmethyl)piperazine (NMP). A structurally diverse series of analogues was synthesized and evaluated for intrinsic antibacterial activity, cytotoxicity, and ability to potentiate antibiotic activity against Escherichia coli. Most derivatives showed low intrinsic antibacterial activity, consistent with an adjuvant mode of action. In combination assays, several compounds enhanced the antibiotic activity of erythromycin and linezolid, with halogenated derivatives showing the strongest potentiating effects. Compound 27 displayed the broadest potentiation profile, showing synergistic interactions with five of the seven tested antibiotics, namely linezolid, novobiocin, fusidic acid, pyridomycin, and clindamycin. Notably, it showed a superior potency to the structurally related reference inhibitor NMP. Experiments with AcrAB-TolC-deficient E. coli mutants, together with dye accumulation (Hoechst 33342) and membrane-permeabilization assays, suggested that 1-cinnamylpiperazine derivatives modulate efflux-associated resistance in a manner distinct from NMP, with increased membrane permeability likely contributing to their overall potentiating effect. Beyond planktonic cultures, compound 27 also potentiated erythromycin and linezolid against mature E. coli biofilms. These findings identify 1-cinnamylpiperazines as promising antibiotic adjuvant scaffolds for further optimization against drug-resistant Gram-negative infections.

Despite the currently incurable nature of Alzheimer's disease (AD), acetylcholinesterase (AChE) inhibitors remain the primary therapeutic strategy for symptom management. In this study, twenty-five novel pyridine-2-tetrazole derivatives were designed, their binding affinities with AChE were predicted using machine learning models, and their drug-likeness were calculated. Following their synthesis, the compounds were evaluated in vitro for AChE inhibitory activity. Based on these findings, lead compounds 11 and 28 were selected for in vivo assessment to determine their effects on cognitive function in trimethyltin (TMT)-induced cognitive impairment mouse models at dosages of 20 mg/kg and 60 mg/kg. Although compound 28 exhibited modest in vitro AChE inhibition, it significantly improved cognitive performance in TMT-induced mice across both dosage groups. This cognitive enhancement was demonstrated through the Object Recognition Test, modified Y-maze, and Passive Avoidance Test. These findings suggest that compound 28 may exert its neuroprotective effects through a different molecular mechanism rather than exclusive AChE inhibition, highlighting its potential as a lead compound for the treatment of cognitive impairment and related neurodegenerative disorders such as AD.

Background: Polycystic ovary syndrome (PCOS) is associated with inflammation, oxidative stress, and hyperandrogenism. This study investigated the effects of chlorogenic acid (CGA) on ovarian alterations in an estradiol valerate (EV)-induced rat model of PCOS, with particular attention to NLRP3-related inflammatory changes.

Methods: Female rats (n = 36) were assigned to control, PCOS, and PCOS+CGA groups. PCOS was induced by a single intramuscular injection of EV (4 mg/kg). After confirmation of PCOS at 8 weeks, CGA (100 mg/kg/day, i.p.) was administered for 8 weeks. Hormonal profiles, ovarian histomorphology and fibrosis, oxidative stress markers, inflammatory mediators, miR-93-5p, TLR4, NF-κB, and NLRP3 expression, and NLRP3 immunoreactivity were evaluated. ADMET prediction, molecular docking, and molecular dynamics (MD) simulations were also performed.

Results: PCOS rats showed increased T, LH, LH/FSH ratio, ROS, MDA, pro-inflammatory mediators, NF-κB, miR-93-5p, TLR4, and NLRP3 expression, NLRP3 immunoreactivity, cystic follicles, and ovarian fibrosis, together with reduced FSH, CAT, IL-10, developing follicles, and corpora lutea. CGA significantly attenuated these alterations, although several parameters remained different from controls. Docking supported the structural plausibility of CGA interactions with the investigated targets. Ligand-centered MD analyses showed relatively persistent CGA association with NLRP3, more variable association with IKKβ, and substantial displacement in the TLR4/MD-2 system.

Conclusions: CGA ameliorated endocrine, oxidative, inflammatory, and histopathological abnormalities in experimental PCOS. These effects were accompanied by coordinated changes in ovarian miR-93-5p expression and TLR4/NF-κB/NLRP3-associated inflammatory markers. Further studies are required to determine the functional relationships among these molecular changes.

Proteolysis-targeting chimeras (PROTACs) have emerged as a revolutionary therapeutic modality. However, their clinical translation is often hindered by high molecular weight, poor cellular permeability, and systemic off-target toxicity. To address these challenges, we report a photocaged click-assembled PROTAC (pcCLIPTAC) for the spatiotemporally controlled degradation of the BRD4 protein. Our system utilizes cycloalkene-based bioorthogonal handles and a light-sensitive photocaged tetrazine-thalidomide as PROTAC precursors. Intracellular PROTAC assembly is initiated by 365 nm UV irradiation, resulting in robust and time-dependent BRD4 degradation only upon light activation. Linker optimization revealed a divergent structure-activity relationship (SAR). While the bulky trans-cyclooctene (TCO) handle favored longer linkers, the compact and rigid cyclopropene (CP) handle achieved maximum potency with minimal linker length. Furthermore, proteomic profiling revealed distinct cycloalkene-dependent protein abundance profiles, with degradation of BRD4 following both TCO2- and CP1-based pcCLIPTAC treatment. These findings provide practical design principles for light-controllable click-assembled degraders and support pcCLIPTAC as a platform for spatiotemporally controlled protein degradation.

Selective near-infrared fluorescent probes for amyloid β aggregates are of considerable interest as molecular imaging tools for the diagnosis and study of Alzheimer's disease. Herein, we describe the rational design and synthesis of DDNP-type donor-π-acceptor fluorophores incorporating a fixed N,N-dimethylamino donor group, while systematically modifying seven aromatic π-bridges and four electron-withdrawing acceptor groups to investigate structure-property relationships. The library of 26 probes is a result of multi-step synthetic routes and exhibits pronounced solvatochromic behaviour together with strong fluorogenic responses. Compounds' photophysical properties, including absorption and emission maxima, Stokes shifts, and quantum yields, are systematically evaluated in five solvents of varying polarity. The study reveals clear structure-property relationships, demonstrating the influence of π-bridge length and electron-acceptor strength on the optical characteristics, including near-infrared emission. Selected fluorophores are further assessed for their affinity towards amyloid β fibrils through a combination of in vitro experiments and in silico molecular docking studies. Among the compounds investigated, the N,N-dimethylamino-stilbene-malononitrile derivative emerges as the lead candidate, showing an optimal balance of favourable photophysical properties and strong amyloid β binding affinity. Subsequent evaluation using brain tissue obtained post mortem from a patient with Alzheimer's disease demonstrates selective staining of amyloid β plaques with minimal background fluorescence.