Journal of Enzyme Inhibition and Medicinal Chemistry最新文献

Alzheimer's disease (AD) still lacks therapies that definitively halt its progression. Dual AChE/MAO-B inhibitors offer a promising strategy to address both symptoms and pathology. Here, we designed and synthesised a series of donepezil-safinamide hybrids. The optimised compound 28c was identified as a potent inhibitor of AChE (IC₅₀ = 1.70 μM) and MAO-B (IC₅₀ = 0.18 μM). Mechanistic studies indicated that 28c acts as a reversible mixed-type inhibitor of AChE and a competitive reversible inhibitor of MAO-B. Molecular docking and molecular dynamic simulations revealed that 28c could strongly and stably bind to MAO-B and AChE mainly through van der Waals interactions. Moreover, compound 28c demonstrated effective blood-brain barrier penetration, exhibited suitable stability in mouse plasma and brain homogenate, and showed a favourable safety profile both in vitro and in vivo. Furthermore, 28c could attenuate AD-related symptoms and exert hippocampal neuroprotection effect in vivo, highlighting its promise as an anti-AD candidate.

Due to their various pharmacological effects, several substituted sulphur heterocycles containing thiophene have recently attracted a great deal of attention. A novel 2,3-diaryl-2,3,5,6,7,8-hexahydro-4H-benzo[4,5]thieno[3,2-e][1,3]oxazin-4-one (9-14) was synthesised starting from cyclohexa[b]thiophene. Compounds 9 and 10 showed the greatest gene expression downregulation of BAX by 75.1% and 79.7%, and upregulation of Bcl-2 gene expression by 8.1 folds for each. It also decreased the level of AChE by 70.2 and 75%; respectively. Compounds 9 and 10 significantly increased Wnt3a levels by 5.8 and 6.6 folds, and β-Catenin levels by 10.1 and 10.5 folds, respectively, compared to donepezil. They significantly downregulated 5-GSK3β gene expression by 77.1%, and 78.7%, respectively. Even though all compounds exhibited potent inhibition of AChE, all synthesised compounds, except for compounds 5 and 11 demonstrated higher selectivity towards BChE (SI < 1). In-silico ADMET calculations as well as molecular docking have been performed for synthetic compounds.

Maltase-glucoamylase (MGAM) is a small-intestinal enzyme comprising two tandem α-glucosidase units, NtMGAM and CtMGAM, each capable of hydrolysing maltodextrins into glucose. MGAM serves as a therapeutic target for managing postprandial hyperglycaemia; comprehensive insights into its full-length three-dimensional structure and inhibitor kinetics remains limited. Here, we demonstrate that the α-glucosidase in porcine serum is comparable to that encoded by the MGAM gene. Using cryo-electron microscopy, we determined the complex structure of serum MGAM with the inhibitor acarviosyl-maltotriose (AC5), which was found to bind exclusively to the active sites of each unit, confirming the presence of independent catalytic sites. AC5 was shown to exhibit mixed-type inhibition towards full-length serum MGAM and competitive inhibition against both recombinant NtMGAM and CtMGAM. The apparent mixed-type inhibition can be more accurately attributed to dual competitive inhibition mechanisms. These findings contribute to the advancement of functional foods and therapeutic interventions for postprandial hyperglycaemia and type 2 diabetes.

To develop eco-friendly pesticides with novel modes of action for insect management, a series of dual-chiral N-cyano sulfilimine-substituted anthranilic diamides were designed and synthesised de novo, and their insecticidal activities were evaluated against Mythimna separata (M. separata) and Plutella xylostella (P. xylostella). Most target compounds exhibited potent insecticidal activity against M. separata. Notably, compounds 6a-b and 6f-g demonstrated near-complete inhibition at 0.1 mg/L, achieving efficacy comparable to the commercial standard chlorantraniliprole (CHL). Furthermore, 6g and 7h outperformed CHL against P. xylostella, suggesting enhanced specificity. 6g matchedCHL's efficacy against M. separata. Specific target compounds, including 6g and 7h, emerged as potential modulators of insect ryanodine receptor (RyR). Molecular docking revealed that 6g probably formed three hydrogen bonds with RyR binding pocket and exhibited stronger binding affinity than CHL (two hydrogen bonds). These findings provide a structural foundation for rational design of novel chiral sulfiliminyl RyR-targeting insecticides.

The serine/threonine kinase IKKε is overexpressed or activated in various cancers, making it a promising therapeutic target. Through a large-scale virtual screening of over 12 million compounds, we identified N8 as a novel IKKε inhibitor, selected for its favourable docking score and drug-likeness profile. The inhibitory activity of N8 on IKKε was validated in vitro across several cancer cell lines, including HCT116 (colorectal), HepG2 (liver), T24 (bladder), MDA-MB-231 (breast), A549 (lung), and HeLa (cervical). N8 demonstrated significant reductions in cell viability, colony formation, and migration, particularly in HCT116 colorectal cancer cells, where it exhibited superior efficacy compared to established IKKε inhibitors. Mechanistically, N8's anticancer activity appears to be mediated through modulation of autophagy rather than apoptosis.

FMS-like tyrosine kinase 3 (FLT3/CD135) regulates haematopoiesis and is frequently mutated as FLT3-internal tandem duplication (FLT3-ITD) in acute myeloid leukaemia (AML), associated with poor prognosis. Although FLT3 inhibitors show clinical benefits, resistance remains a challenge. This study hypothesises that antibody-drug conjugate (ADC) efficacy depends on distinct FLT3 trafficking mechanisms in FLT3-wt and FLT3-ITD cells. Confocal imaging showed that in THP-1 (FLT3-wt) cells, FLT3 mAb trafficked to lysosomes, while in MV4-11 (FLT3-ITD) cells, it accumulated in the Golgi. To evaluate the impact of this trafficking difference, we synthesised an anti-FLT3 mAb-MMAE, linked via a Val-Cit-PAB linker at the Fc N-glycan, which exhibited lower cytotoxicity in MV4-11 than THP-1 cells, indicating that the impaired lysosomal trafficking of FLT3-ITD limits drug release and reduces ADC potency. These findings highlight that effective lysosomal targeting is essential for ADC activity and suggest that optimising linker design or restoring lysosome trafficking may enhance FLT3-targeted ADC in AML.

Lysine-specific demethylase 1 (LSD1) is abnormally overexpressed in various tumour tissues of patients and has been an attractive anticancer target. In this work, a potent LSD1 inhibitor (compound 14) was designed and synthesised by the molecular hybridisation strategy. It displays the potent antiproliferative activity against HepG2, HEP3B, HUH6, and HUH7 cells with IC₅₀ values of 0.93, 2.09, 1.43, and 4.37 μM, respectively. Furthermore, compound 14 is a selective and reversible LSD1 inhibitor with an IC₅₀ value of 0.18 μM and increases the methylation levels of H3K4me1/2. Molecular docking studies showed that it formed hydrogen bonds, hydrophilic interactions and hydrophobic interactions with residues of LSD1. Anticancer mechanisms demonstrated that it suppresses migration and epithelial-mesenchymal transition process in HepG2 cells. Importantly, it exhibits potent anti-liver cancer effects in vivo without obvious toxic effects. These interesting findings suggested that compound 14, a novel LSD1 inhibitor, may be a promising therapeutic agent to treat liver cancer.

Peptidomimetic inhibitors mimic natural peptide substrates, employing electrophilic warheads to covalently interact with the catalytic Cys145 of M^pro. Examples include aldehydes, α-ketoamides, and aza-peptides, with discussions on their mechanisms of action, potency, and structural insights. Non-peptidomimetic inhibitors utilise diverse scaffolds and mechanisms, achieving covalent modification of M^pro.

Decreased proteasome activity is a hallmark of brain and retinal neurodegenerative diseases (Alzheimer's, Parkinson's diseases, glaucoma) boosting the search for molecules acting as proteasome activators. Based on the hypothesis of an electrostatic key code driving catalytic core particle (20S) activation by regulatory particles (RPs), we identified the tetra-anionic meso-Tetrakis(4-sulphonatophenyl)-porphyrin (H2TPPS) as a new activator of human proteasome. By means of an integrated approach, including bioinformatics, enzymatic kinetic analysis, atomic force microscopy, and dynamic docking simulations, we show how binding of H2TPPS affects the closed/open conformational equilibrium of human 20S to ultimately promote substrate gate opening and proteolytic activity. These outcomes support our hypothesis and pave the way to the rational discovery of new proteasome allosteric modulators able to reproduce the key structural elements of regulatory particles responsible for catalytic activation.

A novel chrysin-ferrocene Schiff base (CFSB) was synthesised as a potential anticancer agent. CFSB demonstrated high cytotoxicity against cancer cells with HepG2 (liver) being the most susceptible (IC₅₀ = 3.11 µM). The compound was less toxic towards normal MRC5 cells and exhibited ∼5-fold selectivity towards most cancer cells. CFSB caused G1-phase arrest, induced caspase-dependent apoptosis by increasing Bax/Bcl2 ratio and reduced metastasis by decreasing MMP9 in HepG2. Furthermore, CFSB was inactive against CDK2, EGFR, TrkA and VEGFR, but it strongly inhibited topoisomerase II (IC₅₀ = 20 µM) with potency comparable to etoposide (IC₅₀ = 15 µM), while weak inhibition was observed against tubulin (IC₅₀ = 76 µM). DFT calculations revealed that CFSB had desirable reactivity, while docking indicated high binding affinity with topoisomerase II. Molecular dynamics and MM-GBSA analyses showed that CFSB-topoisomerase II complex was stable with favourable binding energies, while in silico ADMET studies showed drug-like properties for CFSB.