Mathew J, Mishra A, Le TN
… +3 more, Liou JP, Lai MJ, Rao Neralla V
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40698624
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This study investigated the incorporation of C5, a pan-HDAC inhibitor, into a norbornene-derived block copolymer with pH-sensitive hydrolysis (PNEG-b-P(Nor-PABA-C5)) to generate NPs for prostate cancer treatment. Amphiph...This study investigated the incorporation of C5, a pan-HDAC inhibitor, into a norbornene-derived block copolymer with pH-sensitive hydrolysis (PNEG-b-P(Nor-PABA-C5)) to generate NPs for prostate cancer treatment. Amphiphilic PNEG-b-P(Nor-PABA-C5) formed NPs in aqueous environments, with hydrophobic Nor-PABA-C5 monomers in the core and hydrophilic PNEG monomers on the surface. DLS analysis showed a particle size of 122 ± 12 nm with a PDI of 0.35, confirmed by SEM and TEM. TEM imaging revealed spherical morphology, enabling the NPs to transport hydrophobic pan-HDACi drugs to PC-3 tumour sites and facilitate release through hydrolysis under acidic conditions. The NPs exhibited pH-hydrolysis characteristics, with enhanced drug release (61 ± 1.7%) at pH 6.2 compared to pH 7.4 (35 ± 0.8%). MTT assay confirmed antiproliferative effect. Analysis of FITC/(PNEG-b-P(Nor-PABA-C5)) cellular uptake showed increased absorption in prostate tumours. Live/dead cell assays showed loss of viability, with increased red fluorescence and morphological disruption at higher concentrations over 48 and 72 h.
Ignácz R, Bózsity N, Unger D
… +6 more, Kele Z, Zupkó I, Hunyadi A, Gjorgoska M, Rižner TL, Mernyák E
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40676999
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Phenols are important structural elements of natural products and pharmaceuticals. Due to their versatile chemical transformability, phenols are frequently used building blocks in medicinal chemistry. Their aromatic natu...Phenols are important structural elements of natural products and pharmaceuticals. Due to their versatile chemical transformability, phenols are frequently used building blocks in medicinal chemistry. Their aromatic nature allows directed C(sp)-H functionalisations, especially at the positions. In contrast, substitutions are less well known. As a continuation of our recently described metal-catalysed cross couplings, here we report arylations of two nature-inspired phenol derivatives C-H or O-H activation. A directing group (DG) was introduced onto C-3- of 13α-oestrone, and the resulting carbamate was subjected to Cu(II)-catalysed arylation using diaryliodonium triflates as reagents. As a result, C-1-arylated derivatives were obtained. The arylation of the 1'--butyl protoapigenone proceeded regioselectively at C-5-. The 1-(4--butylphenyl)-13α-oestrone carbamate and all -arylated protoflavones substantially inhibited the growth of the applied human cancer cell lines and exerted proapoptotic activity on HeLa cells. The 1-(4--butylphenyl)-13α-oestrone proved to be a potent 17β-HSD1 inhibitor.
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40673704
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Rapid GDP metabolism in mitochondria isolated from wild-type yeast is postulated. The hallmark of exogenous GDP is convergence with the effect of exogenous ADP, typically inducing oxidative phosphorylation (OXPHOS). The...Rapid GDP metabolism in mitochondria isolated from wild-type yeast is postulated. The hallmark of exogenous GDP is convergence with the effect of exogenous ADP, typically inducing oxidative phosphorylation (OXPHOS). The GDP-provoked changes in the presence of ATP, i.e. increased respiratory rate accompanied by decreased inner mitochondrial membrane electrical potential, were curtailed by OXPHOS inhibitors, such as carboxyatractyloside, which apparently merged the GDP effect with OXPHOS. However, all performed tests indicated that the response of mitochondria to GDP is indirect and involves two steps. First, GDP is transphosphorylated nucleoside diphosphate kinase (NDPK), ATP + GDP → ADP + GTP, which is followed by ADP-induced OXPHOS. Importantly, in mitochondria isolated from mutant yeast with a deleted NDPK gene, the stimulatory effect of GDP was eliminated. Therefore, a prerequisite for GDP metabolic action is the cooperation of NDPK with the OXPHOS apparatus. This biological model can help elucidate the molecular basis of some diseases treatment, such as cancer.
Zhao C, Wu H, Liu H
… +4 more, Dong H, Niu MM, Shi K, Wang F
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40662493
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Aberrant expression of PLK1 and PLK4 is closely associated with tumourigenesis, and their simultaneous inhibition can effectively suppress tumour proliferation. In this study, we successfully identified peptide inhibitor...Aberrant expression of PLK1 and PLK4 is closely associated with tumourigenesis, and their simultaneous inhibition can effectively suppress tumour proliferation. In this study, we successfully identified peptide inhibitors (Peptides ) capable of simultaneously targeting PLK1-PBD and PLK4-PB3 via pharmacophore-based virtual screening. Binding affinity analyses demonstrated that all candidate peptides exhibited nanomolar binding affinity for both targets. cancer cell growth inhibition assays revealed that these peptides could suppress the growth of cervical cancer cells. Among them, Peptide- showed the optimal binding affinity and anticancer cell proliferative activity (PLK1-PBD: = 8.02 ± 0.16 nM; PLK4-PB3: = 11.32 ± 0.19 nM; IC = 0.44 ± 0.03). Molecular dynamics (MD) simulations further predicted that Peptide-2 could stably bind to the binding sites of both PLK1-PBD and PLK4-PB3. This study reported a novel peptide inhibitor Peptide-2 with potent dual-target inhibitory activity against PLK1-PBD/PLK4-PB3, providing a novel strategy for cancer therapy.
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40626382
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The escalating threat of antimicrobial resistance calls for novel therapeutic agents. This study employed a ligand-based design approach to develop three series of N-arylpyrrole derivatives (, , and ), refined through mo...The escalating threat of antimicrobial resistance calls for novel therapeutic agents. This study employed a ligand-based design approach to develop three series of N-arylpyrrole derivatives (, , and ), refined through molecular modeling. Synthesized compounds were evaluated against ESKAPE pathogens, MRSA, and . Series showed the most promise, with compounds , , and outperforming levofloxacin against MRSA (MIC = 4 μg/mL vs. 8 μg/mL). also exhibited activity against , and , and showed significant inhibition against (MIC = 8 μg/mL). Compounds were evaluated for antibiofilm and antivirulence properties, targeting resistance mechanisms linked to infection persistence and dissemination. Most exhibited broad-spectrum biofilm inhibition and antivirulence activity. Cytotoxicity studies revealed selectivity for bacterial cells. ADMET studies supported drug-like properties. Docking studies suggested UPPP inhibition as the potential mechanism. SAR analysis was conducted to support future optimizations.
Yuan P, Jiang X, Ni X
… +3 more, Shao X, Qian X, Yang Q
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40619956
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Chitinase h (Chi-h) has been identified as a promising pesticide target due to its exclusive distribution in lepidopteran insects and its essential role in the moulting processes. In this study, we leverage Chi-h from de...Chitinase h (Chi-h) has been identified as a promising pesticide target due to its exclusive distribution in lepidopteran insects and its essential role in the moulting processes. In this study, we leverage Chi-h from destructive agricultural pest (Asian corn borer) as a model target to identify novel chitinase inhibitors. A conformational restriction approach was employed to design a series of novel Chi-h inhibitors. Among these, compound showed the highest inhibitory activity against Chi-h, with a value of 58 nM. Molecular docking analysis suggested that tightly bound to three subsites (-3 to -1) of Chi-h. The binding mode is further confirmed by the co-crystallization data of with the ChiA, a bacterial homologue of Chi-h, at a resolution of 1.8 Å. This research presents a novel approach for the development of highly potent insect chitinase inhibitors, offering potential tools for effective pest control.
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40607666
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Enzyme sequence design has always been a challenging task, particularly in optimising key properties such as enzyme solubility, stability, and activity. This study proposes an innovative approach by utilising a variation...Enzyme sequence design has always been a challenging task, particularly in optimising key properties such as enzyme solubility, stability, and activity. This study proposes an innovative approach by utilising a variational autoencoder (VAE) model integrated with the Gromov-Wasserstein (GW) distance for enzyme sequence optimisation. The GWAE model improves representation learning by using the GW distance, thereby generating functional variants with desired characteristics. We also introduce an innovative enzyme dataset construction method that incorporates multiple sequence alignment (MSA) techniques to address sequence length discrepancies, enhancing the accuracy of the optimisation process. Experimental results show that the GWAE model outperforms the traditional VAE on multiple metrics. The generated enzyme sequences demonstrate superior solubility, stability, and hydrophobicity. Additionally, by integrating AlphaFold3 for structural prediction, we verify the structural stability of the generated sequences, further enhancing their practical applicability.
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40590424
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Small molecule inhibitors of lysine deacetylases (KDACs), exemplified by histone deacetylases (HDACs), exhibit significant promise as cancer therapeutics. Using a modular combinatorial chemistry approach, a novel class o...Small molecule inhibitors of lysine deacetylases (KDACs), exemplified by histone deacetylases (HDACs), exhibit significant promise as cancer therapeutics. Using a modular combinatorial chemistry approach, a novel class of KDAC inhibitors (KDACi) containing the aminophenyl-benzamide headgroup have been developed, which incorporate a vinyl group within the linker region for active site stabilisation and a trifluoromethyl moiety within the capping group to exploit enzyme surface topology. Consequently, a class I selective KDACi () with a preference towards HDAC1 over other class I KDACs was identified. This KDACi orientates differently within the KDAC active site and exhibits an improved antitumour profile relative to the benchmark class I selective KDACi Entinostat (). The clinical potential of is further exemplified by the inhibition of tumour growth in an model of ovarian cancer. These results offer significant scope for the rational development of KDACi with improved selectivity against specific KDAC and widespread therapeutic potential.
Lee H, Hurh S, Kang S
… +4 more, Yoon J, Hwang JI, Logan DT, Kim HR
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40588719
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USP11 is a promising therapeutic target implicated in Alzheimer's disease and various cancers; however, no specific inhibitors are currently available, with the only known inhibitor being mitoxantrone, which primarily ta...USP11 is a promising therapeutic target implicated in Alzheimer's disease and various cancers; however, no specific inhibitors are currently available, with the only known inhibitor being mitoxantrone, which primarily targets topoisomerase II. To identify novel chemical starting points, we conducted high-throughput virtual screening using a USP11 homology model. Screening over 600,000 compounds yielded five structurally distinct hits with significant inhibitory activity. Biochemical validation highlighted two promising scaffolds: benzoxadiazole derivatives and pyrrolo-phenylamidine analogues, both demonstrating structure-dependent inhibition and tractable SAR profiles. Docking studies further characterised their binding modes, supporting their potential for optimisation. Hydroxyphenyl hydrazone analogues raised PAINS-related concerns, while compounds such as squalamine were deprioritized due to weak binding affinity and structural complexity. Overall, this study provides valuable scaffolds and mechanistic insights that can inform future development of potent, selective USP11 inhibitors.
Sabuakham S, Nasoontorn S, Nuramrum N
… +4 more, Silsirivanit A, Rungrotmongkol T, Pingaew R, Mahalapbutr P
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40556424
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Tyrosinase, a key enzyme in melanin synthesis, serves as a primary target for developing depigmenting agents. The search for novel tyrosinase inhibitors is needed due to the adverse effects of current inhibitors. This st...Tyrosinase, a key enzyme in melanin synthesis, serves as a primary target for developing depigmenting agents. The search for novel tyrosinase inhibitors is needed due to the adverse effects of current inhibitors. This study evaluated 16 -thiourea derivatives using and methods, identifying compound , with chlorine substituents, as the most potent inhibitor. Compound outperformed kojic acid in inhibiting mushroom tyrosinase activity and interacted with catalytic copper ions and active site residues, as revealed by molecular docking and copper-chelating assay. Molecular dynamics simulation and MM/PBSA-based free energy calculations confirmed the greater stability and binding affinity of the compound -tyrosinase complex in an aqueous environment compared to kojic acid-tyrosinase complex. Melanin assay revealed that compound significantly suppressed melanin production in B16F10 melanoma cells, showing stronger anti-melanogenic activity than kojic acid. Drug-likeness predictions confirmed its compliance with Lipinski's rule of five, supporting -thiourea derivatives as promising tyrosinase inhibitors.
Al-Wahaibi LH, Abou-Zied HA, Mahmoud MA
… +3 more, Youssif BGM, Bräse S, Rabea SM
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40556275
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A novel series of 5-ethylsulfonyl-indazole-3-carbohydrazides , serving as dual inhibitors of EGFR and VEGFR-2 was developed. The antiproliferative effects of compounds were assessed against four cancer cell lines via th...A novel series of 5-ethylsulfonyl-indazole-3-carbohydrazides , serving as dual inhibitors of EGFR and VEGFR-2 was developed. The antiproliferative effects of compounds were assessed against four cancer cell lines via the MTT assay. Compounds , , and emerged as the most efficient six derivatives, with GI values ranging from 25 nM to 42 nM. Compounds , , and (GI values of 27, 25, and 30, respectively) demonstrated greater potency than erlotinib (GI value of 33 nM), particularly against breast (MCF-7) cancer cell lines, and were identified as the most potent dual EGFR/VEGFR-2 inhibitors. Apoptotic markers assay results showed that increased levels of p53 and Bax proteins, along with lower levels of antiapoptotic Bcl-2, govern the apoptosis process in these new compounds. Computational analyses, encompassing molecular docking, molecular dynamics (MD) simulations, and density functional theory (DFT) computations, elucidated the binding interactions of these drugs with EGFR and VEGFR-2.
Hou S, Diao S, He Y
… +3 more, Li T, Meng W, Zhang J
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40539987
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VEGFR2 is a transmembrane tyrosine kinase receptor expressed on vascular endothelial cells and is closely associated with tumour cell growth. A comparison of traditional Chinese medicines and natural products with existi...VEGFR2 is a transmembrane tyrosine kinase receptor expressed on vascular endothelial cells and is closely associated with tumour cell growth. A comparison of traditional Chinese medicines and natural products with existing VEGFR2 inhibitors revealed that the former exhibited superior anticancer properties while concomitantly showing a reduced incidence of adverse effects. We proposed a novel strategy for screening potential candidates targeting VEGFR2 in a Chinese medicine monomer database using a combination of AI deep learning and structure-based drug design. The graph neural network served as the final predictive model to evaluate the molecular activities within the database, resulting in the selection of six candidate compounds. Kinase inhibition assays showed that the three compounds exhibited significant inhibition of VEGFR2. Molecular docking and molecular dynamics simulations further demonstrated the stability of their binding to VEGFR2. This study identified three compounds that effectively inhibited VEGFR2, making them promising candidates in cancer treatment.
Kim K, Jang A, Han H
… +3 more, Kim T, Park H, Hong S
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40536312
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Interleukin-1 receptor-associated kinase 4 (IRAK4) is a serine/threonine kinase that plays a pivotal role in immune signalling and cytokine regulation, making it a compelling target for the treatment of inflammatory and...Interleukin-1 receptor-associated kinase 4 (IRAK4) is a serine/threonine kinase that plays a pivotal role in immune signalling and cytokine regulation, making it a compelling target for the treatment of inflammatory and autoimmune diseases. We initiated a drug discovery campaign based on the -diphenylpyrimidine-2,4-diamine (DPDA) scaffold, employing an integrated strategy that combined structure-based design, three-dimensional quantitative structure-activity relationship (3D-QSAR) modelling, and biochemical evaluation. This approach emphasised the optimisation of membrane permeability by controlling the 1-octanol/water partition coefficient (Log), while also enforcing configurational constraints to enhance IRAK4-specific binding. Through iterative cycles of computational modelling and chemical synthesis, we identified 10 out of 17 newly synthesised compounds that exhibited potent IRAK4 inhibition at low-nanomolar concentrations in both enzymatic and cellular assays. Among these, compounds and stood out, demonstrating strong IRAK4 inhibitory activity, favourable membrane permeability, and minimal off-target kinase interactions.
Zhu S, Yang S, Chen Y
… +4 more, Niu MM, Wang J, Li J, Pu X
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40518584
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Macrophage migration inhibitory factor (MIF) plays a crucial role in disrupting immune homeostasis and was overexpressed in immune cells. The inhibitors of MIF inhibit the release of inflammatory factors to treat sepsis....Macrophage migration inhibitory factor (MIF) plays a crucial role in disrupting immune homeostasis and was overexpressed in immune cells. The inhibitors of MIF inhibit the release of inflammatory factors to treat sepsis. Herein, a series of compounds (termed as Hits 1-6) were discovered based on pharmacophore modelling, molecular docking, and interaction analysis. The biaryltriazole inhibitor 3a was used as the positive control. MST and ITC experiments showed that compared to 3a, Hit-1 possessed the highest affinity with MIF. MD simulations exhibited that Hit-1 stably bound to the active pocket of MIF. Pull down experiment showed that Hit-1 could interfere with the binding of MIF to CD74. Furthermore, RT-qPCR demonstrated that Hit-1 suppressed the release of pro-inflammatory cytokines in macrophages including TNF-α, IL-6, and IL-1β. These data demonstrate that Hit-1 may be a promising and high-affinity candidate compound treating sepsis.
Vrabie R, Pinteala M, Al-Matarneh CM
… +6 more, Marinas IC, Nicolescu A, Shova S, Silion M, Gaboreanu MD, Chifiriuc MC
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40497717
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Using a one-pot, three-component approach, we synthesised 25 dihydropyrrol-2-one and two 5-oxo-2,5-dihydrofuran compounds, each featuring two trifluoromethyl groups. This method emphasises timeliness and cost-effectivene...Using a one-pot, three-component approach, we synthesised 25 dihydropyrrol-2-one and two 5-oxo-2,5-dihydrofuran compounds, each featuring two trifluoromethyl groups. This method emphasises timeliness and cost-effectiveness, crucial in drug development. Structural verification was conducted using NMR, FT-IR, MALDI-MS, single-crystal, and powder XRD. The antibacterial and antifungal activities of these compounds were evaluated on yeasts ( sp.) and bacteria, including Gram-positive (, a significant opportunistic pathogen, being more susceptible than ) and Gram-negative strains. Compounds with -OH and '-NO groups exhibited superior activity, while those with -OH and -OMe groups showed slightly lower but still significant activity. For furan structures, displayed greater sensitivity than . Additionally, 13 compounds demonstrated haemolysis below 5%, indicating low toxicity.
Madia VN, Garibaldi N, Ialongo D
… +15 more, Patacchini E, Tudino V, Ruggieri G, Zarbo L, Cara E, Coluccia A, Artico M, Scipione L, Messore A, Saccoliti F, Mentegari E, Maga G, Di Santo R, Crespan E, Costi R
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40488680
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Terminal deoxynucleotidyl transferase (TdT) is overexpressed in some cancer types, where it drives the mutagenic repair of double strand breaks through non canonical non-homologous end joining pathway. The TdT enzyme bel...Terminal deoxynucleotidyl transferase (TdT) is overexpressed in some cancer types, where it drives the mutagenic repair of double strand breaks through non canonical non-homologous end joining pathway. The TdT enzyme belongs to the X family of polymerases, together with the DNA polymerase λ (pol λ) and β (pol β). However, TdT exclusively displays template-independent nucleotide polymerisation. Pursuing our studies in developing TdT inhibitors, herein we deepened the structure-activity relationships of new structural analogues of our previously identified hit compounds. The diketo hexenoic acid derivatives here analysed showed high selectivity towards TdT and inhibition potencies spanning from the low micromolar range to the nanomolar. Docking studies highlighted the chemical features involved in the TdT binding, well contributing to the rationalisation of the structural requirements needed for the enzymatic inhibition.
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40485476
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Chalcones represent a privileged scaffold in medicinal chemistry, with pyranochalcones, featuring an additional chromane-like ring, identified as neurogenic and neuroprotective. Reporter gene assays, often used to study...Chalcones represent a privileged scaffold in medicinal chemistry, with pyranochalcones, featuring an additional chromane-like ring, identified as neurogenic and neuroprotective. Reporter gene assays, often used to study these and other effects, can produce false positives due to firefly luciferase stabilisation by inhibitors. The present study demonstrates that pyranochalcones inhibit firefly luciferase activity, with inhibition levels ranging from none to 100% and IC values of 7.82 µM to 92.99 µM. Furthermore, molecular docking offers potential structure-based explanations for the observed selectivity of compounds towards firefly luciferase inhibition. Even slight modifications in the molecular structure lead to significant changes in luciferase inhibition, underscoring the importance of these findings for understanding structure-activity relationships in reporter gene assays. Accordingly, caution is advised when using reporter gene assays based on firefly luciferase and pyranochalcones, as the IC values are within the range of concentrations commonly used in both and assays.
Hou Y, Fu Z, Wang C
… +3 more, Kucharzewska P, Guo Y, Zhang S
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40401382
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27-Hydroxycholesterol (27HC), a cholesterol metabolite, functions both as a selective oestrogen receptor (ER) modulator and a ligand for liver X receptors (LXRs). The discovery of 27HC involvement in carcinogenesis has u...27-Hydroxycholesterol (27HC), a cholesterol metabolite, functions both as a selective oestrogen receptor (ER) modulator and a ligand for liver X receptors (LXRs). The discovery of 27HC involvement in carcinogenesis has unveiled new research avenues, yet its precise role remains controversial and context-dependent. In this review, we provide an overview of the biosynthesis and metabolism of 27HC and explore its cancer-associated signalling, with a particular focus on ER- and LXR-mediated pathways. Given the tissue-specific dual role of 27HC, we discuss its differential impact across various cancer types. Furthermore, we sort out 27HC-contributed drug resistance mechanisms from the perspectives of drug efflux, cellular proliferation, apoptosis, epithelial-mesenchymal transition (EMT), antioxidant defence, epigenetic modification, and metabolic reprogramming. Finally, we highlight the chemical inhibitors to mitigate 27HC-driven cancer progression and drug resistance. This review offers an updated role of 27HC in cancer biology, setting the stage for future research and the development of targeted therapeutics.
Albanese V, Pedriali G, Fabbri M
… +8 more, Ciancetta A, Ravagli S, Roccatello C, Guerrini R, Morciano G, Preti D, Pinton P, Pacifico S
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40399042
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Ischaemia/reperfusion injury (IRI) is a condition that occurs when tissues from different organs undergo reperfusion following an ischaemic event. The mitochondrial permeability transition pore (mPTP), a multiprotein pla...Ischaemia/reperfusion injury (IRI) is a condition that occurs when tissues from different organs undergo reperfusion following an ischaemic event. The mitochondrial permeability transition pore (mPTP), a multiprotein platform including structural components of ATP synthase with putative gate function, is an emerging pharmacological target that could be modulated to facilitate the restoration of organ function after a hypoxic insult. Herein, we reported the synthesis and biological characterisation of new molecules with a 1,4,8-triaza-spiro[4.5]decan-2-one framework of potential interest for the treatment of IRI able to inhibit the opening of mPTP in a cardiac model in vitro. Modelling studies were useful to rationalise the observed structure-activity relationship detecting a binding site for the investigated molecules at the interface between the c-ring and subunit a of ATP synthase. Compound was shown to display high potency as mPTP inhibitor combined with the capability to counteract cardiomyocytes death in an in vitro model of hypoxia/reoxygenation.