Lin C, Hsu JL, Hsu YT
… +5 more, Fan KC, Wu SS, Lin MH, Guh JH, Yu CW
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40013582
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The enigmatic histone deacetylase 6 (HDAC6) is one of a kind among its family. Recent reports revealed that HDAC6 CD1 exhibits E3 ligase activity. Inspired by these researches, we attempted to develop drugs targeting HDA...The enigmatic histone deacetylase 6 (HDAC6) is one of a kind among its family. Recent reports revealed that HDAC6 CD1 exhibits E3 ligase activity. Inspired by these researches, we attempted to develop drugs targeting HDAC6 novel mechanism. Herein, we report a palladium catalysed transformation and purification method for hydroxamic acid dimers, and series of HDAC6 inhibitor-based dimer showing outstanding biological activities and capability of inducing auto-degradation. Our proof-of-concept was highlighted with 2-amino benzamide-based HDAC6 inhibitor dimers that exhibit great HDAC6 inhibition activity (3.9-15.4 nM), good HDAC1/6 selectivity (95-577), and excellent cytotoxicity against human hormone-resistant prostate cancer (HRPC) PC-3 and non-small cell lung cancer (NSCLC) A549 cell lines (5.9-11.3 and 6.6-17.9 μM, respectively) while simultaneously inducing HDAC6 degradation. These dimers not only induce apoptosis and autophagy but also interfere with kinetochore attachment by the detection of BUBR1 phosphorylation at S670.
Pyrczak-Felczykowska A, Kaczorowska AK, Giełdoń A
… +5 more, Braczko A, Smoleński RT, Antosiewicz J, Reekie TA, Herman-Antosiewicz A
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40013402
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The impact of the isoxazole derivative of usnic acid, (formerly known as 2b) on cancer and non-cancerous cell metabolism was investigated. significantly reduced the utilisation of most metabolic substrates that produce...The impact of the isoxazole derivative of usnic acid, (formerly known as 2b) on cancer and non-cancerous cell metabolism was investigated. significantly reduced the utilisation of most metabolic substrates that produce NADH or FADH2, mitochondrial electron flow and oxygen consumption rate (OCR) in MCF-7 breast cancer cells in contrast to HB2 normal epithelial cells. Molecular docking revealed that inhibits mitochondrial respiratory chain complex II, which was confirmed experimentally. Disturbance of electron flow in MCF-7 cells resulted in increased reactive oxygen species (ROS) production. They appeared crucial for -induced cancer cell vacuolization and a drop in survival as an antioxidant, α-tocopherol, protected against these processes. These findings indicate that is a metabolic inhibitor that targets mitochondrial complex II in breast cancer cells resulting in diminished ATP production and increased ROS formation which translates into reduced cell viability.
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40008549
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Increasing the expression of ATP-binding cassette transporter A1 (ABCA1) can lower cellular cholesterol levels and prevent foam cell formation. In this study, a series of 5, 6-dihydro-8-isoquinolino[1, 2-]quinazolin-8-on...Increasing the expression of ATP-binding cassette transporter A1 (ABCA1) can lower cellular cholesterol levels and prevent foam cell formation. In this study, a series of 5, 6-dihydro-8-isoquinolino[1, 2-]quinazolin-8-one derivatives were synthesised and assessed for their ability to up-regulate ABCA1 expression. The structure-activity relationship was explored and summarised. Among the 28 derivatives, compound exhibited the most potent activity in activating the ABCA1 promoter (2.50-fold), significantly up-regulating both ABCA1 mRNA and protein levels in RAW264.7 macrophage cells. Mechanism studies revealed that compound acted by targeting the LXR-involved pathway. In a foam cell model, compound reduced ox-LDL-induced lipid accumulation and thereby inhibited foam cell formation. Moreover, compared to the LXR agonist T0901317, compound led to minimal accumulation of unwanted lipids and triglycerides in HepG2 cells. With little cytotoxicity towards all the tested cell lines, compound holds promise as a novel potential anti-atherogenic agent for further exploration.
Iacono R, Paragliola FMP, Strazzulli A
… +1 more, Moracci M
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 39995088
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GH31 glycosidases are widespread across organisms, but remarkably, less than 1% of them have been biochemically characterised to date. Among them, human lysosomal acid α-glucosidase (GAA) stands out due to its link to Po...GH31 glycosidases are widespread across organisms, but remarkably, less than 1% of them have been biochemically characterised to date. Among them, human lysosomal acid α-glucosidase (GAA) stands out due to its link to Pompe disease, a rare lysosomal storage disorder caused by its deficiency. This disease results in glycogen accumulation, severe cellular damage, motor impairment, and premature death. Structural and functional studies of GAA mutants are challenging due to their instability and lack of activity, hindering their expression and purification. The GH31 enzyme MalA from a hyperthermophilic archaeon is explored here as a stable homolog of GAA. MalA is highly expressible, easy to purify, and structurally characterised. The R400H mutant in MalA, corresponding to the pathogenic GAA R600H mutation, revealed here a 1200-fold drop in specificity constant and >8 °C reduction in thermal stability. We propose MalA's as a robust model for studying GAA mutations and developing therapeutic chaperones.
Albassam H, Almutairi O, Alnasser M
… +3 more, Altowairqi F, Almutairi F, Alobid S
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 39992303
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Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally, driving an urgent need for effective therapies. A promising avenue of research focuses on the PI3K/AKT/mTOR signalling pathway, which...Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally, driving an urgent need for effective therapies. A promising avenue of research focuses on the PI3K/AKT/mTOR signalling pathway, which is frequently disrupted by mutations in the PI3Kα subunit. Our cutting-edge study employed a structure-based virtual screening of ∼3000 compounds, leading to the discovery of F0608-0019, a highly potent and selective PI3Kα inhibitor. F0608-0019 demonstrated remarkable efficacy in suppressing HCT116 colorectal cancer cell proliferation, with an IC of 12.14 µM, while maintaining high selectivity by minimising activity against other PI3K isoforms. Advanced molecular dynamics simulations highlighted the stability of F0608-0019's binding interactions with key amino acids, such as TRP:780, ILE:932, and VAL:850, which are critical for its targeted action. These exciting findings reveal F0608-0019 as a leading candidate for innovative CRC therapies that selectively target PI3Kα dysregulation, offering promising new possibilities for effective CRC treatment.
Gafforov Y, Bekić S, Yarasheva M
… +12 more, Mišković J, Živanović N, Chen JJ, Petri E, Abdullaev B, Rapior S, Lim YW, Abdullaev I, Abbasi AM, Ghosh S, Wan-Mohtar WAAQI, Rašeta M
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 39992291
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This study investigates the mycochemical profile and biological activities of hydroethanolic (EtOH), chloroform (CHCl), and hot water (HO) extracts of from Uzbekistan. Antioxidant capacity was assessed using 2,2-dipheny...This study investigates the mycochemical profile and biological activities of hydroethanolic (EtOH), chloroform (CHCl), and hot water (HO) extracts of from Uzbekistan. Antioxidant capacity was assessed using 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS), NO, and FRAP assays, and hypoglycaemic effects were evaluated through α-amylase and α-glucosidase inhibition. Antiproliferative potential was explored by analysing the binding affinities of EtOH and HO extracts to estrogen receptor α (ERα), ERβ, androgen receptor (AR), and glucocorticoid receptor (GR), with molecular docking providing structural insights. LC-MS/MS analysis revealed solvent-dependent phenolic profiles, with the EtOH extract containing the highest total phenolic content (143.15 ± 6.70 mg GAE/g d.w.) and the best antioxidant capacity. The EtOH extract showed significant hypoglycaemic effects, with 85.29 ± 5.58% inhibition of α-glucosidase and 41.21 ± 0.79% inhibition of α-amylase. Moderate ERβ binding suggests potential for estrogen-mediated cancer therapy, while strong AKR1C3 inhibition by the EtOH extract supports its therapeutic potential.
Lv X, Yang C, Li X
… +7 more, Liu Y, Yang Y, Jin T, Chen Z, Jia J, Wang M, Li L
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 39992186
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Hearing loss profoundly affects social engagement, mental health, cognition, and brain development, with sensorineural hearing loss (SNHL) being a major concern. Linked to ototoxic medications, ageing, and noise exposure...Hearing loss profoundly affects social engagement, mental health, cognition, and brain development, with sensorineural hearing loss (SNHL) being a major concern. Linked to ototoxic medications, ageing, and noise exposure, SNHL presents significant treatment challenges, highlighting the need for effective prevention and regeneration strategies. Ferroptosis, a distinct form of cell death featuring iron-dependent lipid peroxidation, has garnered interest due to its potential role in cancer, ageing, and neuronal degeneration, especially hearing loss. The emerging role of ferroptosis as a crucial mediator in SNHL suggests that it may offer a novel therapeutic target for otoprotection. This review aims to summarise the intricate connection between ferroptosis and SNHL, offering a fresh perspective for exploring targeted therapeutic strategies that could potentially mitigate cochlear cells damage and enhance the quality of life for individuals with hearing impairments.
Xun QQ, Zhang J, Feng L
… +3 more, Ma YY, Li Y, Shi XL
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 39976249
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Herein, a novel pyrrolo[2,3-]pyridine-based glycogen synthase kinase 3β (GSK-3β) inhibitor, , was rationally designed and synthesised to target Alzheimer's disease (AD). inhibited GSK-3β, with an IC of 0.35 ± 0.06 nM, a...Herein, a novel pyrrolo[2,3-]pyridine-based glycogen synthase kinase 3β (GSK-3β) inhibitor, , was rationally designed and synthesised to target Alzheimer's disease (AD). inhibited GSK-3β, with an IC of 0.35 ± 0.06 nM, and had an acceptable kinase selectivity for 24 structurally similar kinases. Western blotting assays indicated that efficiently increased the expression of p-GSK-3β-Ser9 and decreased p-tau-Ser396 levels in a dose-dependent manner. In vitro cell experiments, showed low cytotoxicity to SH-SY5Y cells, significantly upregulated the expression of β-catenin and neurogenesis-related biomarkers, and effectively promoted the outgrowth of differentiated neuronal neurites. Moreover, substantially ameliorated dyskinesia in AlCl-induced zebrafish AD models at a concentration of 0.12 μM, which was more potent than Donepezil (8 μM) under identical conditions. Acute toxicity experiments further confirmed the safety of in vivo. Our findings suggested that is a prospective GSK-3β inhibitor and can be tested as a candidate for treating AD.
Zhang XS, Liu JZ, Mei YY
… +2 more, Zhang M, Sun LW
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 39976248
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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 ) was designed and synt...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 ) was designed and synthesised by the molecular hybridisation strategy. It displays the potent antiproliferative activity against HepG2, HEP3B, HUH6, and HUH7 cells with IC values of 0.93, 2.09, 1.43, and 4.37 μM, respectively. Furthermore, compound is a selective and reversible LSD1 inhibitor with an IC 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 without obvious toxic effects. These interesting findings suggested that compound , a novel LSD1 inhibitor, may be a promising therapeutic agent to treat liver cancer.
Joushomme A, Désilets A, Champagne W
… +9 more, Hassanzadeh M, Lemieux G, Gravel-Trudeau A, Lepage M, Lafrenière S, Froehlich U, List K, Boudreault PL, Leduc R
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 39976239
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TMPRSS13, a member of the Type II Transmembrane Serine Proteases (TTSP) family, is involved in cancer progression and in respiratory virus cell entry. To date, no inhibitors have been specifically developed for this prot...TMPRSS13, a member of the Type II Transmembrane Serine Proteases (TTSP) family, is involved in cancer progression and in respiratory virus cell entry. To date, no inhibitors have been specifically developed for this protease. In this study, a chemical library of 65 ketobenzothiazole-based peptidomimetic molecules was screened against a proteolytically active form of recombinant TMPRSS13 to identify novel inhibitors. Following an initial round of screening, subsequent synthesis of additional derivatives supported by molecular modelling revealed important molecular determinants involved in TMPRSS13 inhibition. One inhibitor, N-0430, achieved low nanomolar affinity towards TMPRSS13 activity in a cellular context. Using a SARS-CoV-2 pseudovirus cell entry model, we further demonstrated the ability of N-0430 to block TMPRSS13-dependent entry of the pseudovirus. The identified peptidomimetic inhibitors and the molecular insights into their potency gained from this study will aid in the development of specific TMPRSS13 inhibitors.
Rivera Antonio AM, Padilla Martínez II, Torres-Ramos MA
… +1 more, Rosales-Hernández MC
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 39950933
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Alzheimer's disease (AD) is a major neurodegenerative disorder more common in older adults. One of the leading AD hypotheses involves the amyloid beta (A) production, it is associated to oxidative stress, neuroinflammati...Alzheimer's disease (AD) is a major neurodegenerative disorder more common in older adults. One of the leading AD hypotheses involves the amyloid beta (A) production, it is associated to oxidative stress, neuroinflammation, and neurovascular damage. The interaction of A with the blood vessel wall contributes to the disruption of the blood-brain barrier (BBB), allowing neutrophil infiltration containing the myeloperoxidase enzyme (MPO), which produces hypochlorous acid (HOCl) a potent oxidant. Also, MPO could be released from the microglia cells and interact with the amyloid beta plaques. This review aims to study the role of MPO in the progression of AD, in particular its contribution to oxidative stress and neuroinflammation. Furthermore, to explore the MPO-potential as AD-biomarker to evaluate the therapeutic potential of its inhibitors to mitigate the neurotoxicity. Finally, revise MPO inhibitors that could act as dual inhibitors acting on MPO and acetylcholinesterase and or another target involved in AD.
Wróbel TM, Grudzińska A, Yakubu J
… +6 more, du Toit T, Sharma K, Harrington JC, Björkling F, Jørgensen FS, Pandey AV
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 39950830
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Prostate cancer (PCa) is one of the most prevalent malignancies affecting men worldwide, and androgen deprivation therapy (ADT) is a primary treatment approach. CYP17A1 inhibitors like abiraterone target the steroidogeni...Prostate cancer (PCa) is one of the most prevalent malignancies affecting men worldwide, and androgen deprivation therapy (ADT) is a primary treatment approach. CYP17A1 inhibitors like abiraterone target the steroidogenic pathway to reduce androgen levels, but their clinical efficacy is limited by drug resistance and adverse effects. This study reports the synthesis and evaluation of novel CYP17A1 inhibitors derived from a previously identified hit compound. Several analogs were synthesised, including an unexpected di-cyano derivative, which demonstrated increased potency against CYP17A1 compared to abiraterone. Biological assays revealed that these compounds significantly inhibited CYP17A1 enzymatic activity and altered steroid biosynthesis. Among the newly synthesised inhibitors, compound showed the highest potency (IC = 4 nM) and the related compound presented a template for further development. A combined docking and molecular dynamics approach was used to identify the possible target binding modes of the compounds.
Zong K, Wei C, Li W
… +7 more, Wang C, Ruan J, Liu X, Zhang S, Yan H, Cao R, Li X
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 39936614
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The DENV-NS5 RNA-dependent RNA polymerase (RdRp) is essential for viral replication, and one of the targets of anti-virus. In this study, the Uni-VSW module was used to virtual screen 1.6 million compounds in the ChemDiv...The DENV-NS5 RNA-dependent RNA polymerase (RdRp) is essential for viral replication, and one of the targets of anti-virus. In this study, the Uni-VSW module was used to virtual screen 1.6 million compounds in the ChemDiv and TargetMol (USA) database, 27 candidates were obtained. Thereby 23 candidates were selected based on their binding free energies by 50 ns MD simulations. The biological activity of the candidates and the reference compounds ( and ) were evaluated on their IC values against DENV-NGC, CC values, and selectivity index. Among these, the IC values of and were 13.06 ± 1.17 μM and 14.79 ± 7.76 μM, respectively, which were better than that of (IC =19.67 ± 1.12 μM). The comprehensive MD simulations were performed on the candidates to assess the stability behaviour and binding mechanisms. The density functional theory (DFT) analysis was also conducted to explore the structural and electronic properties.
Wawruszak A, Luszczki J, Bartuzi D
… +4 more, Kalafut J, Okon E, Czerwonka A, Stepulak A
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 39935420
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Sirtuins (SIRTs) are NAD+-dependent histone deacetylases, which play a key role in cancer progression; however, their prognostic values in breast cancer (BC) remain a subject of debate and controversy. Accumulative evide...Sirtuins (SIRTs) are NAD+-dependent histone deacetylases, which play a key role in cancer progression; however, their prognostic values in breast cancer (BC) remain a subject of debate and controversy. Accumulative evidence suggests that each sirtuin possesses individual character, implicating its role in the regulation of multifaceted biological functions leading to BC initiation, progression and metastasis. Selisistat (EX527) is a potent, cell permeable, highly selective SIRT1 inhibitor. In the study, the tumour-suppressive effects of the SIRT1 inhibitor EX527 (selisistat) alone and in combination with paclitaxel (PAX) in different breast cancer cell lines and zebrafish xenograft models were investigated. The type of pharmacological drug-drug interaction between EX527 and PAX was determined using the isobolographic method. EX527 and PAX used individually inhibited proliferation, induced apoptosis and caused cell cycle arrest in G1 and subG1/G2 phases. Interestingly, the combination of these compounds used in the 1:1 dose-ratio augmented all these effects (IC 29.52 ± 3.29 - 38.45 ± 5.26). The co-treatment of EX527 with PAX generated desirable additive drug-drug interaction. The simultaneous application of EX527 and PAX induced a stronger inhibition of tumour growth compared to individual treatments in zebrafish xenografts. analysis revealed a protein-protein interaction pathway (SIRT1-AKT-S1PR1-GNAI1/GNAO1-Tubulin) connecting molecular targets of both ligands. To summarise, the combination of EX527 and PAX more effectively impairs breast cancer cell growth compared to individual treatments. However, further investigations are required to clarify the specific targets and molecular mechanisms underlying the activity of EX527:PAX in other preclinical models.
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 39912419
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Turcz. is a traditional medicinal plant with a wide range of ethnomedicinal values. The main components of essential oil (EO) were β-pinene (15.41%), β-phellandrene (12.43%), and caryophyllene (7.79%). The EO of showed...Turcz. is a traditional medicinal plant with a wide range of ethnomedicinal values. The main components of essential oil (EO) were β-pinene (15.41%), β-phellandrene (12.43%), and caryophyllene (7.79%). The EO of showed antioxidant activity against ABTS radical and DPPH radical with an IC value of 0.69 ± 0.03 mg/mL and 10.44 ± 2.09 mg/mL, respectively. The FRAP antioxidant value was 81.96 ± 6.17 μmol/g. The EO had activities against acetylcholinesterase, α-glucosidase, and β-lactamase with IC values of 309.30 ± 11.16 μg/mL, 360.47 ± 35.67 μg/mL, and 27.54 ± 1.21 μg/mL, respectively. Molecular docking showed methyl dehydroabietate docked well with all tested enzymes. Sclareol and (+)-borneol acetate showed the strongest binding affinity to α-glucosidase and β-lactamase, respectively. The present study provides a direction for searching enzyme inhibitors for three tested enzymes and shows EO possesses the potential to treat a series of diseases.
Yuan D, Gao Y, Xia L
… +9 more, Liu H, Wu X, Ding X, Huang Y, Deng C, Li J, Dai W, Liu J, Ma J
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 39912413
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Herein, we firstly reported a series of biphenyl compounds bearing hydroxamic acid moiety as PD-L1/class I HDACs dual inhibitors. Among them, compound displayed the strongest inhibitory activity against HDAC2 and HDAC3...Herein, we firstly reported a series of biphenyl compounds bearing hydroxamic acid moiety as PD-L1/class I HDACs dual inhibitors. Among them, compound displayed the strongest inhibitory activity against HDAC2 and HDAC3 with IC values of 27.98 nM and 14.47 nM, and had an IC value of 88.10 nM for PD-1/PD-L1 interaction. Importantly, could upregulate the expression of PD-L1 and CXCL10 in a PD-L1 low-expression cancer cell line (MCF-7), highlighting the potential to enhance efficacy by recruiting T-cell infiltration into TME and improving the response of PD-1/PD-L1 inhibitor associated with PD-L1 low-expression. Besides, we identified another compound, , which possessed the strongest inhibitory activity against PD-1/PD-L1 interaction with an IC value of 12.47 nM, and effectively inhibited the proliferation of three cancer cell lines. Our results suggest that compounds and can be served as lead compounds of PD-L1/class I HDACs dual inhibitors for further optimisation.
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 39912405
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Peptidomimetic inhibitors mimic natural peptide substrates, employing electrophilic warheads to covalently interact with the catalytic Cys145 of M. Examples include aldehydes, α-ketoamides, and aza-peptides, with discuss...Peptidomimetic inhibitors mimic natural peptide substrates, employing electrophilic warheads to covalently interact with the catalytic Cys145 of M. 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.
Phong NV, Kim HS, Zhao Y
… +2 more, Yeom E, Yang SY
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 39840826
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This study investigated the potential of the indirubin-3'-oxime (I3O) compound to mitigate temperature-induced male infertility in . Elevated temperatures significantly reduced egg-hatching rates, but I3O supplementation...This study investigated the potential of the indirubin-3'-oxime (I3O) compound to mitigate temperature-induced male infertility in . Elevated temperatures significantly reduced egg-hatching rates, but I3O supplementation improved these rates, suggesting it can partially restore fertility under heat stress. Additionally, I3O was found to inhibit soluble epoxide hydrolase (sEH), an enzyme involved in the metabolism of epoxyeicosatrienoic acids, which are vital for reproductive health. I3O exhibited sEH inhibitions with an IC value of 59.74 ± 0.41 µM. Enzyme kinetics revealed that I3O acts as a non-competitive inhibitor of sEH with a value of 78.88 µM. Molecular docking showed strong interactions between I3O and key residues in the allosteric regions within the sEH enzyme, with a binding affinity of -9.2 kcal/mol. These interactions were supported by 100 ns molecular dynamics simulations, which confirmed the stability of the sEH-I3O complex.
Caputo A, Elisi GM, Levati E
… +7 more, Barotti G, Sartini S, Wagner J, Burnouf DY, Ottonello S, Rivara S, Montanini B
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 39749973
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Antibiotic resistance stands as the foremost post-pandemic threat to public health. The urgent need for new, effective antibacterial treatments is evident. Protein-protein interactions (PPIs), owing to their pivotal role...Antibiotic resistance stands as the foremost post-pandemic threat to public health. The urgent need for new, effective antibacterial treatments is evident. Protein-protein interactions (PPIs), owing to their pivotal role in microbial physiology, emerge as novel and attractive targets. Particularly promising is the α-subunit/β-sliding clamp interaction, crucial for the replicative competence of bacterial DNA polymerase III holoenzyme. Through pharmacophore-based virtual screening, we identified 4,000 candidate small molecule inhibitors targeting the β-clamp binding pocket. Subsequently, these candidates underwent evaluation using the BRET assay in yeast cells. Following this, three hits and 28 analogues were validated via Protein Thermal Shift and competitive ELISA assays. Among them, thiazolo[4,5-]-pyrimidinedione and benzanilide derivatives exhibited micromolar potency in displacing the β-clamp protein partner and inhibiting DNA replication. This screening campaign unveiled new chemical classes of α/β-clamp PPI disruptors capable of inhibiting DNA polymerase III activity, which lend themselves for further optimisation to improve their antibacterial efficacy.
Trotsko N, Głogowska A, Kaproń B
… +3 more, Kozieł K, Augustynowicz-Kopeć E, Paneth A
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 39749402
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The ever-increasing drug-resistant tuberculosis (TB) has invigorated the focus on the discovery and development of novel therapeutic agents and treatment options. Thiazolidinone-based compounds have shown good antituberc...The ever-increasing drug-resistant tuberculosis (TB) has invigorated the focus on the discovery and development of novel therapeutic agents and treatment options. Thiazolidinone-based compounds have shown good antitubercular properties . Here, we report the design and synthesis of a number of new derivatives inspired by the structure of thiazolidine-2,4-dione (TZD). The TZD-based hybrids with the thiosemicarbazone or the pyridinecarbohydrazone moiety were synthesised and their antimycobacterial activity was investigated against the reference HRv and two wild () strains. In further studies, a two-drug interaction analysis was also performed for assessing their synergism with the current first-line drugs used for the treatment of TB. It was found that some of the compounds showed high antimycobacterial activity with MICs (0.078-0.283 µM) and a synergistic effect with isoniazid or rifampicin, thereby demonstrating their potential as a promising scaffold for the development of novel coadjuvants for the effective treatment of TB.