We synthesised coumarin-based derivatives bearing thio- and selenocyanates to selectively inhibit tumour-associated carbonic anhydrases (CAs) IX and XII and to exert antiproliferative effects on tumour cells. Structural variations included chalcogen atom type (S, Se), substitutions at C-3/C-4, and tether length at C-7 of the coumarin core. Thiocyanates and showed potent CA IX/XII inhibition ( = 17.9-27.4 nM) with >5000-fold selectivity over off-target isoforms (CAs I and II). Selenocyanate exhibited strong antiproliferative activity (GI = 0.78-2.6 µM) across six human solid tumour cell lines. Mechanistic studies revealed a cytostatic effect cell cycle arrest and reduced mitotic progression. assays in confirmed selective cytostatic action of selenocyanate , reducing tumorous germline size without affecting healthy tissues at therapeutic doses.

Inhibition of the Keap1-Nrf2 protein-protein interaction with cyclic peptides represents an attractive strategy to treat inflammation. However, the cyclic peptides for this inhibition are constrained by their low affinity. In this study, the peptides 1-6 were computationally screened using Keap1-pharmacophore modelling, toxicity screening, molecular docking, and interaction analysis. Subsequently, affinity experiments showed that peptide-4 exhibited potent binding affinity for Keap1 ( = 7.1 ± 0.2 nM). MD simulations further demonstrated that peptide-4 stably bound to Keap1. Additionally, MTT assays confirmed that peptides 1-6 induced negligible cytotoxicity in RAW264.7 macrophages. anti-inflammatory experiments indicated that peptide-4 significantly inhibited the mRNA and protein expression of IL-6 and TNFα in LPS-induced RAW264.7 cells. More importantly, experiments in Keap1-knockout RAW264.7 macrophages confirmed that the anti-inflammatory activity of peptide-4 was highly Keap1-dependent. In conclusion, the data demonstrated that the peptide-4 may be a promising candidate cyclic peptide to treat inflammatory disease.

A series of 1, 3-dioxo-phenylisoindoline-5-carboxamide derivatives were designed, synthesised and evaluated as potent human monoamine oxidase B (MAO-B) inhibitors with neuroprotective properties. The structure-activity relationship (SAR) was summarised. The most potent compound identified in the study, compound , exhibited significant MAO-B inhibition (IC = 0.011 μM) and remarkable selectivity (selectivity index > 3636) over MAO-A. Kinetic analysis confirmed that compound acted as a mixed-type, reversible MAO-B inhibitor. Molecular docking studies provided insights into the interactions between the inhibitor and the enzyme. In cellular assays, compound significantly reduced the production of nitric oxide (NO) and tumour necrosis factor-alpha (TNF-α) in lipopolysaccharide (LPS)-stimulated BV-2 cells. Additionally, compound also exhibited notable antioxidant activity. These findings suggested that compound could be developed as a promising lead for further investigation.

Thioredoxin reductase 1 (TrxR1), a selenoprotein enzyme crucial for redox homeostasis in mammals, has emerged as a promising target for anticancer therapy. In this study, we present a non-covalent TrxR1 inhibitor, identified through an integrated experimental and computational approach. After identifying a plausible druggable cavity, a molecular docking-based virtual screening of over 90,000 lead-like compounds was performed. The selected compounds were evaluated for their impact on TrxR1 activity, leading to the identification of the most promising candidate, . The identified compound, already proven to be free from potential ADMET concerns, inhibits TrxR1 in a dose-dependent manner, with an IC value in the micromolar range. C55's activity was confirmed across multiple cancer cell lines, including HepG2, Huh7, MCF-7, and MDA-MB-231 cells. As a metal-free organic molecule capable of non-covalently inhibiting TrxR1, C55 represents a significant breakthrough, offering a solid foundation for hit-to-lead optimisation and the development of new anticancer drug candidates.

Two edaravone derivatives were synthesised and characterised by using several spectral and analytical techniques. The antioxidant activities of these organic compounds were analysed by using HPSA, DPPH and ABTS·+ assays. Anti-inflammatory property of the synthesised derivatives was analysed by evaluating albumin denaturation inhibition abilities. Optical energy band gaps were evaluated using the Tauc plots. Computational method was used to analyse the frontier molecular orbitals of the compounds and MEP surface analysis was used to identify the nucleophilic and electrophilic attacking sites. Owing to the higher antioxidant potential the interaction of the compound with the protein Tyrosinase (isolated from the bacterium, ) was investigated using detailed molecular docking and simulation methods. Compound exhibited higher free radical scavenging activity, good anti-inflammatory property and found to effectively bind to the Tyrosinase protein. These derivatives have potential application in the production of improved antioxidant and anti-inflammatory agents as well as cosmeceuticals.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is crucial in regulating inflammation, apoptosis, and necroptosis. Accumulating evidence highlights RIPK1 as a promising therapeutic target for various human diseases, including neurodegenerative disorders, autoimmune diseases, and cancer. In tumour cells, RIPK1 suppresses immunogenic cell death, promotes an immunosuppressive tumour microenvironment, which facilitates immune evasion, metastatic progression, and therapeutic resistance, contributing to an immunologically cold tumour phenotype. Therefore, targeting RIPK1 represents a promising therapeutic approach to overcome immune checkpoint blockade resistance and convert tumours into an immunologically hot phenotype. In this review, we summarise the biological functions of RIPK1 and elaborate on its roles in cancer progression in terms of the tumour immune microenvironment, tumour metastasis, and chemoresistance. Furthermore, we enumerate several identified RIPK1-targeted inhibitors with potential for cancer therapy. Although RIPK1 has been proposed as a potential anticancer target, there are still great opportunities and challenges that require further investigation.

LIMK1 has been demonstrated to be highly correlated with the progression and overall survival rates of colorectal cancer (CRC) patients. In this study, a series of diarylheptanoid scaffold derivatives were intentionally designed and synthesised to evaluate their potential as LIMK1 inhibitors. Among these compounds, compounds and exhibited LIMK1 inhibitory activity with IC values of 0.94 and 0.57 µM, respectively. We also disclosed the structure-activity relationship of the resulting compounds that exhibited LIMK1 inhibition. Catechol-containing diarylheptanoid was identified as a promising scaffold for LIMK1 inhibitors. Notably, compound demonstrated selectivity in inhibiting the tyrosine kinase-like family and exhibited potent inhibition of CRC cells. Moreover, compound induced an increase in the S phase and a decrease in the G0/G1 phase in a dose-dependent manner, indicating apoptosis induction. These findings establish compound as a lead compound for the further development of anti-CRC agents.

The soluble epoxide hydrolase (sEH) has recently emerged as a promising target for the treatment of several pain-related conditions. Herein, we report the design and synthesis of a peripherally restricted sEH inhibitor with high potency and good Drug Metabolism and Pharmacokinetics (DMPK) properties. Molecular dynamics and X-ray crystallography helped reveal the binding of these inhibitors to sEH. The selected compound showed a robust analgesic effect in a dose-dependent manner in a murine model of chemotherapy-induced neuropathic pain (CINP). Moreover, the compound also prevented the development of paclitaxel-induced neuropathic pain. Overall, these results suggest that peripheral inhibition of sEH might constitute a novel therapy to prevent and treat CINP.

Angiogenesis is pivotal for cancer growth and metastasis, as tumours rely on new blood vessels to progress and spread. Antiangiogenic drugs represent a crucial therapeutic strategy that combats cancer by both obstructing the development of new blood vessels and disrupting existing tumour-associated vasculature. Recently, significant advancements have been made in antiangiogenic cancer therapies, as evidenced by the extensive literature covered in this review. Numerous novel angiogenesis inhibitors have been reported to exhibit significant efficacy: they not only suppress cancer metastasis and angiogenesis but also induce cancer cell apoptosis via multiple distinct mechanisms. This review comprehensively updates (2014-2025) small molecule angiogenesis inhibitors' design and structure-activity relationship (SAR), integrating latest developments. By systematically analysing the mechanisms of action and distinctive characteristics of these compounds, we aim to offer valuable insights and references to guide the ongoing development of next-generation anti-cancer agents targeting angiogenesis.

The excessive synthesis of melanin leads to skin hyperpigmentation. While tyrosinase activity inhibition has demonstrated efficacy in ameliorating hyperpigmentation, its effectiveness remains limited, and tyrosinase inhibitors may induce irritant contact dermatitis. Therefore, there is an imperative need to develop safer and more potent anti-pigmentation agents. Melanin transfer inhibition represents a novel therapeutic strategy for treating hyperpigmentation. This review systematically elucidates the complete process of melanin transfer and its underlying mechanisms. Furthermore, it provides a comprehensive analysis of natural products and small molecule compounds with melanin transfer-inhibiting capabilities, potential compounds that may exhibit anti-pigmentation effects, as well as the binding modes and structure-activity relationships (SARs) of representative compounds. The presented evidence is crucial for identifying and developing novel, highly effective anti-pigmentation medications.

This study presents the first comprehensive phytochemical analysis of var. leaves, resulting in the isolation of 41 secondary metabolites, including four new compounds: one phenolic () and three bis-iridoid glycosides (-). The inhibitory activities of these compounds against PTP1B and α-glucosidase were evaluated. Among them, compound exhibited the most potent dual inhibition, with IC values of 8.0 ± 1.1 µM for PTP1B and 3.4 ± 0.2 µM for α-glucosidase. Compounds and showed notable α-glucosidase inhibitory activity, with IC values of 21.9 ± 0.4 µM and 43.8 ± 2.1 µM, respectively. Enzyme kinetics and molecular docking studies revealed their inhibition mechanisms and binding interactions. This study is the first detailed phytochemical investigation of var. and highlights its potential as a natural source of PTP1B and α-glucosidase inhibitors. These findings underscore the plant's promise for developing antidiabetic agents targeting PTP1B and α-glucosidase.

Microtubules, composed of tubulin subunits, represent a critical target in anticancer drug discovery. The design and evaluation of small-molecule inhibitors targeting tubulin polymerisation continue to hold significant promise for advancing cancer therapeutics. Based on structural insights into tubulin polymerisation inhibitors and tubulin interaction models, a novel series of 3-aryl-4-(3,4,5-trimethoxyphenyl)selenophene derivatives were designed as potential tubulin polymerisation inhibitors. Among the synthesised analogs, compound , featuring a selenophene linker, demonstrated superior antiproliferative activity against Huh7, MCF-7, and SGC-7901 cancer cell lines, with IC values slightly lower than those of combretastatin A-4 (CA-4). Structure-activity relationship studies revealed that electron-donating substituents at the para-position of the B-ring significantly enhanced cytotoxic potency. Mechanistic studies revealed that compound effectively inhibited tubulin polymerisation, disrupted microtubule networks, induced G2/M cell cycle arrest, and triggered apoptosis in cancer cells. These results underscore the potential of incorporating selenophene into the CA-4 scaffold as a promising strategy for developing potent tubulin polymerisation inhibitors, offering new avenues for cancer therapy.

The environmental pollutant benzo[a]pyrene (BaP) can induce cytochrome P450 family 1 subfamily A (CYP1A) or generate metabolic products that disrupt the balance of oxidative stress, triggering inflammatory responses in the lungs and leading to tissue damage. Flavonoids, known for their natural anti-inflammatory and antioxidant properties, are potential targets for intervention. This study used phenacetin, a specific substrate probe for CYP1A, to evaluate the inhibitory effects of 40 flavonoids on CYP1A. Structure-activity relationship analysis revealed that introducing hydroxyl groups at positions 3- and 6-enhances CYP1A inhibition. Notably, 3,6-dihydroxyflavone (DHF) emerged as a significant inhibitor of CYP1A. In vitro experiments confirmed that DHF effectively inhibits BaP-induced cytochrome P450 family 1 subfamily A member 1 (CYP1A1) in airway epithelial cells and shows dose-dependent inhibition of intracellular and mitochondrial reactive oxygen species (ROS) production. In summary, DHF is a promising CYP1A inhibitor and a potential anti-inflammatory candidate for preventing and treating CYP1A-mediated lung diseases.

The constant emergence of SARS-CoV-2 resistance drives the search for new antivirals. We screened the SARS-CoV-2 cysteine proteases, the main protease (M) and papain-like protease (PL), with 141 peptidyl and peptidomimetic inhibitors designed to target a trypanosome cysteine protease. Five compounds (-) inhibited M (IC of 0.1601-16.42 µM), whereas none inhibited PL. Compounds - inhibited human cathepsin L (hCatL; 0.184-10.74 µM), which is important for viral entry into human cells. Compounds and , and its synthesised (R,S) enantiomer, , which share a benzyl carbamate moiety, inhibited the M of SARS-CoV/MERS-CoV (0.0732-0.8295 µM). The three compounds were biochemically characterised as covalent reversible inhibitors. Compounds and , which contain vinyl ketone warheads, were specific for M, and this behaviour was supported by covalent and noncovalent computational simulations. This study highlights the importance of revisiting legacy assets to identify starting points for new antiviral drugs.

ABSTRRACTAlpha-glucosidase inhibitors have been considered as the most effective agents in preventing hyperglycaemia and alternative targets for the treatment of Diabetes mellitus (DM). This study aimed to synthesise novel phenyl carbamoyl methoxy thiosemicarbazone derivatives and evaluate their potential as α-glucosidase inhibitors through biochemical assays, cytotoxicity screening, molecular docking, and molecular dynamics simulations. The tested derivatives exhibited a range of inhibitory potential, from moderate to strong as compared to acarbose. Derivative 7e revealed the least IC50 value among the tested compounds. 7e in the kinetic assay acted as a competitive inhibitor of the α-glucosidase. The cytotoxic effect 7e was assessed against the A549 and MDA-MB-453 cell lines. MD simulation revealed that could affect the stability, flexibility, thermodynamics, and structure of α-glucosidase enzymes such as acarbose. Compound 7e demonstrates strong α-glucosidase inhibitory activity with low cytotoxicity in both cell lines, underscoring its potential as a lead candidate for antidiabetic drug development.

Targeted cancer drug therapy has emerged as a critical treatment modality for advanced hepatocellular carcinoma (HCC). The discovery and development of novel anti-HCC drug therapeutics with improved pharmacological properties remains an urgent priority in oncology drug discovery. In this study, we designed and synthesised a new series of 1,2,3-triazole-cored structures incorporating aryl urea. Fifteen analogs were prepared nucleophilic addition and copper-catalyzed azide-alkyne cycloaddition (CuAAC) with excellent yields. These synthesised compounds were evaluated for their potential antitumor activities. Notably, compounds and exhibited the lowest IC values (10.80 ± 0.14 and 11.62 ± 3.72 μM) against HuH-7 cells. Further investigations suggested compound and induced cell apoptosis, stimulated DNA damage, and autophagy against HuH-7 cells. Acute toxicity measurement also demonstrated the safety of the compounds. These findings suggested the triazole-cored analogs and are suggested to be promising candidates for the treatment of HCC and their potential for further pharmaceutical development.

HCC is a highly lethal cancer characterised by significant sorafenib resistance, leading to poor patient outcomes. Recent studies have suggested that MED8 plays a role in enhancing tumour resistance to drugs, but its role in drug resistance in HCC has not yet been reported. This study found significantly higher MED8 expression in HCC tissues compared to adjacent noncancerous tissues. Increased MED8 expression in HCC correlates with poorer overall survival. Functional assays demonstrated that reduced MED8 expression inhibited HCC cell proliferation and epithelial-mesenchymal transition, promoted apoptosis, and increased sensitivity to sorafenib. Overexpression of MED8 elevated TRIP4 protein levels. TRIP4 overexpression negated the effects of MED8 knockdown, whereas TRIP4 suppression inhibited MED8-driven EMT. Mechanistically, MED8 interacts with TRIP4, reducing its ubiquitination and stabilising TRIP4 protein levels. Our findings indicate that the MED8-TRIP4 axis plays a role in sorafenib resistance in HCC and could serve as a therapeutic target for HCC treatment.

Spinal cord injuries (SCIs) cause irreversible damage and lasting neurological impairments. Current treatments are limited to surgical and pharmaceutical interventions, underscoring the need for novel agents. In this study, 27 novel pyrazole derivatives were designed, synthesised. The anti-inflammatory and antioxidant activities of the compounds were systematically evaluated utilising lipopolysaccharide-stimulated BV2 microglial cells. Anti-inflammatory activity was assessed by quantifying the mRNA expression levels of key pro-inflammatory cytokines [tumour necrosis factor-α, interleukin-1β, and interleukin-6 (IL-6)] via quantitative reverse transcription polymerase chain reaction. Among the synthesised derivatives, compound demonstrated the most potent anti-inflammatory effect, exhibiting an IC value of 9.562 μM for the suppression of IL-6 expression and no significant cytotoxicity was observed. Notable, compound exhibited better inhibitory potency against IL-6 expression compared to the anti-inflammatory drugs dexamethasone and Celecoxib. These findings strongly support the potential of compound as a promising therapeutic candidate for mitigating secondary inflammation in SCI.

Protein kinase CK2 is a promising therapeutic target, and this study explores 54 aurone derivatives as potential CK2 inhibitors. Activity was evaluated using luminescent and capillary electrophoresis assays, identifying 17 compounds with submicromolar activity. The most potent inhibitors shared key structural features: a benzo group on the A-ring, a hydrogen bond acceptor at the R4' position, and an additional substituent at the R3' position of the B-ring. Molecular docking revealed similar binding modes among active compounds, with interactions involving Leu45, Val53, Val66, Met163, Phe113, Lys68, and Ile174. Notably, BFO25 showed the highest activity (IC = 3 nM at 100 μM ATP). These findings highlight aurones as promising CK2 inhibitors and emphasise the significance of specific structural features.

Glioblastoma multiforme (GBM) is a highly aggressive brain tumour with few effective treatment options. This study evaluated two novel triazine-based sulphonamides, MM118 and MM119, for their anticancer effects on GBM cells. cell viability assays showed that both compounds were highly potent, killing GBM cells at low-micromolar concentrations. They induced apoptosis in cancer cells, evidenced by Annexin V/PI staining and caspase-3/7 activation. Both the intrinsic and extrinsic apoptosis pathways were engaged, as shown by mitochondrial depolarisation along with caspase-9 and caspase-8 activation. The compounds also increased reactive oxygen species levels, further promoting apoptosis. Notably, MM118 and MM119 triggered pyroptosis - an inflammatory form of cell death - indicated by caspase-1 activation and NF-κB translocation. In a zebrafish xenograft model, both compounds significantly reduced tumour growth. These findings highlight MM118 and MM119 as promising candidates for GBM therapy that may overcome resistance by engaging multiple cell-death pathways.