Liao BZ, Tan QM, Li YL
… +3 more, Wang YX, Kong LY, Luo JG
Bioorg Med Chem Lett
· 2026 Sep · PMID 42167553
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Activation of nuclear factor erythroid-2-related factor 2 (NRF2) has been proven to be an effective means to prevent the development of inflammatory diseases. In this study, series of trolline derivatives (4 -25) were de...Activation of nuclear factor erythroid-2-related factor 2 (NRF2) has been proven to be an effective means to prevent the development of inflammatory diseases. In this study, series of trolline derivatives (4 -25) were designed and synthesized as potential anti-inflammatory agents. Among them, compound 5 showed the best activity, with an IC₅₀ value of 7.86 μM, by evaluation of the inhibition of NO production in LPS-stimulated RAW264.7 macrophages. Chiral separation of compound 5 further gave 5-S and 5-R, and 5-S proved to be the more active enantiomer in the NO assay (IC₅₀ = 5.89 μM), while 5-R was less active (IC₅₀ = 13.71 μM). Moreover, 5-S significantly reduced the production of TNF-α, IL-1β, and IL-6 in LPS-stimulated RAW264.7 cells. Western blot analysis showed that 5-S increased Nrf2 expression and promoted its nuclear translocation, accompanied by upregulation of the downstream target proteins HO-1 and NQO1. These results suggest that the anti-inflammatory effect of 5-S is associated with activation of the Nrf2 pathway. Overall, 5-S may serve as a potential lead for further development of trolline-based anti-inflammatory agents.
Bioorg Med Chem Lett
· 2026 Sep · PMID 42167552
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4-Phenylbutyric acid (4-PBA) is clinically used for the treatment of urea cycle disorders and has attracted increasing attention due to its ability to modulate endoplasmic reticulum stress through its dual function as a...4-Phenylbutyric acid (4-PBA) is clinically used for the treatment of urea cycle disorders and has attracted increasing attention due to its ability to modulate endoplasmic reticulum stress through its dual function as a chemical chaperone and histone deacetylase (HDAC) inhibitor. In addition to its effects on HDACs, 4-PBA also inhibits pyruvate dehydrogenase kinases (PDKs) and enhances mitochondrial respiration in cancer cells. In this work, a series of novel polyol-based 4-PBA derivatives were designed as potential prodrugs, inspired by the clinically used glycerol phenylbutyrate. Sorbitol, xylitol, and erythritol were fully esterified at all hydroxyl groups with 4-PBA under optimized conditions, affording the corresponding derivatives in high yields (≈85-91%). Structural characterization was confirmed by NMR spectroscopy and high-resolution mass spectrometry (HRMS). Preliminary enzymatic hydrolysis studies using porcine pancreatic lipase were conducted on sorbitol phenylbutyrate as a representative liquid, oily polyol derivative. This compound exhibited significantly slower hydrolysis than glycerol phenylbutyrate, suggesting a sustained-release profile. In contrast, the erythritol derivative, due to its highly crystalline nature, failed to form an enzyme-accessible phase in simulated intestinal fluid, precluding enzymatic evaluation and indicating a potential dissolution-limited release mechanism.
Bioorg Med Chem Lett
· 2026 Sep · PMID 42167551
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pH-labile linkers have garnered significant attention in biomedical applications, particularly in designing the stimuli-responsive carriers for targeted drug delivery systems. In the present work, we have synthesized G-m...pH-labile linkers have garnered significant attention in biomedical applications, particularly in designing the stimuli-responsive carriers for targeted drug delivery systems. In the present work, we have synthesized G-monoacrylate from G-diacrylate using a chemoenzymatic approach, followed by the synthesis of glycerol-based β-thiopropionate esters containing an acid-labile β-thiopropionate linker. The β-thiopropionate esters were obtained via a solvent-free Michael addition reaction between hydrophobic thiol and hydrophilic G-monoacrylate. The reaction conditions and purification by simple solvent extraction, without the need for sophisticated chromatographic techniques, provide a significant advantage for potential biomedical and other applications. The resulting β-thiopropionate esters hold significant potential for biomedical applications, particularly in the encapsulation and controlled release of hydrophobic therapeutics in acidic microenvironments.
Karamtoth S, Ramakrishna M, Sule SA
… +4 more, Shaik BB, Alli VJ, Ummanni R, Jadav SS
Bioorg Med Chem Lett
· 2026 Sep · PMID 42162747
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Immune Checkpoint Inhibitors (ICIs) targeting the PD-1/PD-L1 axis have improved the clinical outcomes and revolutionized oncology treatment. However, monoclonal antibody (mAb)-based ICIs are limited by high production an...Immune Checkpoint Inhibitors (ICIs) targeting the PD-1/PD-L1 axis have improved the clinical outcomes and revolutionized oncology treatment. However, monoclonal antibody (mAb)-based ICIs are limited by high production and treatment cost, poor oral bioavailability, limited tumor penetration, and immune-related adverse effects. To address this, here we have designed, synthesized, and evaluated a series of new thiazole-biphenyl-containing small molecules (15a-j, 16a-n, and 17a-y) targeting the PD-1/PD-L1 interface. Among all, compounds 17t and 17h were identified as potential PD-1/PD-L1 inhibitors, restoring T-cell signalling with EC values of 513 nM and 215 nM in a cell-based PD-1/PD-L1 blockade functional assay. Isothermal titration calorimetry (ITC) confirmed direct binding of both compounds to PD-L1, with 17h exhibiting stronger affinity (Kd = 1.43 μM) compared to 17t (Kd = 19.8 μM). Consistently, competitive PD-1/PD-L1 ELISA demonstrated dose-dependent disruption of the interaction, with 17h showing higher potency (EC₅₀ = 6.06 μM) than 17t (EC₅₀ = 23.83 μM), confirming effective target engagement. Further, co-culture cytokine induction assay involving MDA-MB-231 and activated PBMCs demonstrated the robust upregulation of pro-inflammatory cytokines (IFN-γ, IL-1α, IL-1β) and the cytolytic protein (perforin), suggesting an effective rescue of the small molecule-mediated T-cell exhaustion. The T-cell cytotoxicity assay revealed that 17t and 17h enhanced T-cell-mediated lysis of cancer cells without intrinsic cytotoxicity against MDA-MB-231 cells, confirming a selective immunomodulatory effect. In addition, structure-based molecular simulations of 17t and 17h revealed a key π-π interaction with Y56, as well as hydrogen bonding with the Y123 and I116 residues of the PD-L1 dimer.
Shen C, Zhou Y, Shen X
… +4 more, Zhou Y, Xiong B, Yang D, Liu T
Bioorg Med Chem Lett
· 2026 Sep · PMID 42142713
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The apelin receptor (AplnR) is a prominent peptide-binding Class A G protein-coupled receptor (GPCR) involved in the regulation of cardiovascular, gastrointestinal, and immune functions, as well as skeletal development....The apelin receptor (AplnR) is a prominent peptide-binding Class A G protein-coupled receptor (GPCR) involved in the regulation of cardiovascular, gastrointestinal, and immune functions, as well as skeletal development. Activation of the AplnR-mediated β-arrestin pathway has been associated with adverse effects including pathological cardiac hypertrophy and heart failure. Therefore, the development of G protein-biased small-molecule agonists is expected to provide an improved safety profile for long-term therapeutic use. In this study, a series of 1H-1,2,4-triazole-3-carboxamide derivatives were designed and synthesized as small-molecule AplnR agonists. Among them, the most promising compound B-007 exhibited potent agonist activity with an EC value of 11.6 nM. Notably, compared with an endogenous ligand apelin-13, B-007 demonstrated a pronounced G protein bias with abolished β-arrestin signaling. These results identified a new promising scaffold for the development of G protein-biased agonists.
Mesías-Salazar A, Nogueda-Torres B, Gómez R
… +6 more, Rivera G, Castillo-Velázquez U, Becerra NA, Pereira A, Trofymchuk OS, Vázquez K
Bioorg Med Chem Lett
· 2026 Sep · PMID 42140326
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Chagas disease remains a major public health concern, and the limited efficacy and safety of current therapies underscore the need for new antitrypanosomal agents. In this study, a series of guanidine and bisguanidine de...Chagas disease remains a major public health concern, and the limited efficacy and safety of current therapies underscore the need for new antitrypanosomal agents. In this study, a series of guanidine and bisguanidine derivatives were evaluated for their trypanocidal activity against Trypanosoma cruzi NINOA and INC-5 strains, as well as for their cytotoxicity on J774 murine macrophages. An initial screening at 12.5 μg/mL identified several compounds with activity comparable to the reference drugs nifurtimox and benznidazole, prompting the determination of LC values. Among the tested derivatives, compounds 2d, 2e, and 2f exhibited superior potency against both T. cruzi strains, with compound 2e emerging as the most active. Structure-activity analysis revealed that the incorporation of two iodine atoms into the bisguanidine scaffold significantly enhanced trypanocidal activity, in agreement with previous reports on biologically active bisguanidines. Despite their promising antiparasitic potency, the most active compounds also displayed notable cytotoxicity and limited selectivity profile, highlighting the need for further optimization. Overall, these findings support guanidine- and bisguanidine-based scaffolds as promising leads for antitrypanosomal drug development, while emphasizing the importance of continued structure-activity relationship studies to improve selectivity and safety.
Kalakwade A, Kavalapure RS, Gharge S
… +6 more, Gudasi S, Ranade SD, Alegaon SG, Ramu R, Prashantha Kumar BR, Manu G
Bioorg Med Chem Lett
· 2026 Sep · PMID 42134498
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A new library of quinoline-based hydrazone analogues (7a-7j) was designed and synthesized to evaluate their potential as multifunctional antidiabetic agents. In contrast to earlier quinoline derivatives primarily develop...A new library of quinoline-based hydrazone analogues (7a-7j) was designed and synthesized to evaluate their potential as multifunctional antidiabetic agents. In contrast to earlier quinoline derivatives primarily developed for single-enzyme inhibition, the present series incorporates a quinoline scaffold with a thiocarbohydrazide-derived hydrazone linker and diverse aryl/heteroaryl substituents to investigate a multitarget profile involving α-glucosidase, α-amylase, and PPAR-γ. Biological evaluation showed low-micromolar inhibitory activity against key carbohydrate-metabolizing enzymes. Compounds 7e and 7h exhibited the most potent α-glucosidase inhibition (IC: 18.55 ± 2.34 and 20.73 ± 0.37 μM, respectively), with activity comparable to acarbose (IC: 16.53 ± 0.39 μM). Compound 7g showed the strongest α-amylase inhibition (IC: 7.85 ± 1.92 μM). In addition, compounds 7b and 7f significantly enhanced PPAR-γ transcriptional activity in L6 myotubes, suggesting potential insulin-sensitizing effects. Molecular docking and molecular dynamics simulations supported stable ligand-protein interactions with key catalytic residues across all targets. In silico ADMET analysis indicated acceptable permeability and oral absorption; however, moderate lipophilicity and limited aqueous solubility of some analogues may require further optimization. Overall, these findings highlight quinoline-based hydrazones as promising multitarget scaffolds for further in vivo evaluation.
Hao S, Jiang Y, Chen Q
… +7 more, Zhang Q, Zhang Y, Sriwongta S, Vajragupta O, Rojsitthisak P, Yang Z, Zhu H
Bioorg Med Chem Lett
· 2026 Sep · PMID 42119829
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The immune checkpoint programmed ligand 1 (PD-L1) is expressed in various solid tumors and is associated with immunotherapy prognosis. Dynamic assessment of PDL1 expression levels helps identify patients who may benefit...The immune checkpoint programmed ligand 1 (PD-L1) is expressed in various solid tumors and is associated with immunotherapy prognosis. Dynamic assessment of PDL1 expression levels helps identify patients who may benefit from immunotherapy. Atezolizumab is a monoclonal antibody that targets PD-L1 and is used in the treatment of various hematologic malignancies and solid tumors. However, research on colon cancer is lacking. Approximately 85% of colorectal cancer (CRC) patients have the MSS/pMMR (Microsatellite Stable/proficient Mismatch Repair) subtype, which lacks ideal biomarkers for precise and dynamic screening of potential immune-responsive subpopulations and for predicting combination therapy strategies. Currently, the assessment of PD-L1 is limited to biopsy samples. Molecular immuno-PET imaging can provide an effective solution for guiding clinical immunotherapy selection. This study describes the development of Zr-DFO-atezolizumab, a PD-L1-targeted immuno-imaging agent, and its evaluation in terms of in vitro and in vivo specificity as well as pharmacokinetics. Tumor uptake and heterogeneity were quantified in mouse models via immuno-PET imaging. PET/CT scans using Zr-DFO-atezolizumab revealed a significant difference in tumor uptake between the MC38 model and the MC38 model, and cold anti-atezolizumab effectively blocked this uptake. The preliminary dosimetry study indicated that the organs receiving higher doses are the spleen and the liver. Preclinical PET/CT imaging with Zr-DFO-atezolizumab reveals its potential for the non-invasive detection of PD-L1-positive CRC tumors, which holds potential significance for understanding tumor heterogeneity and monitoring early PD-L1 expression changes induced by therapy.
Vanga MK, Thumma V, Bhukya R
… +5 more, Manthena SK, Ambadipudi SSSSS, Lakshma Nayak V, Andugulapati SB, Manga V
Bioorg Med Chem Lett
· 2026 Sep · PMID 42119828
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A series of 7-Azaindole Linked Imidazole 1,2,3-Triazole hybrids were synthesized and assessed for their anticancer activity across five distinct cancer cell lines: DU-145 (prostate cancer), MCF-7 (breast cancer), HCT 116...A series of 7-Azaindole Linked Imidazole 1,2,3-Triazole hybrids were synthesized and assessed for their anticancer activity across five distinct cancer cell lines: DU-145 (prostate cancer), MCF-7 (breast cancer), HCT 116 (colon cancer), HeLa (cervical cancer), and HepG2 (liver cancer). In the series, compound 7j demonstrated significant efficacy against human breast cancer cells, specifically MCF-7. Cell cycle analysis demonstrated that this compound caused cell cycle arrest at the G2/M phase and triggered apoptosis. The findings were additionally validated through Hoechst staining and the Annexin V-FITC assay. The molecular docking study was conducted using the crystal structure of the epidermal growth factor receptor with ligands 7 g and 7j, which demonstrated optimal binding energy values and notable binding interactions, such as hydrogen bonds, π-π stacking, and various hydrophobic interactions, suggesting their binding efficiency in a favourable manner.
Bioorg Med Chem Lett
· 2026 Sep · PMID 42097519
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Interleukin-1 receptor-associated kinase 4 (IRAK4) is a promising therapeutic target for inflammatory diseases. However, inhibition of its kinase activity alone often results in incomplete blockade of inflammatory signal...Interleukin-1 receptor-associated kinase 4 (IRAK4) is a promising therapeutic target for inflammatory diseases. However, inhibition of its kinase activity alone often results in incomplete blockade of inflammatory signaling and limited therapeutic efficacy. To address this limitation, we designed and synthesized a novel proteolysis-targeting chimera (PROTAC) aimed at degrading IRAK4. Among the synthesized compounds, GSI526 emerged as a potent degrader, demonstrating efficient IRAK4 degradation in THP-1 cells with a DC₅₀ of 40.17 nM. Mechanistic studies confirmed that GSI526 acts via the ubiquitin-proteasome system, effectively suppressing the IRAK4-mediated NF-κB and MAPK signaling pathways. Furthermore, GSI526 exhibited a favorable preliminary safety profile. Collectively, these findings identify GSI526 as a promising IRAK4-targeting degrader, offering an alternative therapeutic strategy and a candidate for further drug development.
Hazarika PK, Kalita S, Mahanta D
… +3 more, Gogoi D, Das B, Sarma D
Bioorg Med Chem Lett
· 2026 Sep · PMID 42097518
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This study addresses the design and development of novel isoxazole molecules tethered with triazole and sulphonamide derivatives to elucidate their pharmacological response for antibacterial and anticancer activities. Th...This study addresses the design and development of novel isoxazole molecules tethered with triazole and sulphonamide derivatives to elucidate their pharmacological response for antibacterial and anticancer activities. The ionic liquid mediated protocol garners the respective derivatives tolerating an array of functionalised and substituted molecular hybrids. Antimicrobial exploration performed against six bacterial strains with antibiotic associated resistance mechanisms, identified five scaffold that exhibited significant inhibitory activity. The sulphonamide-isoxazole moiety demonstrated cross-species effectiveness encompassing both the resistant and non-resistant bacterial strains. ScXRD provides the exact molecular conformation and regioselective formation of 3,5-disubstituted isoxazole-sulphonamide hybrid. The heterocyclic conjugates also elicit a concentration- and time-dependent reduction in hepatocellular carcinoma cell (HepG2) with pronounced cell death observed for triazole hybrids bearing chloro substituents. The binding affinities of these compounds with the microbial protein targets and their interactions with Heat Shock Protein 90 (Hsp90) for the cancer cell line probed by the docking studies corroborates with the experimental findings.
Gong X, Zhang M, Min J
… +5 more, Jiang L, Liu P, Pan Y, Chen Y, Huang W
Bioorg Med Chem Lett
· 2026 Sep · PMID 42092430
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Epidermal growth factor receptor (EGFR) serves as a key therapeutic target for solid tumors such as non-small cell lung cancer (NSCLC), where its mutations and overexpression often lead to sustained activation of oncogen...Epidermal growth factor receptor (EGFR) serves as a key therapeutic target for solid tumors such as non-small cell lung cancer (NSCLC), where its mutations and overexpression often lead to sustained activation of oncogenic signaling pathways. This study represents a comparative analysis of multiple targeted chimeric degradation technologies targeting EGFR allosteric sites, aiming to provide clearer guidance for the future development of allosteric EGFR degraders. Results demonstrate that the VHL-based PROTAC compound III-4 exhibits optimal degradation activity against EGFR and EGFR, degrading approximately 76% and 72% at 0.1 μM, respectively, with degradation partially dependent on the ubiquitin-proteasome pathway. For degrading the acquired resistance mutant EGFR, CRBN-based PROTAC compounds II-3 and II-5 demonstrated significant efficacy (approximately 60% degradation at 0.1 μM) and effectively inhibited H1975 cell proliferation (IC values of 23.32 μM and 14.31 μM, respectively). In contrast, AUTAC and HyT-type compounds exhibited overall weaker degradation activity, relying on the autophagy-lysosomal pathway and proteasome pathway, respectively. Physicochemical analysis indicated that PROTAC compounds exhibited cLogP and polar surface area (PSA) values closer to the ideal range, potentially contributing to their cellular permeability and degradation activity. In summary, this study represents a deepened and extended investigation built directly on previous seminal work, aiming to provide clearer guidance for the future development of allosteric EGFR degraders.
Bioorg Med Chem Lett
· 2026 Sep · PMID 42086107
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Tuberculosis (TB) remains a major global health challenge, particularly due to the rise of drug-resistant Mycobacterium tuberculosis (Mtb). Herein, a focused small library of thiophene-thiazole hybrid derivatives 3a-d be...Tuberculosis (TB) remains a major global health challenge, particularly due to the rise of drug-resistant Mycobacterium tuberculosis (Mtb). Herein, a focused small library of thiophene-thiazole hybrid derivatives 3a-d bearing an imide linker was designed, synthesized, and evaluated against drug-sensitive (H37Ra and H37Rv) and drug-resistant Mtb clinical isolates. Among them, 3c emerged as the most promising compound, exhibiting MIC values of 10-20 μM, including activity against a katG-mutant strain. Drug combination assays revealed no antagonism with first- and second-line anti-TB agents (FICI 0.75-3.0). In silico studies targeting Mtb KatG (PDB ID: 1SJ2) demonstrated a stable induced-fit binding mode, supported by persistent hydrogen bonding with Asp and Tyr. Compound 3c retained bactericidal activity under nutrient-starvation conditions and outperformed isoniazid (INH) in a dormancy model. Cytotoxicity assays in HepG2 and Vero E6 cells showed low toxicity (IC₅₀ > 100 μM). These findings identify 3c as a promising lead scaffold for anti-TB drug development.
Bioorg Med Chem Lett
· 2026 Sep · PMID 42070755
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A novel series of heterocyclic compounds was developed, synthesized, and assessed for their in vitro anticancer efficacy and EGFR inhibitory activities. The cytotoxicity of the synthesized compounds was evaluated against...A novel series of heterocyclic compounds was developed, synthesized, and assessed for their in vitro anticancer efficacy and EGFR inhibitory activities. The cytotoxicity of the synthesized compounds was evaluated against A-549 and NCI-H460 lung cancer cell lines, as well as normal HEK-293 cells, using erlotinib and doxorubicin as reference standards. Multiple compounds had considerable anticancer efficacy, with 8f and 8g identified as the most effective possibilities, with IC₅₀ values ranging from 2.53 to 6.51 μM, surpassing erlotinib. These compounds exhibited significant EGFR inhibition, with 8f (IC₅₀ = 0.26 μM) and 8g (IC₅₀ = 0.36 μM) surpassing the standard drug. Molecular docking analyses of the EGFR kinase domain demonstrated advantageous binding affinities and significant interactions with the hinge region residue MET769, corroborated by many hydrogen bonds and substantial π-interactions. A strong association between docking scores and biological activity was noted, validating EGFR as a potential molecular target. The findings designate 8f and 8g as prospective lead compounds for further development as EGFR-targeted anticancer therapies.
Liu J, Shi X, Yang X
… +12 more, Zhao X, Huang F, Li Z, Liu Y, Gao Y, Feng J, Qu Z, Yi C, Yang Y, Liang Z, Yao Q, Liu B
Bioorg Med Chem Lett
· 2026 Sep · PMID 42049117
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Sphingosine-1-phosphate (S1P) is a critical bioactive lipid mediator that regulates essential cellular processes-including proliferation, survival, migration, and inflammation-through binding to its cognate receptors (S1...Sphingosine-1-phosphate (S1P) is a critical bioactive lipid mediator that regulates essential cellular processes-including proliferation, survival, migration, and inflammation-through binding to its cognate receptors (S1PRs) on the cell membrane or via direct intracellular actions. Sphingosine Kinase 2 (SphK2) has thus emerged as a promising therapeutic target. In this study, we designed and synthesized a novel series of SphK2 inhibitors (Q-series) based on the lead compound K145. Among these, compounds Q20 (IC = 2.6 ± 0.46 μM), Q24 (IC = 4.27 ± 1.51 μM), and Q25 (IC = 6.25 ± 0.62 μM) displayed potent and selective inhibition of SphK2, while showing negligible activity against SphK1 (IC > 50 μM). Notably, Q25 exhibited significant anti-proliferative effects against multiple colorectal cancer cell lines (LOVO, SW480, SW620, HT-29), with IC values of 8.09 ± 4.36, 7.77 ± 2.48, 7.38 ± 3.41, and 6.41 ± 2.46 μM, respectively. Mechanistically, Q25 induced S-phase cell cycle arrest and apoptosis. The Q-series compounds (Q20, Q24, Q25) also demonstrated favorable metabolic stability in human liver microsomes, characterized by prolonged half-lives (T > 90 min), low intrinsic clearance (CLint(mic) < 15 μL/min/mg), and high parent compound recovery (∼50% remaining after incubation). In vivo pharmacokinetic studies in mice indicated that Q25 is rapidly metabolized, classified as a high-clearance compound, and undergoes extrahepatic elimination. In a SW480 xenograft mouse model, Q25 effectively inhibited tumor growth without observable toxicity. Western blot analysis suggested that its anti-tumor effect is associated with reduced S1P production and subsequent suppression of the NF-κB pathway. In summary, these findings identify Q25 as a promising, selective SphK2 inhibitor worthy of further development as an anticancer agent.
Li W, Gao Y, Huang A
… +6 more, Li M, Ye S, Wu Y, Zhang Y, Zhang H, Miao Z
Bioorg Med Chem Lett
· 2026 Aug · PMID 42025882
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The NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome plays a critical role in mediating intracellular caspase-1 activation, IL-1β release, and pyroptosis with its excessive activation be...The NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome plays a critical role in mediating intracellular caspase-1 activation, IL-1β release, and pyroptosis with its excessive activation being closely associated with the pathogenesis of various inflammatory diseases. In this study, a series of novel hydroxime-based NLRP3 inflammasome inhibitors were designed and synthesized. Among them, compound ZM734 exhibited potent inhibitory activity against IL-1β secretion in mouse bone marrow-derived macrophages (BMDMs). In addition, compound ZM734 effectively inhibited NLRP3 inflammasome activation induced by diverse stimuli. Compound ZM734 demonstrated a definite protective effect and was capable of alleviating pulmonary inflammation in a C57BL/6 mouse model of acute lung injury. Notably, the cytotoxicity of compound ZM734 toward human hepatic stellate LX-2 cells was significantly reduced. Furthermore, the increases in serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in mice treated with compound ZM734 at the same dose were significantly lower than that of MCC950. These findings thereby provide a new direction to the further structural optimization for the discovery of low toxicity NLRP3 inflammasome inhibitors.
Bioorg Med Chem Lett
· 2026 Aug · PMID 42009208
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Leishmaniasis is a parasitic disease caused by Leishmania species, transmitted by infected sandflies. It remains a major health challenge in tropical and subtropical regions, with high morbidity and mortality. Current tr...Leishmaniasis is a parasitic disease caused by Leishmania species, transmitted by infected sandflies. It remains a major health challenge in tropical and subtropical regions, with high morbidity and mortality. Current treatments, such as miltefosine, are limited by toxicity, resistance, and poor accessibility, highlighting the need for safer, more effective alternatives. This study reports the synthesis and characterization of pyridine-2,6-dicarboxylic acid derivatives, their antileishmanial activities, and suggested mechanisms of action. The synthetic method afforded sufficient yields and purities, making these compounds attractive for further study. Structures were confirmed by spectroscopic methods and elemental analyses. In-vitro evaluation against promastigote and amastigote forms of L. major showed that all compounds exhibited activity, with compound 4 being the most potent, displaying IC values of 2.86 ± 0.14 μM and 3.84 ± 0.16 μM, respectively, nearly three times more effective than miltefosine. Molecular docking indicated folate pathway inhibition, with compound 4 fitting well with Lm-PTR1. Cytotoxicity tests revealed a superior safety profile (IS = 108.2), significantly better than miltefosine. In-silico ADMET predictions supported favorable bioavailability and safety. These findings suggest that pyridine-2,6-dicarboxylic acid derivatives, particularly compound 4, represent promising candidates for future anti-leishmanial drug development.
Werle J, Bergo AM, Houdkova M
… +2 more, Havlik J, Kokoska L
Bioorg Med Chem Lett
· 2026 Aug · PMID 42009207
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Volatile monoterpenoids represent promising candidates for inhalation-based therapies of respiratory infections due to their volatility and antimicrobial properties. Using the broth microdilution volatilization method, t...Volatile monoterpenoids represent promising candidates for inhalation-based therapies of respiratory infections due to their volatility and antimicrobial properties. Using the broth microdilution volatilization method, this study assessed the in vitro growth-inhibitory effect of 31 monoterpenoids against common pneumonia-causing pathogens, including Haemophilus influenzae, Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes, with the aim to determine the relationship between their chemical structure and antibacterial activity in vapor phase. Among all compounds tested, β-thujaplicin, carvacrol, thymol, and thymoquinone produced the strongest antibacterial effect. A comprehensive structure-activity relationship analysis of the chemical structure indicated that monoterpenoids bearing hydroxyl or ketone functional groups on six- or seven-membered ring structures, double bonds and hydrophobic groups exhibited enhanced antibacterial potency, in vapor phase. Furthermore, statistical analysis of molecular descriptors identified critical physicochemical characteristics which are linked to their antibacterial efficacy. Those include increased polar atom content, higher electronegativity, overall hydrophobicity, and π-electron distribution. The findings of this study add valuable insights into structural and molecular determinants of antimicrobial activity and provide theoretical background for development of inhalation therapies of respiratory infections based on volatile antimicrobial terpenoids.
Kers A, Gabos B, Borhade S
… +12 more, Andersson E, Andersson H, Wellmar U, Jönsson M, Gummeson S, Dreisch K, Rajabi N, Sköld N, Ferreira RJ, Azar MR, Lowe JA, Burstein ES
Bioorg Med Chem Lett
· 2026 Aug · PMID 42002053
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A growing body of evidence indicates that inadequate symptom-relief from medical treatment with SSRIs may be enhanced by concomitant blockade of 5-HT. In a discovery program directed towards finding novel SSRIs suitable...A growing body of evidence indicates that inadequate symptom-relief from medical treatment with SSRIs may be enhanced by concomitant blockade of 5-HT. In a discovery program directed towards finding novel SSRIs suitable for combining with the 5-HT inverse agonist pimavanserin, we used a published in silico generated template as the starting point. Through a stepwise optimization of the template, we discovered that by first exchanging a benzyl substituent for a pyridyl-methyl substituent and then by introducing either a 5- or 6-membered aromatic heterocycle on the core benzene-ring, new compounds with improved metabolic stability and enhanced SERT-potency were obtained. The novel SSRIs had desirable ADME properties, decreased CYP-inhibition and comparable in vivo activity to commonly prescribed SSRIs. One compound (21d) selected for further characterization displayed high selectivity across 90 targets, and synergistic actions with pimavanserin in behavioral tests of anxiety and in microdialysis assessments of neurotransmitter release.