Sun H, Yan X, Mo C
… +9 more, Chen J, Liu Y, Liu Y, Han X, Gao J, Yin L, Xu J, Chen Y, He X
Bioorg Med Chem Lett
· 2026 Apr · PMID 41455492
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Monophosphorylation is a key rate-limiting step for the efficacy of broad-spectrum nucleoside antiviral drugs, and designing phosphate prodrugs is an effective method to enhance antiviral efficacy. N4-hydroxycytidine (NH...Monophosphorylation is a key rate-limiting step for the efficacy of broad-spectrum nucleoside antiviral drugs, and designing phosphate prodrugs is an effective method to enhance antiviral efficacy. N4-hydroxycytidine (NHC) has a broad-spectrum antiviral effect. Based on the mechanism of action and metabolic inactivation characteristics of NHC, we designed a series of dual ester prodrugs targeting the N4-hydroxyl group and the 5'-phosphate of the ribose ring. Twenty-nine compounds were designed and synthesized. The cytotoxicity assay results showed low cytotoxicity (no significant toxicity at 160 μM). Using the Vesicular Stomatitis Virus expressing Green Fluorescent Protein (VSV-GFP) virus screen, it was found that all of them have antiviral activity. Compounds 2328 and 2322 showed better antiviral activity than molnupiravir. The ECs of 2328 against VSV, HMPV-A2, and RSV-A2 viruses were 2.19 μM, 35.6 μM, and 53.5 μM, respectively, and the ECs of 2322 against VSV, HMPV-A2, and RSV-A2 were 6.23 μM, 52.8 μM, and 28.2 μM, respectively. Structure-activity relationships indicate that the antiviral activity of compounds at the cellular level is closely linked to the structure of the prodrug's phosphate ester, whereas the ester group on the N4-hydroxyl is more tolerant of diverse functional groups.
Bioorg Med Chem Lett
· 2026 Apr · PMID 41453692
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Parasitic diseases like leishmaniasis and Chagas pose significant global health challenges due to limited treatment options and drug resistance. In this study, a series of novel cinnamoyl aryl hydrazone derivatives was s...Parasitic diseases like leishmaniasis and Chagas pose significant global health challenges due to limited treatment options and drug resistance. In this study, a series of novel cinnamoyl aryl hydrazone derivatives was synthesized and tested against Leishmania donovani and Trypanosoma cruzi. Four compounds showed promising antileishmanial activity (from 1.27 to 19.53 μM), with two analogues displaying superior potency compared to some current first-line treatments, such as sodium stibogluconate and paromomycin. Computational analyses revealed that activity is driven by specific electronic properties rather than steric factors, while a methyl group consistently reduced potency. The compounds demonstrated favorable predicted ADME properties and were not flagged as aggregators. This research identifies cinnamoyl aryl hydrazones as a promising scaffold for leishmanicidal drug discovery, providing a rational basis for future optimization efforts.
Chan HY, Huang PS, Chiu PF
… +5 more, Lin TS, Huang LJ, Liang PH, Guh JH, Lin MH
Bioorg Med Chem Lett
· 2026 Apr · PMID 41453691
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Abiraterone, a CYP17A1 inhibitor, is approved by the FDA for castration-resistance prostate cancer. To mimic the structure of abiraterone, we designed and synthesized nine tetrahydroindeno[4,5-c]chromen-4(3H)-one derivat...Abiraterone, a CYP17A1 inhibitor, is approved by the FDA for castration-resistance prostate cancer. To mimic the structure of abiraterone, we designed and synthesized nine tetrahydroindeno[4,5-c]chromen-4(3H)-one derivatives with pyridine congeners at C-1 position. Notably, 13c and 14c exhibited the GI of 10 nM against PC-3 cells compared to 21.4 μM for abiraterone. The docking studies further revealed that 14c shares a similar binding mode with abiraterone at the CYP17A1 active site.
He Y, Zhang Y, Wang W
… +4 more, Cui C, Hao Q, Xie H, Yang R
Bioorg Med Chem Lett
· 2026 Apr · PMID 41448442
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The endophytic fungus Alternaria sp. S4, derived from Ruta graveolens, shows significant antimicrobial potential, but its active components and mode of action require clarification. Through bioassay-guided fractionation,...The endophytic fungus Alternaria sp. S4, derived from Ruta graveolens, shows significant antimicrobial potential, but its active components and mode of action require clarification. Through bioassay-guided fractionation, alternariol (1) and alternariol-5-O-methyl ether (2) were isolated from the ethyl acetate fraction of Alternaria sp. S4 and characterized spectroscopically. Compound 1 exhibited potent bactericidal activity against Staphylococcus aureus (MIC = 4 μg/mL, MBC = 16 μg/mL), whereas compound 2 was inactive. Time-growth assays confirmed concentration-dependent bacterial eradication, with 2× MIC of compound 1 achieving complete growth inhibition. Mechanistic investigations revealed that compound 1 targets the bacterial membrane, inducing depolarization, compromising permeability (evidenced by ion leakage and release of intracellular constituents), and causing ultrastructural damage visualized via SEM. Furthermore, compound 1 prevented biofilm formation via bacterial eradication and disrupted preformed biofilms. Checkerboard assays indicated additive effects when combined with conventional antibiotics. Notably, compound 1 displayed no hemolytic activity even at 1024 μg/mL, highlighting its membrane selectivity. This work identifies alternariol as a promising membrane-targeting bactericidal agent from an endophytic source, capable of preventing biofilm establishment, with potential for combinatorial therapy against S. aureus.
Du J, Wang W, Ma Y
… +4 more, Cui C, Zhang Y, Yang J, Yang R
Bioorg Med Chem Lett
· 2026 Apr · PMID 41448441
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This study aimed to develop novel antifungal agents through the design and synthesis of two series of 4-aminoquinoline derivatives (1-21 and their demethylated analogs 1'-16'). These compounds were synthesized via cycliz...This study aimed to develop novel antifungal agents through the design and synthesis of two series of 4-aminoquinoline derivatives (1-21 and their demethylated analogs 1'-16'). These compounds were synthesized via cyclization in POCl, amine substitution, and BBr-mediated demethylation, with structures confirmed by NMR and HRMS. Antifungal evaluation showed that while most compounds were weakly active (MICs ≥128 μg/mL), several-particularly those with 6-position hydroxy or methoxy substituents (14, 16, and 14'-16')-displayed notable activity (MICs = 4-32 μg/mL) against Candida albicans, Candida tropicalis, and Cryptococcus neoformans. Compound 14' exhibited potent fungicidal action against C. albicans (MIC = MFC = 4 μg/mL), rapid time-kill kinetics, membrane disruption evidenced by PI/DAPI staining, and strong biofilm inhibition (>90 % at ≥16 μg/mL). SEM imaging revealed extensive ultrastructural damage to fungal cells. Importantly, 14' showed low cytotoxicity toward human epithelial cells and favorable in silico predicted ADMET profiles. These findings highlight 14' as a promising lead compound with membrane-targeting antifungal mechanisms and an improved safety profile relative to amphotericin B.
Cho S, Zhu R, Kuncewicz K
… +2 more, Duan H, Gabr M
Bioorg Med Chem Lett
· 2026 Apr · PMID 41435973
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Triggering receptor expressed on myeloid cells 2 (TREM2) plays a central role in regulating microglial function in the central nervous system and has emerged as a promising therapeutic target for Alzheimer's disease. Des...Triggering receptor expressed on myeloid cells 2 (TREM2) plays a central role in regulating microglial function in the central nervous system and has emerged as a promising therapeutic target for Alzheimer's disease. Despite advances in antibody-based therapeutics, small molecules and peptides capable of modulating TREM2 remain limited. Here, we present a cyclic peptide design pipeline that integrates CycleRFdiffusion, ProteinMPNN for sequence design, and HighFold for structural prediction and screening. Using the TREM2 structure as input, we generated and screened 1500 peptide-target complexes, prioritizing four candidates that met structural and energetic criteria. Subsequent biophysical evaluation identified TP4 as a weak but reproducible TREM2 binder, demonstrating consistent binding in spectral shift, microscale thermophoresis, and surface plasmon resonance. Pharmacokinetic profiling indicated that TP4 possesses favorable plasma stability and moderate metabolic stability, supporting its potential for further optimization. This study establishes a generalizable framework for AI-driven cyclic peptide discovery and provides the first proof-of-concept demonstration of TREM2-targeted cyclic peptide binders.
Bioorg Med Chem Lett
· 2026 Apr · PMID 41422850
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As a key intracellular pattern-recognition receptor, NLRP3 senses diverse pathogen- and damage-associated molecular patterns (PAMPs and DAMPs), initiating inflammasome assembly and pyroptotic cell death. Aberrant NLRP3 a...As a key intracellular pattern-recognition receptor, NLRP3 senses diverse pathogen- and damage-associated molecular patterns (PAMPs and DAMPs), initiating inflammasome assembly and pyroptotic cell death. Aberrant NLRP3 activation contributes to various chronic inflammatory diseases, including atherosclerosis, Alzheimer's disease, and rheumatoid arthritis, underscoring its therapeutic relevance. In this study, we designed and synthesized compound 8a, a structurally optimized derivative of the diterpenoid alkaloid songorine. In lipopolysaccharide (LPS)- and nigericin-stimulated macrophage models, 8a markedly reduced lactate dehydrogenase (LDH) release (IC₅₀ = 2.69 μM in THP-1 cells and 1.75 μM in J774A.1 cells) and effectively inhibited gasdermin D (GSDMD) cleavage and interleukin-1β (IL-1β) secretion, demonstrating potent suppression of pyroptosis. Hydrogenation of the C16-C17 double bond afforded compound 8b, which lost inhibitory activity, indicating that the α,β-unsaturated carbonyl moiety is essential for function, likely via covalent modification of cysteine residues on NLRP3. This mechanism was further substantiated by Drug Affinity Responsive Target Stability (DARTS) assays and mass spectrometry, confirming direct binding between 8a and NLRP3. We also conducted structure-activity relationship studies by modifying the C1 position and found that such modifications did not significantly impact the compound's activity. Collectively, these findings identify 8a as a novel songorine-derived covalent NLRP3 inhibitor and provide the first elucidation of its structure-activity relationship and molecular mechanism, offering valuable insights for the rational design of safe and effective anti-inflammatory agents targeting NLRP3.
Thao LT, Kim HK, Ngan NP
… +11 more, Cuong BQ, Oanh DTK, Dung DTM, Kang DH, Kim HY, Song EH, Kang JS, Anh DT, Tung TT, Han SB, Nam NH
Bioorg Med Chem Lett
· 2026 Mar · PMID 41421683
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Histone deacetylases (HDACs) are key therapeutic targets in oncology, and hydroxamic acid derivatives represent one of the most effective inhibitor classes. To explore the structure-activity relationships of this scaffol...Histone deacetylases (HDACs) are key therapeutic targets in oncology, and hydroxamic acid derivatives represent one of the most effective inhibitor classes. To explore the structure-activity relationships of this scaffold, a series of 2-mercaptoquinazoline-based hydroxamic acid derivatives (4a-e, 7a-i, and 10a-e) were synthesized and evaluated for HDAC inhibition and anticancer activity, with SAHA serving as a positive control. The 4a-e series emerged as the most potent HDAC inhibitors, with IC values of 0.33-0.87 μM, led by 4a (0.33 ± 0.02 μM), though weaker than SAHA (0.06 ± 0.01 μM). Cytotoxicity assays across colorectal (SW620, HCT116), breast (MDA-MB-231), prostate (PC-3), and lung (A549) cancer cell lines demonstrated that 4b (6-CH) and 4c (7-CH) were the most effective, achieving IC values of 0.93-1.34 μM in HCT116 and 1.79-2.08 μM in SW620. In the 7a-i series, compounds 7b (6-CH), 7d (6-Cl), and particularly 7f (7-F) demonstrated notable cytotoxicity with IC values of 1.14-3.64 μM across SW620, HCT116, and MDA-MB-231 cells, comparable to the most active derivatives in the 4-series; conversely, bulky halogen substituents (7g, 7i) or the unsubstituted analog 7a led to markedly reduced activity (> 4.5 μM). The 10a-e series was significantly less active, and 10e (7-F) showed undesirable toxicity toward normal MRC-5 fibroblasts (IC = 0.72 ± 0.02 μM). Mechanistic studies further confirmed that 4c and 7f induced G/M arrest and apoptosis in SW620 cells. Collectively, these findings highlight 4a-c and 7f as promising lead compounds, combining submicromolar HDAC inhibition, potent antiproliferative effects, and acceptable selectivity, providing a strong foundation for further development of quinazoline-based HDAC inhibitors. Molecular docking studies supported these results by revealing favorable interactions of the hydroxamate zinc-binding group and the 2-mercaptoquinazoline scaffold within the HDAC active site, consistent with the observed structure-activity relationship (SAR) trends.
Nie W, Ding B, Chen X
… +4 more, Jiang L, He Q, Cao J, Zhu CL
Bioorg Med Chem Lett
· 2026 Mar · PMID 41421682
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Histone deacetylase 7 (HDAC7) is a key member of the class IIa HDAC subfamily (HDAC4, 5, 7, and 9) that is characterized by a key tyrosine-to-histidine substitution in its active site, a feature that renders these HDACs...Histone deacetylase 7 (HDAC7) is a key member of the class IIa HDAC subfamily (HDAC4, 5, 7, and 9) that is characterized by a key tyrosine-to-histidine substitution in its active site, a feature that renders these HDACs catalytically inefficient and underscores their versatile roles beyond intrinsic deacetylation. Structurally, HDAC7 is distinguished from its paralogs by its lack of the conserved N-terminal glutamine-rich domain. This combination of functional duality and a unique structural context enables HDAC7 to regulate a vast array of cellular processes. Consequently, its dysregulation is implicated in numerous pathologies, including cancer and autoimmune disorders, establishing it as a compelling therapeutic target. However, effectively and selectively targeting HDAC7 is complicated by its context-dependent biological modes of actions and the high structural homology it shares with other class IIa isoforms. This review first provides a current overview of the multifaceted roles of HDAC7 in human diseases and discusses how its contributions are dictated by the complex interplay between its catalytic and diverse scaffolding functions. We then summarize the recent medicinal chemistry efforts, from the class-selective deacetylase inhibitors to the recently emerged targeted protein degraders that not only achieve superior isoform selectivity but also modulate HDAC7's deacetylase-independent functions. By bridging the functional complexity of HDAC7 with the latest advances in chemical biology tools, we aim to provide a timely summary of the current status of HDAC7 as a druggable target and offer a perspective on strategies guiding the development of next-generation modulators.
Liu Y, Wu J, Gao N
… +8 more, Zheng L, Zhang W, Zhao F, Meng B, Liu X, Liu L, Zhao H, Kang D
Bioorg Med Chem Lett
· 2026 Mar · PMID 41412329
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STING allosteric agonists targeting the cryptic pocket in the transmembrane domain (TMD) could overcome the limitations of membrane permeability and oligomerization instability that are inherent to conventional cGAMP mim...STING allosteric agonists targeting the cryptic pocket in the transmembrane domain (TMD) could overcome the limitations of membrane permeability and oligomerization instability that are inherent to conventional cGAMP mimetics. Although compounds such as C53 and NVS-STG2 have been reported as TMD-targeting agonists, their therapeutic potential is restricted by insufficient potency. In this work, compound LA24 was identified as a novel potent STING allosteric agonist through structure-based multilevel virtual screening combined with rational optimization. It exhibited an EC₅₀ value of 0.82 μM, being superior to that of the reference C53 (EC = 2.80 μM). Molecular modeling studies revealed that LA24 exhibited enhanced STING agonistic activity by forming hydrogen bonds with key transmembrane domain residues G114 and Y106, as well as π-π stacking interactions with H50. These findings suggested that LA24 holds promise as a novel lead compound for the development of STING-targeted immunomodulatory therapies.
Latterell KR, Keil E, Kraemer BR
… +11 more, Huisken JB, Thomas BA, Daniels N, Kaushik A, Olson ML, Noriega PM, Daniels MAP, Janzen DE, Lamichhane G, Campo M, Ippoliti JT
Bioorg Med Chem Lett
· 2026 Mar · PMID 41397658
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Oxazolidinones are a class of antibiotics used to treat bacterial infections in humans and are a component of the treatment regimen for multidrug-resistant tuberculosis. However, current clinically used examples of the c...Oxazolidinones are a class of antibiotics used to treat bacterial infections in humans and are a component of the treatment regimen for multidrug-resistant tuberculosis. However, current clinically used examples of the class display poor safety profiles, and improved, next-generation drugs are urgently needed. Here we report the synthesis of two novel oxazolidinones: T504 and its regioisomer T542. Alongside the previously reported compound T145, we evaluate their inhibitory activity against the causative agent of tuberculosis, Mycobacterium tuberculosis. We also explore their antimycobacterial activity in a human monocyte-derived macrophage model of infection. Both T145 and T504 demonstrate potent activity and low cellular toxicity in human macrophages. The investigation reveals vast discrepancies in activities between the two regioisomers (T504 and T542), offering insights into the structure-activity relationship of substitutions on the oxanthrene scaffold.
Duan R, Zhou L, Chen R
… +5 more, Huang Y, Wu D, Ohwada T, Yi W, Huang J
Bioorg Med Chem Lett
· 2026 Apr · PMID 41397657
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Dual α-adrenergic receptor (AR) antagonists are a mainstay treatment for lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). Building on the phenylpiperazine pharmacophore of naftopidi...Dual α-adrenergic receptor (AR) antagonists are a mainstay treatment for lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). Building on the phenylpiperazine pharmacophore of naftopidil, our previous work identified the linker region as a critical structural determinant for subtype selectivity. However, we recognized that the secondary hydroxyl group within the previously employed linker (e.g., in lead R-17) could represent a potential metabolic liability. In this study, we strategically optimized the linker moiety to achieve a precise balance between subtype selectivity and metabolic stability. We designed and synthesized nineteen novel propane-linked derivatives by eliminating the hydroxyl group and introducing diverse aromatic carboxamide moieties. Among them, compound 15 featuring a 5-benzo[d][1,3]dioxole group emerged as a highly potent α antagonist. Structure-activity relationship (SAR) and molecular docking confirmed that the streamlined propane linker retains the optimal chain length to prevent the key salt bridge interaction with D in the α subtype, thereby preserving the structural basis for high selectivity. Crucially, our head-to-head evaluation in rat liver microsomes validated our design hypothesis: the removal of the hydroxyl group dramatically improved metabolic stability, extending the half-life (T) from 6.1 min (R-17) to 31.5 min (15). This work establishes compound 15 as a promising lead candidate that successfully integrates the selectivity-determining linker scaffold with enhanced drug-like properties.
Bioorg Med Chem Lett
· 2026 Mar · PMID 41391497
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STK17A (serine/threonine kinase 17a), also known as DRAK1 (death-associated protein kinase-related apoptosis-inducing protein kinase 1), is a member of the death-associated protein kinase (DAPK) family and acts as a posi...STK17A (serine/threonine kinase 17a), also known as DRAK1 (death-associated protein kinase-related apoptosis-inducing protein kinase 1), is a member of the death-associated protein kinase (DAPK) family and acts as a positive regulator of apoptosis. STK17A is a dark kinase and is an understudied member in the DAPK family. Thus far, it has been found to serve a significant role in cell proliferation, apoptosis, tumor metastasis, and tumorigenesis. This review summarizes the structure of STK17A, its reported biological functions, and expression in cancer. Small molecule inhibitors for STK17A, including those specifically developed for STK17A and those designed for other kinases but also inhibit STK17A as an unintended target, are discussed. Finally, some outlooks for drug discovery regarding STK17A are described.
Kong Y, Li S, Xue X
… +5 more, Liu H, Fu R, Gao Y, Zhang Y, Xue X
Bioorg Med Chem Lett
· 2026 Apr · PMID 41389892
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Dual inhibition of ALK and HDACs might be an effective cancer treatment approach. We designed and synthesized novel dual ALK and HDAC inhibitors using molecular hybridization and pharmacophore merging. In enzymatic assay...Dual inhibition of ALK and HDACs might be an effective cancer treatment approach. We designed and synthesized novel dual ALK and HDAC inhibitors using molecular hybridization and pharmacophore merging. In enzymatic assays, compound 19b showed dual inhibitory activity against ALK (ALK WT IC = 8.0 ± 1.2 nM) and HDACs (HeLa cell nuclear extract IC = 1.18 ± 0.22 μM). Notably, 19b exhibited ~5-fold greater inhibition than Staurosporine and approved ALK inhibitor Brigatinib against the ALK G1202R mutant. Additionally, 19b demonstrated strong activity in ALK-related neuroblastoma SK-N-BE2 cells, comparable to controls SAHA, MS275, and Brigatinib. In SK-N-BE2 cells, 19b treatment led to increased apoptosis and G2/M arrest. Docking studies explained the potent dual inhibition by 19b. These findings support the promise of 19b as a dual ALK/HDAC inhibitor for managing neuroblastoma, especially ALK-positive cancer.
Bioorg Med Chem Lett
· 2026 Mar · PMID 41386540
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A series of tryptanthrin derivatives were designed, synthesized and evaluated for their antibacterial activity against the marine pathogen Vibrio parahaemolyticus. The bioactivity assessment revealed that compounds 7h an...A series of tryptanthrin derivatives were designed, synthesized and evaluated for their antibacterial activity against the marine pathogen Vibrio parahaemolyticus. The bioactivity assessment revealed that compounds 7h and 8c exhibited potent antibacterial effects against V. parahaemolyticus without cytotoxicity toward mammalian cells. Structure-activity relationship (SAR) analysis indicated that electron-withdrawing substituents on the phenyl ring played a crucial role in enhancing antibacterial activity. Furthermore, compounds 7h and 8c demonstrated strong antibiofilm activity at concentrations of 8 μg/mL and 6 μg/mL, respectively, effectively inhibiting both biofilm formation and maturation in V. parahaemolyticus. These results demonstrate that compounds 7h and 8c exhibited efficacy against drug-resistant Vibrio strains, providing insight into the application of tryptanthrin derivatives as potential antibacterial agents.
Qiu X, Dong L, Shu H
… +4 more, Yu G, Tong Y, Ni H, Zhang S
Bioorg Med Chem Lett
· 2026 Mar · PMID 41386539
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Novel selective histone deacetylase 6 (HDAC6) inhibitors using coumarin moiety as the cap were designed, synthesized and evaluated for HDAC enzymatic assays and anti-inflammatory tests. Among them, compound 24 emerged as...Novel selective histone deacetylase 6 (HDAC6) inhibitors using coumarin moiety as the cap were designed, synthesized and evaluated for HDAC enzymatic assays and anti-inflammatory tests. Among them, compound 24 emerged as the most promising candidate, demonstrating potent HDAC6 inhibition with an IC value of 17 nM and exhibiting 32.39-fold selectivity over HDAC1. In vitro studies revealed that compound 24 efficiently suppressed nitric oxide production in RAW264.7 mouse macrophages, with an IC value of 2.31 μM. Furthermore, human liver microsome tests confirmed its excellent metabolic stability, with a half-life of 59.74 min. Following administration at 30 mg/kg, compound 24 effectively maintain the integrity of colon tissue of DSS-induced ulcerative colitis mice model. Notably, its therapeutic efficacy was comparable to that of tofacitinib. These findings suggested that compound 24 was a promising anti-inflammatory candidate for selective HDAC6 inhibitor and deserves further investigation.
Wang XJ, Lu MX, Jin QY
… +3 more, Lang ZY, Yang ML, Ji J
Bioorg Med Chem Lett
· 2026 Mar · PMID 41371313
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In this study, five novel SKF-83566 derivatives (8a-8e) were synthesized by covalently linking pomalidomide to SKF-83566, which features a benzazepine skeleton, via flexible linker chains. Their structures were confirmed...In this study, five novel SKF-83566 derivatives (8a-8e) were synthesized by covalently linking pomalidomide to SKF-83566, which features a benzazepine skeleton, via flexible linker chains. Their structures were confirmed using H NMR, C NMR, and high-resolution mass spectrometry. The antiproliferative activity against HeLa (cervical cancer) and MDA-MB-231 (breast cancer) cells was evaluated using the MTT assay, with SKF-83566, pomalidomide, and 5-fluorouracil (5-FU) serving as controls. The results indicate that most derivatives demonstrated superior activity compared to the control drug, with compound 8a exhibiting the highest potency: an IC₅₀ of 5.50 ± 0.28 μM against MDA-MB-231 cells and 10.13 ± 0.95 μM against HeLa cells. Further experiments demonstrated that 8a inhibits MDA-MB-231 cell colony formation, adhesion, and migration in a concentration-dependent manner, exhibiting a stronger anti-migration effect than 5-Fu. In the MDA-MB-231 cell chicken embryo chorioallantoic membrane (CAM) xenograft model, 8a also showed superior tumor growth inhibition compared to 5-Fu. Structure-activity relationship analysis shows that pomalidomide can enhance the compound's cytotoxicity and targeting ability, while flexible alkyl chains improve cell permeability and target binding capacity. This study confirms that compound 8a has the potential to become a candidate drug for breast cancer treatment, providing a foundation for the development of new antitumor therapies.
Zhou W, Li Y, Shi W
… +8 more, Cheng B, Liang J, Zhou Z, Tian H, Shao X, Li H, Fang L, Liu K
Bioorg Med Chem Lett
· 2026 Mar · PMID 41371312
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Plasma membrane proteins at cell surface are critical for numerous physiological and pathological processes and are primary targets for clinical drugs. Given that clustering of plasma membrane proteins by endogenous stim...Plasma membrane proteins at cell surface are critical for numerous physiological and pathological processes and are primary targets for clinical drugs. Given that clustering of plasma membrane proteins by endogenous stimuli or pharmaceutical interventions serves as a key trigger for their internalization and degradation, this process critically influences their function and turnover. Inspired by this natural process, we developed a modular, protein-of-interest (POI) targeting degradation strategy by using a bifunctional chimera molecule composed of a POI-binding ligand and a self-assembling peptide (WIII/YIII). We term this strategy SAILTAC (Self-Assembling Peptide Induced Lysosomal Targeting Chimera) and demonstrate that these chimeras could efficiently degrade membrane-anchored GFP and the therapeutically relevant immune checkpoint PD-L1. An optimized dimeric chimera (YIII-BMS)₂ potently reduced PD-L1 across multiple cancer cell lines through the lysosomal pathway. Collectively, the SAILTAC strategy offers a versatile and targeted approach to degrade plasma membrane proteins, providing a new tool for nanomedicine application.
Ikenogami T, Yokota M, Fujioka S
… +13 more, Ogawa N, Noguchi M, Nomura A, Adachi T, Katsuda Y, Arita K, Miyagawa N, Aratsu Y, Asahina K, Crowe P, Tao H, Thacher S, Shiozaki M
Bioorg Med Chem Lett
· 2026 Mar · PMID 41371311
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Retinoic acid receptor-related orphan receptor γ (RORγ) is a master transcriptional regulator of Th17 cell differentiation as well as of the production of pro-inflammatory cytokines such as IL-17 and IL-22. Its critical...Retinoic acid receptor-related orphan receptor γ (RORγ) is a master transcriptional regulator of Th17 cell differentiation as well as of the production of pro-inflammatory cytokines such as IL-17 and IL-22. Its critical role in Th17 cell function and cytokine production makes it a promising therapeutic target for autoimmune diseases. As a result of our high-throughput screening (HTS) campaign to discover novel chemotypes, we identified Cpd 1, a dihydropyrimidinone scaffold with desirable drug-like properties, including favorable ligand efficiency (LE) and fraction of sp carbons (Fsp). Initial structure-activity relationship (SAR) exploration led to the identification of Cpd 17. Target specificity studies of Cpd 17 indicated high selectivity characteristics for the dihydropyrimidinone scaffold. Subsequent X-ray structural analysis revealed its binding mode against RORγ, enabling further optimization by structure-based drug design (SBDD). These efforts culminated in the identification of Cpd 21, which exhibited significantly improved RORγ inhibitory potency along with LE, and Fsp compared to Cpd 1. These results highlight Cpd 21 as a promising lead compound to explore a novel clinical candidate for the development of RORγ-targeted therapies.
Su Y, Wang Y, Zhao J
… +6 more, Guo K, Duan X, Wu H, Sun D, Zhang J, Cen S
Bioorg Med Chem Lett
· 2026 Mar · PMID 41371310
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Due to issues of high transmissibility, immune evasion, and drug resistance in SARS-CoV-2 variants, there is an urgent need for novel antiviral drugs. Plant-derived flavonoids such as baicalein (EC₅₀ = 4.5 μM) and baical...Due to issues of high transmissibility, immune evasion, and drug resistance in SARS-CoV-2 variants, there is an urgent need for novel antiviral drugs. Plant-derived flavonoids such as baicalein (EC₅₀ = 4.5 μM) and baicalin (EC₅₀ = 9.0 μM) exhibit broad-spectrum antiviral potential via RNA-dependent RNA polymerase (RdRp) inhibition. Based on this, our study identified two derivatives through pharmacophore alignment between flavonoid scaffolds and the main protease (Mpro) inhibitor 13b: a psoralen-derived lignan (Comp.1) and a novel isoflavone analog (Comp.2), with dual-targeting capability against SARS-CoV-2 RdRp and Mpro. Computational docking elucidated the binding interactions of compounds with RdRp, Mpro, and the L50F/E166V double mutant Mpro. In vitro assays demonstrated that Comp.1 exhibited micromolar-range inhibitory effects on both RdRp (EC₅₀: 25.45 μM) and Mpro (IC₅₀: 125.4 μM), outperforming Comp.2. Both compounds maintained inhibitory activity against the PF07321332-resistant L50F/E166V double mutant Mpro, with IC₅₀ fold-change values of 1.23 and 1.18, respectively, compared to an 8.62-fold reduction for PF07321332. However, ADMET evaluation indicated that although compounds met basic physicochemical criteria (including molecular weight, TPSA, and compliance with Lipinski's Rule of Five), they still presented critical toxicological liabilities, including high genotoxicity risk (Comp.1: 0.838 probability) and CYP3A4 inhibition (>0.97), necessitating extensive structural optimization. This study confirms that flavonoid derivatives represent promising starting points for developing resistance-aware antiviral agents, though their current profiles classify them as early-stage leads requiring substantial optimization.