Bioorg Med Chem Lett
· 2026 Jun · PMID 41679444
·
Publisher ↗
Tyrosinase is a copper-dependent oxidase that catalyzes the rate-limiting steps of melanogenesis, directly linking its overexpression to hyperpigmentation disorders and melanoma progression. Previously our researcher tea...Tyrosinase is a copper-dependent oxidase that catalyzes the rate-limiting steps of melanogenesis, directly linking its overexpression to hyperpigmentation disorders and melanoma progression. Previously our researcher team found that a coumarin-thiosemicarbazone analog exhibited potent anti-tyrosinase activity (IC = 42.16 ± 5.16 μM). Herein, as part of our efforts in this field of study, we report the synthesis and biological evaluation of a new series of coumarin derivatives functionalized with thiosemicarbazone and/or oxime moieties as potent tyrosinase inhibitors. The most active compound, B5, exhibited an IC₅₀ value of 21.91 ± 0.26 μM, showing 3.3- and 17.6-fold higher inhibitory potency than kojic and ascorbic acids, respectively. Kinetic studies revealed a mixed inhibition pattern, suggesting multiple enzyme-inhibitor interactions. In silico 100-ns molecular dynamics simulations against Agaricus bisporus tyrosinase (PDB ID: 2Y9X) confirmed the structural stability of the B5-tyrosinase complex, with a mean RMSD of 1.85 Å for the enzyme and 0.3 Å for the ligand. The thiosemicarbazone moiety played a pivotal role in complex stabilization through hydrogen bonding and coordination with catalytic Cu ions, while hydrophobic and π-stacking contacts contributed to binding persistence. Altogether, these findings highlight compound B5 as a promising lead compound for developing next-generation tyrosinase inhibitors with potential dermatological and photoprotective applications.
Bioorg Med Chem Lett
· 2026 Jun · PMID 41654236
·
Publisher ↗
Parthenolide is a natural IκB kinase β (IKKβ) inhibitor. Converting it into a PROTAC (proteolysis-targeting chimeras) may lead to improved pharmacological efficacy. Herein, we report the design, synthesis, and biological...Parthenolide is a natural IκB kinase β (IKKβ) inhibitor. Converting it into a PROTAC (proteolysis-targeting chimeras) may lead to improved pharmacological efficacy. Herein, we report the design, synthesis, and biological evaluation of a novel series of parthenolide-based PROTACs. Among them, compound 8 exhibited potent anti-proliferative activity, especially against triple-negative breast cancer MDA-MB-231 cells. Mechanistic studies revealed that 8 acts as an effective IKKβ degrader, inducing degradation via the ubiquitin-proteasome system (DC = 7.15 μM, 91.24% degradation at 10 μM). Furthermore, treatment with 8 was associated with significant apoptosis and G1-phase cell cycle arrest in MDA-MB-231 cells. This work provides initial evidence that the parthenolide scaffold can be leveraged for targeted protein degradation, supporting the future development of IKKβ-directed degraders.
Burton M, Cains C, Fenwick DJC
… +7 more, Foster A, Preece CL, Saleem S, Stanforth SP, Turner HJ, Turnbull G, Perry JD
Bioorg Med Chem Lett
· 2026 Jun · PMID 41654235
·
Publisher ↗
We describe the synthesis and evaluation of six halogenated nitrophenyl glycosides for detection of β-galactosidase and β-glucuronidase enzyme activity among Enterobacterales ("coliforms") and Escherichia coli, respectiv...We describe the synthesis and evaluation of six halogenated nitrophenyl glycosides for detection of β-galactosidase and β-glucuronidase enzyme activity among Enterobacterales ("coliforms") and Escherichia coli, respectively. These were evaluated alongside the established substrates; o-nitrophenyl-β-D-galactopyranoside (ONPG), p-nitrophenyl-β-D-galactopyranoside (PNPG) and p-nitrophenyl-β-D-glucuronide (PNP-GUR). The evaluation was performed using 30 isolates of Enterobacterales including 19 isolates of E. coli. Hydrolysis of 2-fluoro-p-nitrophenyl-β-D-galactopyranoside (2-fluoro-PNPG) yielded a significantly stronger yellow coloration after a six-hour incubation period compared to hydrolysis of ONPG and PNPG, potentially allowing for a more sensitive detection of Enterobacterales. Similarly, hydrolysis of the novel substrate 2-fluoro-p-nitrophenyl-β-D-glucuronide sodium salt (2-fluoro-PNP-GUR Na) by producers of β-glucuronidase also yielded a significantly stronger yellow colouration, potentially allowing for a more sensitive detection of E. coli. The yellow chromophore 2-fluoro-PNP retained high colour intensity at reduced pH when compared to o-nitrophenol and p-nitrophenol. Both substrates potentially offer enhanced sensitivity for the detection of Enterobacterales and E. coli in environmental samples as markers of faecal pollution.
Texidor K, Uyghur D, Wiese N
… +14 more, Davis LO, Green M, Sharmen F, Ijaz A, Barnes KM, Bagett M, Ye J, Abbang SM, Piao W, Chan JYK, Ng YK, Lui VWY, Orecchioni M, Borgini M
Bioorg Med Chem Lett
· 2026 Jun · PMID 41654234
·
Publisher ↗
Covalent inhibitors have re-emerged as powerful therapeutic agents, offering the ability to modulate "undruggable" proteins including oncogenic drivers that have eluded traditional drug discovery efforts. Expanding the r...Covalent inhibitors have re-emerged as powerful therapeutic agents, offering the ability to modulate "undruggable" proteins including oncogenic drivers that have eluded traditional drug discovery efforts. Expanding the repertoire of electrophilic moieties remains a critical frontier in covalent drug discovery. Here, we report a Rh(I)-catalyzed cycloisomerization of N-allyl bicyclo[1.1.0]butane amides (BCB amides) to access the 5-methylene-3-azabicyclo[5.1.0]octan-4-one (MABO) scaffold via strain-release reactivity. Both N-allyl BCB amides and MABOs can react with nucleophiles, highlighting their potential as electrophilic moieties for covalent drug design. Kinetic assays against glutathione revealed that selected N-allyl BCB amides and MABOs exhibit half-lives comparable to that of (±)-sotorasib, whose enantiomerically pure form received FDA approval as an anticancer drug. Biological evaluation in human-derived head and neck squamous cell carcinoma (HNSCC) models identified specific BCB amides and MABO compounds capable of modulating cancer cell growth. The toxicity of the compounds was evaluated by flow cytometry in human peripheral blood mononuclear cells (PBMCs) and by monitoring LDH release in the monocytic cell line THP-1, both under basal and activated conditions. Together, these findings suggest that BCB amides and MABOs represent promising classes of electrophilic scaffolds for covalent drug discovery.
Bioorg Med Chem Lett
· 2026 Jun · PMID 41638593
·
Publisher ↗
Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality and disease burden worldwide, and its clinical management continues to face substantial challenges. Sorafenib, a widely used sy...Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality and disease burden worldwide, and its clinical management continues to face substantial challenges. Sorafenib, a widely used systemic therapy for advanced HCC, frequently develops acquired resistance upon long-term treatment, in part due to the overexpression of anti-apoptotic Bcl-2 family proteins. Herein, guided by the structural features of Sorafenib, the selective Bcl-2 inhibitor Venetoclax, and the selective Mcl-1 inhibitor AZD5991, we designed and synthesized a series of novel Sophocarpine-derived analogues bearing a pyridylethyl moiety via a molecular-hybridization strategy. Molecular docking suggested a favorable binding mode, in which the resulting scaffold could occupy the hydrophobic binding pockets of both Bcl-2 and Mcl-1 and engage key residues through hydrogen-bond interactions. In vitro antiproliferative screening (MTT assay) against three human HCC cell lines (Huh-7, MHCC-97H, and HepG2) showed that most compounds exhibited moderate to good activity. Notably, compound S6 emerged as the most potent analogue, with IC₅₀ values of 9.13 ± 0.29 μM (Huh-7), 6.76 ± 0.06 μM (MHCC-97H), and 15.9 ± 0.98 μM (HepG2). Mechanistic studies demonstrated that S6 markedly suppressed proliferation and migration of MHCC-97H cells, induced G1-phase arrest, and promoted apoptosis. Western blot analysis revealed that S6 downregulated anti-apoptotic proteins Bcl-2 and Mcl-1, induced mitochondrial membrane potential (ΔΨm) depolarization, and activated the caspase-dependent apoptotic cascade, as evidenced by caspase-3 activation and PARP1 cleavage. In parallel, a 3D-QSAR (CoMFA) model was constructed to rationalize the structure-activity relationship and to inform further lead optimization. Collectively, these findings identify S6 as a promising Sophocarpine derivative with a putative dual Bcl-2/Mcl-1 targeting profile, with significant anti-HCC activity and potential for preclinical development.
Wang D, Cui S, Yuan J
… +5 more, Li Y, Zhang Y, Zhang Y, Fan W, Tang C
Bioorg Med Chem Lett
· 2026 Jun · PMID 41628742
·
Publisher ↗
This study addresses drug resistance in castration-resistant prostate cancer by developing novel inhibitors of CYP11A1, the key rate-limiting enzyme in androgen synthesis. Based on the clinical candidate Opevesostat, two...This study addresses drug resistance in castration-resistant prostate cancer by developing novel inhibitors of CYP11A1, the key rate-limiting enzyme in androgen synthesis. Based on the clinical candidate Opevesostat, two series of 23 new compounds were designed and synthesized using a 4H-pyran-4-one core to explore structure-activity relationships at the C2 and C6 positions.Compound II-4 exhibited potent inhibitory activity (95.2% at 100 nM; IC₅₀ = 26.7 nM), comparable to Opevesostat (IC₅₀ = 20.4 nM). Importantly, II-4 showed superior selectivity against CYP1A2, 2C9, and 2D6 (2- to 4-fold improvement), attributed to hydrophobic interactions between its C6 methyl group and Ile 84.These results highlight II-4 as a promising lead compound with optimized activity and selectivity, providing valuable insights for overcoming resistance in prostate cancer therapy.
Gwinn RK, Mannangatti P, Mir SM
… +5 more, Kumari S, Le MK, Das SK, Fisher PB, Santos WL
Bioorg Med Chem Lett
· 2026 Jun · PMID 41628741
·
Full text
Developing small molecule drugs to treat metastatic cancer remains challenging and relies on the identification of novel druggable targets within the multistep metastatic cascade. To this end, the pro-metastatic scaffold...Developing small molecule drugs to treat metastatic cancer remains challenging and relies on the identification of novel druggable targets within the multistep metastatic cascade. To this end, the pro-metastatic scaffolding protein, MDA-9/Syntenin-1 was identified and confirmed as a suitable target uniquely involved in the multiple stages of metastasis. Recently, the first-in class PDZ1 domain inhibitor for MDA-9, PDZ1i, was identified displaying significant anti-invasion activity improving survival in an in vivo glioblastoma and in multiple metastatic cancer mouse models. Herein, we report a focused library of substituted 1-(benzo[d]thiazol-2-yl)-3-phenylurea derivatives inspired by the anti-invasion and anti-metastatic agent, PDZ1i. Our studies revealed that 1-(benzo[d]thiazol-2-yl)-3-phenylurea analogs bearing 6-trifluoromethyl (3y) and 6-bromo (3aa) substituents display anti-invasion activity comparable to PDZ1i. However, compounds 3y and 3aa displayed overall decreased cancer cell selectivity and MDA-9 activity relative to PDZ1i. Nonetheless, the reported 1-(benzo[d]thiazol-2-yl)-3-phenylurea derivatives serve as promising starting points for future development of small molecule anti-invasion agents with potential to prevent and treat metastatic cancers.
Ibrahim OF, Morsy RMI, Menon V
… +4 more, Ramadan WS, El-Awady R, Abdu-Allah HHM, Bakhite EA
Bioorg Med Chem Lett
· 2026 May · PMID 41621723
·
Publisher ↗
Inspired by the known anticancer activities of hydroxychalcones and acetamidochalcones, a series of novel hybrid molecules integrating these motifs with a paracetamol core were designed and synthesized. The synthesized c...Inspired by the known anticancer activities of hydroxychalcones and acetamidochalcones, a series of novel hybrid molecules integrating these motifs with a paracetamol core were designed and synthesized. The synthesized chalcone-paracetamol hybrids were evaluated for their antiproliferative activity against a panel of eight human cancer cell lines. Compounds 6a, 6b, and 9, showed good activity against four cancer cell lines (U937, Jurkat, HCT-116 and MCF-7 cells). Notably, derivative 9 was the most potent with IC ranging from 1.50 to 4.50 μM, while showing no significant toxicity toward normal cells. Mechanistic investigations revealed that compound 9 induced cell cycle arrest at G0/G1 phase and stimulated apoptosis. Further biochemical analysis identified it (9) as a multi-target agent, with significant inhibitory activity against EGFR (0.62 ± 0.02 μM), VEGFR-2 (2.26 ± 0.01 μM), COX-2 (17.38 ± 0.13 μM), and tubulin polymerization (19.31 ± 0.29 μM). Molecular docking analysis supported these results, showing strong binding affinities for the respective target proteins, with high binding scores of compound 9 ranging from (-9.2 to -10.0) kcal/mol. Collectively, these findings highlight that compound 9 is worthy of further investigation as a potential anticancer lead.
Zabiulla KM, Ranjan P, Ranganatham A
… +2 more, Athar M, Yellappa S
Bioorg Med Chem Lett
· 2026 Jun · PMID 41621722
·
Publisher ↗
This study reports a structure-guided design, synthesis, and biological evaluation of a novel class of hybrid molecules combining indole and pyrazole scaffolds-both known for their broad pharmacological profiles. A serie...This study reports a structure-guided design, synthesis, and biological evaluation of a novel class of hybrid molecules combining indole and pyrazole scaffolds-both known for their broad pharmacological profiles. A series of 5-indolyl-pyrazole derivatives (n = z1-z44) were synthesized and characterized through H/C NMR and HR-MS analysis. The synthesized compounds were screened against H37Rv and two multidrug-resistant clinically isolated strains M.tb* and M.tb**. Several derivatives (notably z1 and z8) showed potent inhibition at concentrations as low as 25 μg/mL may be even more potent at lower concentrations and a comparative analysis could be possible. Complementary molecular docking studies were conducted using the InhA enzyme (PDB ID: 4TZK), a validated target in mycolic acid biosynthesis. Lead compounds demonstrated favorable binding energies (e.g., -6.35 kcal/mol for z1), engaging key active-site residues (PHE97, MET103, PHE149, TYR158) through hydrophobic, π-stacking, and van der Waals interactions, alongside critical contact with the NAD cofactor. Interaction fingerprint analysis correlated ligand-residue contacts with biological activity, underscoring the importance of aromatic planarity and substituent modulation for effective InhA inhibition. This integrated synthetic-biological-computational workflow lays a promising foundation for the development of next-generation anti-TB agents with improved efficacy against resistant strains.
Xiang S, Lv M, Wang C
… +4 more, Wang Z, Chen H, Lv P, Yang C
Bioorg Med Chem Lett
· 2026 Jun · PMID 41620144
·
Publisher ↗
Targeted therapies have pioneered a more effective new pathway in cancer treatment by leveraging their precision-targeting advantages. Spiro tetramic acids are a kind of unique pyrrolidine-2,4-dione core structure contai...Targeted therapies have pioneered a more effective new pathway in cancer treatment by leveraging their precision-targeting advantages. Spiro tetramic acids are a kind of unique pyrrolidine-2,4-dione core structure containing a spiro ring structure, primarily employed as agro-chemicals with limited application in the field of anti-cancer. In this paper, fourteen novel 3-acetyl and 3-phenyl spiro tetramic acids were designed, synthesized, and evaluated for anti-proliferation in cancer cells. 3-Acetyl and 3-phenyl spirotetramic acids exhibited toxic effects against tested cancer cell lines. Among the 14 compounds, compound 8d was the most effective against RKO and H1299 with Half Maximal Inhibitory Concentration (IC) 3 ± 1 and 19 ± 2 μM. Further molecular structural prediction, bioinformatics analysis, and molecular docking revealed that compound 8d may target MMP1, MMP7 and PLK1. Additionally, 8d induced cell cycle arrest in G1 phase by increasing the expression of p21 protein and decreasing the expression of CCND1 and CCNB1 proteins. 8d also induced cell apoptosis through the mitochondrial pathways, as evidenced by alterations in the expressions of pertinent proteins, including Bcl-2 and Bax. These results indicated that the novel spirotetramine derivative 8d is a potential anti-cancer candidate drug and provides a new structural basis for the development of anti-cancer drugs.
Bioorg Med Chem Lett
· 2026 May · PMID 41617114
·
Publisher ↗
The hypoxic microenvironment within tumors serves as a pivotal factor that propels malignant progression and fosters resistance to both radiotherapy and chemotherapy. Therefore, non-invasive hypoxia imaging using radionu...The hypoxic microenvironment within tumors serves as a pivotal factor that propels malignant progression and fosters resistance to both radiotherapy and chemotherapy. Therefore, non-invasive hypoxia imaging using radionuclides is crucial for establishing personalized treatment plans. This review summarizes research progress on various radiolabeled hypoxia imaging probes. It focuses on bioreductive nitroimidazole derivatives, metal complexes, novel molecules targeting hypoxia-induced proteins (such as CA IX), and dual-targeting probes. The review elucidates the relationship between probe structural design and in vivo imaging performance. The development of probes has transitioned from an initial emphasis on high lipophilicity and uptake (e.g., [F]FMISO) to a novel phase centered on hydrophilic modifications, including glycosylation and PEGylation. These modifications optimize pharmacokinetics and improve the signal-to-noise ratio. This review details the impact of various strategies on probe uptake in tumor and non-target tissues. These strategies encompass the nitroimidazole positional isomer effect, particularly highlighting the benefits of the 2-position, along with multivalent implementations. They also include the precise regulation of linker types and lengths, the selection of radionuclide chelators, and molecular charge adjustment. Furthermore, a comparative analysis elucidates the pivotal function of "fine-tuning the redox potential" in augmenting specificity. Modifying probes by incorporating electron-donating groups moderately decreases their reduction potential. This strategy effectively reduces non-specific background signals and achieves an optimal redox potential window. Finally, this review provides a concise summary of the existing challenges associated with hypoxia-targeting probes and puts forth innovative concepts for their future development. Ideal probe design should aim for the precise synergy of "appropriate pharmacokinetics", "optimal redox potential", and dual-targeting or multi-targeting strategies. These methodologies furnish a theoretical foundation and design concepts for the forthcoming generation of tumor hypoxia imaging agents.
Fine J, Perkins JB, Gullo V
… +3 more, Cohen RD, Lu J, Singh SB
Bioorg Med Chem Lett
· 2026 May · PMID 41610998
·
Publisher ↗
Kibdelomycin and kibdelomycin A are antibiotics biosynthesized by Kibdelosporangium banguiense CA-240109. Kibdelomycin demonstrates broad-spectrum activity, exhibiting significant activity against antibiotic-resistant Gr...Kibdelomycin and kibdelomycin A are antibiotics biosynthesized by Kibdelosporangium banguiense CA-240109. Kibdelomycin demonstrates broad-spectrum activity, exhibiting significant activity against antibiotic-resistant Gram-positive bacteria. These compounds inhibit DNA GyrB and ParE through a distinct U-shaped multi-contact binding mechanism and do not display cross-resistance with established antibiotics. To investigate structure-activity relationships, various methodologies were employed to identify new congeners, including the implementation of repeat batch fermentation. This study presents the discovery, isolation, structural elucidation, and antibacterial assessment of two mono des-chloro congeners of kibdelomycin A produced via repeat batch fermentation. The newly discovered compounds displayed inhibitory effects on bacterial growth in Staphylococcus aureus and Escherichia coli, with minimum inhibitory concentrations (MIC) ranging from 16 to 64 μg/mL. The MIC values for E. coli are comparable to kibdelomycin, whereas for S. aureus the MIC is 64 times less potent than that of kibdelomycin. AI-assisted docking studies involving DNA gyrase B enzymes provide reasonable support for varying activities of the congeners.
Wang J, Luo J, Mang Z
… +5 more, Zhang S, Sun C, Kai G, Xu H, Li H
Bioorg Med Chem Lett
· 2026 Jun · PMID 41610997
·
Publisher ↗
1,6,6-Trimethyl-2-((4-methylpiperazin-1-yl)methyl)phenanthrol[1,2-b]furan-7,10,11(6H)-trione (TA401), a newly synthesized tanshinone IIA analog, was developed to enhance the anti-tumor effect of CPT-11 in combined therap...1,6,6-Trimethyl-2-((4-methylpiperazin-1-yl)methyl)phenanthrol[1,2-b]furan-7,10,11(6H)-trione (TA401), a newly synthesized tanshinone IIA analog, was developed to enhance the anti-tumor effect of CPT-11 in combined therapy and alleviate its gastrointestinal side effect. The combined cytotoxicity on HT29 and HCT116 colorectal cancer cells induced by TA401 and CPT-11 was comprehensively evaluated in vitro. The classical apoptosis pathway, including Bax, BCL-2, caspase 3, the phosphorylation level of ERK and AKT, was also examined to illustrate molecular mechanisms of the synergistic apoptosis both in vitro and in vivo. Synergistic suppression of colorectal cancer cell proliferation by TA401 and CPT-11 was observed at a fixed ratio (TA401:CPT-11 at 1:20). The apoptosis induced by combined treatment was triggered by activation of classical apoptotic pathway and decreased expression of TOP I, which was further confirmed in vivo. In addition, diarrheic side effect of CPT-11 was reduced by TA401 in the combined treatment. TA401 effectively promoted the anti-tumor effects of CPT-11 with alleviated side effects, which may be developed as a potential candidate for the combined therapy with CPT-11 against colorectal cancer.
Tian J, Zhang R, Xing Z
… +6 more, Liu Y, Lin W, Huang X, Rao Z, Peng W, Fang Y
Bioorg Med Chem Lett
· 2026 May · PMID 41605335
·
Publisher ↗
Pks13 is a promising target for tuberculosis (TB) treatment, offering a new pathway for anti-TB drug development. Although benzofuran derivatives such as TAM16 have demonstrated significant efficacy in vitro and in vivo,...Pks13 is a promising target for tuberculosis (TB) treatment, offering a new pathway for anti-TB drug development. Although benzofuran derivatives such as TAM16 have demonstrated significant efficacy in vitro and in vivo, their development was discontinued due to concerns about hERG inhibition. Herein, we designed and synthesized a series of novel furo[2,3-b]isoquinoline derivatives using ring fusion and basicity-reduction strategies. Through SAR studies, compound B23 was identified as a potent Pks13 inhibitor (IC = 1.12 μM) with significantly reduced hERG inhibition (IC > 10 μM). The markedly improved hERG selectivity not only validates our structural strategy for mitigating cardiotoxicity risks, but also provides a solid foundation for further development of Pks13-TE inhibitors that combine potent anti-TB activity with an improved safety profile.
Shi C, Zhong W, Qiang G
… +4 more, Ying P, Guo J, Si Y, Mou J
Bioorg Med Chem Lett
· 2026 Jun · PMID 41581674
·
Publisher ↗
The tumor microenvironment (TME) plays a pivotal role in determining tumor progression and treatment response. Within the TME, redox processes mediated by reactive oxygen species (ROS) and nitric oxide (NO) are criticall...The tumor microenvironment (TME) plays a pivotal role in determining tumor progression and treatment response. Within the TME, redox processes mediated by reactive oxygen species (ROS) and nitric oxide (NO) are critically involved in regulating intercellular and intracellular signaling. In this study, we hypothesized that conjugating an NO-releasing moiety to paeonol derivatives and introducing a chalcone structure to enhance thioredoxin reductase (TrxR) targeting would yield compounds with potent anticancer activity. Accordingly, a series of mono- and di-substituted nitrate derivatives were synthesized. The inhibitory activities of all synthesized compounds were evaluated against BGC823, HCT116, Hep G2, and MCF-7 cell lines using the CCK-8 assay. Among the paeonol chalcone derivatives, compound 11f exhibited significant antiproliferative activity across the tested cancer cell panel. It was identified as a promising candidate with potent TrxR inhibitory activity (IC = 0.26 ± 0.17 μM in vitro; IC = 0.33 μM in vivo). Furthermore, compound 11f induced S-phase arrest and promoted apoptosis in MCF-7 cells. These findings underscore the enhanced anticancer potential of paeonol chalcone derivatives, attributable to the synergistic effects of NO and ROS.
Tien LQ, Phung HTT, Do HH
… +6 more, Khac TN, Minh PTN, Linh VNH, Thang NQ, Wang S, Tran PT
Bioorg Med Chem Lett
· 2026 May · PMID 41580137
·
Publisher ↗
In this study, a series of thirty-five novel imidazolium salts bearing a 2-oxindoles were designed and synthesized as potent acetylcholinesterase (AChE) inhibitors for Alzheimer's disease. Structural diversity was introd...In this study, a series of thirty-five novel imidazolium salts bearing a 2-oxindoles were designed and synthesized as potent acetylcholinesterase (AChE) inhibitors for Alzheimer's disease. Structural diversity was introduced through substituent variation on both the oxindole and phenyl rings to investigate structure-activity relationships. All compounds were evaluated in vitro by the modified Ellman assay, revealing several highly potent inhibitors in the nanomolar to subnanomolar range. The most active compound, 32, exhibited an IC of 0.17 nM, surpassing galantamine and donepezil. Enzyme kinetic study indicated that all compounds act as mixed-type AChE inhibitors. Machine learning-based binding affinity predictions (ΔG = -10.30 to -8.18 kcal/mol) correlated well with experimental activity. Molecular docking against AChE (PDB ID: 4EY6 and 7E3H) revealed that compounds bearing electron-withdrawing substituents exhibited superior binding scores and favorable interactions with key catalytic residues and aromatic residues. Molecular dynamics (200 ns) simulations demonstrated that compound 32 maintained a highly stable conformation within the AChE active site, with consistent hydrogen bonding and low root-mean-square deviation (RMSD) fluctuations. In addition, MM-PBSA binding free energy analysis (ΔG = -33.42 kcal/mol) further confirmed its strong and stable interactions compared with galantamine (-17.82 kcal/mol) and donepezil (-21.20 kcal/mol). Furthermore, in silico ADME predictions suggested favorable oral absorption and potential blood-brain barrier permeability for compound 32, while maintaining an acceptable safety profile compared to galantamine and donepezil. These promising findings highlight the potential of oxindole-imidazolium hybrids as effective AChE inhibitors and warrant further investigation for the development of novel anti-Alzheimer agents.
Bioorg Med Chem Lett
· 2026 May · PMID 41577017
·
Publisher ↗
Cancer remains one of the leading causes of mortality worldwide. As a result, bioactive compounds derived from herbal medicines have gained increasing attention in cancer research. Ardicrenin, extracted from Ardisia cren...Cancer remains one of the leading causes of mortality worldwide. As a result, bioactive compounds derived from herbal medicines have gained increasing attention in cancer research. Ardicrenin, extracted from Ardisia crenata, has been evaluated for its ability to suppress the growth of MG-63 cells. Remarkably, its inhibitory effect on MG-63 cell proliferation is comparable to that of Taxol. Unlike Taxol, which induces apoptosis by stabilizing microtubules, ardicrenin regulates cell proliferation and death through the integrin signaling pathway. These findings highlight ardicrenin as a promising candidate for anti-tumor drug development.
Pérez-Ramos P, Gomez-Escobedo R, Nogueda-Torres B
… +6 more, Moreno-Rodriguez A, Llamedo A, Rodríguez-Solla H, Soto SM, Rivera G, Soengas RG
Bioorg Med Chem Lett
· 2026 May · PMID 41577016
·
Publisher ↗
Chagas disease or American trypanosomiasis remains a serious public health concern with unsatisfactory treatment outcomes. The serious problems with the efficacy and toxicity of the drugs currently used to treat Chagas d...Chagas disease or American trypanosomiasis remains a serious public health concern with unsatisfactory treatment outcomes. The serious problems with the efficacy and toxicity of the drugs currently used to treat Chagas disease, along with the emergence of resistant strains, have made the development of new chemotherapy strategies a priority. In this work, fourteen (C^S)-cyclometallated gold(III) complexes were evaluated as potential trypanocidal agents. All the tested compounds had better trypanocidal activity against trypomastigotes than the reference drugs, with five complexes presenting an SI above ten for both strains, and two complexes displaying a SI value >200 for the NINOA strain. Among them, complex 6b was identified as a highly selective agent against T. cruzi amastigotes of the NINOA strain. Furthermore, cytotoxicity to mouse macrophage cells is very low for this compound, resulting in a better selectivity index than that of reference drugs Bnz and Nfx. These results suggest the potential of (C^S)-cyclometallated gold (III) complexes as promising antiparasitic drug candidates.
Tvrdoňová M, Zuzak Y, Pilátová MB
… +3 more, Jáger D, Mezencev R, Martinková M
Bioorg Med Chem Lett
· 2026 May · PMID 41571011
·
Publisher ↗
A novel 4-C-branched sugar mimetic based on a 1,4-dideoxy-1,4-imino-d-lyxitol (DIL) scaffold was designed and synthesised. Its construction features an early-stage introduction of the side chain via an OCM reaction follo...A novel 4-C-branched sugar mimetic based on a 1,4-dideoxy-1,4-imino-d-lyxitol (DIL) scaffold was designed and synthesised. Its construction features an early-stage introduction of the side chain via an OCM reaction followed by an alkylative cyclisation, providing the desired heterocyclic system. The subsequent interconversion of functional groups accompanied by the selective deprotection protocol allowed the tetrahydrofuran ring to be cleaved. Cell viability experiments revealed a cytotoxic effect of the target compound comparable to that of cisplatin on the A2058 and MCF-7 cancer cell lines. Moreover, 4-C-tridecyl-DIL proved to be moderately active against Jurkat and HeLa cells (IC = 20.58 μM and 22.7 μM, respectively). In addition, docking studies identified the binding modes of this novel pyrrolidine-based iminosugar to human β-glucocerebrosidase.