Bioorganic Chemistry最新文献

{"title":"Novel chalcone candidates as potential in vitro and in vivo anti-inflammatory agents: Synthesis, in silico docking, multitarget bioevaluation and molecular dynamic simulation","authors":"Alshimaa Kh.M. Ahmed ,&nbsp;Eman A.M. Beshr ,&nbsp;Ibrahim M. Salem ,&nbsp;Osama A.A. Ahmed ,&nbsp;Tarek S. Ibrahim ,&nbsp;Deiaa E. Elsayed Abouzed ,&nbsp;Ahmed Mostafa Mahmoud ,&nbsp;Mamdouh F.A. Mohamed","doi":"10.1016/j.bioorg.2025.108540","DOIUrl":"10.1016/j.bioorg.2025.108540","url":null,"abstract":"<div><div>Managing inflammation with the commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) represents a critical challenge in modern medicine because of its strong influence on the cyclooxygenase-1 (COX-1) enzyme might induce substantial adverse effects. Therefore, there is urgent necessity for the exploration of safer alternatives, particularly cyclooxygenase-2 (COX-2) inhibitors. This study aimed to address this issue through the synthesis and evaluation of 19 new chalcone derivatives (<strong>2a-m</strong> and <strong>4a-f</strong>) for their <em>in vitro</em> anti-inflammatory activity against various biotargets including iNOS, COX-2, 5-LOX, PGE2, and TNFα. Moreover, these compounds showed moderate to strong anti-inflammatory activity in the carrageenan rat paw edema test. Compounds <strong>2a</strong>, <strong>2f</strong>, <strong>2</strong> <strong>h</strong>, <strong>2</strong> <strong>m</strong>, and <strong>4b</strong> are promising candidates for the treatment of inflammatory diseases. In particular, compound <strong>4b</strong> was demonstrated to be the most effective derivative as a nitric oxide release inhibitor, exhibiting a 61.7 % inhibition rate. It exhibited substantial selectivity for COX-2 (IC₅₀ = 1.933 μM) compared to COX-1 (IC₅₀ = 5.526 μM). Compound <strong>4b</strong> exhibited notable inhibitory activity against 5-LOX (IC₅₀ = 2.112 μM) and demonstrated considerable inhibitory activity against iNOS, PGE2, and TNF-α biotargets in LPS-stimulated RAW cells, with IC₅₀ values of 114.18, 37.13, and 58.15 nM, respectively. The <em>in vivo</em> anti-inflammatory effects demonstrated the significant efficacy of compound <strong>4b</strong>, as evidenced by a notable edema inhibition rate of 37.05 %, along with minimal ulcerogenic activity observed in the histopathological findings. <em>In silico</em> experiments demonstrated that the intermolecular contacts of the most active chemical <strong>4b</strong> with the biotargets COX-2, 5-LOX, and iNOS were analyzed by docking, revealing significant binding interactions. The stability of the interactions between compound <strong>4b</strong> and the targets COX-2, 5-LOX, and iNOS was assessed using a standard 100 ns atomistic dynamic simulation method. Various parameters derived from MD simulation trajectories were adjusted and validated to confirm the stability of the generated complexes under dynamic settings. Ultimately, compound <strong>4b</strong> exhibited favorable physicochemical properties and satisfactory drug-likeness, indicating its potential as an oral anti-inflammatory agent, warranting additional structure-activity relationship investigation and optimization.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"161 ","pages":"Article 108540"},"PeriodicalIF":4.5,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143887212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the antivirulence mechanisms of ZnO-PEG-quercetin nanoparticles: Biofilm disruption, attenuation of virulent factors, and cell invasion suppression against pathogenic Pseudomonas aeruginosa","authors":"Fatemeh Esnaashari ,&nbsp;Ghazaleh Nikzad ,&nbsp;Hossein Zahmatkesh ,&nbsp;Hojjatolah Zamani","doi":"10.1016/j.bioorg.2025.108527","DOIUrl":"10.1016/j.bioorg.2025.108527","url":null,"abstract":"<div><div>The dense biofilm architecture and efflux pump activity play critical roles in <em>Pseudomonas aeruginosa</em> infections by hindering the accumulation and long-term efficacy of antibacterial agents within bacterial cells. The development of engineered nanoparticles capable of penetrating the polysaccharide matrix of biofilms represents a promising strategy for addressing bacterial infections. This is the first report on the synthesis of quercetin-functionalized PEGylated ZnO nanoparticles (ZnO-PEG-QUE NPs) and the evaluation of their anti-biofilm activity against pathogenic strains of <em>P. aeruginosa</em>. The synthesized NPs exhibited spherical shapes with an average size of 59.52 nm. ZnO-PEG-QUE NPs demonstrated biofilm inhibitory levels between 49 % and 67 %, and significantly reduced the production of total exopolysaccharides, alginate, and pellicle by 64.61 %–71.69 %, 30.47 %–45.36 %, and 24.22 %–85.97 %, respectively. ZnO-PEG-QUE NPs not only inhibited early-stage biofilm formation but also disrupted mature biofilms, indicating a dual mode of action against both biofilm development and persistence. Based on our findings, ZnO-PEG-QUE NPs effectively eradicated mature biofilms by 67.2 %–72 % and significantly reduced the metabolic activity and viable cells of preformed biofilms to 34.12 %–55.57 % and 6.25–8.15 log CFU, respectively. Electron and fluorescence microscopy analyses also confirmed the antibiofilm potential of ZnO-PEG-QUE NPs. Furthermore, bacterial adhesion and invasion to HDF cells were significantly diminished in the NP-treated groups. The attenuation of efflux pump activity in the NP-treated strains was confirmed using the EtBr-agar cartwheel assay. Taken together, these findings highlight the therapeutic potential of ZnO-PEG-QUE NPs as a novel and effective strategy to combat biofilm-associated infections, warranting further investigation in preclinical models.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"161 ","pages":"Article 108527"},"PeriodicalIF":4.5,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143887213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design and synthesis of thiolutin derived PSMD14/HDAC dual-target inhibitors against esophageal squamous cell carcinoma","authors":"Guoguo He ,&nbsp;Zhenhui Wu ,&nbsp;Xuan Yang ,&nbsp;Xinrong Luo ,&nbsp;Lili Zhang ,&nbsp;Zhenting Du ,&nbsp;Shuwei Li ,&nbsp;Chuanxing Wan","doi":"10.1016/j.bioorg.2025.108500","DOIUrl":"10.1016/j.bioorg.2025.108500","url":null,"abstract":"<div><div>Esophageal cancer is one of the most migratory, invasive, and lethal malignancies and has a poor prognosis, highlighting the urgent need to develop more effective drugs for its treatment. Given tha<strong>t</strong> PSMD14 and HDAC play an important role in the treatment of esophageal cancer, thiolutin is used as a lead compound to design and synthesize a series of dual-target PSMD14/HDAC small molecule inhibitors, aiming to discover more effective anti-esophageal cancer drugs. Through the <em>in vitro</em> screening of PSMD14/HDAC enzyme inhibitory activities of a series of thiolutin derivatives, it was found that compound 8b, with a linker length of 8 and a Zn²⁺-chelating group of 1,2-phenylenediamine, exhibited the most balanced inhibitory activity against PSMD14/HDAC.The impact of <strong>8b</strong> on PSMD14/HDAC at the cellular level was evaluated, and its drug-like properties were further assessed <em>in vivo</em>. Compound <strong>8b</strong> demonstrates balanced dual-target activity (PSMD14 IC₅₀ = 238.7 ± 27 nM, HDAC1 IC₅₀ = 141.2 ± 10.3 nM) and excellent cytotoxicity against esophageal cancer cells (IC₅₀ = 30–250 nM), effectively reversing epithelial-mesenchymal transition in cancer cells. Moreover, <strong>8b</strong> exhibited excellent pharmacokinetic characteristics. More importantly, in a nude mouse xenograft model with subcutaneous transplantation of KYSE 30 cells, compound <strong>8b</strong> (0.8 mg/kg, BID, PO, TGI = 81 %; 0.8 mg/kg, Q3D, SC, TGI = 77 %) significantly inhibited tumor growth, outperforming single-agent or combination treatments, thereby highlighting the therapeutic advantages of dual-target inhibition. These findings highlight the potential of dual-target PSMD14/HDAC inhibitors as a promising strategy for developing anti-esophageal cancer drugs.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"161 ","pages":"Article 108500"},"PeriodicalIF":4.5,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143892182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Precise structure manipulation of selective estrogen receptor modulators led to first-in-class thiophene-3-benzamide derivatives as potential ER-antagonists without uterotrophic activity","authors":"Bader Huwaimel ,&nbsp;Amr S. Abouzied ,&nbsp;Abdul-Hamid Emwas ,&nbsp;Al-Shaimaa F. Ahmed ,&nbsp;Mohamed K.S. El-Nagar ,&nbsp;Hamdoon A. Mohammed ,&nbsp;Nader M. Alrashidi ,&nbsp;Marwan A. Alrashidi ,&nbsp;Rakan E. Alshammari ,&nbsp;Abdulelah Y. Albladi ,&nbsp;Saad Alqarni ,&nbsp;Shaymaa E. Kassab","doi":"10.1016/j.bioorg.2025.108512","DOIUrl":"10.1016/j.bioorg.2025.108512","url":null,"abstract":"<div><div>The present study introduces two sets of compounds: panel A, which features thiophene-3-benzamide, and panel B, which includes pyrazole-4-benzamide. We designed these compounds to target estrogen receptors (ER) while minimizing uterotrophic activities. The chemical structures of the two panels have been derived from structural modifications of the selective estrogen modulator, methyl-piperidinopyrazole (MPP). These modifications aim to reduce uterotrophic effects. In our design, we incorporated amide, amine, and ketone spacers between the three phenyl rings, substituting the central thiophene and pyrazole rings in the target ER antagonists. This structural strategy aims to alter the formation of tris-<em>p</em>-phenol metabolites, which are associated with the potential estrogenic activity of this class of compounds. The cytotoxicity of the compounds from panel A revealed significant activity against MCF7 cells, which are estrogen-dependent breast cancer cells. Importantly, these compounds demonstrated minimal cytotoxicity against other cell lines, including skin, osteosarcoma, and triple-negative breast cancer. Among the compounds tested, 5-benzoyl-thiophene-3-carboxamide <strong>5a</strong> and 5-(4-chlorobenzoyl)-thiophene-3-carboxamide <strong>5d</strong> exhibited the highest cytotoxicity against MCF7 cells, with IC₅₀ values of 7.38 μM and 8.50 μM, respectively. Furthermore, both <strong>5a</strong> and <strong>5d</strong> showed potential as antiestrogens, exhibiting no estrogenic activity in the uterine tissues of immature rats. In the dose-response experiment, the <strong>5d</strong> antiestrogenic potency (EC₅₀ = 5.530 μM) was comparable to that of Tamoxifen (EC₅₀ = 7.625 μM). Molecular Docking and Molecular Dynamics simulations elucidated the antiestrogenic activity of <strong>5d</strong> and inactivity of 5-fluorobenzoyl counterpart, <strong>5e.</strong> The inactive derivative <strong>5e</strong> in the active site exhibited an unfavorable conformation and unstable drug-receptor complex formation.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"161 ","pages":"Article 108512"},"PeriodicalIF":4.5,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143887211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antimicrobial peptide mimic 329 potentiates minocycline against carbapenem-resistant Klebsiella pneumoniae","authors":"Yongqing Liu ,&nbsp;Tingting Yan ,&nbsp;Hongtao Kong ,&nbsp;Leizi Chi ,&nbsp;Dejun Liu ,&nbsp;Shangshang Qin ,&nbsp;Yang Wang ,&nbsp;Muchen Zhang ,&nbsp;En Zhang","doi":"10.1016/j.bioorg.2025.108517","DOIUrl":"10.1016/j.bioorg.2025.108517","url":null,"abstract":"<div><div>As antibiotic resistance increases and new drug development lags, the effectiveness of single antibiotics has drastically diminished for clinical infection treatment. The resistance crisis is exacerbated by the swift development and dissemination of Gram-negative bacteria that are extensively drug-resistant (XDR), particularly strains resistant to carbapenems in clinical settings. In this scenario, antibiotic adjuvants play a crucial role in revitalizing existing treatments to combat carbapenem-resistant bacterial infections. In this study, we synthesized ten small molecular antimicrobial peptide mimics and identified antimicrobial peptide mimic 329 (A329), which exhibited a synergistic effect with minocycline (FICI = 0.023), enhancing its efficacy by 4- to 128-fold, and significantly enhanced the antibacterial efficacy of minocycline against carbapenem-resistant <em>Klebsiella pneumoniae</em> (CRKP, 0.015 ≤ FICI ≤0.141), prevented the emergence of minocycline resistance, improved the survival rate of mice, and decreased bacterial load in tissues at 8 + 8 mg/kg. Mechanistic studies revealed that A329 increases bacterial membrane permeability and disrupts the proton-motive force. Additionally, A329 combined with minocycline boosts intracellular minocycline accumulation, induces intracellular production of reactive oxygen species (ROS), and ultimately triggers bacterial death. These findings advised that A329 in combination with minocycline is a potential combination therapy against XDR-associated infections.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"161 ","pages":"Article 108517"},"PeriodicalIF":4.5,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143892171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of polycyclic polyprenylated acylphloroglucinols with antitumor activities from Garcinia pedunculata Roxb. fruits based on molecular networking","authors":"De-Li Zou ,&nbsp;Wen-Zhuo Liao ,&nbsp;Han-Gao Yang ,&nbsp;Bin Lin ,&nbsp;Hua-Rong Xu ,&nbsp;Hui-Ming Hua ,&nbsp;Da-Hong Li","doi":"10.1016/j.bioorg.2025.108513","DOIUrl":"10.1016/j.bioorg.2025.108513","url":null,"abstract":"<div><div>Garpedvinin A (<strong>1</strong>), a novel polycyclic polyprenylated acylphloroglucinol (PPAP) with a bicyclo[4,2,1]nonane core, 13 previously undescribed PPAPs, garpedvinins B-N (<strong>2-14</strong>) and 6 known analogs (<strong>15-20</strong>) were isolated from <em>Garcinia pedunculata</em> by various chromatographic methods combined with Global Natural Products Social Molecular Networking. The structures were identified by the analyses of spectral characteristics, computational chemistry calculations and single-crystal X-ray diffraction. A plausible biosynthetic pathway for garpedvinin A was suggested based on the isolated precursor, cambogin. Compounds <strong>2-6</strong>, <strong>8</strong>, <strong>11</strong>, <strong>13, 15-18</strong> and <strong>20</strong> displayed cytotoxic effects on three cancer cell lines, HepG2, A549 and MCF-7. <strong>6</strong> showed the strong inhibitory effect on the proliferation of HepG2 cells in vitro, inducing cell apoptosis in a concentration-dependent manner and blocking the cell cycle at the S phase. Furthermore, <strong>6</strong> affected the expression of apoptosis-related proteins Bax, Bcl2 and pro-Caspase-3.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"161 ","pages":"Article 108513"},"PeriodicalIF":4.5,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143892172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of novel adjuvants: Identification of saponins from Hylomecon japonica (Thunb.) Prantl & Kündig and insights into their in vitro and in vivo activities.","authors":"Peixin Shi,&nbsp;Lichun Zhao,&nbsp;Min Zhang,&nbsp;Jingjing Zhao,&nbsp;Jianan Niu,&nbsp;Jianxiu Zhai,&nbsp;Jun Yin","doi":"10.1016/j.bioorg.2025.108501","DOIUrl":"10.1016/j.bioorg.2025.108501","url":null,"abstract":"<div><div>Bioassay-guided approach resulted in the isolation of fourteen triterpenoid saponins were isolated from the herba of <em>Hylomecon japonica</em> (Thunb.) Prantl &amp; Kündig including eight novel saponins (<strong>1</strong>–<strong>8</strong>) and six known saponins (<strong>9</strong>–<strong>14</strong>). Their chemical structures were unequivocally determined through comprehensive spectral data analysis. By screening all compounds to enhance the ability of RAW 264.7 cells to produce NO, the novel compound <strong>1</strong> (HA) was identified as a candidate for immune adjuvant. <em>In vitro</em> experiments demonstrated that HA promotes the proliferation of spleen lymphocytes, DC 2.4, and RAW 264.7 cells, while also enhancing the phagocytic activity of DC 2.4 and RAW 264.7 cells. HA also counteracts the LPS-induced decline in dendritic cell phagocytosis and works with LPS to further improve macrophage phagocytosis. The network pharmacology analysis identified a total of 46 targets and 20 pathways through which HA exerts its immune-enhancing effects. <em>In vivo</em> experiments, HA enhanced immune organ development, boosted specific serum antibodies, increased Th1 and Th2 cytokines, and amplified related gene expression. And HA could boost lymphocyte proliferation, increased CD3⁺ T cells and altered CD4⁺ and CD8⁺ levels. It also promoted dendritic cell maturation in lymph nodes, raised MHC II molecules and co-stimulatory factors. HA triggered the upregulation of TL4, MyD88, and IKK proteins and promoted the phosphorylation of NF-κB P65 and P-IkBα within the TLR4/NF-κB signaling pathway, while simultaneously suppressing IκBα protein expression. HA has the characteristics and functions of enhancing immunity and could be applied as an immune adjuvant. The findings presented herein establish a fundamental basis for investigating the immune adjuvant effect of triterpenoid saponins.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"161 ","pages":"Article 108501"},"PeriodicalIF":4.5,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143894513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and profiling (in vitro and in silico) of the 6-methoxy/hydroxy substituted 7-acetyl-2-aryl-5-bromobenzofurans for antihyperglycemic, cytotoxic and antioxidant properties","authors":"Abdufatai T. Ajiboye ,&nbsp;Jackson K. Nkoana ,&nbsp;Garland K. More ,&nbsp;Ahmed A. Elhenawy ,&nbsp;Malose J. Mphahlele","doi":"10.1016/j.bioorg.2025.108465","DOIUrl":"10.1016/j.bioorg.2025.108465","url":null,"abstract":"<div><div>A small library of the 7-acetyl-2-aryl-5-bromo-6-methoxybenzo[<em>b</em>]furans <strong>2a</strong>–<strong>f</strong> was synthesized and transformed into the corresponding <em>ortho-</em>(hydroxyacetyl) substituted 2-arylbenzo[<em>b</em>]furan derivatives <strong>3a</strong>–<strong>f</strong>. The structures of both series of compounds were characterized using a combination of spectroscopic techniques complemented with single crystal X-ray diffraction (XRD) analysis of a representative example from each category. Both series of compounds were evaluated through enzymatic assays <em>in vitro</em> for potential to inhibit α-glucosidase, α-amylase and/or protein tyrosine phosphatase 1 beta (PTP1B) all of which are associated with the pathogenesis and progression of type 2 diabetes mellitus (T2DM). The test compounds exhibited moderate to significant antigrowth effect against the breast cancer (MCF-7) cell line and reduced cytotoxicity against the human embryonic kidney derived (Hek293-T) cell line compared to the anticancer drug, doxorubicin. The anti-oxidation potential of the test compounds was evaluated spectrophotometrically using the nitric oxide (NO) radical scavenging assay. A cell-based antioxidant activity assay involving lipopolysaccharide (LPS) induced reactive oxygen species production in the MCF-7 and Hek293-T cells revealed their potential to mitigate against oxidative stress. Molecular docking analysis revealed hydrogen bonding, hydrophobic and π-π stacking interactions to play a significant role in the binding affinity and interactions of the test compounds with amino acid residues in the active sites of the test enzymes.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"161 ","pages":"Article 108465"},"PeriodicalIF":4.5,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143879285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dialkyloxyphenyl hybrids as PDE4B inhibitors: Design, synthesis, in vitro/in vivo anti-inflammatory activity and in silico insights","authors":"Aya M. Almatary ,&nbsp;Mohamed S.H. Salem ,&nbsp;Mohamed R. Elnagar ,&nbsp;Mohamed H. Aboutaleb ,&nbsp;Tarek S. Ibrahim ,&nbsp;Abdelrahman Hamdi ,&nbsp;Magda A.-A. El-Sayed","doi":"10.1016/j.bioorg.2025.108511","DOIUrl":"10.1016/j.bioorg.2025.108511","url":null,"abstract":"<div><div>A series of novel dialkyloxyphenyl hybrids <strong>11a-11</strong><strong>h</strong> and <strong>12a-12c</strong> were designed and synthesized as PDE4 inhibitors with anti-inflammatory activity. All compounds demonstrated nanomolar-range inhibitory activity against both PDE4B and PDE4D isoforms with notable selectivity for PDE4B. The 3,4-dimethoxyphenyl derivative <strong>11e</strong> exhibited superior PDE4B inhibitory activity (IC₅₀ = 2.82 nM), with nine-fold selectivity compared to 1.5 of Rolipram. In TNF-α inhibition assays, <strong>11e</strong> demonstrated remarkable potency (IC₅₀ = 7.20 nM), comparable to roflumilast, followed by <strong>11d</strong> (IC₅₀ = 15.54 nM) and <strong>11b</strong> (IC₅₀ = 28.52 nM). <em>In vivo</em> evaluation using LPS-induced sepsis model revealed that <strong>11e</strong> achieved the highest inhibition of both TNF-α (52.19 %) and neutrophilia (56.47 %) compared to reference compounds. Molecular docking and dynamics studies revealed that hybrids <strong>11b</strong>, <strong>11d</strong>, and <strong>11e</strong> exhibit a characteristic binding mode within the PDE4 active sites, rationalizing their activity through specific interactions, and demonstrating higher stability in the active site compared to Roflumilast.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"161 ","pages":"Article 108511"},"PeriodicalIF":4.5,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143892168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Study of tamoxifen derived perfluoroalkylated olefins in breast cancer treatment","authors":"Wojciech Chaladaj ,&nbsp;María C. Arufe ,&nbsp;Fátima Lucio-Martínez ,&nbsp;Juan Fafián-Labora","doi":"10.1016/j.bioorg.2025.108525","DOIUrl":"10.1016/j.bioorg.2025.108525","url":null,"abstract":"<div><div>Estrogen-responsive breast cancer has been treated with tamoxifen since 1998, yet challenges such as limited selectivity and emerging resistance remain significant hurdles to improving therapeutic outcomes. In recent years, the incorporation of fluorine atoms in the structure of potential drugs has gained importance due to their unique properties. Perfluoroalkyl chains, known for their chemical inertness and ability to target estrogen, offer promising modifications to improve treatment efficacy. In this study, we evaluated the biological activity of 21 perfluoroalkylated tamoxifen derivatives, synthesized under mild conditions with high stereoselectivity. Seven of these compounds exhibited superior cytotoxic and selectivity activity against estrogen receptor-positive breast cancer cells (MCF-7), with IC50 values of 10.68–18.18 nM compared to 29.41 nM for 4-hydroxytamoxifen, which is used in standard therapy. Preliminary mechanism-of-action studies, supported by siRNA knockdown of <em>ESR1</em> (the estrogen receptor gene), revealed that the compounds act through a similar mechanism to tamoxifen, further confirming their potential as next-generation therapeutic agents for estrogen receptor-positive breast cancer.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"161 ","pages":"Article 108525"},"PeriodicalIF":4.5,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143887216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}