Bioorganic & Medicinal Chemistry Letters最新文献

{"title":"Structural modification of atractylenolides: synthesis and evaluation of derivatives with potent anti-Aβ aggregation and neuroprotective activities against Alzheimer's disease","authors":"Tiancheng Sun ,&nbsp;Zhonghua Li ,&nbsp;Bingyu Xiao ,&nbsp;Jige Yang ,&nbsp;Mengyu Han ,&nbsp;Jiaxin Zhang ,&nbsp;Sijia Liu ,&nbsp;Jinlian Ma ,&nbsp;Pan Wang","doi":"10.1016/j.bmcl.2025.130478","DOIUrl":"10.1016/j.bmcl.2025.130478","url":null,"abstract":"<div><div>Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) deposition, hyperphosphorylated Tau tangles, and neuronal loss, lacks effective disease-modifying therapies. Herbal medicines like <em>Atractylodes macrocephala</em> (AM) offer promising candidates for AD drug development, given their structural diversity and neuroprotective potential. Our prior work involved systematic phytochemical isolation of AM and preliminary anti-AD activity evaluation, through which we identified atractylenolide A1 as a neuroprotective lead. To further optimize efficacy, we herein synthesized a small series of novel atractylenolide derivatives via structural modification of A1's exocyclic. Among derivatives, B7 exhibited the broadest activity such as inhibiting self- and Cu²⁺-induced Aβ aggregation, protecting neurons and microglia, and mitigating Aβ toxicity in vivo. The exocyclic ester of A1 proves a viable modification site, with B7 emerging as a promising multi-target lead for AD therapy</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130478"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145561965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammation and diabetic inhibitors from Amanita abrupta and Amanita pantherina: experimental and computational results","authors":"Dao C. To ,&nbsp;Minh Q. Pham ,&nbsp;Phuong D.N. Nguyen ,&nbsp;Phi H. Nguyen ,&nbsp;Huu T. Nguyen ,&nbsp;Viet T. Trinh ,&nbsp;Le M. Hoang ,&nbsp;Hoa T. Nguyen ,&nbsp;Thi V.H. Truong","doi":"10.1016/j.bmcl.2025.130438","DOIUrl":"10.1016/j.bmcl.2025.130438","url":null,"abstract":"<div><div>This study investigates potential inhibitors of nitric oxide (NO) production, <em>α</em>-glucosidase, and protein tyrosine phosphatase 1B (PTP1B) from <em>Amanita abrupta</em> and <em>Amanita pantherina</em>. Sixteen compounds (<strong>1</strong>–<strong>16</strong>) were isolated by chromatographic techniques and high-performance liquid chromatography (HPLC), and their structures were elucidated by nuclear magnetic resonance (NMR) and literature comparison. Biological activities were evaluated <em>via in vitro</em> assays: the Griess assay for NO inhibition, the <em>p</em>-nitrophenol assay for <em>α</em>-glucosidase, and enzymatic assays for PTP1B. Molecular docking was employed to investigate protein–ligand interactions. The isolates included alanine (<strong>1</strong>), threonine (<strong>2</strong>), 2-amino-4-pentynoic acid (<strong>3</strong>), 4-hydroxy-2-pyrrolidinone (<strong>4</strong>), ibotenic acid (<strong>5</strong>), serotonin (<strong>6</strong>), uracil (<strong>7</strong>), hypoxanthine (<strong>8</strong>), bufotenine (<strong>9</strong>), <em>β</em>-sitosterol (<strong>10</strong>), stigmasterol (<strong>11</strong>), cycloeucalenol (<strong>12</strong>), spinasterol (<strong>13</strong>), daucosterol (<strong>14</strong>), stigmasterol-3-O-<em>β</em>-D-glucoside (<strong>15</strong>), and betulin (<strong>16</strong>). Compounds <strong>1</strong> and <strong>2</strong> exhibited weak NO inhibition (IC₅₀ = 68.76 and 52.47 μM). Compound <strong>14</strong> displayed the strongest <em>α</em>-glucosidase inhibition (IC₅₀ = 10.56 μM), while compounds <strong>10</strong>–<strong>13</strong> and <strong>16</strong> showed moderate effects (IC₅₀ = 19.52–32.14 μM). Serotonin (<strong>6</strong>) also had moderate activity (IC₅₀ = 78.23 μM). For PTP1B inhibition, betulin (<strong>16</strong>) was most potent (IC₅₀ = 16.80 μM), followed by compounds <strong>10</strong>, <strong>11</strong>, and <strong>13</strong> with weaker activities (IC₅₀ = 36.28–48.17 μM). Overall, selected compounds (<strong>1</strong>, <strong>2</strong>, <strong>10</strong>–<strong>14</strong>, and <strong>16</strong>) exhibited promising bioactivities, warranting further docking studies against inducible nitric oxide synthase (iNOS), PTP1B, and 3AJ7. ADMET (absorption, distribution, metabolism, excretion, and toxicity) predictions supported favorable pharmacokinetic properties and potential drug-likeness, highlighting these molecules as leads for anti-inflammatory and anti-diabetic drug discovery.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130438"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145306457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioactive peptoids against vector-borne parasitic diseases","authors":"Hannah L. Bolt ,&nbsp;Marcel Kaiser ,&nbsp;Yu Luo ,&nbsp;Fionnuala T. Lundy ,&nbsp;Libbi Moon ,&nbsp;Ronald N. Zuckermann ,&nbsp;Paul W. Denny ,&nbsp;Steven L. Cobb","doi":"10.1016/j.bmcl.2025.130457","DOIUrl":"10.1016/j.bmcl.2025.130457","url":null,"abstract":"<div><div>Protozoan parasites represent a severe threat to global human health as they are responsible for infection in Malaria, and a range of Neglected Tropical Diseases (NTDs) including Chagas disease, leishmaniasis and African sleeping sickness. Often treatments for protozan parasites are limited in their efficacy and drug resistance is an emerging problem. The current efforts to develop new treatments for the aforementioned diseases have been met with limited success and as such novel compound classes for development are being actively sought. Peptoids are peptidomimetics that have showed promise as antimicrobial agents but their application in the field of vector-borne parasitic diseases is highly underdeveloped. Herein, a library of over 50 peptoids containing a wide variety of chemical functionalities has been prepared and biologically evaluated against a range of protozoan parasitic targets. Selected members of the peptoid library were found to have potent anti-parasitic activity and good selectivity indices (SI). For example, peptoid <strong>29</strong> [<em>N</em>amy<em>N</em>spe<em>N</em>spe)(<em>N</em>hArg<em>N</em>spe<em>N</em>spe)]₂ had an IC₅₀ of 0.05 μM against <em>Plasmodium falciparum</em> and a SI &gt; 100.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130457"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145426408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of DS79540454 via fragment-based drug discovery strategy: New scaffolds of hypoxia-inducible factor prolyl hydroxylase inhibitor","authors":"Takeshi Fukuda,&nbsp;Tatsuya Nishi,&nbsp;Takashi Ishiyama,&nbsp;Ryoko Kitazawa,&nbsp;Ken Ishii,&nbsp;Shinichi Takahashi,&nbsp;Yuki Kawabata,&nbsp;Kyoji Yamaguchi,&nbsp;Daichi Baba,&nbsp;Shuichiro Ito,&nbsp;Naoki Tanaka","doi":"10.1016/j.bmcl.2025.130476","DOIUrl":"10.1016/j.bmcl.2025.130476","url":null,"abstract":"<div><div>The inhibition of hypoxia-inducible factor prolyl hydroxylase domain proteins (HIF-PHDs) represents a promising strategy for treating renal anemia. We identified a hydroxypyrimidine core with HIF-PHD inhibitory activity based on a fragment-based drug discovery strategy using various X-ray crystal structures of the HIF-PHD2 domain in complex with a compound. We discovered brand-new amino succinic acid scaffolds by combining the structural information on the crystal structure complexed with 6-acetamide nicotinic acid. DS79540454 exhibits high enzyme inhibitory activity equivalent to that of DS-1093a, which has advanced to clinical trials.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130476"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145561929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis and biological evaluation of novel HIF-1α PROTACs degrader as potent anti-cervical cancer agents","authors":"En-Jie Zhu ,&nbsp;Xing-Sheng Bu ,&nbsp;Ying Yue ,&nbsp;Yong-Sheng Hou ,&nbsp;Jia-Rong Liu ,&nbsp;Tharcisse Gatera ,&nbsp;Shu-Yang Ni ,&nbsp;Tian Chai ,&nbsp;Xing-Rong Wang ,&nbsp;Jun-Li Yang","doi":"10.1016/j.bmcl.2025.130443","DOIUrl":"10.1016/j.bmcl.2025.130443","url":null,"abstract":"<div><div>Cervical cancer is the fourth most common and deadly cancer globally. Hypoxia-inducible factor-1α (HIF-1α) plays a key promoter of tumor progression and treatment resistance, making it an important anticancer target. Here, we designed and synthesized a series of novel HIF-1α-targeting PROTAC degraders based on LW-6 and its derivative <strong>W-1</strong>. Among them, <strong>Z12</strong> showed the strongest anti-proliferative and HIF1α degradation activities in HeLa cells. <strong>Z12</strong> promoted HIF-1α degradation <em>via</em> the ubiquitin-proteasome pathway by facilitating the formation of a HIF-1α/VHL ternary complex. Furthermore, <strong>Z12</strong> inhibited HeLa cell proliferation, migration, and colony formation, induced apoptosis, and reduced p-MEK and p-AKT expression in the MAPK and PI3K/AKT pathways. This work offers a promising strategy for developing HIF1α-PROTAC degraders and treating cervical cancer.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130443"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145353176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancement of anticancer potential of novel β-carboline derivatives by ACS81 hybridization","authors":"Xu Hu ,&nbsp;Xiaoni Yu ,&nbsp;Yutian Zhang ,&nbsp;Biao Zhou ,&nbsp;Chao Li ,&nbsp;Dahong Li ,&nbsp;Shengge Li ,&nbsp;Xianzhang Huang","doi":"10.1016/j.bmcl.2025.130440","DOIUrl":"10.1016/j.bmcl.2025.130440","url":null,"abstract":"<div><div>Natural <em>β</em>-carboline alkaloids are currently under extensive scrutiny for their antitumor properties. To improve the antitumor efficacy of <em>β</em>-carboline, a range of <em>β</em>-carboline-ACS81 hybrids were created through molecular hybridization with diallyl disulfide derivatives, and preliminary structure-activity relationships (SAR) were established. Furthermore, the newly synthesized hybrids (<strong>12a-c</strong>, <strong>13a-d</strong>, <strong>14a-d</strong>, and <strong>15a-d</strong>) were evaluated for <em>in vitro</em> cytotoxicity against a panel of six human cancer cell lines (HL-60, U937, HepG2, HCT-116, A375, and A549), as well as one normal human hepatic cell line (L-02). Among them, hybrid <strong>12c</strong> exhibited the strongest inhibitory activity against the HL-60 cell line, with an IC₅₀ value of 1.52 μM, surpassing the efficacy of the positive control drug 5-FU. Moreover, this compound displayed minimal cytotoxicity against L-02 cells (IC₅₀ &gt; 30 μM), indicating a favorable selectivity profile between tumor cells and normal cells. Comprehensive investigations revealed that <strong>12c</strong> induced apoptosis by arresting the cell cycle at the G2/M phase. This effect was achieved by inducing alterations in nuclear morphology and the collapse of mitochondrial membrane potential. These findings suggested that <strong>12c</strong> exerted an antiproliferative impact by triggering apoptosis through the mitochondrial pathway. Given these observations, <strong>12c</strong> may represent a promising anti-leukemia agent and warrants further investigation.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130440"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145353199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of a novel small-molecule inhibitor of heterochromatin protein 1","authors":"Akari Tokuyama ,&nbsp;Yasunobu Yamashita ,&nbsp;Ryo Maeda ,&nbsp;Toshiki Akiyama ,&nbsp;Yuri Takada ,&nbsp;Ryunosuke Yoshino ,&nbsp;Hiroki Kato ,&nbsp;Shengwang Yu ,&nbsp;Yukihiro Itoh ,&nbsp;Makoto Tachibana ,&nbsp;Takayoshi Suzuki","doi":"10.1016/j.bmcl.2025.130469","DOIUrl":"10.1016/j.bmcl.2025.130469","url":null,"abstract":"<div><div>Heterochromatin protein 1 (HP1), one of the epigenetic “reader” proteins, recognizes trimethylated lysine 9 of histone H3 (H3K9me3) to repressively regulate gene transcription by promoting chromatin aggregation. Overexpression of HP1 plays a role in the growth of various cancer cells. Therefore, inhibiting its interaction with H3K9me3 is considered a promising therapeutic strategy for cancer treatment. This study aimed to identify small molecules that bind to HP1 and inhibit the HP1/H3K9me3 interaction. We performed <em>in silico</em> screening of the compounds from the Osaka University Library and selected 61 virtual hit compounds. As a result of <em>in vitro</em> evaluation of the hits by an HP1/H3K9me3 interaction inhibition assay, we identified compound <strong>1</strong>, which exhibited 36 % inhibitory activity at 100 μM. Furthermore, the structural optimization of <strong>1</strong> led to the identification of (<em>R</em>)-<strong>18</strong> (IC₅₀: 18.1 μM)—a novel small molecule that inhibits the HP1/H3K9me3 interaction.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130469"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145493777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-based discovery of sulfamoyl-ethyl-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidine amides and sulfonamides as potent B-Cell Lymphoma 6 (BCL6)-BTB inhibitors","authors":"Ahmed Mamai ,&nbsp;Mohammed M. Morshed ,&nbsp;Michael Prakesch ,&nbsp;Gennady Poda ,&nbsp;Pandiaraju Subramanian ,&nbsp;Anh M. Chau ,&nbsp;Iain D.G. Watson ,&nbsp;Babu Joseph ,&nbsp;Brian Wilson ,&nbsp;Justin A. Morin ,&nbsp;Richard Marcellus ,&nbsp;Brigitte Theriault ,&nbsp;Mohammed Mohammed ,&nbsp;Ayome Abibi ,&nbsp;Manuel Chan ,&nbsp;Taira Kiyota ,&nbsp;Ahmed Aman ,&nbsp;Ratheesh Subramaniam ,&nbsp;Craig Strathdee ,&nbsp;Jeffrey Winston ,&nbsp;Rima Al-awar","doi":"10.1016/j.bmcl.2025.130471","DOIUrl":"10.1016/j.bmcl.2025.130471","url":null,"abstract":"<div><div>Diffuse Large B-Cell Lymphoma (DLBCL) is one of the most aggressive forms of lymphoid malignancies. About 40 % of patients eventually relapse and succumb to the disease within 5 years after diagnosis, underscoring the need for new treatment modalities. B-Cell Lymphoma 6 protein (BCL6) is a repressive transcription factor that is dysregulated in about 40 % of DLBCLs. As a rationale for pursuing BCL6 as a drug target, disrupting complexes between this protein and its co-repressors is thought to mitigate the downstream oncogenic effects of this pathway. However, drugging transcription factors presents a formidable undertaking since targeting protein–protein interactions has historically been challenging. In this study, we used X-ray structures of BCL6-SMRT (a silencing mediator for retinoid or thyroid-hormone receptors, also known as the nuclear receptor co-repressor 2, NCOR2) peptide and compound <strong>79-6</strong> to conduct a virtual screen of a library of 5.2 million compounds. Through this exercise, we identified the pyrrolopyridone <strong>3</strong> as a viable hit, which in turn led to the identification of pyrrolopyrimidone lead compound <strong>4</strong>. The X-ray crystal structure of <strong>4</strong> bound to the BTB (Broad-Complex, Tramtrack, and Bric à brac) domain of BCL6 revealed a large back pocket as well as a left-hand channel adjacent to the ligand that could be leveraged to optimize these compounds. Sulfonamide side chains were therefore introduced to target this space, leading to compounds <strong>11d</strong> and <strong>11e</strong> having sub-micromolar binding to the BTB domain of BCL6.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130471"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145530303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ferrocene-modified cyclic asymmetric curcumin analogs: Synthesis and enhanced antitumor activity","authors":"Haotian Xie ,&nbsp;Wenjie Xiao ,&nbsp;Ruichen Xie ,&nbsp;Lifang Xu ,&nbsp;Shuhui Ren ,&nbsp;Hanfeng Cui","doi":"10.1016/j.bmcl.2025.130446","DOIUrl":"10.1016/j.bmcl.2025.130446","url":null,"abstract":"<div><div>Tumors remain a leading cause of mortality worldwide, and existing clinical treatments face challenges such as high toxicity, poor efficacy, and multidrug resistance. Natural products have emerged as promising sources for developing anticancer drugs due to their high efficacy and low toxicity. Curcumin, a yellow polyphenolic compound with diverse biological activities (anti-tumor, antiviral, antibacterial, and anti-HIV), is particularly notable for its minimal toxic side effects. However, its clinical application is hindered by low oral bioavailability and instability. To address these limitations, this study designed and synthesized nine novel monocarbonyl curcumin analogs by removing the unstable β-diketone group and introducing ferrocene-based structures with piperidone derivatives. Using ferrocene as a starting material, these asymmetric compounds were synthesized through Vilsmeier and Claisen-Schmidt reactions, followed by structural confirmation using ¹<em>H</em> NMR, MS, and ¹³<em>C</em> NMR. Antitumor activity was evaluated against MCF-7, PC-3, and A549 tumor cells using the CCK-8 method, with curcumin as a control. Notably, several analogs exhibited dramatically enhanced potency. Compound <strong>1a</strong> was identified as the most promising derivative, showing 4.7-, 7.4-, and 2.0-fold higher potency than curcumin against A549, PC-3, and MCF-7 cells, respectively (IC₅₀ = 6.11, 5.21, and 10.37 μM vs. 28.92, 38.53, and 20.82 μM for curcumin). These findings provide a foundation for further development of ferrocene-modified curcumin analogs as potential anticancer agents.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130446"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145413910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis of novel 6-azacytidine prodrugs as potent influenza A inhibitors","authors":"Omar Moukha-Chafiq ,&nbsp;Larry D. Bratton ,&nbsp;Shuklendu D. Karyakarte ,&nbsp;Kathy Keith ,&nbsp;Yohanka Martinez-Gzegozewska ,&nbsp;Sarath C. Sarngadharan ,&nbsp;Lynn Rasmussen ,&nbsp;Bob Bostwick ,&nbsp;Ashish K. Pathak ,&nbsp;Richard Whitley ,&nbsp;Corinne E. Augelli-Szafran","doi":"10.1016/j.bmcl.2025.130473","DOIUrl":"10.1016/j.bmcl.2025.130473","url":null,"abstract":"<div><div>We report the synthesis and evaluation of novel prodrugs of 6-azacytidine (6-AzaCyd) to identify potent and bioavailable inhibitors of influenza A viruses. Prodrug <em>N</em>^<em>4</em>–2-propylpentanamide 6-AzaCyd <strong>6a</strong> was identified, through a nucleoside prodrug strategy, with a promising potency profile [H1N1-EC₉₀ = 2.6 μM, VTR = 3 at 10 μM; H3N2-EC₉₀ = 3.5 μM, VTR = 2.8 at 10 μM in MDCK cells; EC₅₀ = 2.1 μM from cap snatching polymerase U2-PB2 assay; cytotoxicity CC₅₀ &gt; 40 μM in A549 cells; CC₅₀ &gt; 20 μM in MDCK cells] and an acceptable absorption, distribution, metabolism and excretion (ADME) profile [mouse liver microsome (MLM) t_1/2 = 105 min, human liver microsome (HLM) t_1/2 = 65 min, Solubility = 77 μM]. Compound <strong>6a</strong> also exhibited acceptable pharmacokinetic properties <em>via</em> intraperitoneal (i.p<em>.</em>) route of administration. The details for the synthesis of 6-AzaCyd prodrugs and anti-influenza A activity are described herein.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130473"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145533851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}