Bioorganic & Medicinal Chemistry Letters最新文献

{"title":"Synthesis and biological activity evaluation of aromatic bisselenocyanate compounds","authors":"Chunrui Cai ,&nbsp;Wenhao Tian ,&nbsp;Meizhen Wei,&nbsp;Taichen Yang,&nbsp;Qiang Hu,&nbsp;Yanmin Huang,&nbsp;Zhiping Liu,&nbsp;Jianguo Cui","doi":"10.1016/j.bmcl.2025.130533","DOIUrl":"10.1016/j.bmcl.2025.130533","url":null,"abstract":"<div><div>Motivated by the significant physiological activities of selenocyanate pharmacophores in biomedicine and the relative scarcity of research on diselenocyanates, this study designed and synthesized a series of novel aromatic diselenocyanate derivatives (including aniline-type <strong>3a</strong>-<strong>3f</strong>, phenol-type <strong>6a</strong>-<strong>6f</strong>, and biphenyl-type <strong>8</strong>) using aniline and phenol as parent structures through aromatic ring electrophilic substitution and amide bond/ether bond bridging strategies, and systematically evaluated their biological activities. The results demonstrated that multiple compounds exhibited significant inhibitory activity against specific cancer cell lines. Among them, compound <strong>3f</strong> showed an <em>IC</em>₅₀ value of 2.93 μmol/L against breast cancer MCF-7 cells, while compound <strong>6c</strong> displayed superior <em>IC</em>₅₀ values compared to Cisplatin against SK-OV-3, HepG-2, and MCF-7 cells. The compounds also demonstrated excellent activity against drug-resistant bacteria MRSA/VRE (<strong>3f</strong> exhibited an <em>MIC</em> of 2 μg mL⁻¹ against MRSA, outperforming Vancomycin) and agricultural crop pathogens (citrus canker, rice bacterial leaf streak/leaf blight pathogens). Notably, compound <strong>8</strong> achieved sub-microgram <em>EC</em>₅₀ values against these phytopathogens. Structure-activity relationship analysis revealed that aniline derivatives showed better activity against breast cancer, while phenol derivatives exhibited stronger inhibition against ovarian cancer and phytopathogens. Molecular-docking studies corroborate enhanced binding stability of optimized compounds to validated biological targets. Collectively, these findings provide both mechanistic insight and lead candidates for novel antineoplastic agents and low-toxicity agricultural antimicrobials.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"133 ","pages":"Article 130533"},"PeriodicalIF":2.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145898807","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":"Evaluation of the efflux inhibitory potential of aminopyrazole derivative to restore azole sensitivity in Candida albicans","authors":"Vineetha K. Unnikrishnan ,&nbsp;Niranjana sri Sundaramoorthy ,&nbsp;Ramaravinth Manivannan ,&nbsp;Markabandhu Shanthi ,&nbsp;Divya Prakash Gnanadhas ,&nbsp;Soundarya Alexander ,&nbsp;Venkatasubramanian Ulaganathan ,&nbsp;Ramesh Subburethinam ,&nbsp;Saisubramanian Nagarajan","doi":"10.1016/j.bmcl.2025.130529","DOIUrl":"10.1016/j.bmcl.2025.130529","url":null,"abstract":"<div><div><em>Candida albicans</em> is an opportunistic fungus that causes infections in people with weakened immune system. Candida has the propensity to gain drug resistance by mutation, and its ability to extrude antifungals through drug transporters. Efflux pump inhibitors increase the intracellular drug concentration and restore drug sensitivity in resistant strains. We synthesized and screened 10 azole heterocyclic derivatives (pyrazole-5-amine and 2H-indazole) against Mdr1p/Cdr1p overexpressing and knock-out strains of <em>Candida albicans.</em> Among the derivatives screened, sulfenylated pyrazole-5-amine (designated as <strong>4a)</strong> displayed strong efflux inhibitory potential and caused a 64-fold reduction in the fluconazole MIC. Compound <strong>4a</strong> inhibited the Mdr1p pump, as MIC reversal was not observed in the Mdr1p knock-out strain. <strong>4a</strong> exhibited synergy with fluconazole only against Mdr1p harboring strains, as discerned by the Checkerboard assay. Combining <strong>4a</strong> with fluconazole restricted microbial growth and reduced cell counts by 4 log fold relative to treatment with fluconazole in a time-kill assay. Infection of RAW macrophages followed by treatment with a combination of sulfenylated aminopyrazole &amp; fluconazole resulted in a significant 2 log reduction in intracellular cell counts relative to treatment with fluconazole. <strong>4a</strong> also inhibited biofilm formation and yeast to hyphal shift in <em>Candida</em>, thereby reducing virulence. Combining EPIs with antifungal drugs has the potential to improve the treatment of <em>C. albicans</em> infections and reduce the risk of drug resistance. However, further research is needed to determine the safety and efficacy of these compounds in humans.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"133 ","pages":"Article 130529"},"PeriodicalIF":2.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888389","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":"Dioscin attenuates hyperlipidemia by dual modulation of intestinal triglyceride and cholesterol absorption","authors":"Jufeng Sun ,&nbsp;Yixiao Wang ,&nbsp;Rufei Wang ,&nbsp;Yuan Yao ,&nbsp;Jiarui Wang ,&nbsp;Guojun Pan ,&nbsp;Renshuai Zhang ,&nbsp;Xiaoguang Zhao","doi":"10.1016/j.bmcl.2025.130531","DOIUrl":"10.1016/j.bmcl.2025.130531","url":null,"abstract":"<div><div>Dioscin, a natural steroidal saponin derived from <em>Dioscorea</em> species, has been reported to exhibit lipid-lowering activity despite its extremely low oral bioavailability. This study aimed to elucidate whether dioscin exerts its lipid-lowering effects through intestinal mechanisms. Using both high-fat diet (HFD)-induced and acute lipid-challenge rat models, dioscin significantly reduced plasma triglyceride (TG) and total cholesterol (TC) levels, indicating an inhibitory effect on intestinal lipid absorption. In vitro assays demonstrated that dioscin inhibited pancreatic triglyceride lipase (PTL) activity with moderate potency and suppressed Niemann-Pick C1-Like 1 (NPC1L1)-mediated cholesterol uptake in Caco-2 cells. Surface plasmon resonance (SPR) analysis and molecular docking suggested direct interactions between dioscin and both PTL and NPC1L1, suggesting that dioscin interferes with intestinal lipid absorption through mechanisms involving TG hydrolysis and cholesterol transport. These findings provide mechanistic insight into the intestinal lipid-lowering activity of dioscin and highlight its potential as a natural lead compound for the development of safe and intestine- restricted lipid-lowering agents.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"133 ","pages":"Article 130531"},"PeriodicalIF":2.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145891827","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":"N-[3-(4-(2-methoxyphenyl) piperazine-1-yl) propyl]-heteroaromatic carboxamide as selective α1A/1D-adrenoceptor antagonists: SAR study and metabolic stability evaluation","authors":"Ruxia Duan ,&nbsp;Linxin Zhou ,&nbsp;Ran Chen ,&nbsp;Yajian Huang ,&nbsp;Dan Wu ,&nbsp;Tomohiko Ohwada ,&nbsp;Wei Yi ,&nbsp;Junjun Huang","doi":"10.1016/j.bmcl.2025.130507","DOIUrl":"10.1016/j.bmcl.2025.130507","url":null,"abstract":"<div><div>Dual α_1A/1D-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 <strong><em>R</em>-17</strong>) 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 <strong>15</strong> featuring a 5-benzo[d][1,3]dioxole group emerged as a highly potent α_1A/1D 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^3.32 in the α_1B 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 (<em>T</em>_1/2) from 6.1 min (<strong><em>R</em>-17</strong>) to 31.5 min (<strong>15</strong>). This work establishes compound <strong>15</strong> as a promising lead candidate that successfully integrates the selectivity-determining linker scaffold with enhanced drug-like properties.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"133 ","pages":"Article 130507"},"PeriodicalIF":2.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145761746","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":"Cinnamoyl aryl hydrazones as potent leishmanicidal agents: design, synthesis, and structure–activity relationships","authors":"Renan Augusto Gomes ,&nbsp;Leonardo Luiz Gomes Ferreira ,&nbsp;Witor Ribeiro Ferraz ,&nbsp;Rodrigo Alves Heleno ,&nbsp;Fernando Moura Gatti ,&nbsp;Mariana Laureano de Souza ,&nbsp;Cleydson Breno Rodrigues dos Santos ,&nbsp;Adriano Defini Andricopulo ,&nbsp;Gustavo Henrique Goulart Trossini","doi":"10.1016/j.bmcl.2025.130523","DOIUrl":"10.1016/j.bmcl.2025.130523","url":null,"abstract":"<div><div>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 <em>Leishmania donovani</em> and <em>Trypanosoma cruzi</em>. 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.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"133 ","pages":"Article 130523"},"PeriodicalIF":2.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843331","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 4-aminoquinoline derivatives as potent membrane-targeting antifungal agents","authors":"Jing Du ,&nbsp;Wei Wang ,&nbsp;Yanni Ma ,&nbsp;Chaoyong Cui ,&nbsp;Yuwan Zhang ,&nbsp;Jian Yang ,&nbsp;Rui Yang","doi":"10.1016/j.bmcl.2025.130514","DOIUrl":"10.1016/j.bmcl.2025.130514","url":null,"abstract":"<div><div>This study aimed to develop novel antifungal agents through the design and synthesis of two series of 4-aminoquinoline derivatives (<strong>1</strong>–<strong>21</strong> and their demethylated analogs <strong>1′</strong>–<strong>16′</strong>). These compounds were synthesized via cyclization in POCl₃, amine substitution, and BBr₃-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 (<strong>14</strong>, <strong>16</strong>, and <strong>14′</strong>–<strong>16′</strong>)—displayed notable activity (MICs = 4–32 μg/mL) against <em>Candida albicans</em>, <em>Candida tropicalis</em>, and <em>Cryptococcus neoformans</em>. Compound <strong>14′</strong> exhibited potent fungicidal action against <em>C. albicans</em> (MIC = MFC = 4 μg/mL), rapid time-kill kinetics, membrane disruption evidenced by PI/DAPI staining, and strong biofilm inhibition (&gt;90 % at ≥16 μg/mL). SEM imaging revealed extensive ultrastructural damage to fungal cells. Importantly, <strong>14′</strong> showed low cytotoxicity toward human epithelial cells and favorable in silico predicted ADMET profiles. These findings highlight <strong>14′</strong> as a promising lead compound with membrane-targeting antifungal mechanisms and an improved safety profile relative to amphotericin B.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"133 ","pages":"Article 130514"},"PeriodicalIF":2.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145831782","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 and synthesis of Tetrahydroindeno[4,5-c]chromen-4(3H)-one derivatives as antiproliferative agents for prostate Cancer cells","authors":"Hui-Yu Chan ,&nbsp;Pin-Shuo Huang ,&nbsp;Pei-Fang Chiu ,&nbsp;Tzung-Sheng Lin ,&nbsp;Li-Jou Huang ,&nbsp;Pi-Hui Liang ,&nbsp;Jih-Hwa Guh ,&nbsp;Mei-Hsiang Lin","doi":"10.1016/j.bmcl.2025.130515","DOIUrl":"10.1016/j.bmcl.2025.130515","url":null,"abstract":"<div><div>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-<em>c</em>]chromen-4(3<em>H</em>)-one derivatives with pyridine congeners at C-1 position. Notably, <strong>13c</strong> and <strong>14c</strong> exhibited the GI₅₀ of 10 nM against PC-3 cells compared to 21.4 μM for abiraterone. The docking studies further revealed that <strong>14c</strong> shares a similar binding mode with abiraterone at the CYP17A1 active site.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"133 ","pages":"Article 130515"},"PeriodicalIF":2.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843385","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 macrocyclic NTRK heterobifunctional degraders","authors":"Corey Anderson,&nbsp;Jennifer Han-Chun Tsai,&nbsp;Oscar Ingham,&nbsp;Richard W. Deibler,&nbsp;Bridget Kreger,&nbsp;Prasoon Chaturvedi,&nbsp;Ka Ying Sharon Hung,&nbsp;Christopher G. Nasveschuk,&nbsp;James A. Henderson,&nbsp;Mathew E. Sowa","doi":"10.1016/j.bmcl.2025.130516","DOIUrl":"10.1016/j.bmcl.2025.130516","url":null,"abstract":"<div><div>Aberrant <em>NTRK</em> gene fusions leading to constitutively activated NTRK proteins are a key driver for a range of adult and pediatric tumors. Small molecule NTRK inhibitors targeting the NTRK ATP site have shown success in the clinic resulting in two approved drugs. Unfortunately, resistance mutations have created the need for additional therapies. In this study, we detail the design, synthesis, and evaluation of novel NTRK BiDAC™ degraders containing a macrocyclic, mutant active, NTRK targeting ligand.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"133 ","pages":"Article 130516"},"PeriodicalIF":2.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145896042","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 theaflavin-3′-gallate oxidation products and their impact on α-amylase activity","authors":"Jiale An ,&nbsp;Keyu Zhao ,&nbsp;Yangping Ding","doi":"10.1016/j.bmcl.2025.130532","DOIUrl":"10.1016/j.bmcl.2025.130532","url":null,"abstract":"<div><div>This study optimized the oxidation of theaflavin-3′-gallate (TF-3′-G), yielding two isolated products: theadibenzotropolone_(TF-3_′_-G+EC) and theanaphthoquinone-3-gallate (TNQ-3-G). All compounds exhibited significant α-amylase inhibitory activity, with potency descending in the order: theadibenzotropolone_(TF-3_′_-G+EC)&gt;TNQ-3-G&gt;TF-3′-G ≈ acarbose. IC₅₀ analysis revealed that TNQ-3-G and theadibenzotropolone_(TF-3_′_-G+EC) were over 2-fold and 5-fold more potent than acarbose, respectively. These findings provide a foundation for developing efficient and low-toxicity α-amylase inhibitors.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"133 ","pages":"Article 130532"},"PeriodicalIF":2.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145896073","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 ALK/HDAC dual-targeting agents","authors":"Ye Kong ,&nbsp;Shunda Li ,&nbsp;Xintong Xue ,&nbsp;Huiping Liu ,&nbsp;Ruiwei Fu ,&nbsp;Yan Gao ,&nbsp;Yingjie Zhang ,&nbsp;Xia Xue","doi":"10.1016/j.bmcl.2025.130495","DOIUrl":"10.1016/j.bmcl.2025.130495","url":null,"abstract":"<div><div>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 <strong>19b</strong> showed dual inhibitory activity against ALK (ALK WT IC₅₀ = 8.0 ± 1.2 nM) and HDACs (HeLa cell nuclear extract IC₅₀ = 1.18 ± 0.22 μM). Notably, <strong>19b</strong> exhibited ~5-fold greater inhibition than Staurosporine and approved ALK inhibitor Brigatinib against the ALK G1202R mutant. Additionally, <strong>19b</strong> demonstrated strong activity in ALK-related neuroblastoma SK-N-BE2 cells, comparable to controls SAHA, MS275, and Brigatinib. In SK-N-BE2 cells, <strong>19b</strong> treatment led to increased apoptosis and G2/M arrest. Docking studies explained the potent dual inhibition by <strong>19b</strong>. These findings support the promise of <strong>19b</strong> as a dual ALK/HDAC inhibitor for managing neuroblastoma, especially ALK-positive cancer.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"133 ","pages":"Article 130495"},"PeriodicalIF":2.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145751442","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}