Bioorganic & Medicinal Chemistry最新文献

{"title":"Machine learning in antiviral drug design","authors":"Anja Kolarič ,&nbsp;Marko Jukič ,&nbsp;Urban Bren","doi":"10.1016/j.bmc.2025.118426","DOIUrl":"10.1016/j.bmc.2025.118426","url":null,"abstract":"<div><div>Viral infections pose a significant health threat worldwide. Due to the high mutation rates of many viruses and their reliance on host cellular machinery, the development of effective antiviral therapies is particularly difficult. As a result, only a limited number of antiviral agents is currently available. In parallel to modern vaccines, traditional antiviral drug development is both time-consuming and costly, underscoring the need for faster, more efficient approaches. In recent years, particularly since the beginning of the COVID-19 pandemic, machine learning (ML) together with broader artificial intelligence (AI), have emerged as powerful methodologies for drug discovery and offer the potential to accelerate the identification and development of antiviral agents. This review examines the application of ML in the early stages of antiviral drug discovery, with a particular focus on recent studies where ML methods have successfully identified hit compounds with experimentally demonstrated activity in biological assays. By highlighting these successful case studies, the review illustrates the growing impact of ML in advancing the discovery of urgently needed novel antivirals.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118426"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145247958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-based design, synthesis, and evaluation of tetrahydrotriazolothiazepine derivatives as novel 11β-hydroxysteroid dehydrogenase type 1 inhibitors","authors":"Yukinobu Numata ,&nbsp;Toru Hasegawa ,&nbsp;Makoto Mori ,&nbsp;Tsuyoshi Shinozuka ,&nbsp;Yuko Yamamoto ,&nbsp;Masatoshi Honzumi ,&nbsp;Chinami Kanayama ,&nbsp;Atsushi Aoyagi ,&nbsp;Manabu Abe ,&nbsp;Yuka Ofune ,&nbsp;Kanae Suzuki ,&nbsp;Yuichiro Imamura ,&nbsp;Chizuko Yahara ,&nbsp;Wataru Obuchi ,&nbsp;Ayako Moritomo ,&nbsp;Mizuki Takahashi","doi":"10.1016/j.bmc.2025.118418","DOIUrl":"10.1016/j.bmc.2025.118418","url":null,"abstract":"<div><div>11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an enzyme that converts cortisone to cortisol, and the therapeutic inhibition of this enzyme has attracted substantial attention for the treatment of various disorders including metabolic syndrome, cognitive decline, skin diseases, liver fibrosis, glaucoma, and osteoporosis. With the aim of developing a novel and potent 11β-HSD1 inhibitor, we designed and synthesized a series of tetrahydrotriazolothiazepine derivatives containing a sulfur atom in the seven-membered ring. An optimization study guided by structure-based drug design led to the discovery of compound <strong>3f</strong> as a potent and orally bioavailable 11β-HSD1 inhibitor. The oral administration of <strong>3f</strong> demonstrated good pharmacokinetic profiles and <em>in vivo</em> inhibition of 11β-HSD1 in mice and monkeys.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118418"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design of arylfurans as potential FAAH inhibitors: therapeutic potential in pain management","authors":"Pedro Augusto Lemos Santana,&nbsp;Rafael Christian de Matos,&nbsp;Ana Flávia Alvarenga Bitencourt,&nbsp;Vinícius Gonçalves Maltarollo,&nbsp;Marta Marques Gontijo de Aguiar,&nbsp;Renes Resende Machado,&nbsp;Renata Barbosa de Oliveira","doi":"10.1016/j.bmc.2025.118471","DOIUrl":"10.1016/j.bmc.2025.118471","url":null,"abstract":"<div><div>The endocannabinoid system plays a critical role in regulating pathophysiological processes and represents a promising target for novel therapies aimed at neurodegenerative disorders. Anandamide (AEA) mediates its therapeutic effects, particularly in pain modulation; however, its clinical potential is constrained by rapid degradation via fatty acid amide hydrolase (FAAH). The keto-oxazolopyridine derivative OL-135 is a potent FAAH inhibitor (IC₅₀ = 4.7 nM). In this study, molecular docking simulations using three distinct protocols were performed to evaluate the binding modes of 44 arylfuran analogs of OL-135 at the FAAH enzyme binding site. These analyses identified several promising candidates, including analogs <strong>2</strong> and <strong>24</strong>, which were subsequently synthesized, characterized, and tested in experimental models of pain and inflammation in mice. Carrageenan-induced pain and paw edema were used to investigate the antinociceptive and anti-inflammatory activities. Also, hot plate test was employed to evaluate the antinociceptive activity. Compound <strong>2</strong> significantly reduced mechanical allodynia and acute paw edema induced by carrageenan. Compounds <strong>2</strong> and <strong>24</strong> (5, 25 and 100 mg/Kg, i.p.) reduced the nociceptive response in model of nociceptive pain (hot plate). The activity of compound 2 (100 mg/Kg) in the model of nociceptive pain was attenuated by previous administration of AM251 (4 and 8 mg/Kg, i.p.). Importantly, compound <strong>2</strong> demonstrated no adverse effects on key biochemical parameters indicative of cardiotoxicity, hepatotoxicity, or nephrotoxicity. These findings underscore the potential of arylfuran analogs as analgesic and anti-inflammatory agents, paving the way for further development of therapeutic molecules.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118471"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145413938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and biological evaluation of some pyrimidine derivatives as multifunctional ligands for the treatment of Alzheimer's disease","authors":"Ozge Kuyrukcu Ozturk ,&nbsp;Ozlem Oyardi ,&nbsp;Rahsan Ilikci Sagkan ,&nbsp;Yasemin Dundar","doi":"10.1016/j.bmc.2025.118445","DOIUrl":"10.1016/j.bmc.2025.118445","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a neurodegenerative disorder and acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and sphingomyelinase (SMase) enzymes are among its therapeutic targets. In this study, a series of tetrahydropyrimidine and hexahydropyrimidine derivatives were synthesized and evaluated for their inhibition of <em>Bacillus cereus</em> SMase, electric eel AChE (<em>Ee</em>AChE), and equine BuChE (eqBuChE) as potential agents against AD. Among the synthesized compounds, 4-oxo-6-(pyridin-2-yl)-2-thioxohexahydropyrimidine-5‑carbonitrile (compound <strong>24</strong>) was found to be the most active compound against <em>B. cereus</em> SMase, with an IC₅₀ value of 1.61 μM. In addition, 2-(benzylthio)-4-octyl-6-oxo-1,6-dihydropyrimidine-5‑carbonitrile (compound <strong>14</strong>) and 4-octyl-6-oxo-2-(phenethylthio)-1,6-dihydropyrimidine-5‑carbonitrile (compound <strong>16</strong>) exhibited selective eqBuChE inhibition with IC₅₀ values of 3.68 and 1.65 μM, respectively. The mode of inhibition of the selected compounds was determined by enzyme kinetic study. These compounds were also examined for their metal-chelating properties with various biometals and effect of <em>B. cereus</em>-induced hemolysis on sheep erythrocytes. Additionally, compound <strong>24</strong> showed no cytotoxic effect on the HUVEC cell line at its IC₅₀ concentration. The biological data were supported by the results of molecular docking studies, and <em>in-silico</em> physicochemical properties/ADME predictions of the selected compounds were determined.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118445"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145322852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug design and synthesis of new N-substituted-thienopyridine based on 2-aminothiophene derivatives as antileishmanial agents","authors":"Vitória Gaspar Bernardo ,&nbsp;Rodrigo Santos Aquino de Araújo ,&nbsp;Natália Barbosa de Mélo ,&nbsp;Ricardo Eduardo Pereira Coutinho ,&nbsp;Julyanne Maria Saraiva de Sousa ,&nbsp;Maria Gabrielly Gonçalves da Silva Sousa ,&nbsp;Natália Ferreira de Sousa ,&nbsp;Wadja Feitosa dos Santos Silva ,&nbsp;Paulo Fernando da Silva Santos-Júnior ,&nbsp;Teresinha Gonçalves da Silva ,&nbsp;Eduardo René Pérez González ,&nbsp;Edeildo Ferreira da Silva Junior ,&nbsp;Marcus Tullius Scotti ,&nbsp;Anuraj Nayarisseri ,&nbsp;Klinger Antonio da Franca Rodrigues ,&nbsp;Francisco Jaime Bezerra Mendonça-Junior","doi":"10.1016/j.bmc.2025.118475","DOIUrl":"10.1016/j.bmc.2025.118475","url":null,"abstract":"<div><div>Leishmaniasis is a neglected tropical disease with limited and often toxic treatment options. This study explores the antileishmanial potential of <em>N</em>-substituted thieno[2,3-<em>c</em>]pyridine derivatives through combined <em>in vitro</em> and <em>in silico</em> approaches. Initially, <em>N</em>-Boc-thieno[2,3-<em>c</em>]pyridine (<strong>2a–i</strong>) and <em>N</em>-Boc-thieno[2,3-<em>b</em>]pyridine (<strong>1a–f</strong>) derivatives were synthesized and evaluated against <em>Leishmania amazonensis</em>, <em>L. braziliensis</em>, <em>L. infantum</em>, and RAW 264.7 macrophages. Only <em>N</em>-Boc-thieno[2,3-<em>c</em>]pyridine derivatives with substituted nitrogen at position 6 (<strong>2b</strong>, <strong>2c</strong>, <strong>2f</strong>, <strong>2g</strong>) were active (IC₅₀ &lt; 10 μM). Based on this, a series of <em>N</em>-benzyl-thieno[2,3-<em>c</em>]pyridine analogs (<strong>3a–i</strong>) was synthesized, with compounds <strong>3c</strong>, <strong>3f</strong>, and <strong>3g</strong> showing improved antipromastigote activity and selectivity índices (SI). Notably, compound <strong>3f</strong> demonstrated potent amastigote activities (IC₅₀ between 0.83 and 1.13 μM), comparable to amphotericin B, but with a 250-fold higher SI and low in vivo toxicity (LD₅₀ = 2000 mg/kg in <em>Zophobas morio</em>). Physicochemical and pharmacokinetic predictions using SwissADME and Osiris indicated favorable drug-like properties and oral bioavailability for <strong>3f</strong>. Molecular docking and dynamics simulations revealed strong binding affinities to Nucleoside Diphosphate Kinase (NDK) (PDB: <span><span>5GO1</span><svg><path></path></svg></span>), Dihydroorotate Dehydrogenase (DHODH) (PDB: <span><span>4WZH</span><svg><path></path></svg></span>), and Sterol 14α-Demethylase (CYP51) (PDB: <span><span>3L4D</span><svg><path></path></svg></span>), surpassing reference ligands, with stable complexes, key catalytic site interactions, low RMSD, compact Radius of gyration, and reduced RMSF, supporting their potential as conformationally stable and specific enzyme inhibitors for leishmaniasis treatment. Altogether, these findings strongly highlight the potential of <em>N</em>-substituted thieno[2,3-<em>c</em>]pyridine as promising scaffolds for antileishmanial drug development and highlight compound <strong>3f</strong> as a lead candidate for further optimization.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118475"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145443530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Triazole-based STING inhibitors","authors":"Anju Singh ,&nbsp;Leonard Barasa ,&nbsp;Leo DeOrsey ,&nbsp;Maeve D. O'Reilly ,&nbsp;Shruti Choudhary ,&nbsp;Sara E. Cahill ,&nbsp;Thomas Rossetti ,&nbsp;Robert Madison Green ,&nbsp;Fiachra Humphries ,&nbsp;Paul R. Thompson","doi":"10.1016/j.bmc.2025.118484","DOIUrl":"10.1016/j.bmc.2025.118484","url":null,"abstract":"<div><div>Aberrant activation of the DNA sensing cGAS–STING pathway has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), systemic lupus erythematosus (SLE), and autoinflammatory disorders such as Aicardi-Goutières syndrome (AGS) and STING-associated vasculopathy with onset in infancy (SAVI). Consequently, considerable efforts have been directed toward the development of STING inhibitors. We previously reported that <strong>BB-Cl-amidine</strong> and <strong>LB244</strong> inhibit STING-dependent signalling with nanomolar potency both <em>in vitro</em> and <em>in vivo</em>. The nitrofuran warhead on <strong>LB244</strong> provided superior potency and proteome-wide selectivity. Moreover, <strong>LB244</strong> mirrored the efficacy of <strong>BB-Cl-amidine</strong> <em>in vivo</em>. Herein, we describe the development of a series of triazole-based analogues designed to inhibit STING signalling. These efforts led to the development of <strong>ASF24,</strong> a highly potent inhibitor of STING signalling (IC₅₀ = 0.49 μM). In summary, our findings identify a novel triazole-based STING inhibitor and establish a promising scaffold for the development of therapeutics targeting STING-mediated inflammatory diseases.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118484"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145525969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pyranotacrines as prospective multi-target compounds against Alzheimer's disease","authors":"Salma Fares,&nbsp;Walaa M. El Husseiny,&nbsp;Khalid B. Selim,&nbsp;Mohammed A.M. Massoud","doi":"10.1016/j.bmc.2025.118480","DOIUrl":"10.1016/j.bmc.2025.118480","url":null,"abstract":"<div><div>A series of tacrine-based 4-<em>H</em>-pyran derivatives were synthesized and biologically estimated as multifactorial ligands against Alzheimer's disease. Pyranotacrines were characterized by having the main core tacrine (ChE inhibition) and tetrahydro-4<em>H</em>-pyran (calcium channel blockers and β-amyloid activity). Among the series, compound <strong>6c</strong> displayed a well-balanced multi-targeted activity against Alzheimer's disease and it was a potent AChE inhibitor with IC₅₀ = 0.06 <strong>±</strong> 0.005 μM, approximately 3-folds more active than tacrine as a reference drug. Kinetic analysis and molecular docking displayed that <strong>6c</strong> targeted both key binding regions of AChE. Moreover, its inhibitory activity against BuChE was 8-folds more active than rivastigmine with IC₅₀ = 0.09 ± 0.016 μM. Compound <strong>6c</strong> showed blockade power of 46 % as a Ca²⁺ blockade agent and strong inhibition activity against β-amyloid with IC₅₀ = 1.09 ± 0.05 μM (71 % aggregation inhibition). Additionally, it showed higher anti-oxidative activity with 10.36 TE and chelating anchors activity for metal ions. The safety of <strong>6c</strong> towards <em>SH-SY5Y</em> normal cells and HepG2 cancer cells was interesting with safety index ratio (<em>Si</em> = 2273), in addition to its BBB permeability and pharmacokinetic profile.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118480"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145494239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep seeking covalent DNA encoded library for novel JAK3 inhibitor discovery","authors":"Tao Chen ,&nbsp;Longying Cai ,&nbsp;Xiaofei Dong ,&nbsp;Lifang Zhang ,&nbsp;Xuemin Cheng ,&nbsp;Jingsong Qu ,&nbsp;Guanyu Yang ,&nbsp;Sen Gao ,&nbsp;Linfu Luo ,&nbsp;Huiyong Ma ,&nbsp;Shuai Xia ,&nbsp;Guansai Liu ,&nbsp;Jin Li ,&nbsp;Jianyou Shi ,&nbsp;Dengfeng Dou","doi":"10.1016/j.bmc.2025.118448","DOIUrl":"10.1016/j.bmc.2025.118448","url":null,"abstract":"<div><div>To better understand how pre-installed covalent warheads affect the ligand discovery in DNA encoded library (DEL), we have designed three individual covalent DELs incorporating 7, 32 and 64 cysteine-targeting covalent warheads respectively, and screened these DELs against JAK3 purified protein. The experiments resulted 6 novel series of covalent inhibitors with drug-like properties, where the most potent compounds achieved picomolor IC₅₀ and good selectivity against a mini panel of kinases. The mass spec study confirmed their covalent MOAs by targeting JAK3 Cys909. More importantly, we confirmed the synergistic effect of the binding moiety and warhead by comparing the activities with their close analogs, suggesting that these compounds may not able to be designed by installation of covalent warheads to reversible binders. Further analysis revealed that 7 warheads were sufficient for identifying JAK3 covalent ligands. This work deepens our understanding of the design and screening of covalent DEL, and also demonstrate the power of DEL in the identification of diverse inhibitors.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118448"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145375484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 in vitro anti-renal fibrotic effects of imidazopyridazine-based homeodomain-interacting protein kinase 2 inhibitors","authors":"Mengmeng Yao ,&nbsp;Yan Wu ,&nbsp;Xinlan Hu ,&nbsp;Chunyu Feng ,&nbsp;Jie Xu ,&nbsp;Zhuo Chen ,&nbsp;Qianbin Li","doi":"10.1016/j.bmc.2025.118456","DOIUrl":"10.1016/j.bmc.2025.118456","url":null,"abstract":"<div><div>Renal fibrosis, a progressive pathology in chronic kidney disease (CKD), is primarily driven by HIPK2 (homeodomain-interacting protein kinase 2)-mediated activation of the TGF-β/Smad3 and NF-κB signaling pathways, leading to excessive extracellular matrix deposition and inflammation. Current therapeutic strategies targeting HIPK2 show limited efficacy, highlighting the need for more effective inhibitors. We developed compound <strong>c4</strong> through rational optimization of the lead compound CHR-6494. This derivative exhibits potent dual activities, with IC₅₀ values of 0.68 ± 0.18 μM for HIPK2 inhibition and 0.15 ± 0.02 μM for anti-proliferative effects in NRK-49F cells. Molecular dynamics simulations confirmed the stable binding of the <strong>c4</strong>-HIPK2 complex. Functional assays in TGF-β-stimulated NRK-49F cells and TNF-α-stimulated HK-2 cells demonstrated that <strong>c4</strong>, even at low concentrations, significantly downregulated fibrosis markers (Collagen I, Fibronectin, α-SMA) and inflammatory mediators (p-P65, IL-6), while suppressing fibrotic responses (cell proliferation, migration). These findings establish <strong>c4</strong> as a promising HIPK2 kinase inhibitor for developing effective anti-fibrotic therapies targeting HIPK2 in CKD.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118456"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145413939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 amino acid-Osimertinib conjugates as potential EGFR inhibitors","authors":"Hong-Ning Men ,&nbsp;Peng-Fei Gu ,&nbsp;Zheng Li ,&nbsp;Yue Yu ,&nbsp;Lin An ,&nbsp;Ling Zhang ,&nbsp;Tong-Hui Huang ,&nbsp;You-Guang Zheng","doi":"10.1016/j.bmc.2025.118482","DOIUrl":"10.1016/j.bmc.2025.118482","url":null,"abstract":"<div><div>In this study, a series of novel amino acid-conjugated <strong>Osimertinib</strong> scaffold derivatives were designed and synthesized as EGFR (T790M/L858R) mutations inhibitors. Notably, compound <strong>10a</strong> potently inhibited EGFR (IC₅₀ = 0.046 μM) and displayed anti-proliferative activities against mutant non-small cell lung cancer cells (H1975 IC₅₀: 1.619 μM). Furthermore, compound <strong>10a</strong> down-regulated the phosphorylation of EGFR, ERK and AKT in a dose-dependent manner in H1975 cells. At 5 μM, <strong>10a</strong> suppressed p-ERK and p-AKT levels to 38 % and 40 % of control in H1975 cells, respectively. Cell cycle analysis revealed that compound <strong>10a</strong> inhibited the proliferation of cells by inducing cell cycle arrest in the G1 phase. Molecular modeling indicated that compound <strong>10a</strong> exhibited a binding mode analogous to that of <strong>Osimertinib</strong>. Overall, these results demonstrate the potential of <strong>10a</strong> as an anticancer agent warranting further development.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118482"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145494266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}