Medicinal Chemistry Research最新文献

{"title":"Centanafadine (Simtriyo®): a first-in-class triple reuptake inhibitor approved for attention-deficit/hyperactivity disorder (ADHD)","authors":"Longqin Hu","doi":"10.1007/s00044-026-03612-8","DOIUrl":"10.1007/s00044-026-03612-8","url":null,"abstract":"<div><p>Centanafadine (Simtriyo^®, <b>3</b>) is a recently approved therapy for attention-deficit/hyperactivity disorder (ADHD) that introduces a first-in-class triple reuptake inhibition mechanism. Featuring a naphthyl group and a rigid azabicyclic scaffold, centanafadine functions as a norepinephrine, dopamine, and serotonin reuptake inhibitor (NDSRI) with a potency profile of NET &gt; DAT &gt; SERT. Unlike flexible phenethylamine stimulants such as (meth)amphetamine (<b>1</b>), which enter presynaptic neurons and actively trigger monoamine release, or piperidine derivatives like methylphenidate (<b>2</b>), which selectively block dopamine and norepinephrine reuptake, centanafadine inhibits all three monoamine transporters without inducing neurotransmitter release. Centanafadine represents a modern medicinal chemistry strategy aimed at managing ADHD symptoms through combined catecholaminergic and serotonergic mechanisms, offering sustained efficacy while potentially mitigating the abuse liability, insomnia, and cardiovascular risks typical of traditional psychostimulants.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 9","pages":"1548 - 1552"},"PeriodicalIF":3.5,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-026-03612-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148817023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Review of promising benzimidazole-based anticancer agents (2023-2026)","authors":"Elena Y. Shumilova,&nbsp;Sergey V. Sysolyatin,&nbsp;Svetlana V. Strokova","doi":"10.1007/s00044-026-03610-w","DOIUrl":"10.1007/s00044-026-03610-w","url":null,"abstract":"<div><p>Benzimidazoles represent a key class of heterocyclic compounds that stand out for their wide range of biological activity. This scaffold has become particularly important in medicinal chemistry due to its ability to mimic the purine bases of natural nucleosides, which ensures active interaction with biological targets. Today, the benzimidazole moiety provides a basis for many clinically significant drugs, such as omeprazole, albendazole, pantoprazole, and others. The potential of benzimidazole derivatives as inhibitors of cancer cell proliferation has actively been studied in recent years. In this regard, the development of highly selective, low-toxicity cytostatic molecules based on benzimidazole is highly relevant for modern oncopharmacology. This paper provides a systematic overview of advances reported over 2023–2026 in the anticancer activity of benzimidazole derivatives. The focus is on the results of preclinical studies on a panel of cell lines, including cervical carcinoma (HeLa), bladder carcinoma (HTB-9), non-small cell lung cancer (A-549), colorectal carcinoma (HCT-116), colon cancer (HT-29), chronic myeloid leukemia (K-562), acute lymphoblastic leukemia (CCRF-CEM), breast adenocarcinoma (MCF-7), triple-negative breast cancer (MDA-MB-231), hepatocellular carcinoma (HepG2), and glioblastoma (LN-18). The data analysis revealed the most promising compounds that exhibit a pronounced cytostatic activity against cancer cells. The relationship between the molecular structure and activity of the examined compounds was evaluated. This review summarizes the latest achievements in this field and can serve as a basis for a further search for novel benzimidazole skeleton-containing anticancer agents.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 9","pages":"1722 - 1743"},"PeriodicalIF":3.5,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786762","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, biological activity and computational simulation evaluation of pyrimidine-2-aminoacetamide derivatives as cholinesterase inhibitors","authors":"Yi-Xuan Wang,&nbsp;Shi-Hao Qin,&nbsp;Qian Liu,&nbsp;Xue-Wei Zhou,&nbsp;Chao-Yue Zhang,&nbsp;Zheng-Yue Ma","doi":"10.1007/s00044-026-03611-9","DOIUrl":"10.1007/s00044-026-03611-9","url":null,"abstract":"<div><p>To search for novel anti-Alzheimer’s disease candidate molecules, a series of pyrimidine-2-aminoacetamide derivatives were designed and synthesized, and their cholinesterase (ChE) inhibitory activities were systematically evaluated. The results showed that all target compounds exhibited varying degrees of inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among them, compound <b>17v</b> had the most excellent activity, with IC₅₀ values of 0.96 and 7.12 μM for AChE and BuChE, respectively, which were superior to the positive control galantamine (AChE: IC₅₀ = 5.10 μM, BuChE: IC₅₀ = 14.76 μM). In terms of antioxidant activity, the results indicated that the overall activity of all compounds was relatively weak, with the most active compound <b>17d</b> having an IC₅₀ value of 115.77 μM, which was inferior to ascorbic acid (IC₅₀ = 41.17 μM). Molecular docking revealed that <b>17v</b> binds to both catalytic and peripheral anionic sites of AChE, supporting a mixed-type inhibition mechanism confirmed by enzyme kinetics. A 100 ns molecular dynamics simulation confirmed stable binding of <b>17v</b> within AChE and BuChE pockets. Target prediction and toxicity assessment suggested that compound <b>17v</b> may possess multi-target neuroprotective potential and a favorable preliminary safety profile, supporting its further investigation as a potential therapeutic candidate for Alzheimer’s disease. SwissADMET prediction indicated favorable physicochemical properties and drug-likeness profiles. In conclusion, compound <b>17v</b> represents a promising lead compound for anti-Alzheimer’s therapy.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 9","pages":"1801 - 1818"},"PeriodicalIF":3.5,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786677","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":"Zidesamtinib (Jideytro®): a new selective, brain-penetrant ROS1 inhibitor approved for the treatment of ROS1-positive non-small cell lung cancer","authors":"Sumi Lee,&nbsp;Longqin Hu","doi":"10.1007/s00044-026-03606-6","DOIUrl":"10.1007/s00044-026-03606-6","url":null,"abstract":"<div><p>ROS1-targeted therapies have improved outcomes in ROS1-positive non-small cell lung cancer (NSCLC), but acquired resistance, CNS progression, and off-target toxicities remain important limitations. Zidesamtinib (Jideytro^®, NVL-520) is a next-generation, brain-penetrant, tropomyosin receptor kinase (TRK)-sparing ROS1 inhibitor designed to retain activity against resistance mutations, including G2032R. In preclinical models, it demonstrated potent, selective ROS1 inhibition, broad resistance coverage, and durable intracranial activity. Administered orally at 100 mg once daily, zidesamtinib exhibits a favorable pharmacokinetic profile. Data from the ARROS-1 phase 1/2 trial demonstrated durable clinical efficacy and manageable safety in previously treated ROS1-positive NSCLC, including patients with CNS metastases and G2032R resistance. These results led to its accelerated FDA approval on July 22, 2026, for patients previously treated with a ROS1-targeted tyrosine kinase inhibitor.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 9","pages":"1543 - 1547"},"PeriodicalIF":3.5,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-026-03606-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A comprehensive review on phytochemistry and pharmacological activities of genus Saussurea","authors":"Ayesha Bibi","doi":"10.1007/s00044-026-03603-9","DOIUrl":"10.1007/s00044-026-03603-9","url":null,"abstract":"<div><p>The genus <i>Saussurea</i> (family Asteraceae) comprises more than 400 species that are widely distributed in alpine and temperate regions of Asia, Europe, and North America. Many species of this genus have been traditionally used in Tibetan, Chinese, and Ayurvedic medicine for the treatment of various diseases. In recent years, increasing scientific attention has been directed toward <i>Saussurea</i> species due to their remarkable phytochemical diversity and wide range of medicinal applications. Although several individual research have reported the isolation of bioactive compounds and their biological activities, a comprehensive review summarizing the secondary metabolites of this genus is still lacking. Therefore, the present work provides a consolidated overview of the identified phytochemicals of <i>Saussurea</i> species by compiling and classifying them into their major chemical groups, encompassing sesquiterpene lactones, flavonoids, phenolic acids, alkaloids, lignans, terpenoids, and other phytoconstituents. It correlates chemical structures, compound identities, botanical sources, analytical characterization, and documented therapeutic activities including anti-inflammatory, antioxidant, antimicrobial, antidiabetic, antifungal, antiviral, antihypoxic, anti-lithic, and vasorelaxant activity to establish a unified reference framework for the genus. In addition, the present study summarizes the analytical and quantitative methods employed for the identification of key constituents and critically evaluates the available pharmacological evidence from in vitro, in vivo, and mechanistic studies. Furthermore, it highlights the strengths and limitations of current research, identifies key knowledge gaps covering limited standardization, inadequate in vivo validation, and the scarcity of clinical investigations. Collectively, this article serves as a valuable reference for researchers working on the phytochemistry and therapeutic applications of <i>Saussurea</i> species, while emphasizing the need for further phytochemical and clinical investigations to fully explore their medicinal value.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 9","pages":"1587 - 1625"},"PeriodicalIF":3.5,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786654","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":"Dual-target carbonic anhydrase inhibitors in cancer therapy: progress, challenges, and opportunities","authors":"Meizhen Luo,&nbsp;Yong Wang,&nbsp;Yinmei Xia,&nbsp;Qin-Min Wang,&nbsp;Jifa Zhang,&nbsp;Lianhai Shan","doi":"10.1007/s00044-026-03605-7","DOIUrl":"10.1007/s00044-026-03605-7","url":null,"abstract":"<div><p>Carbonic anhydrases (CA) are metalloenzymes that mediate diverse physiological and pathological processes, including pH, metabolism, and electrolyte balance, making them key therapeutic targets. Although numerous carbonic anhydrase inhibitors are clinically used for glaucoma, mountain sickness, hypoxic tumors and epilepsy, their efficacy is often limited by systemic toxicity, drug resistance, and poor activity against multifactorial diseases. Multi-target combination therapy, particularly via dual-target agents, offers a promising strategy to overcome these hurdles. Given the synergistic relationships between CA and epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR) and histone deacetylase (HDAC), among other common drug targets, dual-target carbonic anhydrase inhibitors (CAIs) hold great potential to circumvent current limitations and enhance treatment outcomes. This review summarizes recent progress in dual-target CAIs, emphasizing design strategies, structure-activity relationships (SAR), and translational challenges, and provides a theoretical foundation and innovative perspectives for next-generation CA-directed therapies.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 9","pages":"1626 - 1666"},"PeriodicalIF":3.5,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786647","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":"The genus Laggera: an extensive review of phytochemistry, pharmacology, clinical study, and chemical modification","authors":"Huynh Thi Ngoc Ni,&nbsp;Do Thi Lan Huong,&nbsp;Duong Quang Huan,&nbsp;Huy Dinh Vu,&nbsp;Tran Thi Thanh Thuy,&nbsp;Nguyen Thanh Hao,&nbsp;Dong Huy Gioi,&nbsp;Dinh Thi Thu Huong,&nbsp;Ninh The Son","doi":"10.1007/s00044-026-03609-3","DOIUrl":"10.1007/s00044-026-03609-3","url":null,"abstract":"<div><p>The genus <i>Laggera</i> (Asteraceae) comprises medicinal plants traditionally used for treating inflammatory, infectious, and respiratory disorders. However, a comprehensive review of its phytochemistry and pharmacological potential is still limited. A systematic literature search was conducted across major scientific databases, including PubMed, Scopus, Web of Science, and Google Scholar, covering publications through April, 2026. Keywords such as “<i>Laggera</i>”, “phytochemistry”, “essential oil”, “pharmacology”, and “synthesis” were used. Relevant studies were selected based on their focus on chemical constituents, biological activities, clinical investigations, and chemical modifications. Data were categorized into phytochemical classes and pharmacological effects, and critically analyzed to provide an integrated overview of the genus. About 218 secondary metabolites have been identified, including terpenoids, flavonoids, phenolic acids, lignans, and others, with eudesmane-type sesquiterpenoids as the dominant class. Essential oils showed significant variability, with major constituents such as 2,5-dimethoxy-p-cymene and β-caryophyllene. <i>Laggera</i> constituents exhibited diverse pharmacological activities, including anticancer, antioxidant, anti-inflammatory, antimicrobial, antiviral, anti-insect, and organ protective effects. These activities are primarily associated with the signaling pathways, such as nuclear factor-kappa B (NF-κB), mitogen activated-protein kinase (MAPK), and vascular endothelial growth factor (VEGF). Preliminary clinical evidence reveals the therapeutic potential of <i>L. pterodonta</i> in respiratory diseases. In addition, semisynthesis and nanoformulation have been explored to enhance biological efficacy.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 9","pages":"1690 - 1721"},"PeriodicalIF":3.5,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786824","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 antitumor activity through structural optimization of 2-(Benzylamino)-thieno[2,3-d]pyrimidin-4(3H)-ones","authors":"Nazariy Pokhodylo,&nbsp;Kostiantyn Levchenko,&nbsp;Nataliya Finiuk,&nbsp;Yuliia Kozak,&nbsp;Olha Klyuchivska,&nbsp;Rostyslav Stoika","doi":"10.1007/s00044-026-03604-8","DOIUrl":"10.1007/s00044-026-03604-8","url":null,"abstract":"<div><p>We used our previously developed one-pot green trans-annulation approach involving thermally induced 1 H-tetrazole ring cleavage and in situ pyrimidine formation for synthesis of combinatorial library of substituted 2-(benzyl/phenethylamino)-thieno[2,3-/3,2-d]pyrimidin-4(3H)-ones. Scaffold selection was guided by identification of 2-(benzylamino)-5,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-one as a highly cytotoxic lead. Biological evaluation revealed that <b>4c</b> and <b>4b</b> compounds exhibited the most potent and broad-spectrum cytotoxicity. <b>4c</b> compound demonstrated sub-micromolar IC₅₀ values against Jurkat (0.84 µM), KB3-1 (0.77 µM), and HCT116 (2.43 µM) cells, whereas 4b compound showed moderate cytotoxic activity (7.92–17.33 µM). Other derivatives displayed moderate cytotoxicity (8–70 µM) and generally higher IC₅₀ values in non-cancerous HaCaT, BEAS-2B, and Balb/3T3 cells. Mechanistic studies showed that <b>4b</b>, <b>4c</b>, and <b>7b</b> compounds induced pro-apoptotic DNA damage in Jurkat T-leukemia and HCT116 wt carcinoma cells. They also significantly increased intracellular ROS levels, thus suggesting that their cytotoxicity is mediated by oxidative stress–related pathways, rather than direct DNA binding or intercalation. Compounds <b>4b</b>, <b>4c</b> trigger tumor cell apoptosis, characterised by activation of caspase 3 and subsequent cleavage of PARP1, and Bcl-2 suppression. Notably, the <b>4c</b> compound did not exhibit acute in vivo toxicity upon extended study. Thus, the obtained findings demonstrated potential of 2-benzylaminothienopyrimidin-4(3H)-ones as promising scaffolds for further development of anticancer agents.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 9","pages":"1755 - 1773"},"PeriodicalIF":3.5,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786701","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":"Indole-based derivatives as anticancer agents: recent advances in structure–activity relationships and biological mechanisms","authors":"Aashik Malik,&nbsp;Mayank Yadav,&nbsp;Jai Parkash Kadian,&nbsp;Komal Mishra,&nbsp; Ramsha,&nbsp;Anurag Rathore,&nbsp; Manisha,&nbsp;Nishant Rathour","doi":"10.1007/s00044-026-03607-5","DOIUrl":"10.1007/s00044-026-03607-5","url":null,"abstract":"<div><p>Despite significant advances in cancer therapy, the clinical efficacy of many anticancer agents remains limited by poor selectivity, systemic toxicity, and the emergence of drug resistance, highlighting the need for novel therapeutic strategies. Among privileged heterocyclic scaffolds, indole has emerged as a versatile pharmacophore for the development of targeted anticancer agents owing to its structural diversity and broad biological activity. This review critically evaluates recent advances in indole-based anticancer agents, with particular emphasis on structure–activity relationships (SAR), molecular mechanisms, and target-oriented drug design. The discussion encompasses major therapeutic targets, including protein kinases (EGFR, VEGFR-2, CDKs, and Aurora kinases), tubulin, topoisomerases I and II, Bcl-2 family proteins, and histone deacetylases (HDACs). Comparative analysis identifies key SAR trends, successful optimization strategies, and the influence of structural modifications on potency, selectivity, and target specificity. The review further discusses current translational challenges, including pharmacokinetic limitations, toxicity, and resistance, while highlighting emerging approaches such as molecular hybridization, dual-target inhibitors, and rational scaffold optimization. Collectively, this review provides an integrated medicinal chemistry perspective that may facilitate the rational design and clinical translation of next-generation indole-based anticancer therapeutics.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 9","pages":"1667 - 1689"},"PeriodicalIF":3.5,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148757835","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 mechanistic evaluation of chalcone–quinoline–triazole hybrids as antifungal CYP51 inhibitors","authors":"Rudi Hendra,&nbsp;Rahmad Setiawan Rabby,&nbsp;Tengku Anggia Fitri,&nbsp;Hilwan Yuda Teruna,&nbsp;Neni Frimayanti","doi":"10.1007/s00044-026-03608-4","DOIUrl":"10.1007/s00044-026-03608-4","url":null,"abstract":"<div><p>A series of novel chalcone–quinoline–triazole hybrid compounds were rationally designed, synthesised, and evaluated for antifungal activity against clinically relevant <i>Candida</i> species, including <i>C. albicans</i>,<i> C. glabrata</i>, and <i>C. krusei</i>. Among the synthesized derivatives, compound <b>7b</b> exhibited the most potent antifungal activity, with minimum inhibitory concentration (MIC) values ranging from 6.25 to 12.5 µM, surpassing the reference antifungal ketoconazole under identical experimental conditions. Time–kill kinetic studies further confirmed its concentration- and time-dependent fungicidal activity. Mechanistic investigations demonstrated that compound <b>7b</b> markedly disrupted fungal sterol biosynthesis, as evidenced by significant ergosterol depletion, lanosterol accumulation, and a pronounced reduction in the ergosterol/lanosterol ratio across all tested <i>Candida</i> species. Concentration–response analysis of the normalised ergosterol/lanosterol ratio yielded low apparent IC₅₀ values for compound <b>7b</b>, supporting potent inhibition of CYP51-dependent sterol conversion at the cellular level. Cytotoxicity assessment in mammalian cell lines (HepG2, HK2, and Vero) indicated that compound <b>7b</b> possessed lower cytotoxicity and a more favourable selectivity profile than ketoconazole. Molecular docking studies revealed favourable binding interactions of compound <b>7b</b> within the CYP51 active site, while 100 ns molecular dynamics simulations supplemented by MM–PBSA energy decomposition and hydrogen-bond occupancy analysis supported persistent non-covalent stabilisation of the ligand–protein complex. Collectively, the integration of synthetic chemistry, antifungal evaluation, cellular sterol profiling, and complementary computational modelling identifies compound 7b as a promising antifungal lead scaffold associated with disruption of CYP51-dependent ergosterol biosynthesis.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 9","pages":"1774 - 1800"},"PeriodicalIF":3.5,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148756802","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}