Medicinal Chemistry Research最新文献

{"title":"Current CMC challenges in oligonucleotide API development: from IND to NDA","authors":"Daoqian Chen,&nbsp;Xiaobing Zhang,&nbsp;Songgen Xu,&nbsp;Deming Liu","doi":"10.1007/s00044-026-03569-8","DOIUrl":"10.1007/s00044-026-03569-8","url":null,"abstract":"<div>\u0000 \u0000 <p>Oligonucleotide therapeutics are becoming representatives of the “Third Wave” of pharmaceutical innovation, expending from initial rare diseases to oncology and chronic indications, following small molecules and proteins. Globally, hundreds of clinical trials are currently underway, in addition to the 26 oligonucleotide drugs that have already been approved. Although nearly thirty years have elapsed since the initial approval of Fomivirsen, oligonucleotide therapeutics continue to pose unique CMC (Chemistry, Manufacturing, and Controls) challenges that are distinct from small molecules. Furthermore, the lack of harmonized ICH guidelines specifically for oligonucleotides forces developers to navigate a “regulatory grey area” between new molecular entities (NMEs) and biologics. This perspective focuses on the technical and regulatory hurdles of API (Active Pharmaceutical Ingredient) CMC development, covering synthesis (including conjugation strategies with delivery systems), analysis and regulatory aspects, with a specific emphasis on stage-appropriate requirements from the Investigational New Drug (IND) application to the New Drug Application (NDA).</p>\u0000 <span>AbstractSection</span>\u0000 Graphical Abstract\u0000 <div><figure><div><div><picture><source><img></source></picture><span>The alternative text for this image may have been generated using AI.</span></div></div></figure></div>\u0000 \u0000 </div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 4","pages":"711 - 725"},"PeriodicalIF":3.1,"publicationDate":"2026-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754384","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":"Integrated 3D-QSAR and cellular profiling of sulfated and hydrophobic aminoglycoside glycans to modulate heparanase activity","authors":"Junzhe Wang,&nbsp;Livia Philip,&nbsp;Tharuka Beragama Vithanage,&nbsp;Andrew Gulewicz,&nbsp;Hawau Abdulsalam,&nbsp;Hien M. Nguyen","doi":"10.1007/s00044-026-03553-2","DOIUrl":"10.1007/s00044-026-03553-2","url":null,"abstract":"<div><p>Heparanase (HPSE) plays a critical role in tumor progression by degrading heparan sulfate chains in the extracellular matrix and modulating the tumor microenvironment. As a result, it has emerged as a promising therapeutic target. Aminoglycoside-derived sulfated glycan mimetics have shown potential as HPSE inhibitors, but rational optimization is challenged by complex steric and electrostatic interactions. Here, we used three-dimensional quantitative structure–activity relationship (3D-QSAR) modeling to identify key structural features governing HPSE inhibition, providing new predictive structure–activity insights for sulfated aminoglycoside-based HPSE inhibitors. Guided by these insights, we evaluated the lead compound <b>L17</b> in HPSE-dependent cancer cell lines and observed concentration-dependent inhibition of proliferation, suppression of invasion, and reduction of extracellular HPSE levels. In silico ADMET predictions flagged CYP3A4 as a potential liability, but experimental assays confirmed minimal inhibition, indicating a favorable metabolic profile. This integrated approach provides mechanistic insight into aminoglycoside-based HPSE inhibitors and supports their rational optimization as anticancer therapeutics.</p><div><figure><div><div><picture><source><img></source></picture><span>The alternative text for this image may have been generated using AI.</span></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 4","pages":"834 - 846"},"PeriodicalIF":3.1,"publicationDate":"2026-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754473","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":"Special issue of Medicinal Chemistry Research in honor of Prof. Richard B. Silverman on the occasion of his 80th birthday","authors":"Pathum M. Weerawarna,&nbsp;Isaac T. Schiefer,&nbsp;Matthew J. Moschitto","doi":"10.1007/s00044-026-03561-2","DOIUrl":"10.1007/s00044-026-03561-2","url":null,"abstract":"","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 4","pages":"665 - 667"},"PeriodicalIF":3.1,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754474","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":"Exploring NiCl2, PdCl2 and PtCl2 as a catalyst for [3 + 2] cycloaddition in Kopsane alkaloid synthesis by density functional theory study","authors":"Sanghee Yoon,&nbsp;Pratanphorn Nakliang,&nbsp;Bilal Shaker,&nbsp;Tao Ye,&nbsp;Sun Choi","doi":"10.1007/s00044-026-03556-z","DOIUrl":"10.1007/s00044-026-03556-z","url":null,"abstract":"<div><p>Kopsane alkaloids possess a complex heptacyclic scaffold and exhibit significant biological activities, including cholinergic, anti-inflammatory, and anti-cancer effects. While we previously reported PtCl₂-catalyzed [3 + 2] cycloaddition for their synthesis, the high cost and toxicity of platinum necessitate sustainable alternatives. In this study, we employed density functional theory (DFT) to investigate MCl₂ (M = Ni, Pd, and Pt) catalyzed [3 + 2] cycloaddition in Kopsane alkaloid synthesis. Our results indicate consistent reaction characteristics across all metals, with the second cyclization acting as the diastereoselectivity-determining step. The calculated energy gaps between transition states (TS2s) for NiCl₂, PdCl₂, and PtCl₂ were 5.57, 1.45, and 12.25 kcal/mol, respectively. These energy profiles suggest that NiCl₂ can achieve high diastereoselectivity similar to PtCl₂ due to its significant energy gap (&gt; 4 kcal/mol). The implementation of this computational chemistry technique provides theoretical evidence that could help to improve the efficiency of the catalyst designing process.</p><div><figure><div><div><picture><source><img></source></picture><span>The alternative text for this image may have been generated using AI.</span></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 4","pages":"784 - 791"},"PeriodicalIF":3.1,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-026-03556-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754390","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":"Molecular sonification: a multi-modal approach for enhanced ai in drug discovery","authors":"Charles Jianping Zhou,&nbsp;Emily Rong Zhou","doi":"10.1007/s00044-026-03549-y","DOIUrl":"10.1007/s00044-026-03549-y","url":null,"abstract":"<div><p>Artificial intelligence (AI) has achieved remarkable success in the molecular sciences; however, a critical constraint has emerged: prediction without mechanistic understanding. To bridge this gap, we present a multi-modal molecular AI framework based on our patented molecular sonification technology (USP 9,018,506). This approach unifies three critical applications: (1) mapping chemical structures to sound for intuitive human interpretation, (2) transforming spectroscopic data into audio streams for mechanistic AI training, and (3) encoding reaction dynamics for real-time monitoring. Critically, our method is modality-agnostic, providing a universal encoding scheme applicable to diverse systems including small molecules, protein sequences, and crystalline materials. By mapping molecular data to the human audible range, we enable high-efficiency transfer learning from pre-trained voice AI models (such as Wav2Vec 2.0), achieving greater computational efficiency compared to training from scratch. Validation on standard benchmarks demonstrates that this multi-modal spatial intelligence achieves competitive accuracy with a dramatically reduced computational footprint, offering a new paradigm for both global science education and accelerated discovery across chemistry, biology, and materials informatics.</p><div><figure><div><div><picture><source><img></source></picture><span>The alternative text for this image may have been generated using AI.</span></div><div><p>Overview of the Molecular Spatial Intelligence framework. The full architecture supports four input modalities. The current experimental validation (Tables 1–3) evaluates the audio and descriptor pathways (highlighted); graph and spectroscopy channels are planned for future integration.</p></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 4","pages":"778 - 783"},"PeriodicalIF":3.1,"publicationDate":"2026-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754387","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":"Protein kinases as therapeutic targets in Alzheimer’s disease: challenges, insights, and new frontiers","authors":"Chanwool Tak,&nbsp;Swapnil P. Bhujbal,&nbsp;Jung-Mi Hah","doi":"10.1007/s00044-026-03557-y","DOIUrl":"10.1007/s00044-026-03557-y","url":null,"abstract":"<div><p>Alzheimer’s disease (AD) remains the leading cause of dementia worldwide, imposing an enormous and growing societal burden with more than 55 million people affected globally. Despite decades of intensive investigation, existing therapeutic options provide only modest symptomatic relief and fail to prevent or slow disease progression, emphasizing the critical need for interventions that target the fundamental molecular mechanisms of neurodegeneration. Pathologically, Alzheimer’s disease is characterized by extracellular accumulation of amyloid-β plaques, intracellular neurofibrillary tangles formed by hyperphosphorylated tau, profound synaptic loss, chronic neuroinflammation, and extensive neuronal degeneration. Although amyloid-focused strategies have long dominated drug development, their limited clinical benefit and safety liabilities highlight the multifactorial nature of AD and the need to move beyond amyloid-centric paradigms. Protein kinases have emerged as key integrators of multiple pathogenic processes in AD, governing tau phosphorylation, amyloid precursor protein processing, synaptic signaling, and neuroimmune responses. Aberrant kinase signaling drives tau pathology and propagation, promotes amyloidogenic pathways, disrupts synaptic function, and perpetuates inflammatory cascades. While extensive work on kinases such as GSK-3β, CDK5, JNKs, and CSF1R has firmly established the relevance of kinase dysregulation in AD, no kinase-directed therapy has yet translated into clinical success. This review highlights emerging kinase targets beyond these classical pathways, including Fyn, Casein Kinase 1 Delta (CK1δ), Tau-Tubulin Kinase 1 (TTBK1), and Dual Leucine Zipper Kinase (DLK), which are supported by mechanistic insights and compelling preclinical evidence. Continued advances in brain-penetrant, isoform-selective, and mechanism-driven kinase inhibitor design may enable the development of next-generation disease-modifying therapies for Alzheimer’s disease.</p><div><figure><div><div><picture><source><img></source></picture><span>The alternative text for this image may have been generated using AI.</span></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 4","pages":"726 - 756"},"PeriodicalIF":3.1,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754385","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":"Development and evaluation of mitochondria-targeted caseinolytic protease (ClpP) agonist chemical probes in in vitro breast cancer models","authors":"Xiaoyu Hao,&nbsp;Gunjan Purohit,&nbsp;Yahani P. Jayasinghe,&nbsp;Donald R. Ronning,&nbsp;Oleh Khalimonchuk,&nbsp;Paul C. Trippier","doi":"10.1007/s00044-026-03551-4","DOIUrl":"10.1007/s00044-026-03551-4","url":null,"abstract":"<div><p>Mitochondria carry out a plethora of functions that are vital for cellular physiology and metabolism. Mitochondrial caseinolytic protease (ClpP) is part of the larger CLPXP machinery that is critical for mitochondrial protein homeostasis and has emerged as a prospective molecular target in several types of cancer. ClpP agonists based around the imipridone scaffold have shown some promise in acute myeloid leukemia, but the polypharmacology of these compounds limits their utility. Effective methods to deliver drugs specifically to mitochondria have emerged, involving covalent linking of either a lipophilic cation, such as an alkyltriphenylphosphonium moiety, or a XJB peptide sequence to a pharmacophore of interest. Taking advantage of the evolutionary conservation of ClpP and combination with mitochondria targeting strategies, we designed, synthesized, and tested a series of mitochondria-targeted probe compounds based on the cyclic acyldepsipeptides (ADEP) scaffold, a natural product antibiotic and potent bacterial ClpP agonist. Herein, we report the synthesis and characterization of several ClpP agonist chemical probes that afford specific, and effective targeting of the mitochondrial protein in triple-negative breast cancer cell lines, with XJB conjugation significantly increasing cytotoxicity of the ADEP pharmacophore to triple-negative breast cancer BT549 cells, providing valuable chemical tools for further study.</p><div><figure><div><div><picture><source><img></source></picture><span>The alternative text for this image may have been generated using AI.</span></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 4","pages":"814 - 833"},"PeriodicalIF":3.1,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-026-03551-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754433","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":"Advances in the development of N-acylbenzo[d][1,2,3]diazaborinin-1(2H)-ols as antibacterial agents by synthesis, characterization, and antimicrobial assay","authors":"Chloe A. Woods,&nbsp;Betty Gutierrez,&nbsp;Naidine Aguinaldo,&nbsp;Prince Kanukwa,&nbsp;Yutong Li,&nbsp;Bethany Hubbard,&nbsp;Juan Daniel Avila,&nbsp;Anthony Jones,&nbsp;Fatime Sebok,&nbsp;Michael P. Groziak,&nbsp;Phattananawee Nalaoh,&nbsp;David M. Jenkins,&nbsp;Matthew B. Carbajal,&nbsp;Heidi T. Chow,&nbsp;H. Howard Xu","doi":"10.1007/s00044-026-03550-5","DOIUrl":"10.1007/s00044-026-03550-5","url":null,"abstract":"<div><p>The ability of bacteria to quickly adapt to environmental stresses, such as exposure to antimicrobial drugs, has necessitated a continued search for novel antibacterial agents with new mechanisms of attack, forever in competition with the rate of adaptation of these pathogens. Antibiotic resistant strains of a multitude of infectious diseases have appeared, imposing a huge burden from diseases once believed to have been reduced to minor health issues. Building on prior work, twenty-one new <i>N</i>-acyl-1-hydroxy-2,3,1-benzodiazaborinines were synthesized and characterized by high-field NMR, FTIR, ESI-MS, and other methods including X-ray crystallography for one unexpected structure. The syntheses by direct condensation using acylhydrazides gave products found to exist in one of three structural forms connected by (de/re)hydration reactions: open hydrazone (<b>a</b>), boron heterocycle (<b>b</b>), and anhydro dimer (<b>c</b>). Multisolvent ¹H and ¹³C NMR analyses showed that in solution these forms can readily interconvert in a solvent-dependent manner. The unanticipated structure of one target was established to be a rare ammonium borate salt arising from an extremely facile intramolecularly boron-catalyzed primary amide group hydrolysis. The new compounds were screened for activity against <i>Escherichia coli</i> in disk diffusion assays and seven of them demonstrated inhibitory activity, thus advancing the development of boron heterocycles towards the goal of producing next-generation antibacterial agents to combat persistently evolving resistant strains.</p><div><figure><div><div><picture><source><img></source></picture><span>The alternative text for this image may have been generated using AI.</span></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 4","pages":"847 - 862"},"PeriodicalIF":3.1,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754382","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":"Dynamic tail amine interactions drive isoform selectivity for potent human neuronal nitric oxide synthase inhibitors","authors":"Amardeep Awasthi,&nbsp;Koon Mook Kang,&nbsp;Richard B. Silverman","doi":"10.1007/s00044-026-03552-3","DOIUrl":"10.1007/s00044-026-03552-3","url":null,"abstract":"<div><p>Achieving isoform-selective inhibition of neuronal nitric oxide synthase (nNOS) remains a significant challenge due to the high structural similarity with other NOS isoforms. Here, we report the design, synthesis, and characterization of novel nNOS inhibitors <b>3</b> and <b>4</b>, incorporating dimethylamino-substituted tail groups to exploit hnNOS-specific peripheral pocket interactions. Both compounds retained sub-20 nM potency against human nNOS with enhanced selectivity over endothelial (hn/he &gt; 1500-fold) and inducible (hn/hi &gt; 229-fold) isoforms. Molecular dynamics simulations and MM-GBSA calculations suggested that hnNOS selectivity arises from a dynamically formed cation-π interaction between the terminal amino group and W311(B), which is precluded in heNOS due to the steric hindrance from F105. PAMPA-BBB assays inḍdicated moderate blood-brain barrier permeability, supporting CNS applications. These findings highlight peripheral pocket interactions as key drivers of isoform selectivity and guide future nNOS inhibitor optimization for neurodegenerative diseases and melanoma.</p><div><figure><div><div><picture><source><img></source></picture><span>The alternative text for this image may have been generated using AI.</span></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 4","pages":"757 - 764"},"PeriodicalIF":3.1,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-026-03552-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754471","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":"Tropanes in natural products, syntheses, and drugs: some insights from the new millennium","authors":"Maris A. Cinelli,&nbsp;Sabrina A. Mata,&nbsp;Tyler Watson","doi":"10.1007/s00044-026-03547-0","DOIUrl":"10.1007/s00044-026-03547-0","url":null,"abstract":"<div><p>The term “tropane” refers to the 8-azabicyclo[3.2.1]octane core, first discovered in the tropane alkaloids produced by certain families of plants. These alkaloids, which are likely plant defense compounds, have well-precedented bioactivities such as muscarinic receptor antagonism and dopamine transporter (DAT) inhibition. The long-standing usefulness of alkaloids such as atropine, scopolamine, and cocaine has encouraged the incorporation of the tropane moiety into multiple other approved drugs, likely cementing its place as a privileged scaffold. Because of their diverse utility and efficacy, tropane-containing compounds are still an area of very active investigation. A quarter of the way through the new century, novel tropane alkaloids are still being discovered, imaginative and applicable ways to make these compounds are being revealed, and tropane-containing molecules have proven to be promising avenues for treatment of central nervous system (CNS) disorders, cancer, diabetes, viral infections, and many other conditions, as well as effective diagnostic agents and tool compounds. This review summarizes recent (2015–2025) developments concerning tropane-containing molecules. New natural products, synthetic strategies to construct and functionalize the tropane core, drug hits, leads, and clinical candidates, and other relevant molecules containing tropane moieties are described. An overview of where the “tropane field” is headed, with focus on finding, analyzing, and obtaining high-value alkaloids and analogs (and re-imagining drug synthesis and discovery in an increasingly technological and environmentally conscious age) is also provided.</p><div><figure><div><div><picture><source><img></source></picture><span>The alternative text for this image may have been generated using AI.</span></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 4","pages":"686 - 710"},"PeriodicalIF":3.1,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754438","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}