ChemMedChem最新文献

{"title":"Breaking Down Barriers: CorA Effectively Targets Staphylococcal Biofilms in Vitro and in Vivo","authors":"Stefania De Benedetti,&nbsp;Nikolay Krasimirov Kirilov,&nbsp;Haoxuan Zeng,&nbsp;Carolin Ade,&nbsp;Isabel Bodenstein,&nbsp;Maximilian Förster,&nbsp;Noran Abdel-Wadood,&nbsp;Ahmad Aljohmani,&nbsp;Gabriela Krasteva-Christ,&nbsp;Daniela Yildiz,&nbsp;Sabryna Junker,&nbsp;Syeda Javariya Khalid,&nbsp;Katharina Rox,&nbsp;Hedda Schrey,&nbsp;Miriam Große,&nbsp;Andrea Schiefer,&nbsp;Sören Leif Becker,&nbsp;Kenneth Pfarr,&nbsp;Achim Hoerauf,&nbsp;Markus Bischoff,&nbsp;Mathias Müsken,&nbsp;Tanja Schneider","doi":"10.1002/cmdc.202501057","DOIUrl":"10.1002/cmdc.202501057","url":null,"abstract":"<p>Biofilm-associated infections caused by <i>Staphylococcus aureus</i> (<i>S. aureus</i>) remain notoriously difficult to treat due to their pronounced tolerance to most antibiotics. Here, we evaluated the antibiofilm efficacy of the natural product antibiotic corallopyronin A (CorA) across a panel of strains, including clinically relevant strains differing in their biofilm-forming capacities and antibiotic resistance profiles. CorA is an alpha-pyrone antibiotic produced by <i>Corallococcus coralloides</i>. It targets the switch region of the bacterial DNA-dependent RNA polymerase, thereby blocking transcription initiation at a site distinct from the rifampicin-binding pocket, and displays potent activity against staphylococci, including MRSA and rifampicin-resistant <i>S. aureus</i>. In vitro, CorA eradicated and inhibited biofilm formation, outperforming the biofilm-active antibiotics dalbavancin and rifampicin both in optical density measurements and in microscopic analyses. Importantly, CorA had activity against rifampicin-resistant strains in these assays. In a murine foreign body infection model with <i>S. aureus</i> SA113, CorA treatment resulted in <i>a</i> &gt; 4-<i>log</i>₁₀ reduction in bacterial loads on implanted devices and surrounding tissues, comparable with high-dose rifampicin, and significantly reduced local inflammation. These findings position CorA as a promising candidate for preventing and managing staphylococcal biofilm-associated infections, warranting further investigation into its clinical potential.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 7","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://chemistry-europe.onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.202501057","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147687041","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":"How and Why Does Knowledge-Based Biased Docking Improve Molecular Docking Performance?","authors":"Juan Manuel Prieto, Jorge Octavio Lannot, Camila Mara Clemente, Carlos Modenutti, Adrian Turjanski, Marcelo A Martí","doi":"10.1002/cmdc.202501058","DOIUrl":"https://doi.org/10.1002/cmdc.202501058","url":null,"abstract":"<p><p>Since 2012, with the publication of our foundational work \"Solvent structure improves docking prediction in lectin-carbohydrate complexes,\" our group has been devoted to the study of protein-ligand interactions using molecular simulation tools. Over the past decade, we have shown that protein-solvent interactions, particularly when simulated in mixed solvents containing probes such as ethanol, phenol, and isopropanol, often mimic the interactions observed in experimental protein-ligand complexes. This knowledge can be used to improve docking performance by guiding pose prediction and scoring. We termed this strategy-biased docking. Over the years, we demonstrated its applicability to pose prediction, virtual screening (VS), protein-protein docking, and metalloprotein docking. In this short review, we summarize our results and contextualize them within the broader literature, offering a concise description of how to implement the biased docking strategy using current docking software. We also explore the physicochemical rationale behind its effectiveness and discuss how this knowledge can inform emerging Machine Learning and AI-based methodologies.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 7","pages":"e202501058"},"PeriodicalIF":3.4,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147758228","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":"2-Phenylquinolines Exhibit Anti-Severe Acute Respiratory Syndrome Coronavirus-2 Activity Through the Nonstructural Protein 13 Helicase Inhibition","authors":"Giada Cernicchi,&nbsp;Maria Giulia Nizi,&nbsp;Roberta Emmolo,&nbsp;Leentje Persoons,&nbsp;Manon Laporte,&nbsp;Dirk Jochmans,&nbsp;Isabella Romeo,&nbsp;Giacomo Pepe,&nbsp;Ciro Milite,&nbsp;Pietro Campiglia,&nbsp;Jacopo Spezzini,&nbsp;Alma Martelli,&nbsp;Simone Brogi,&nbsp;Francesca Esposito,&nbsp;Tommaso Felicetti,&nbsp;Serena Massari,&nbsp;Giuseppe Manfroni,&nbsp;Stefano Sabatini,&nbsp;Gianluca Sbardella,&nbsp;Stefano Alcaro,&nbsp;Johan Neyts,&nbsp;Angela Corona,&nbsp;Enzo Tramontano,&nbsp;Steven De Jonghe,&nbsp;Oriana Tabarrini","doi":"10.1002/cmdc.202501063","DOIUrl":"10.1002/cmdc.202501063","url":null,"abstract":"<p>The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic has highlighted the fragility of our therapeutic arsenal against human coronaviruses and the urgent need to develop new antivirals. They should exhibit broad-spectrum activity to address future pandemics and target alternative viral proteins to mitigate resistance. We have previously identified a hit compound based on a 2-phenylquinoline scaffold that is able to hinder SARS-CoV-2 replication through nonstructural protein 13 (nsp13) helicase inhibition. Here we reported a SAR study that led to identify new analogs such as 2-(4-butoxyphenyl)-4-[2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy]−5,7-dimethoxyquinoline (<b>14</b>) and 4-[2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy]-2-(4-isopropoxyphenyl)−5,7-dimethoxyquinoline (<b>15</b>), which exhibited a good antiviral profile (EC₅₀ = 8.06 and 9.11 µM) coupled with a low micromolar inhibition of nsp13 helicase. Time-of-addition assays and binding analyses confirmed helicase as their primary target, while kinetic studies revealed ATP-competitive inhibition. The butoxy derivative <b>14</b> also inhibited HCoV-229E and HCoV-OC43 replication, indicating broad-spectrum potential. The safety of the compounds was validated in bronchial epithelium cells BEAS-2B cells and H9c2 cardiac cells, where they did not affect cell viability or reactive oxygen species (ROS) production. Finally, preliminary ADME studies on <b>15</b> showed a positive profile in terms of membrane permeability and metabolic stability in plasma and human liver microsomes. This SAR study, along with mechanistic exploration, paves the way for further optimization of 2-phenylquinoline-based compounds.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 7","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13068633/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147653544","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":"Targeting Cyclic GMP–AMP Synthase: Novel Therapeutic Inhibitors for Autoimmune Diseases","authors":"Chuanfeng Hao,&nbsp;Chen Zhou,&nbsp;Dechang Li,&nbsp;Sishuo Liu,&nbsp;Qidong You,&nbsp;Xiaoli Xu","doi":"10.1002/cmdc.202501066","DOIUrl":"10.1002/cmdc.202501066","url":null,"abstract":"<p>Cyclic GMP–AMP synthase (cGAS) is a crucial cytosolic DNA sensor in the innate immune system. Upon detecting intracellular double-stranded DNA (dsDNA), it activates the cGAS-STING signaling pathway, leading to the production of type I interferons and pro-inflammatory cytokines, which are essential for host defense against pathogens and antitumor immunity. However, persistent or aberrant activation of this pathway can trigger pathological immune responses, contributing to various autoimmune and inflammatory diseases. Consequently, the development of potent and specific cGAS inhibitors has emerged as a promising therapeutic strategy. This review comprehensively summarizes recent advances in cGAS inhibitor research. The article details the discovery, structural characteristics, mechanisms of action, structure–activity relationships, and preclinical efficacy of these inhibitors. It also discusses key challenges, such as species specificity and the disparity between biochemical and cellular potency. Finally, the review provides an outlook on future directions and the therapeutic potential of cGAS inhibitors.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 7","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147653576","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":"Coordination of Anle138b to Silver Results in Selective Reduction of a C-Terminal Truncated α-Synuclein Protein and Increased Aggregate Size","authors":"Kelly L. Rue,&nbsp;Susana Herrera,&nbsp;Zhi-Chun Shi,&nbsp;Indranil Chakraborty,&nbsp;Jeremy Tachiki,&nbsp;Josue Ballesteros,&nbsp;Julie K. Andersen,&nbsp;Gordon J. Lithgow,&nbsp;Wisam A. Al Isawi,&nbsp;Gellert Mezei,&nbsp;Minna Schmidt,&nbsp;Raphael G. Raptis","doi":"10.1002/cmdc.202500890","DOIUrl":"10.1002/cmdc.202500890","url":null,"abstract":"<p>Parkinson's disease (PD) is a prevalent age-related neurodegenerative syndrome, partially thought to be caused by a decrease in α-synuclein proteostasis. Anle138b = 5-(1,3-benzodioxol-5-yl)-3-(3-bromophenyl)-1<i>H</i>-pyrazole (<b>HL</b>) is undergoing clinical trials as a promising mitigator of α-synuclein aggregation. Because complexation to metals is known to modulate the activity of several drugs, we have prepared and characterized: <b>H</b>_<b>2</b><b>L(ClO</b>_<b>4</b><b>)</b>, <b>[Cu</b>^<b>I</b><b>(</b><b>µ</b><b>-L)]</b>_<b>3</b>, and <b>[Ag</b>^<b>I</b><b>(</b><b>µ</b><b>-L)]</b>_<b>3</b>. To better understand the bioviability of these compounds, we monitored their effects in a cell culture model of α-synuclein protein aggregation using human α-synuclein preformed fibrils (PFFs). Using two different anti-α-synuclein antibodies, our data suggest that <b>[Ag</b>^<b>I</b><b>(</b><b>µ</b><b>-L)]</b>_<b>3</b> decreases a C-terminal truncated protein that is approximately 12.4 kDa, as well as increases the size and alters the shape of PFF-induced aggregates. This indicates that <b>[Ag</b>^<b>I</b><b>(</b><b>µ</b><b>-L)]</b>_<b>3</b> impacts aggregation in a manner different from <b>HL</b> and may serve as a novel tool for studying C-terminal truncation-related aggregation chemistry.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 7","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147643431","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":"Insights into the Chemico-Biological Interactions of Natural Sesquiterpene Lactones with the Thiol-Redox Metabolism of Pathogenic Trypanosomatids","authors":"Florencia Sardi,&nbsp;Orlando Elso,&nbsp;Lucía Fiestas,&nbsp;Karen Perelmuter,&nbsp;Diego Benítez,&nbsp;Aldana M. Corlatti,&nbsp;Fernando B. Da Costa,&nbsp;Mairin Lenz,&nbsp;Thomas J. Schmidt,&nbsp;Mariela Bollati-Fogolín,&nbsp;Andrea Medeiros,&nbsp;Valeria P. Sülsen,&nbsp;Marcelo A. Comini","doi":"10.1002/cmdc.202500618","DOIUrl":"10.1002/cmdc.202500618","url":null,"abstract":"<p>Terpenoids, a diverse class of bioactive molecules found in all organisms, exhibit significant antimicrobial, antiviral, antitumor, and anti-inflammatory activities, though their mechanisms are often uncharacterized. This study investigated the anti-trypanosomatid activity and interference with intracellular thiol-redox homeostasis of seven sesquiterpene lactones from Asteraceae plants. To address this question, we used redox-reporter cell lines of <i>Leishmania infantum</i> promastigotes, bloodstream <i>Trypanosoma brucei brucei</i>, and human epithelial kidney (HEK-293). Helenalin acetate (EC₅₀ = 0.3 μM, selectivity index = 7) and estafietin (EC₅₀ = 6 μM, selectivity index = 3) were the most potent and selective against bloodstream <i>T. b. brucei</i>. All tested sesquiterpene lactones selectively induced intracellular oxidation of the redox biosensor. For example, estafietin caused redox perturbations in both trypanosomatid species but not in HEK-293 cells. Eupahakonenin B, helenalin acetate, and budlein A induced biosensor oxidation exclusively in the bloodstream <i>T. b. brucei</i>. Conversely, arglabin oxidized the biosensor in both trypanosomatids and HEK-293, suggesting nonspecific activity. Helenalin acetate, budlein A, and arglabin exhibited enhanced cytotoxicity against parasites with depleted low molecular weight thiols (LMWT) but did not inhibit LMWT biosynthesis and reduction. This study provides crucial insights into the cytotoxic mechanisms of sesquiterpene lactones, offering a basis for optimizing their potency and selectivity against trypanosomatids.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 7","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147637436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure- and Ligand-Based Discovery of Novel 3-Chymotrypsin-Like Protease Nonpeptidomimetic Hits","authors":"Sabrina Silva-Mendonça,&nbsp;Donald Seanego,&nbsp;Christopher Jurisch,&nbsp;Melina Mottin,&nbsp;Flávia Nader Motta,&nbsp;Beatriz S. A. Rodrigues,&nbsp;Gilberto S. M. Junior,&nbsp;Alexandra Maria dos Santos Carvalho,&nbsp;Fábio Muniz de Oliveira,&nbsp;Sunniva Sigurdardóttir,&nbsp;Per Sunnerhagen,&nbsp;Izabela Marques Dourado Bastos,&nbsp;Richard Gessner,&nbsp;Kelly Chibale,&nbsp;Carolina Horta Andrade","doi":"10.1002/cmdc.202501083","DOIUrl":"10.1002/cmdc.202501083","url":null,"abstract":"<p>The SARS-CoV-2 3-chymotrypsin-like (3CL^pro) protease is a key target for the development of COVID-19 therapeutics. While ensitrelvir and nirmatrelvir are approved drugs for treatment, the continuous research and development for new antiviral drugs is necessary to combat the emergence of variants and other related viruses. This study employed structure- and ligand-based computer-assisted approaches to identify new 3CL^pro nonpeptidomimetic inhibitors. Using data from COVID Moonshot, NCATS, and the literature, computational methods such as shape-based, ensemble docking, and machine learning (ML) techniques were developed, achieving robust validation metrics: AUC = 87%, EF = 7, BEDROC = 60% for shape-based; AUC = 87%, EF = 7.03, BEDROC = 62% for ensemble docking, and ACC = 81%, MCC = 62% for ML models, combing Random forest + ECFP4 fingerprint. These models were utilized in virtual screening (VS) campaigns using the H3D and ChemBridge libraries, from which six promising hits with IC₅₀ values ≤80 µM were identified, including LabMol-499 with an IC₅₀ of 13.71 µM and a <i>K</i>_i of 21.74 µM. Moreover, we found that LabMol-499 acts as a noncompetitive, reversible inhibitor of 3CL^pro. These findings provide a foundation for hit-to-lead optimization of new nonpeptidomimetic 3CL^pro inhibitors.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 7","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13065885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147643445","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":"Development of Styryl-Modified 3,4-Dihydropyrimidin-2(1H)-ones as Potential Antitumor Agents","authors":"Konstantinos Panagoulias,&nbsp;Woonghee Kim,&nbsp;Murat Ozdemir,&nbsp;Busra Turan,&nbsp;Adil Mardinoglu,&nbsp;Hasan Turkez,&nbsp;Daniela Trisciuzzi,&nbsp;Orazio Nicolotti,&nbsp;Antonio Di Stefano,&nbsp;Stamatia Vassiliou,&nbsp;Ivana Cacciatore","doi":"10.1002/cmdc.202501073","DOIUrl":"10.1002/cmdc.202501073","url":null,"abstract":"<p>Monastrol, a DHPM-based Eg5 inhibitor with well-known antiproliferative activity but limited therapeutic potential due to poor solubility and low bioavailability, was selected as the lead compound for the design of styryl-modified 3,4-dihydropyrimidin-2(1<i>H</i>)-ones with an improved pharmaceutical profile. Twelve derivatives (<b>10–21</b>) were synthesized via the Biginelli reaction and evaluated for cytotoxicity in HeLa and MCF-7 cells. Styryl derivatives <b>16</b> and <b>17</b> emerged as the most active. In HeLa cells, derivatives <b>17</b> (IC50 = 1.3 µM) and <b>16</b> (IC50 = 3.7 µM) were approximately 85-fold and 30-fold more potent than monastrol (IC50 = 111 µM), respectively. In MCF-7 cells, derivatives <b>16</b> and <b>17</b> displayed 18- to 20-fold higher potency than monastrol, respectively. Biological results also indicate that styryl derivatives <b>16</b> and <b>17</b> induce apoptosis in both HeLa and MCF-7 cells. In HeLa cells, activation of caspase-8, -9, and -3 suggests the involvement of both intrinsic and extrinsic pathways. In contrast, in MCF-7 cells, the increased expression of p53 and p21, together with PARP cleavage, suggests a p53-dependent apoptotic response. Derivatives <b>16</b> and <b>17</b> emerged as promising Eg5 inhibitors from docking studies, but their poor aqueous solubility (0.2–0.7 µM), despite high biological stability, highlights the need for formulation strategies to improve drug-like properties.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 7","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13056349/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147632082","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":"Modulating IDO1 and TDO Inhibition Through Structural Modification of Diaryl Hydroxylamines","authors":"Angeliki S. Foscolos,&nbsp;Alexandros Pappas,&nbsp;Christos N. Petroulias,&nbsp;Anna Kapella,&nbsp;Georgia M. Prifti,&nbsp;Grigoris Zoidis,&nbsp;Minas Papadopoulos,&nbsp;Anastasia Mpakali,&nbsp;Aristeidis Chiotellis","doi":"10.1002/cmdc.202501087","DOIUrl":"10.1002/cmdc.202501087","url":null,"abstract":"<p>Diaryl hydroxylamines have emerged as promising scaffolds for targeting the tryptophan-catabolizing enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO), key drivers of tumor immune escape. Building on the reported dual IDO1/TDO inhibitory activity of <i>O</i>-((3,5-difluorophenyl)(phenyl)methyl)hydroxylamine, a series of diaryl hydroxylamines and related analogs were designed and synthesized to probe structure–activity relationships governing dioxygenase inhibition. Structural modifications included variation of the aryl framework toward heteroaromatic and highly electron-deficient motifs, amide-linked scaffold elongation, bioisosteric replacement of the hydroxylamine group with thiol or oxime functionalities, and <i>O</i>-benzylhydroxylamine derivatives. Inhibition studies revealed that 1,1′-diaryl hydroxylamines bearing five-membered heterocycles and electron-deficient aryl groups favored micromolar to submicromolar inhibition of both enzymes, whereas scaffold elongation promoted pronounced IDO1 preference and thiol or oxime analogs exhibited diminished potency. Among the compounds evaluated, <i>O</i>-benzylhydroxylamine <b>28l</b> (IDO1/TDO IC₅₀ = 0.031/2.9 μM) and 1,1′-diaryl hydroxylamine <b>16j</b> (IDO1/TDO IC₅₀ = 0.18/5.5 μM) displayed the most favorable activity profiles. This SAR study defines key determinants of IDO1 potency while retaining significant TDO inhibition and identifies fluorinated hydroxylamines as potential starting points for future PET imaging probe development.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 7","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13056353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147632086","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":"Benzimidazole as a Versatile Scaffold for Developing Neurotherapeutics Against Neurodegenerative Diseases","authors":"Nivedita Barnwal,&nbsp;Sonal Dubey,&nbsp;Prashant Tiwari","doi":"10.1002/cmdc.202500869","DOIUrl":"10.1002/cmdc.202500869","url":null,"abstract":"<p>Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are characterized by progressive neuronal loss, leading to severe cognitive and motor dysfunction. Benzimidazole, a privileged heterocyclic scaffold, has emerged as a promising pharmacophore in modulating key pathological targets across these disorders. In AD, benzimidazole derivatives inhibit cholinesterases, glycogen synthase kinase-3β (GSK-3β), and glutaminyl cyclase (QC), thereby addressing cholinergic dysfunction, tau phosphorylation, and amyloid aggregation. In PD and HD, they act as monoamine oxidase-B (MAO-B) inhibitors, dopamine D1/D2 receptor modulators, and N-methyl D-aspartate receptor antagonists, improving dopaminergic signalling and reducing excitotoxicity. In ALS, benzimidazoles regulate acetylcholine dysfunction and inhibit receptor-interacting protein kinase 1 (RIPK1), limiting neuroinflammation and cell death. Preclinical studies demonstrate potent enzyme inhibition, often with IC₅₀ values in the nanomolar to micromolar range, alongside favourable ADMET properties enabling blood-brain barrier penetration. Clinically, the glutaminyl cyclase inhibitor Varoglutamstat has advanced to Phase II trials for AD, while Riluzole remains the only food and drug administration (FDA)-approved benzimidazole drug for ALS. The structural versatility of benzimidazoles supports their development as multi-target-directed ligands, addressing overlapping mechanisms such as protein aggregation, oxidative stress, and neuroinflammation. Emerging strategies including hybrid molecules, nanocarrier delivery, and AI-driven design may accelerate their clinical translation.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 7","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147632034","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}