Medicinal Chemistry Research最新文献

{"title":"From propofol to cipepofol (Cypsedo®), a new intravenous general anesthetic approved for adults undergoing surgery","authors":"Longqin Hu","doi":"10.1007/s00044-026-03600-y","DOIUrl":"10.1007/s00044-026-03600-y","url":null,"abstract":"<div><p>Propofol (<b><i>1</i></b>) remains the gold standard intravenous general anesthetic despite such drawbacks as injection pain, respiratory depression, and cardiovascular instability. The newly FDA-approved cipepofol (Cypsedo^®, <b><i>2</i></b>) is a chiral analog incorporating a cyclopropyl ring to enhance stereospecifc binding to GABA_A receptors. Due to its four- to five-fold greater potency, cipepofol achieves anesthetic efficacy at lower induction doses (0.4–0.5 mg/kg). It retains favorable pharmacokinetic properties of propofol, including rapid onset and short duration of action, while requiring a lower lipid load in its formulation. Clinical studies have demonstrated reduced post-induction hypotension, markedly less injection pain, and improved hemodynamic stability, making it an attractive alternative for patients at increased cardiovascular or respiratory risk.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 8","pages":"1385 - 1388"},"PeriodicalIF":3.5,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-026-03600-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148682961","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 nucleotide-based P2Y₁ antagonism: implications for cardiovascular therapeutics","authors":"Nandanan Erathodiyil,&nbsp;Vineesh V. Raveendran,&nbsp;Jackie Y. Ying","doi":"10.1007/s00044-026-03595-6","DOIUrl":"10.1007/s00044-026-03595-6","url":null,"abstract":"<div><p>Cardiovascular diseases (CVDs) remain a leading cause of global mortality, emphasizing the need for novel, mechanism-driven therapeutics. The P2Y₁ receptor (P2Y₁R), a G protein-coupled purinergic receptor activated by extracellular nucleotides, has emerged as a key regulator of cardiovascular function and dysfunction. Upon activation, P2Y₁R triggers phospholipase C (PLC)-dependent signaling, modulating platelet activation, vascular tone, endothelial integrity, and fibrotic remodeling. Dysregulated P2Y₁R signaling is implicated in thrombosis, atherosclerosis, hypertension, and abnormal platelet reactivity, highlighting its therapeutic potential. Nucleotide bisphosphate antagonists have played a pivotal role in elucidating P2Y₁R pharmacology and guiding drug discovery. The first-generation antagonist MRS2179 demonstrated proof-of-concept for competitive inhibition, but was limited by low potency and metabolic instability. Structural optimization led to MRS2279, exhibiting improved receptor affinity and enzymatic stability. Further refinement produced MRS2500, a highly potent and selective antagonist with nanomolar activity and robust in vivo antithrombotic efficacy without compromising hemostasis. This review integrates advances in P2Y₁R signaling, pharmacology, and structure-based design, emphasizing the evolution of nucleotide antagonists and their translational potential. These insights establish P2Y₁R antagonism as a promising strategy for next-generation cardiovascular 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 10","pages":"1951 - 1974"},"PeriodicalIF":3.5,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148682992","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":"From traditional uses to biochemical evidence: phytochemical diversity and bioactivities of Calotropis gigantea—a comprehensive update since 2013","authors":"Pham Van Huyen,&nbsp;Nguyen Huu Toan Phan,&nbsp;Nguyen Thi Thu Hien,&nbsp;Tran Thi Ngoc Hanh,&nbsp;Tran Kim Diep,&nbsp;Phan Nha Hoa,&nbsp;Nguyen Huu Huong Duyen,&nbsp;Nguyen Thi Dieu Thuan","doi":"10.1007/s00044-026-03602-w","DOIUrl":"10.1007/s00044-026-03602-w","url":null,"abstract":"<div><p><i>Calotropis gigantea</i> has long been used in traditional medicine for the management of pain, inflammation, wounds, infections, and other disorders. This review critically updates the phytochemical and pharmacological evidence published from 2013 to 2026 by integrating compound-isolation studies, LC-MS/GC-MS profiling, activity-guided fractionation, mechanistic assays, and available safety data. Recent investigations have considerably expanded the chemical profile of <i>C. gigantea</i>, particularly its cardiac glycosides and cardenolides, together with triterpenoids, sterols, lignans, flavonoids, <i>β</i>-carboline alkaloids, and pyrrole derivatives. Studies of the latex, leaves, flowers, and root and stem bark consistently identify cardenolides as major contributors to biological potency. In vitro, several cardenolides exhibit nanomolar cytotoxicity against cancer cell lines and regulate HIF-1, Wnt/β-catenin, and Notch signaling, partly through Na⁺/K⁺-ATPase–Ca²⁺-associated mechanisms. Extracts, fractions, and isolated compounds also display antimicrobial, antioxidant, anti-inflammatory, wound-healing, anti-migraine, and organ-protective effects. These activities are supported by mechanistic findings involving oxidative stress, mitochondrial dysfunction, apoptosis, autophagy, and CYP450 modulation, the latter highlighting potential herb–drug interactions. In vivo findings provide preliminary support for several pharmacological effects, although translational evidence remains limited. The plant has also been applied in the green synthesis of Ag, ZnO, CuO, and MgO nanoparticles with additional biomedical properties. The novelty of this review lies in linking updated chemical evidence with potency-driving constituents, molecular mechanisms, safety considerations, and research gaps. Collectively, the findings establish <i>C. gigantea</i> as a valuable source of multi-target lead compounds while emphasizing the need for standardized quality markers, rigorous toxicological assessment, and well-designed preclinical and clinical studies.</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":"1553 - 1586"},"PeriodicalIF":3.5,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148683011","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":"Overview of the DREADDs chemogenetics and the patent landscape of their actuators","authors":"Subhradeep Dutta,&nbsp;Malliga R. Iyer","doi":"10.1007/s00044-026-03585-8","DOIUrl":"10.1007/s00044-026-03585-8","url":null,"abstract":"<div><p>The ability to manipulate specific neural populations with high temporal and spatial precision has revolutionized our understanding of brain-behavior relationships. Among the most versatile tools in the chemogenetic arsenal are Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). By introducing engineered proteins that remain inert to endogenous neurotransmitters but react potently to synthetic actuators, chemogenetics provides unparalleled control over neural circuits in vivo. With the field evolving, new designer ligands and designer receptors have been reported. This review provides an update on the latest advances in DREADD chemogenetics, focusing on the development of next-generation ligands and the patent landscape innovations driving the next era of precision neuromodulation.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 10","pages":"1930 - 1950"},"PeriodicalIF":3.5,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-026-03585-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148663029","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":"Taming the reactive intermediates: the nazarov cyclization as a programmable platform","authors":"Yunfei Cheng,&nbsp;Ye Yuan,&nbsp;Qun Sun","doi":"10.1007/s00044-026-03598-3","DOIUrl":"10.1007/s00044-026-03598-3","url":null,"abstract":"<div><p>The Nazarov cyclization has evolved from a traditional acid-driven electrocyclization into a flexible synthetic platform. This review summarizes its transformation through a strategic framework centered on three control points: initiation, diverting, and stereochemistry. Modern initiation strategies (substrate pre‑activation, cooperative catalysis, photochemical excitation) replace harsh acids; diverting the oxyallyl cation delivers complex structures via intra‑ or intermolecular trapping; and stereochemical control ranges from chiral auxiliaries to novel catalytic systems. Key advances are illustrated through natural product syntheses.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 8","pages":"1454 - 1478"},"PeriodicalIF":3.5,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148629185","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":"Characterization of beddomeilactone amide as bacterial DNA gyrase inhibitor: in vitro evaluation and computational insights","authors":"Tashi Palmo,&nbsp;Vishwani Jamwal,&nbsp;Karan Goel,&nbsp;Anuj Kumar,&nbsp;Somdutt Mujwar,&nbsp;Yogesh P. Bharitkar,&nbsp;Kuljit Singh","doi":"10.1007/s00044-026-03599-2","DOIUrl":"10.1007/s00044-026-03599-2","url":null,"abstract":"<div><p>The rapid rise of antimicrobial resistance (AMR), marked by declining efficacy of existing antibiotics against bacterial pathogens, has become a serious global health threat. Increasing resistance in the <i>Staphylococcus aureus</i> pathogen urgently demands the development of effective novel antibacterial agents. In this study, we investigated the previously reported antibacterial beddomeilactone amide (<b>3g</b>) as a potential DNA gyrase inhibitor of <i>S. aureus</i>. The potent hit (<b>3g</b>) exhibited &gt; 90% reduction in DNA supercoiling at an effective concentration of 100 µM. Further, computational studies including molecular docking and dynamics simulation showed that the <b>3g</b> molecule exhibited a favourable binding affinity of -12.33 kcal/mol, reflecting predicted stable interactions with DNA gyrase. Moreover, Density functional theory (DFT) findings further revealed key electronic properties, frontier molecular orbitals, and chemical reactivity of the compounds. These findings underscore potent hit (<b>3g</b>) as a promising candidate for the development of an antibacterial agent against <i>S. aureus</i> by targeting DNA gyrase.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 8","pages":"1529 - 1542"},"PeriodicalIF":3.5,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148597484","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":"Understanding Biased Signaling and Small-Molecule Binding for Treatment of Type 2 Diabetes Mellitus and Obesity at the Glucagon-Like Peptide-1 Receptor (GLP-1R) Based on Molecular Dynamics Simulations","authors":"Jack Brubaker,&nbsp;Soo-Kyung Kim,&nbsp;Bo Li,&nbsp;Moon Young Yang,&nbsp;William A. Goddard III","doi":"10.1007/s00044-026-03579-6","DOIUrl":"10.1007/s00044-026-03579-6","url":null,"abstract":"<div><p>Glucagon-like peptide-1 receptor (GLP-1R) is a class B1 G protein-coupled receptor expressed in multiple tissues and is a major therapeutic target for type 2 diabetes mellitus and obesity. Here, we investigate the mechanisms of GLP-1R binding and activation using molecular dynamics (MD) simulations of semaglutide, tirzepatide, danuglipron, and CHU-128bound GLP-1R-Gs complexes. We analyze these simulations as a function of temperature, ligand class (peptide vs. small molecule), and signaling profile (biased vs. non-biased) to assess how these factors affect GLP-1R interactions and conformational dynamics. Our results reveal distinct interaction patterns and structural features associated with each factor which persist over the MD trajectories. Together, these findings deepen our mechanistic understanding of GLP-1R agonism and further aid in the design of effective, orally available GLP-1R agonists with reduced side effects.</p></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 10","pages":"2073 - 2093"},"PeriodicalIF":3.5,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148590182","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":"7-azaindole as privileged scaffold: Advances in drug design and structural modification","authors":"Yichun Shi,&nbsp;Guangjun Yu,&nbsp;Yidan Xu,&nbsp;Xindan Liao","doi":"10.1007/s00044-026-03597-4","DOIUrl":"10.1007/s00044-026-03597-4","url":null,"abstract":"<div><p>7-azaindole is a nitrogen-containing heterocycle derived from indole, which has emerged as a privileged scaffold in drug design owing to its unique electronic distribution, spatial conformation, and dual-site hydrogen-bonding pharmacophore. Compared with indole, it exhibits enhanced hydrogen-bonding capacity, improved stability, and metabolic tolerance, while also allowing facile optimization of solubility, selectivity, and pharmacokinetic (PK) properties. Consequently, the 7-azaindole scaffold has been widely employed in the development of kinase inhibitors, anti-inflammatory agents, and neuro-modulatory agents. Approved drugs such as vemurafenib, pexidartinib, and venetoclax exemplify its successful translation from fragment to drug. This review comprehensively summarizes medicinal chemistry advances based on the 7-azaindole scaffold from 2020 to 2026, and critically consolidates SAR trends, pinpoints the most frequently successful substitution vectors, and dissects recent clinical failures. It aims to provide a reference for the future development of novel 7-azaindole-based 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 8","pages":"1414 - 1453"},"PeriodicalIF":3.5,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148560332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design and synthesis of pyrrolo[2,3-d]pyrimidine linked diazospiro and piperazine – piperidine libraries as anticancer agents","authors":"Sridhar Guda,&nbsp;Srilakshmi V Patri,&nbsp;Krishna Reddy V,&nbsp;Vishnu Thumma,&nbsp;Santosh Kumar Guru","doi":"10.1007/s00044-026-03596-5","DOIUrl":"10.1007/s00044-026-03596-5","url":null,"abstract":"<div><p>Three libraries containing pyrrolo[2,3-d]pyrimidine moiety linked to diazospiro[3.5]nonane, diazospiro[5.5]undecane and piperazine - piperidine hybrid derivatives were synthesized involving various <i>N</i>-deprotection and acid amine coupling reactions. They were tested for their invitro cytotoxicity against triple negative human breast cancer cells MDA-MB-231 and BT-549. Promising results were obtained by pyrrolo[2,3-d]pyrimidine linked diazospiro[3.3]nonane compounds (<b>7a</b> and <b>7c</b>) containing <i>ortho</i>-trifluoro and <i>meta</i>-bromo functional groups against MDA-MB-231 cells. Their dose response curves were plotted and their IC₅₀ value found to be <b>11.66 µM</b> (<b>7a</b>) and <b>10.37 µM (7b)</b>. Additionally, performed acridine orange and rhodamine 123 straining tests to study the cell deformation at various dosages, which garnered promising results.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 8","pages":"1515 - 1528"},"PeriodicalIF":3.5,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148468229","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":"Isolation, modification, structure-activity relationship (SAR) and molecular docking studies of isoflavones from Derris scandens as potent dual AChE/BuChE inhibitors","authors":"Yuttana Siriwattanasathien,&nbsp;Pathumwadee Yotmanee,&nbsp;Kanokporn Lehboon,&nbsp;Ratchanaporn Chokchaisiri,&nbsp;Kinnicha Nunparn,&nbsp;Warangkana Chunglok,&nbsp;Apichart Suksamrarn","doi":"10.1007/s00044-026-03594-7","DOIUrl":"10.1007/s00044-026-03594-7","url":null,"abstract":"<div><p>The stems of <i>Derris scandens</i> are rich sources of isoflavonoids including a new isoflavone and nine known isoflavone<b>s</b>. Some isolated isoflavones exhibited considerable acetyl cholinesterase (AChE) and butyryl cholinesterase (BuChE) inhibitory activities. Preliminary SAR studies have indicated that one of the essential structural requirements for a 5,7,4′-trioxygenated isoflavone to exhibit high ChE inhibitory activities is the presence of prenyl group(s). Structural modifications of the isoflavone <b>5</b> to ester and ether derivatives did not enhance the ChE inhibitory potential. Molecular docking studies have indicated that, if the isoflavone structure is more flexible, the better binding of isoflavone molecule to the receptor should be achieved. The more flexible dihydro analog of the prenyl moiety was therefore prepared from the isoflavone <b>5</b> to give corresponding dihydro analog <b>19</b> and the tetrahydro analog <b>20</b>. It was found that the dihydro analog <b>19</b> was the most active analog for AChE and BuChE inhibitions, with the IC₅₀ values of 0.41 ± 0.07 µM and 0.64 ± 0.01µM, respectively. It was 3.3- and 4.8-fold, respectively, more active than galanthamine. In addition, the dihydro analog <b>19</b> exhibited lower cytotoxicity toward Vero and RAW 264.7 cells than the isoflavone <b>5</b>. Molecular docking studies indicated that <b>19</b> could simultaneously interact with the PAS, AS and CT of AChE and BuChE. The presence of an isopentyl group on isoflavone ring B is necessary for the dihydro analog to exhibit anti-ChE activity. Hence, an isoflavone with an isopentyl group on ring B, a prenyl group on ring A and suitable hydroxy groups on the aromatic ring could be a possible lead candidate for a dual-target-directed ligand for the treatment of Alzheimer’s disease.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 8","pages":"1497 - 1514"},"PeriodicalIF":3.5,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148468170","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}