Medicinal Chemistry最新文献

{"title":"Optimized Strategies for the Synthesis and Structure-Activity Relationship of Imidazole as an Antiepileptic Drug.","authors":"Saloni Mangal, Salahuddin, Avijit Mazumder, Rajnish Kumar, Sapna Rani, Vimal Datt, Mohamed Jawed Ahsan, Mohammad Shahar Yar","doi":"10.2174/0115734064377779250529172030","DOIUrl":"https://doi.org/10.2174/0115734064377779250529172030","url":null,"abstract":"<p><p>Imidazole is believed to be a highly multifunctional compound in the medicinal and biological sectors. This literature focuses on information about the synthesis and anticonvulsant activity presented by the imidazole nucleus. Epilepsy is a chronic brain disorder including multiple seizures and brain cell abnormalities. Due to its old and less effective treatment, with the increase in the number of patients suffering from epilepsy, researchers need to concentrate on the emergence of finding new treatments for epilepsy. Imidazole-containing analogs are found to be significant in the field of medicinal chemistry and the treatment for epilepsy. These studies prompted us to synthesize and provide insights into developing new imidazole-bearing antiepileptic drugs.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144285403","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":"Novel Pyrrolopyrimidines as Inhibitors of CLK4 and HER2: Targeting Promising Anticancer Pathways.","authors":"Jonathan Gries, Frank Totzke, Andreas Hilgeroth","doi":"10.2174/0115734064386606250410111952","DOIUrl":"https://doi.org/10.2174/0115734064386606250410111952","url":null,"abstract":"<p><strong>Background: </strong>Dysregulated cellular signaling pathways involving protein kinases are critically implicated in cancer development. Consequently, protein kinases have emerged as key targets for novel anticancer therapies. A range of kinase inhibitors, including small molecules and monoclonal antibodies, has been developed. Although early strategies focused on achieving high specificity to minimize adverse effects, resistance to these targeted therapies has limited their effectiveness. As a result, broader-spectrum inhibitors that act on multiple cancer-related kinases are now considered more promising therapeutic options.</p><p><strong>Objective: </strong>We developed twenty-five new pyrrolopyrimidine derivatives featuring diverse substitution patterns to assess their potential as small-molecule inhibitors of the protein kinases CLK4 and HER2, both of which are significant therapeutic targets in metastatic breast cancer.</p><p><strong>Method: </strong>Pyrrolopyrimidine derivatives were synthesized and purified by column chromatography. Their protein kinase inhibitory activity was evaluated through a radioactive ATPcompetition assay.</p><p><strong>Results: </strong>The compounds were obtained through a multi-step synthetic procedure, concluding with substitution reactions. The effects of different substituents on the inhibitory properties of the observed protein kinases are analyzed and discussed.</p><p><strong>Conclusion: </strong>Aniline-substituted derivatives exhibited the most potent activities, which were further modulated by N-substituted pyrroles. Consequently, we identified both selective and dual inhibitors of the target kinases, demonstrating activity in the nanomolar range.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216278","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":"Potential Inhibitors of SARS-CoV-2 Developed through Machine Learning, Molecular Docking, and MD Simulation.","authors":"Arshiya Khan, Anushka Bhrdwaj, Khushboo Sharma, Ravali Arugonda, Navpreet Kaur, Rinku Chaudhary, Uzma Shaheen, Umesh Panwar, V Natchimuthu, Abhishek Kumar, Taniya Dey, Aravind Panicker, Leena Prajapati, Nhattuketty Krishnan Shainy, Muhammed Marunnan Sahila, Francisco Jaime Bezerra Mendonça Junior, Tajamul Hussain, Salman Alrokayan, Anuraj Nayarisseri","doi":"10.2174/0115734064370188250527043536","DOIUrl":"https://doi.org/10.2174/0115734064370188250527043536","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;The advent of Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of the Coronavirus Disease 2019 (COVID-19) pandemic, has impacted physical and mental health worldwide. The lack of effective antiviral drugs necessitates a robust therapeutic approach to develop anti-SARS-CoV-2 drugs. Various investigations have recognized ACE2 as the primary receptor of SARS-CoV-2, and this amalgamation of ACE2 with the spike protein of the coronavirus is paramount for viral entry into the host cells and inducing infection. Consequently, restricting the virus's accessibility to ACE2 offers an alternative therapeutic approach to averting this illness.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;The study aimed to identify potent inhibitors with enhanced affinity for the ACE2 protein and validate their stability and efficacy against established inhibitors via molecular docking, machine learning, and MD simulations.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methodology: &lt;/strong&gt;202 ACE2 inhibitors (PDB ID and 6LZG), comprising repurposed antiviral compounds and specific ACE2 inhibitors, were selected for molecular docking. The two most effective compounds obtained from docking were further analyzed using machine learning to identify potential compounds with enhanced ACE2-binding affinity. To refine the dataset, molecular decoys were generated through the Database of Useful Decoys: Enhanced (DUD-E) server, and Singular Value Decomposition (SVD) was applied for data preprocessing. The Tree-based Pipeline Optimization Tool (TPOT) was then utilized to optimize the machine learning pipeline. The most promising ML-predicted compounds were re-evaluated through docking and subjected to Molecular Dynamics (MD) simulations to evaluate their structural stability and interactions with ACE2. Finally, these compounds were evaluated against the top two pre-established inhibitors using various computational tools.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The two best pre-established inhibitors were identified as Birinapant and Elbasvir, while the best machine-learning-predicted compounds were PubChem ID: 23658468 and PubChem ID: 117637105. Pharmacophore studies were conducted on the most effective machine-learning-predicted compounds, followed by a comparative ADME/T analysis between the best ML-screened and pre-established inhibitors. The results indicated that the top ML compound (PubChem ID: 23658468) demonstrated favorable BBB permeability and a high HIA index, highlighting its potential for therapeutic applications. The ML-screened ligand demonstrated structural stability with an RMSD (0.24 nm) and greater global stability (Rg: 2.08 nm) than Birinapant. Hydrogen bonding interactions further validated their strong binding affinity. MM/PBSA analysis confirmed the ML-screened compound's stronger binding affinity, with a binding free energy of - 132.90 kcal/mol, indicating enhanced stability in complex formation.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;The results emp","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216279","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":"Research Progress of G Protein-coupled Receptor 52 on Central Nervous System Diseases.","authors":"Qingkun Wu, Jun Li, Xiaojie Hu, Ying Zhuang, Lu Zheng","doi":"10.2174/0115734064372441250527031957","DOIUrl":"https://doi.org/10.2174/0115734064372441250527031957","url":null,"abstract":"<p><p>The G protein-coupled receptor 52 (GPR52) is a Gs-coupled receptor and is located principally in the striatum alongside D₂ receptor and in the pre-frontal cortex alongside D₁ receptor. Its stimulation leads to potentiation of intracellular cAMP levels, producing effects on cAMP levels similar to those of a Gi-coupled D₂ receptor antagonist in the striatum and a Gscoupled D₁ receptor agonist in the prefrontal cortex. This dual mechanism suggests that GPR52 activation could result in antipsychotic effects akin to D₂ antagonism and pro-cognitive effects resembling D₁ agonism. As a result, GPR52 has emerged as a promising therapeutic target for central nervous system (CNS) disorders, including schizophrenia and substance use disorder. Additionally, knocking out (KO) GPR52 not only significantly reduces mutant huntingtin protein (mHTT) levels in the striatum but also rescues Huntington's disease-associated behavioral phenotypes in a knock-in Huntington's disease mouse model, which provides evidence that GRP52 may also serve as a potential target for Huntington's disease. This review summarizes the current state of small-molecule ligand/drug discovery for GPR52, focusing on the latest findings about the role of GPR52 in schizophrenia and Huntington's disease.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144187262","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":"Natural Mimetic 4,6-dihydroxyaurone Derivatives as Tyrosinase Inhibitors: Design, Synthesis, and Biological Evaluation.","authors":"Quoc-Thai Nguyen, Giao Quynh Tran, Huy Thanh Ta, Quang Dang Do, Quynh Xuan Vu, Bich-Loan T Phung, Thanh-Dao Tran, Khac-Minh Thai, Cam-Van T Vo","doi":"10.2174/0115734064371213250508115259","DOIUrl":"https://doi.org/10.2174/0115734064371213250508115259","url":null,"abstract":"<p><strong>Introduction: </strong>Tyrosinase, a key enzyme in melanin biosynthesis and food browning, has become an important target for inhibitor development.</p><p><strong>Aim: </strong>This study aimed to investigate the inhibitory potential of 4,6-dihydroxyaurone derivatives with varied ring B substituents on mushroom tyrosinase.</p><p><strong>Method: </strong>Twenty derivatives were designed and subjected to computational studies, revealing their potential to bind to the enzyme's active site and interact with key residues and copper ions.</p><p><strong>Result: </strong>In vitro UV-Vis spectrophotometry assays on these twenty synthesized aurones demonstrated that compound 5h, featuring a 3,4-dichlorophenyl group at ring B, exhibited the most potent inhibitory activity (IC₅₀ = 6.3 ± 0.3 μM) compared to kojic acid (IC₅₀ = 136.5 ± 11.5 μM). Further kinetic analysis and docking simulations suggested that 5h operated via a mixed inhibition mechanism with competitive and uncompetitive inhibitory constants of 21 μM and 68 μM, respectively.</p><p><strong>Conclusion: </strong>These findings highlight the promising potential of 4,6-dihydroxyaurone derivatives as potent tyrosinase inhibitors for applications in pharmaceuticals, cosmetics, and agriculture.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078997","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":"Recent Advances in the Medicinal Chemistry of Cancer (Part 1).","authors":"Işıl Yıldırım","doi":"10.2174/0115734064404732250513074411","DOIUrl":"https://doi.org/10.2174/0115734064404732250513074411","url":null,"abstract":"","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078999","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":"Discovering the Cholinesterase Inhibitory Potential of Thiosemicarbazone Derivatives through <i>In vitro</i>, Molecular Docking, Kinetics, and Dynamics Studies.","authors":"Manel Essid, Aftab Alam, Ghulam Fareed, Sudais Rahman, Imtiaz Ahmad, Imen Zghab, Zainab Hassan Alnakhli, Abid Ali, Masroor Kamal, Momin Khan","doi":"10.2174/0115734064375028250427171931","DOIUrl":"https://doi.org/10.2174/0115734064375028250427171931","url":null,"abstract":"<p><strong>Background: </strong>The current study explored the cholinesterase inhibitory activities of some thiosemicarbazone derivatives bearing 2,4-dichloro phenylacetic acid scaffold.</p><p><strong>Objective: </strong>This study aimed to screen the synthesized derivatives for their <i>in vitro</i> acetylcholine and butyrylcholinesterase inhibition.</p><p><strong>Methods: </strong>These compounds were synthesized by refluxing 2,4-dichloro phenylacetic acid with sulfuric acid in ethanol to get the ester, which was further refluxed with thiosemicarbazide in ethanol to get the desired compound (2). Different benzaldehydes were treated with compound (2) in ethanol having a catalytic amount of acetic acid to get thiosemicarbazones.</p><p><strong>Results: </strong>In the series, seven compounds, including compounds 2c, 2a, 2b, 2d, 2g, 2e, and 2f, displayed excellent acetylcholinesterase inhibition activities in the range of IC₅₀ values from 41.51 ± 3.88 to 95.48 ± 0.70 μM, surpassing than the standard galantamine (IC₅₀ = 104.5 ± 1.20 μM). Also, compounds 2a, 2g, 2h, 2f, 2b, and 2d with IC₅₀ values ranging from 64.47 ± 2.74 to 80.62 ± 0.73 μM exhibited potent inhibition against butyrylcholinesterase enzyme, being similar to the standard galantamine (IC₅₀ = 156.8 ± 1.50 μM). The molecular docking investigation was performed to assess the binding affinity of the compounds with the active site of the enzyme. These compounds, along with the docked complexes, specifically AChE-compound 2a and BuChE-compound 2g, were chosen and subjected to 100-nanosecond molecular dynamics simulations. The simulations demonstrated strong stability of the ligands within the active pockets of AChE and BuChE enzymes.</p><p><strong>Conclusion: </strong>These derivatives exhibited superior acetylcholinesterase and butyrylcholinesterase inhibitory activities compared to galantamine, with molecular docking and dynamic simulations confirming their strong binding affinity with the active sites of the enzymes.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144028716","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":"Synthesis, Characterization, and Pharmacological Evaluation of Zn₄O(BDC)₃: Anticancer, Antidiabetic, and Drug Delivery Potential.","authors":"Sabir Khan, Muhammad Fazal Hameed, Imran Zafar, Rubina Bibi, Mohamed Mohany, Sadia Nazir, Mohammad Amjad Kamal, Muhammad Shafiq","doi":"10.2174/0115734064362203250222050726","DOIUrl":"https://doi.org/10.2174/0115734064362203250222050726","url":null,"abstract":"<p><strong>Introduction: </strong>This study presents a comprehensive exploration of the biomedical potential of the synthesized metal-organic framework Zn₄O(BDC)₃, focusing on its applications in cancer and diabetes treatment and its advanced drug delivery capabilities.</p><p><strong>Methods: </strong>The structural and physicochemical properties of Zn₄O(BDC)₃ were characterized using FTIR, TGA, ¹H NMR, PXRD, and elemental analysis, revealing its exceptional stability and coordination properties. Molecular docking, molecular dynamics simulations (100 ns), and MM-GBSA calculations were performed to assess binding affinities and stability.</p><p><strong>Results: </strong>The interactions of Zn₄O(BDC)₃ with salmon sperm DNA (SSDNA) and bovine serum albumin (BSA) demonstrated significant anticancer potential, evidenced by binding constant values of 6.0 × 10⁶M^-1 and Gibbs free energy changes of -17.93 and -19.61 kcal/mol, respectively, highlighting its ability to suppress tumor cell proliferation. With doxorubicin (DOX) loading and reloading efficiencies of 88% and 87.5%, Zn₄O(BDC)₃ exhibited superior drug delivery capabilities. The anti-diabetic potential was validated by the formation of human insulin (HI) hexamers with ΔG values of 0.8 ± 0.1 and a significant decrease in absorption intensity (5.8 to 0.05 at 250 nm). Molecular docking studies revealed moderate to high binding affinities (-10.0 to -5.3 kcal/mol) with biomolecular targets, supported by molecular dynamics simulations over 100 ns and MM-GBSA calculations indicating robust stability (ΔG = -33.31 kcal/mol).</p><p><strong>Conclusion: </strong>These <i>in-silico</i> and <i>in-vitro</i> analyses underscore the significant pharmacological promise of Zn₄O(BDC)₃ as a multifunctional agent for anticancer, antidiabetic, and drug delivery applications.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144009281","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":"Screening of Novel Inhibitors Targeting the Non-ATP-binding Domain of <i>Staphylococcus aureus</i> SecA1.","authors":"Yan Liu, Qing Su, Zonglin Wang, Peiyao Liu, Jinjin Hong, Hyuk-Kyu Seoh, Xu Jia, Sen-Fang Sui, Phang-Cheng Tai, Xinhe Huang","doi":"10.2174/0115734064370398250426162503","DOIUrl":"https://doi.org/10.2174/0115734064370398250426162503","url":null,"abstract":"<p><strong>Objective: </strong><i>Staphylococcus aureus (S. aureus)</i> has been one of the pathogenic bacteria for clinical infections, and there is an urgent need for the development of novel anti-<i>S. aureus</i> drugs. SecA is a conserved and essential protein in bacteria and is considered as an ideal target for development. Current screening of inhibitors against SecA has focused on the ATP-binding structural domain, which increases the risk of drug side effects, so a novel screening strategy based on the non-ATP-binding structural domain was chosen in this paper.</p><p><strong>Methods: </strong>A three-dimensional structural model of <i>S. aureus</i> SecA1N75 was constructed, and molecular docking was utilized to screen small molecules with strong interactions with the non- ATP binding domains from a compound library, and four candidate compounds were finally targeted. Molecular dynamics simulations of the candidate molecules were performed to evaluate their drug potential.</p><p><strong>Results: </strong>The four candidate compounds formed stable interactions with key residues of the SecA binding pocket. Molecular dynamics simulations further showed that the candidate molecules bound to the receptor in a stable conformation with nM-level inhibition constants, displaying potent SecA inhibitory activity. It lays the foundation of a lead compound for the development of antimicrobial drugs targeting SecA.</p><p><strong>Conclusion: </strong>In this thesis, an inhibitor screening strategy based on non-ATP binding structural domains was successfully constructed, which breaks through the limitations of traditional methods to screen candidate molecules with high activity and low risk of potential side effects, and provides an innovative solution to meet the challenge of <i>S. aureus</i> drug resistance.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144016401","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":"Inhibitors of Phosphatidylinositol-specific Phospholipase C with <i>Myo</i>-inositol Scaffold.","authors":"Christian Bierkamp, Walburga Hanekamp, Christoph Arenz, Matthias Lehr","doi":"10.2174/0115734064384345250415073648","DOIUrl":"https://doi.org/10.2174/0115734064384345250415073648","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Phosphatidylinositol-specific phospholipase C (PI-PLC) enzymes catalyze the conversion of phosphatidylinositol-4,5-bisphosphate into the second messengers diacylglycerol and inositol- 1,4,5-trisphosphate, both of which play crucial roles in regulating biochemical processes. Despite the wellestablished link between elevated PI-PLC activity and pathophysiological conditions, no PI-PLC inhibitors are currently in clinical development. Moreover, existing inhibitors demonstrate only limited potency.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;Due to the structural similarity with known inhibitors with a myo-inositol backbone, DL-1-Ododecylsulfonyl- myo-inositol-3,5-bisphosphate, designated as acid sphingomyelinase inhibitor, and derivatives thereof should be tested for inhibition of PI-PLC activity.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;The newly synthesized compounds were evaluated for their ability to inhibit PI-PLC activity in porcine platelet lysate and porcine brain homogenate, as well as their inhibitory potency against the recombinant isoenzymes PLCγ1 and PLCγ2. The assay measured the release of diacylglycerol from L-α- phosphatidylinositol using HPLC coupled with MS detection. Furthermore, the specificity of selected compounds was assessed by determining their inhibitory potency against other surface-active enzymes through HPLC-based assays.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;It was found that DL-1-O-dodecylsulfonyl-myo-inositol-3,5-bisphosphate inhibits PI-PLC activity at micromolar concentrations. However, its maximum achievable inhibitory effect was limited to approximately 70%. Through structural modifications, inhibitors were developed that led to near complete inhibition of PIPLC activity. The study also revealed that the alleged PI-PLC inhibitor U73122, still frequently cited in the literature to demonstrate PI-PLC involvement in biochemical processes, is unsuitable for this purpose. Consistent with observations by others, its inhibitory activity in bionucleophile-containing cell or tissue preparations was found to be significantly lower than its activity against purified PI-PLC enzymes. Additionally, U73122 was shown to inhibit other enzymes, such as cytosolic phospholipase A2α, fatty acid amide hydrolase, and monoacylglycerol lipase, which, like PI-PLC, metabolize lipophilic substrates. In contrast, the newly developed myo-inositol derivatives exhibited reduced sensitivity to bionucleophiles and significantly improved selectivity against the tested surface-active enzymes compared to U73122.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;New compounds exhibiting significant inhibitory activity against PI-PLC have been identified. The findings could prove valuable in the development of clinically applicable PI-PLC inhibitors, particularly for the treatment of cancer. Additionally, the myo-inositol derivatives developed demonstrated greater suitability for studying PI-PLC's role in physiological processes in tissue homogenates compared ","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144009301","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}