RSC medicinal chemistry最新文献

{"title":"Unravelling the potency of the 4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile scaffold with <i>S</i>-arylamide hybrids as PIM-1 kinase inhibitors: synthesis, biological activity and <i>in silico</i> studies.","authors":"Soha R Abd El Hadi, Manar A Eldinary, Amna Ghith, Hesham Haffez, Aya Salman, Ghadir A Sayed","doi":"10.1039/d5md00021a","DOIUrl":"10.1039/d5md00021a","url":null,"abstract":"<p><p>PIM-1 is a type of serine/threonine kinase that plays a crucial role in controlling several vital processes, including proliferation and apoptosis. New synthetic <i>S</i>-amide tetrahydropyrimidinone derivatives were designed and synthesized as PIM-1 inhibitors with potential anticancer activity. Several biochemical assays were performed for anticancer assessment, including PIM-1 inhibitory assays, MTT, apoptosis and cell cycle, gene expression analysis, <i>c-MYC</i> analysis, and ATPase inhibitory assays. Compounds (8c, 8d, 8g, 8h, 8k, and 8l) exhibited strong <i>in vitro</i> broad antiproliferative activity against MCF-7, DU-145, and PC-3, with a relatively higher SI index suggesting minimal cytotoxicity to normal cells. Furthermore, these compounds induced mixed late apoptosis and necrosis with cell cycle arrest at the G2/M phase. Moreover, compounds 8b, 8f, 8g, 8k, and 8l showed potent inhibitory action against PIM-1 kinase, with corresponding IC₅₀ values of 660, 909, 373, 518, and 501 nM. <i>In silico</i> prediction studies of physiochemical properties, molecular dynamics, and induced fit docking studies were performed for these compounds to explain their potent biological activity. In conclusion, new pyrimidinone compounds (8c, 8d, 8g, 8h, 8k, and 8l) exhibit potential PIM-1 inhibitory activity and can be used as promising scaffolds for further optimization of new leads with selective PIM-inhibitors and anticancer activity.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951167/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143754376","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":"Thiochromenes and thiochromanes: a comprehensive review of their diverse biological activities and structure-activity relationship (SAR) insights.","authors":"Jatin, Solai Murugappan, Shivani Kirad, Chandu Ala, Pranali Vijaykumar Kuthe, Chandra Sekhar Venkata Gowri Kondapalli, Murugesan Sankaranarayanan","doi":"10.1039/d4md00995a","DOIUrl":"10.1039/d4md00995a","url":null,"abstract":"<p><p>Thiochromene and thiochromane scaffolds, sulfur containing heterocycles, have gained significant attention in medicinal chemistry due to their diverse pharmacological activities. This review provides a comprehensive analysis of their antibacterial, antifungal, antiviral, anti-parasitic, and anticancer properties, emphasizing their therapeutic potential. SAR studies highlight key molecular modifications such as electron withdrawing substituents, sulfur oxidation, and tailored ring substitutions that enhance bioactivity, potency, and target specificity. Mechanistic insights reveal their ability to inhibit microbial enzymes, disrupt cellular pathways, and modulate key biological targets. By summarizing recent advancements, this review underscores the potential of thiochromene and thiochromane based therapeutics and encourages further research to address existing limitations and enhance their drug development prospects.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11931433/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143711140","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":"Contributors to our Emerging Investigators collection.","authors":"","doi":"10.1039/d5md90009c","DOIUrl":"https://doi.org/10.1039/d5md90009c","url":null,"abstract":"<p><p><i>RSC Medicinal Chemistry</i> profiles the contributors to the 'Emerging Investigators' themed collection.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11932122/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143711005","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":"Methods for kinetic evaluation of reversible covalent inhibitors from time-dependent IC₅₀ data.","authors":"Lavleen K Mader, Jeffrey W Keillor","doi":"10.1039/d5md00050e","DOIUrl":"10.1039/d5md00050e","url":null,"abstract":"<p><p>Potent reversible covalent inhibitors are often slow in establishing their covalent modification equilibrium, resulting in time-dependent inhibition. While these inhibitors are commonly assessed using IC₅₀ values, there are no methods available to analyze their time-dependent IC₅₀ data to provide their inhibition (<i>K</i> _i and ) and covalent modification rate (<i>k</i> ₅ and <i>k</i> ₆) constants, leading to difficulty in accurately ranking drug candidates. Herein, we present an implicit equation that can estimate these constants from incubation time-dependent IC₅₀ values and a numerical modelling method, EPIC-CoRe, that can fit these kinetic parameters from pre-incubation time-dependent IC₅₀ data. The application of these new methods is demonstrated by the evaluation of a known inhibitor, saxagliptin, providing results consistent with those obtained by other known methods. This work introduces two new practical methods of evaluation for time-dependent reversible covalent inhibitors, allowing for rigorous characterization to enable the fine-tuning of their binding and reactivity.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143754357","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":"Investigation of the <i>in vitro</i> anticancer potential of bis(imino)acenaphthene-N-heterocyclic carbene transition metal complexes revealed TrxR inhibition and triggering of immunogenic cell death (ICD) for allyl palladates.","authors":"Chiara Donati, Ishfaq Ibni Hashim, Nestor Bracho Pozsoni, Laurens Bourda, Kristof Van Hecke, Catherine S J Cazin, Fabiano Visentin, Steven P Nolan, Valentina Gandin, Thomas Scattolin","doi":"10.1039/d5md00039d","DOIUrl":"10.1039/d5md00039d","url":null,"abstract":"<p><p>Immunogenic cell death (ICD) is a regulated form of cell death that activates an immune response through the release of danger-associated molecular patterns (DAMPs), including calreticulin, ATP, and HMGB1. Gold complexes are known to induce ICD, but the ICD-inducing potential of palladium complexes remains largely unexplored. We report the first examples of palladium compounds capable of inducing ICD, specifically allyl palladates bearing bis(imino)acenaphthene-NHC (BIAN-NHC) ligands. Cytotoxicity tests on human cancer cell lines revealed that allyl palladates outperform their cinnamyl analogues and gold(i)/copper(i) BIAN-NHC complexes. Notably, [BIAN-IMes·H][PdCl₂(allyl)] 2a showed excellent TrxR inhibition, reducing activity by 67% and surpassing auranofin. This inhibition strongly correlates with ICD induction, as evidenced by enhanced DAMP marker expression, including superior ATP and HMGB1 release compared to doxorubicin. These findings establish allyl palladates as a novel class of ICD inducers with dual anticancer activity and immune activation potential.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11956031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764959","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":"Synthesis, <i>in silico</i> and <i>in vitro</i> antimicrobial efficacy of some amidoxime-based benzimidazole and benzimidamide derivatives.","authors":"Gbolahan O Oduselu, Olayinka O Ajani, Temitope A Ogunnupebi, Oluwadunni F Elebiju, Damilola S Bodun, Oluwabukayo Toluwunmiju Opebiyi, Ezekiel Adebiyi","doi":"10.1039/d5md00114e","DOIUrl":"10.1039/d5md00114e","url":null,"abstract":"<p><p>Amidoximes are employed as building blocks to synthesise heterocyclic motifs with biological significance. They are very reactive and are used as prodrugs of amidine. This present study unveils the synthesis of amidoxime-based benzimidazole and benzimidamide motifs and evaluates their <i>in silico</i> and <i>in vitro</i> antimicrobial potential as future drug candidates. The compounds (2a, 2b, 4a-c) were synthesized using multi-step synthetic pathways. The synthesised compounds were characterised using physico-chemical examination, ¹H- and ¹³C-NMR, DEPT-135, and FT-IR spectroscopic analyses. The <i>in silico</i> antimicrobial potentials of the synthesized compounds were carried out against glucosamine-6-phosphate synthase of <i>E. coli</i> (PDB ID: 2VF5), and <i>N</i>-myristoyltransferase (NMT) of <i>C. albicans</i> (PDB ID: 1IYL), while the <i>in vitro</i> antimicrobial screening was investigated against selected bacteria and fungi. The <i>in silico</i> studies were carried out using predicted ADMET screening, molecular docking, MM-GBSA, induced-fit docking (IFD), and molecular dynamics (MD) simulation studies. Furthermore, the <i>in vitro</i> experimental validations were performed using the agar diffusion method and the standard antibacterial and antifungal drugs used were gentamicin and ketoconazole respectively. The predicted toxicity test of the compounds showed no significant risk, except for 4c, which showed high tumorigenic risk. Compounds 2b and 2a gave better binding energies; -8.0 kcal mol^-1 for 2VF5 and -11.7 kcal mol^-1 for 1IYL, respectively. The antimicrobial zone of inhibition and minimum inhibitory concentration values were 40 mm and 3.90 mg mL^-1 against <i>S. mutans</i>, then 42 mm and 1.90 mg mL^-1 against <i>C. albicans</i>. Potential antimicrobial drug candidates have been identified in this report and should be explored for future preclinical research.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950986/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143754362","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":"Structure-guided design of a truncated heterobivalent chemical probe degrader of IRE1α.","authors":"Breanna L Zerfas, Yingpeng Liu, Jianwei Che, Katherine A Donovan, John M Hatcher, Fidel Huerta, Rebecca J Metivier, Radosław P Nowak, Leah Ragosta, Tiffany Tsang, Eric S Fischer, Lyn H Jones","doi":"10.1039/d5md00028a","DOIUrl":"10.1039/d5md00028a","url":null,"abstract":"<p><p>IRE1α is an ER protein involved in the unfolded protein response (UPR) and dysregulation of the ER stress pathway has been implicated in several diseases. Inhibitors of the cytoplasmic endonuclease or kinase domains of the enzyme have limited utility and targeted degradation would address additional scaffolding functions of the protein. Here, we describe the design and development of IRE1α proteolysis targeting chimeras (PROTACs) based on a lysine-reactive salicylaldehyde RNase inhibitor, and present the structure-activity relationships (SARs) that delivered the first highly selective degraders of a native ER-membrane associated protein. Medicinal chemistry optimization exploited ternary complex computational modelling to inform design, HiBiT-SpyTag IRE1α degradation and NanoBRET cereblon occupancy cell-based assays to generate SARs, and mass spectrometry-based proteomics to assess broad selectivity in an unbiased manner. Merging IRE1α and CRBN ligand chemotypes provided the truncated chimera CPD-2828 with physicochemical properties more akin to an oral molecular glue degrader than a traditional PROTAC.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938282/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143731477","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":"Light-activatable photochemically targeting chimeras (PHOTACs) enable the optical control of targeted protein degradation of HDAC6.","authors":"Silas L Wurnig, Maria Hanl, Thomas M Geiger, Shiyang Zhai, Ina Dressel, Dominika E Pieńkowska, Radosław P Nowak, Finn K Hansen","doi":"10.1039/d4md00972j","DOIUrl":"10.1039/d4md00972j","url":null,"abstract":"<p><p>Proteolysis targeting chimeras (PROTACs) are heterobifunctional modalities that induce protein degradation <i>via</i> a catalytic mode of action. Photochemically targeting chimeras (PHOTACs) are a subset of PROTACs designed for light-activated protein degradation, thereby offering precise spatiotemporal control. In this study, we report the design, solid-phase synthesis, and characterization of the first PHOTACs targeting histone deacetylase 6 (HDAC6). We achieved this by incorporating an azobenzene photoswitch into our previously developed HDAC6-selective PROTAC A6. Among the synthesized compounds, PHOTAC 12 demonstrated no HDAC6 degradation in the absence of light but showed significant degradation upon activation to its <i>cis</i>-state with 390 nm light irradiation. Notably, we find that PHOTAC 12 in the <i>cis</i>-state shows significantly improved ternary complex formation compared to the <i>trans</i>-state correlating with its degradation efficacy. Overall, PHOTAC 12 is a promising lead compound for the development of light-activatable HDAC6 degraders.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11931564/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143711138","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, biological evaluation, and molecular modelling of novel isocytosine and guanidine derivatives as BACE1 inhibitors using a fragment growing strategy.","authors":"Asmaa M Atta, Nouran Rihan, Ahmad M Abdelwaly, Mohamed S Nafie, Mohamed S Elgawish, Samia M Moustafa, Mohamed A Helal, Khaled M Darwish","doi":"10.1039/d4md00698d","DOIUrl":"https://doi.org/10.1039/d4md00698d","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a neurodegenerative condition characterized by significant synaptic loss and neuronal death in brain regions critical for cognitive functions. The disease is characterized by the formation of amyloid plaques, which are extracellular constructs consisting mainly of aggregated Aβ42. The latter is a peptide formed by the proteolytic cleavage of β-amyloid precursor protein (APP) by two enzymes, β- and γ-secretase. Therefore, inhibition of the aspartic protease β-secretase (BACE1) is considered a promising therapeutic approach for the treatment and prevention of Alzheimer's disease. Unfortunately, a limited number of β-secretase inhibitors have reached human trials and eventually failed due to inconclusive therapeutic and/or safety profiles. In this study, we developed drug-like molecules with a β-secretase inhibitory activity using a fragment growing strategy on isocytosine and acyl guanidine warheads. Our approach is based on optimizing the hydrophobic part of the molecules to obtain a conformationally restrained scaffold complementary to the hydrophobic pockets within the enzyme active site. We developed 32 compounds with promising <i>in vitro</i> inhibitory activity against BACE1 down to sub-micromolar IC₅₀. Docking simulation studies were performed to understand the mode of binding of the prepared compounds. We demonstrated that compounds with superior activities, such as 16b and 16g, are able to provide the best balance between the steric shape and position of the polar substituent for achieving preferential anchoring into the S1, S3, S1', and S2' sub-pockets. Further, <i>in vivo</i> characterization of selected drug-like candidates of the benzimidazole series AMK-IV, namely 16a and 16k, demonstrated their ability to reduce oxidation stress and their safety within brain and liver tissues.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11904611/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143650241","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":"Exploring medium and long arm extensions of 1,2,4-triazole derivatives as <i>Candida albicans</i> 14α-demethylase (CYP51) inhibitors.","authors":"Marwa Alsulaimany, Faizah A Binjubair, Esra Tatar, Diane E Kelly, Steven L Kelly, Andrew G Warrilow, Mikhail V Keniya, Brian C Monk, Josie E Parker, Claire Simons","doi":"10.1039/d4md00863d","DOIUrl":"10.1039/d4md00863d","url":null,"abstract":"<p><p>Fungal infections have been described as a silent crisis affecting more than one billion people each year. At least 150 million of these cases involve severe and life threatening invasive fungal infections, accounting for approximately 1.7 million deaths annually. 1,2,4-Trizoles such as fluconazole and posaconazole are widely used antifungal agents, but azole resistance is an increasing problem requiring further study. 1,2,4-Triazole derivatives with medium and long arm extensions designed to bind within the <i>Candida albicans</i> CYP51 (CaCYP51) access channel were synthesised to study their inhibition of CaCYP51 (IC₅₀, MIC) and binding affinity (<i>K</i> _d). A long arm extension using the amide linker was found to be most effective (<i>e.g.</i>13), giving an antifungal profile <i>vs.</i> wild-type and resistant model fungal strains comparable with posaconazole.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11931565/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143711100","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}