RSC medicinal chemistry最新文献

{"title":"Recent advancements in the development of next-generation dual-targeting antibacterial agents.","authors":"Firdoos Ahmad Sofi, Mayank, Mubashir H Masoodi, Nahida Tabassum","doi":"10.1039/d4md00934g","DOIUrl":"https://doi.org/10.1039/d4md00934g","url":null,"abstract":"<p><p>DNA gyrase and topoisomerase IV are validated targets for developing dual-targeting antibacterial agents. The development of novel molecules targeting both enzymes has gained tremendous importance in circumventing the development of bacterial resistance. In the present review, we highlight the recent developments and discovery of dual-targeting inhibitors over the last five years. The structure-activity relationships, molecular docking analysis, and pharmacological activity are presented to facilitate the rational design and development of novel dual-targeting inhibitors to bridge the gap in antibiotic drug discovery.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143543256","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":"Simple accessible clemastine fumarate analogues as effective antileishmanials.","authors":"Rebecca L Charlton, Douglas O Escrivani, Christopher Brown, Niranjan Thota, Victor S Agostino, Exequiel O J Porta, Timur Avkiran, Andrew T Merritt, Paul W Denny, Bartira Rossi-Bergmann, Patrick G Steel","doi":"10.1039/d4md01004c","DOIUrl":"10.1039/d4md01004c","url":null,"abstract":"<p><p>Current therapeutic options for leishmaniasis are severely limited, highlighting an urgent need to develop more effective and less toxic drugs to combat a major global public health challenge. Clemastine fumarate displays good levels of antileishmanial efficacy, but further optimisation is challenged by its difficult synthesis. Here, we demonstrate that simple N-linked analogues are easier to access, can exhibit higher <i>selectivity</i> and show comparable efficacy in a mouse model of <i>Leishmania amazonensis</i> infection.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11862611/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143524280","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":"Hinokitiol potentiates antimicrobial activity of bismuth drugs: a combination therapy for overcoming antimicrobial resistance.","authors":"Tiffany Ka-Yan Ip, Yuchuan Wang, Suyu Wang, Keyuan Pu, Runming Wang, Bingjie Han, Peng Gao, Yanxuan Xie, Richard Y Kao, Pak-Leung Ho, Hongyan Li, Hongzhe Sun","doi":"10.1039/d4md00860j","DOIUrl":"https://doi.org/10.1039/d4md00860j","url":null,"abstract":"<p><p>Antimicrobial resistance (AMR) poses a significant global health threat, rendering many infections untreatable. To combat AMR, repurposing approved drugs has emerged as a cost-effective strategy. Bismuth drugs, when combined with antibiotics, have been proven to be effective against <i>Helicobacter pylori</i>, including antibiotic-resistant strains. However, bismuth drugs alone exhibit limited antimicrobial activity against a narrow spectrum of pathogens. Therefore, a novel approach to enhance the efficacy and broaden the antimicrobial spectrum of bismuth drugs is highly desirable. Herein, we show that a naturally occurring monoterpenoid, hinokitiol, could potentiate the antimicrobial activity of bismuth drugs. We demonstrate a strong synergy between hinokitiol and colloidal bismuth subcitrate (CBS) against various Gram-positive and Gram-negative bacterial strains, including methicillin-resistant <i>Staphylococcus aureus</i> (MRSA). Moreover, the combination of hinokitiol and CBS exhibits anti-biofilm activity by preventing biofilm formation and eliminating <i>S. aureus</i> persister cells. Importantly, the combination therapy demonstrates promising antimicrobial efficacy in murine infection models including skin wound, gastrointestinal and blood infections. Mechanistic studies reveal that hinokitiol enhances bismuth ion (Bi(iii)) accumulation and reduces intracellular iron levels. By using thermal proteome profiling combined with dynamic quantitative proteomics analysis, we demonstrate that the bismuth-hinokitiol combination propagated the bismuth binding and interfered with ribosome synthesis, the glycolysis process, impaired bacterial cell wall synthesis and pathogenesis in MRSA. Our finding highlights the potential of combinatorial hinokitiol and bismuth drugs in the fight against AMR.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11865920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143543252","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":"Effect of mono-guanidine-like derivatives on platelet aggregation and tumour cell induced platelet aggregation.","authors":"Nadhim Kamil Hante, Aaron P Keogh, Yanni Huang, Tanya Kapoor, Harriet Bennett-Lenane, Eleanor Walsh, Isabel Rozas, Carlos Medina, Maria Jose Santos-Martinez","doi":"10.1039/d4md00793j","DOIUrl":"https://doi.org/10.1039/d4md00793j","url":null,"abstract":"<p><p>Antiplatelet agents are the cornerstone for the treatment and prevention of cardiovascular diseases. However, they can induce severe side effects such as gastrointestinal bleeding. The main aim of this study is to determine the effect that novel guanidine-based derivatives exert on platelet aggregation. From a screening, in collaboration with the Psychoactive Drug Screening Project service of several compounds from our in-house library of α2-adrenoceptors' ligands, four compounds showed high to medium affinity towards α2C-adrenoceptors and H2 histamine receptors. Based on the structure of these compounds, another two in-house α2-adrenoceptors' ligands were also selected. The effect of the six compounds on platelet aggregation was investigated by light transmission aggregometry and optical microscopy. Flow cytometry was used to analyse their effect on platelet activation by measuring the expression of GPIIb/IIIa and P-selectin platelet receptors. Finally, the potential effect of those compounds on tumour cell-induced platelet aggregation was studied on three cancer cell lines from different origins using optical microscopy. We found that three of these compounds, with very good affinity towards H2 histamine receptors, significantly inhibited platelet aggregation, induced by both ADP and collagen, at the highest concentrations tested, and that tumour cell-induced platelet aggregation was also modulated by these derivatives. Our findings suggest that these aryl guanidine-like systems have an antiplatelet effect that could be also beneficial to reduce tumour cell-platelet interactions.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11865921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143543123","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":"Antimicrobial triazinedione inhibitors of the translocase MraY-protein E interaction site: synergistic effects with bacitracin imply a new mechanism of action.","authors":"Julia A Fairbairn, Rachel V Kerr, Nika-Kare A Pierre-White, Anthony Jacovides, Becca W A Baileeves, Phillip J Stansfeld, Gerhard Bringmann, Andrew T Merritt, Timothy D H Bugg","doi":"10.1039/d4md00937a","DOIUrl":"10.1039/d4md00937a","url":null,"abstract":"<p><p><i>Escherichia coli</i> translocase MraY is the target for bacteriolytic protein E from bacteriophage ϕX174, interacting at a site close to Phe-288 on helix 9, on the extracellular face of the protein. A peptide motif Arg-Trp-x-x-Trp from protein E was used to design a set of triazinedione peptidomimetics, which inhibit particulate MraY (6d IC₅₀ 48 μM), and show antimicrobial activity against Gram-negative and Gram-positive antibiotic-resistant clinical strains (7j MIC <i>Acinetobacter baumannii</i> 16 μg mL^-1, <i>Staphyloccoccus aureus</i> MRSA 2-4 μg mL^-1). Docking against a predicted structure for <i>E. coli</i> MraY revealed two possible binding sites close to helix 9, the binding site for protein E. Antimicrobial activity of analogue 6j was found to be synergistic with bacitracin in <i>Micrococcus flavus</i>, consistent with a link between this inhibition site and undecaprenyl phosphate uptake. Alkaloid michellamine B, also predicted to bind in the cleft adjacent to helix 9, was also found to be synergistic with bacitracin. These data provide experimental evidence that the unusual hydrophobic cleft adjacent to helix 9 in MraY is involved in uptake of undecaprenyl phosphate, in addition to recently identified transporters UptA and PopT, and that this process can be targeted by small molecules as a novel antibacterial mechanism.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11812184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143410136","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":"Discovery of selective, metabolically stable pyrazole-based FLT3 inhibitors for the treatment of acute myeloid leukemia.","authors":"Lorenza Destro, Valentina Crippa, Daniela Gabbia, Marco Roverso, Sara Bogialli, Paolo Zardi, Giovanni Marzaro, Luca Mologni, Alfonso Zambon","doi":"10.1039/d4md00956h","DOIUrl":"10.1039/d4md00956h","url":null,"abstract":"<p><p>Acute myeloid leukemia (AML) is the most prevalent form of acute leukemia in adults, representing a substantial medical need, as the standard of care has not changed for the past two decades, and the long-term outcome remains dismal for a large fraction of patients. Approximately 30% of AMLs carry activating mutations of the FLT3 kinase. Unfortunately, single-agent FLT3 inhibitor therapy has met limited clinical efficacy, underscoring a strong rationale for the development of more selective and more potent inhibitors. Here we present the design, synthesis and biological evaluation of a series of biphenyl substituted pyrazoyl-ureas, an underexplored scaffold in medicinal chemistry, as novel FLT3 inhibitors with a putative type II binding mode. Optimized compounds show nanomolar activity against isolated FLT3 (230 nM for compound 10q) and on FLT3-driven cell lines (280 nM and 18 nM for compound 10q against MV4.11 and MOLM-14 cells respectively), with no toxicity against control cell lines, limited metabolism in human microsomes and a reliable SAR; furthermore, profiling of compound 10q against a panel of kinases highlights c-Kit as the only other hit. Overall, we show that the series has a narrow selectivity profile and metabolic stability, and the mode of action of the inhibitors through FLT3 is confirmed by strong suppression of FLT3 and STAT5 phosphorylation.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11843578/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483512","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":"Identification of 5-amino-1,3,4-thiadiazole appended isatins as bioactive small molecules with polypharmacological activities.","authors":"Uzma Azam, Waqar Ahmed Humayun, Amrutha K Avathan Veettil, Yang Liu, Oguz Hastürk, Mao Jiang, Sonja Sievers, Peng Wu, Muhammad Moazzam Naseer","doi":"10.1039/d4md00770k","DOIUrl":"10.1039/d4md00770k","url":null,"abstract":"<p><p>The identification of heterocyclic small molecules that cover unexplored chemical space is of great importance for the development of new small-molecule therapeutics. In this study, we synthesized a series of 5-amino-1,3,4-thiadiazoles appended isatins (UZ-1-20) that exhibited polypharmacological properties, as evaluated in a cell-painting assay assessing induced cellular morphological changes. A high hit rate ranging from 55% to 80% was observed for the tested compounds at varied concentrations. The most active compounds showed significant activity in inducing cellular morphological changes with a measured induction value of more than 30% and shared a high biological profiling similarity with an antifungal agent itraconazole and a chemokine receptor inhibitor. The synthesized compounds exhibited moderate to good antiproliferative activity against tested cancer cell lines in the MTT assay. Molecular docking studies were performed to theoretically probe and compare the binding modes between the most active UZ compounds and ITZ or BI-6901, respectively. Additionally, ADMET analysis indicated favorable pharmacokinetic parameters including good oral bioavailability, balanced hydrophilicity, and minimal toxicity. Overall, the findings in this study highlight the potential of developing the aminothiadiazole appended isatins as bioactive agents.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11841741/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483517","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":"Discovery of potent measles virus fusion inhibitor peptides <i>via</i> structure-guided derivatization.","authors":"Ziwei Gao, Jiei Sasaki, Tateki Suzuki, Tomoaki Suzuki, Yuki Miwa, Shinsuke Sando, Takao Hashiguchi, Jumpei Morimoto","doi":"10.1039/d4md01006j","DOIUrl":"10.1039/d4md01006j","url":null,"abstract":"<p><p>Fusion inhibitor peptide (FIP), a short peptide known as a measles virus (MeV) infection inhibitor, inhibits membrane fusion between the viral envelope of MeV and the host cell membrane. Therefore, FIP is potentially useful as a drug candidate for treating MeV infection, but improvement of inhibitory activity is desirable. In this study, we conducted a structure-activity relationship study of FIP and, based on the result and the previously reported crystal structure of the complex, we designed FIP derivatives. From a series of derivatives, we discovered an FIP derivative with a strong inhibitory activity (IC₅₀ = 210 nM) derived from the enhanced binding affinity (<i>K</i> _D = 6.6 nM) to the MeV fusion protein.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11799930/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143383214","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":"X-ray crystallographic and kinetic studies of biguanide containing aryl sulfonamides as carbonic anhydrase inhibitors.","authors":"Chiara Baroni, Murat Bozdag, Gioele Renzi, Viviana De Luca, Clemente Capasso, Carla Bazzicalupi, Silvia Selleri, Marta Ferraroni, Fabrizio Carta, Claudiu T Supuran","doi":"10.1039/d4md01018c","DOIUrl":"10.1039/d4md01018c","url":null,"abstract":"<p><p>Here, we report a small series of dual-targeting compounds that combine the prototypical carbonic anhydrase (CA) zinc-binding sulfonamide moiety with the biguanide group of metformin, an emerging anticancer drug. The compounds reported similar <i>in vitro</i> inhibition profiles on a panel of physiologically relevant human (h)CAs, with marked selectivity for the cancer related IX and XII isoforms. The binding modes of representative inhibitors 5b and 5c within the active site of the hCA isoforms II and XII-mimic were assessed by X-ray crystallography, thus allowing us to clarify molecular features that may be useful for the design of more specific and potent inhibitors. For instance, we identified a mutation in the hCA XII-mimic which was found responsible for the selectivity of the ligands toward the tumor associated isoform. Interestingly, in the hCA II/5c complex, a second inhibitor molecule was bound to the catalytic cleft, probably affecting the inhibition properties of the canonical zinc-bound inhibitor.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11809658/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399920","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":"Aspirin <i>vs.</i> ibuprofen: unveiling the distinct cyclooxygenase-1/2 behaviour and dual efficacy of their synthesized analogues <i>via</i> molecular modeling and <i>in vitro</i> biological assessment.","authors":"Amandeep Kaur, Hafiz Muzzammel Rehman, Vipin Kumar Mishra, Gurmeet Kaur, Mandeep Kaur, Mohammad K Okla, Masaud Shah, Manisha Bansal","doi":"10.1039/d4md00751d","DOIUrl":"https://doi.org/10.1039/d4md00751d","url":null,"abstract":"<p><p>Dual inhibition of cyclooxygenase isozymes along with the platelet aggregation activities <i>via</i> the arachidonic acid pathway may offer a better anti-inflammatory agent with enhanced cardiac safety. Although the literature is more focused on COX-2 selectivity, sufficient or improved COX-1/COX-2 selectivity has garnered significant attention recently since it can ensure cardiovascular safety. Herein, in this regard, novel derivatives of non-steroidal anti-inflammatory drugs containing amide, thiourea, thiosemicarbazide, and triazole functionalities were synthesized and characterized. Calculations on the <i>in silico</i> drug-likeness and toxicological properties demonstrated the suitability of the compounds for oral administration. Meanwhile, the molecular docking results suggested two different mechanistic pathways for the anti-inflammatory and anti-platelet effects <i>via</i> COX-2 and COX-1 inhibition. Compounds 3 and 12 were shown to be the most efficient based on their excellent docking scores and favorable interactions, particularly with the selective side-pocket residues of COX-2 and main catalytic residues of COX-1. Furthermore, molecular dynamics simulation confirmed that compounds 3 and 12 exhibited good interactions at the active sites, having stable binding throughout 100 ns. Overall, two major findings were made in the current study. (i) Compound 12 bearing the triazole moiety proved to be the most effective cyclooxygenase inhibitor with IC₅₀ values of 95.11 and 98.73 μM against COX-1 and COX-2 isozymes, respectively. It also maintained its anti-platelet activity (IC₅₀ = 277.67 μM), confirming the dual functioning of compound 12. (ii) Compound 3 purely behaved as an anti-platelet agent (IC₅₀ = 261.0 μM) in contrast to aspirin with fare inhibitory effects against COX-2.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11865951/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143543005","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}