MedChemComm最新文献

{"title":"Unveiling the potent activity of a synthetic ion transporter against multidrug-resistant Gram-positive bacteria and biofilms†","authors":"Sudip Mukherjee, Sopan Valiba Shinde, Pinaki Talukdar and Jayanta Haldar","doi":"10.1039/D4MD00002A","DOIUrl":"10.1039/D4MD00002A","url":null,"abstract":"<p >The increasing prevalence of drug-resistant infections caused by Gram-positive bacteria poses a significant threat to public healthcare. These pathogens exhibit not only smart resistance mechanisms but also form impenetrable biofilms on various surfaces, rendering them resilient to conventional therapies. In this study, we present the potent antibacterial activity of a synthetic ion transporter <strong>T</strong> against multi-drug resistant (MDR) Gram-positive pathogens, with minimum inhibitory concentration (MIC) values ranging from 0.5 to 2 μg mL<small>⁻¹</small>. The compound demonstrates high selectivity with negligible toxicity towards mammalian cells (HC<small>₅₀</small> = 810 μg mL<small>⁻¹</small>). It exhibits fast killing kinetics, completely eliminating &gt;5 log bacterial cells within 12 h. Moreover, the compound displays efficacy against both planktonic bacteria and preformed biofilms of methicillin-resistant <em>S. aureus</em> (MRSA), reducing the bacterial burden within the biofilm by 2 log. Mechanistic investigations reveal that the ion transporter depolarizes the bacterial membrane potential and enhances membrane permeability. Additionally, it generates reactive oxygen species, contributing to its bactericidal activity. Notably, MRSA did not exhibit detectable resistance to the ion transporter even after serial passaging for 10 days. Collectively, this novel class of ion transporter holds promise as a therapeutic candidate for combating infections caused by multi-drug resistant Gram-positive bacteria.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 2127-2137"},"PeriodicalIF":3.597,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141062084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Photodynamic treatment of Staphylococcus aureus with non-iron hemin analogs in the presence of hydrogen peroxide†","authors":"Badhu Prashanthika Sivasubramaniam, Benjamin M. Washer, Yuichiro Watanabe, Kathryn E. Ragheb, J. Paul Robinson and Alexander Wei","doi":"10.1039/D4MD00148F","DOIUrl":"10.1039/D4MD00148F","url":null,"abstract":"<p >Bacteria subjected to antiseptic or antibiotic stress often develop tolerance, a trait that can lead to permanent resistance. To determine whether photodynamic agents could be used to counter tolerance, we evaluated three non-iron hemin analogs (M-PpIX; M = Al, Ga, In) as targeted photosensitizers for antimicrobial photodynamic inactivation (aPDI) following exposure to sublethal H<small>₂</small>O<small>₂</small>. Al-PpIX is an active producer of ROS whereas Ga- and In-PpIX are more efficient at generating singlet oxygen. Al- and Ga-PpIX are highly potent aPDI agents against <em>S. aureus</em> and methicillin-resistant strains (MRSA) with antimicrobial activity (3 log reduction in colony-forming units) at nanomolar concentrations. The aPDI activities of Al- and Ga-PpIX against <em>S. aureus</em> were tested in the presence of 1 mM H<small>₂</small>O<small>₂</small> added at different stages of growth. Bacteria exposed to H<small>₂</small>O<small>₂</small> during log-phase growth were less susceptible to aPDI but bacteria treated with H<small>₂</small>O<small>₂</small> in their postgrowth phase exhibited aPDI hypersensitivity, with no detectable colony growth after treatment with 15 nM Ga-PpIX.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 2138-2145"},"PeriodicalIF":3.597,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d4md00148f?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141062087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating a quinone substructure into histone deacetylase inhibitors to cope with Alzheimer's disease and cancer†","authors":"Melissa Guardigni, Giulia Greco, Eleonora Poeta, Alan Santini, Elisa Tassinari, Christian Bergamini, Chiara Zalambani, Angela De Simone, Vincenza Andrisano, Elisa Uliassi, Barbara Monti, Maria Laura Bolognesi, Carmela Fimognari and Andrea Milelli","doi":"10.1039/D4MD00175C","DOIUrl":"10.1039/D4MD00175C","url":null,"abstract":"<p >Alzheimer's disease (AD) and cancer are among the most devastating diseases of the 21st century. Although the clinical manifestations are different and the cellular mechanisms underlying the pathologies are opposite, there are different classes of molecules that are effective in both diseases, such as quinone-based compounds and histone deacetylase inhibitors (HDACIs). Herein, we investigate the biological effects of a series of compounds built to exploit the beneficial effects of quinones and histone deacetylase inhibition (compounds <strong>1–8</strong>). Among the different compounds, compound <strong>6</strong> turned out to be a potent cytotoxic agent in SH-SY5Y cancer cell line, with a half maximal inhibitory concentration (IC<small>₅₀</small>) value lower than vorinostat and a pro-apoptotic activity. On the other hand, compound <strong>8</strong> was nontoxic up to the concentration of 100 μM and was highly effective in stimulating the proliferation of neural precursor cells (NPCs), as well as inducing differentiation into neurons, at low micromolar concentrations. In particular, it was able to induce NPC differentiation solely towards a neuronal-specific phenotype, without affecting glial cells commitment.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 2045-2062"},"PeriodicalIF":3.597,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d4md00175c?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140838010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heterocyclic compounds as xanthine oxidase inhibitors for the management of hyperuricemia: synthetic strategies, structure–activity relationship and molecular docking studies (2018–2024)","authors":"Arshdeep Singh, Rabin Debnath, Viney Chawla and Pooja A. Chawla","doi":"10.1039/D4MD00072B","DOIUrl":"10.1039/D4MD00072B","url":null,"abstract":"<p >Hyperuricemia is characterized by higher-than-normal levels of uric acid in the bloodstream. This condition can increase the likelihood of developing gout, a form of arthritis triggered by the deposition of urate crystals in the joints, leading to inflammation and pain. An essential part of purine metabolism is played by the enzyme xanthine oxidase (XO), which transforms xanthine and hypoxanthine into uric acid. Despite its vital role, diseases such as gout have been associated with elevated uric acid levels, which are linked to increased XO activity. To manage hyperuricemia, this study focuses on potential nitrogen based heterocyclic compounds that may serve as XO inhibitors which may lower uric acid levels and prevent hyperuricemia. Xanthine oxidase inhibitors are a class of medications used to treat conditions like gout by reducing the production of uric acid. The present study demonstrates numerous compounds, particularly nitrogen containing heterocyclic compounds including their synthesis, structure–activity relationship, and molecular docking studies. This paper also contains drugs undergoing clinical studies and the xanthine oxidase inhibitors that have been approved by the FDA.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 1849-1876"},"PeriodicalIF":3.597,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140838207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Can large language models predict antimicrobial peptide activity and toxicity?†","authors":"Markus Orsi and Jean-Louis Reymond","doi":"10.1039/D4MD00159A","DOIUrl":"10.1039/D4MD00159A","url":null,"abstract":"<p >Antimicrobial peptides (AMPs) are naturally occurring or designed peptides up to a few tens of amino acids which may help address the antimicrobial resistance crisis. However, their clinical development is limited by toxicity to human cells, a parameter which is very difficult to control. Given the similarity between peptide sequences and words, large language models (LLMs) might be able to predict AMP activity and toxicity. To test this hypothesis, we fine-tuned LLMs using data from the Database of Antimicrobial Activity and Structure of Peptides (DBAASP). GPT-3 performed well but not reproducibly for activity prediction and hemolysis, taken as a proxy for toxicity. The later GPT-3.5 performed more poorly and was surpassed by recurrent neural networks (RNN) trained on sequence-activity data or support vector machines (SVM) trained on MAP4C molecular fingerprint-activity data. These simpler models are therefore recommended, although the rapid evolution of LLMs warrants future re-evaluation of their prediction abilities.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 2030-2036"},"PeriodicalIF":3.597,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d4md00159a?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140837995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of dibenzylbutane lignan LCA derivatives as potent anti-inflammatory agents†","authors":"Zhen Wang, Juan Zhang, Conghao Gai, Jing Wang, Xiaobin Zhuo, Yan Song, Yan Zou, Peichao Zhang, Guige Hou, Qingguo Meng, Qingjie Zhao and Xiaoyun Chai","doi":"10.1039/D4MD00053F","DOIUrl":"10.1039/D4MD00053F","url":null,"abstract":"<p >Inflammation is the body's response to defence against infection or injury, and is associated with the progression of many diseases, such as inflammatory bowel disease (IBD) and rheumatoid arthritis (RA). LCA, a dibenzylbutane lignan extracted from the roots of traditional medicinal plant <em>Litsea cubeba</em> (Lour.) Pers., has demonstrated promising anti-inflammatory activity. In this study, a series of novel LCA derivatives were designed, synthesized, and evaluated for anti-inflammatory activity. Lipopolysaccharide (LPS)-induced RAW 264.7 cell model experiments showed that compound <strong>10h</strong> (at 20 μM of concentration) had the strongest inhibitory effect on NO release, and inhibited the secretion and gene expression levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α <em>in vitro.</em> In addition, western blot, immunofluorescence, and molecular docking showed that the anti-inflammatory mechanism of compound <strong>10h</strong> may be related to the nuclear factor (NF)-κB signalling pathway. <em>In vivo</em> studies based on a carrageenan-induced mouse paw edema model have shown significant anti-inflammatory activity of compound <strong>10h</strong> at 20 mg kg<small>⁻¹</small>. Preliminary <em>in vitro</em> and <em>in vivo</em> studies indicate that compound <strong>10h</strong> has the potential to be developed as a novel anti-inflammatory agent.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 2114-2126"},"PeriodicalIF":3.597,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140925329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The importance of tyrosines in multimers of cyclic RGD nonapeptides: towards αvβ6-integrin targeted radiotherapeutics†","authors":"Neil Gerard Quigley, Maximilian Alexander Zierke, Beatrice Stefanie Ludwig, Frauke Richter, Nghia Trong Nguyen, Falco Reissig, Jakub Šimeček, Susanne Kossatz and Johannes Notni","doi":"10.1039/D4MD00073K","DOIUrl":"10.1039/D4MD00073K","url":null,"abstract":"<p >In a recent paper in this journal (<em>RSC Med. Chem.</em>, 2023, <strong>14</strong>, 2429), we described an unusually strong impact of regiospecific exchange of phenylalanines by tyrosines in 10 gallium-68-labeled trimers of certain cyclic RGD peptides, c[XRGDLAXp(<em>N</em>Me)K] (X = F or Y), on non-specific organ uptakes. We found that there was, in part, no correlation of liver uptake with established polarity proxies, such as the octanol–water distribution coefficient (log <em>D</em>). Since this observation could not be explained straightforwardly, we suggested that the symmetry of the compounds had resulted in a synergistic interaction of certain components of the macromolecules. In the present work, we investigated whether a comparable effect also occurred for a series of 5 tetramers labeled with lutetium-177. We found that in contrast to the trimers, liver uptake of the tetramers was well correlated to their polarity, indicating that the unusual observations along the trimer series indeed was a unique feature, probably related to their particular symmetry. Since the Lu-177 labeled tetramers are also potential agents for treatment of a variety of αvβ6-integrin expressing cancers, these were evaluated in mice bearing human lung adenocarcinoma xenografts. Due to their tumor-specific uptake and retention in biodistribution and SPECT imaging experiments, these compounds are considered a step forward on the way to αvβ6-integrin-targeted anticancer agents. Furthermore, we noticed that the presence of tyrosines in general had a positive impact on the <em>in vivo</em> performance of our peptide multimers. In view of the fact that a corresponding rule was already proposed in the context of protein engineering, we argue in favor of considering peptide multimers as a special class of small or medium-sized proteins. In summary, we contend that the performance of peptide multimers is less determined by the <em>in vitro</em> characteristics (particularly, affinity and selectivity) of monomers, but rather by the peptides' suitability for the overall macromolecular design concept, and peptides containing tyrosines are preferred.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 2018-2029"},"PeriodicalIF":3.597,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140838215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cytotoxicity of phosphoramidate, bis-amidate and cycloSal prodrug metabolites against tumour and normal cells†","authors":"Rebecca E. Farrell, Harrison Steele, Ryan J. Middleton, Danielle Skropeta and Guo-Jun Liu","doi":"10.1039/D4MD00115J","DOIUrl":"10.1039/D4MD00115J","url":null,"abstract":"<p >Phosphonate and phosphate prodrugs are integral to enhancing drug permeability, but the potential toxicity of their metabolites requires careful consideration. This study evaluates the impact of widely used phosphoramidate, bis-amidate, and cycloSal phosph(on)ate prodrug metabolites on BxPC3 pancreatic cancer cells, GL261-Luc glioblastoma cells, and primary cultured mouse astrocytes. 1-Naphthol and 2-naphthol demonstrated the greatest toxicity. Notably, 2-naphthol exhibited an ED<small>₅₀</small> of 21 μM on BxPC3 cells, surpassing 1-naphthol with an ED<small>₅₀</small> of 82 μM. Real-time xCELLigence experiments revealed notable activity for both metabolites at a low concentration of 16 μM. On primary cultured mouse astrocyte cells, all prodrugs exhibited reduced viability at 128 to 256 μM after only 4 hours of exposure. A cell-type-dependent sensitivity to phosph(on)ate prodrug metabolites was evident, with normal cells showing greater susceptibility than corresponding tumour cells. The results suggest it is essential to consider the potential cytotoxicity of phosph(on)ate prodrugs in the drug design and evaluation process.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 1973-1981"},"PeriodicalIF":3.597,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140801307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling sultam in drug discovery: spotlight on the underexplored scaffold","authors":"Yie Kie Chong, Yee Swen Ong and Keng Yoon Yeong","doi":"10.1039/D3MD00653K","DOIUrl":"10.1039/D3MD00653K","url":null,"abstract":"<p >Decades ago, the application of cyclic sulfonamide (sultam) and its derivatives primarily focused on their antibacterial properties. However, recent years have seen a shift in research attention towards exploring their potential as anticancer, anti-inflammatory, antidiabetic, and antiviral agents. Despite this broadening scope, only a few sultam drugs have made it to the commercial market, as much of the research on sultams remains in the discovery phase. This class of compounds holds significant promise and remains pertinent in pharmaceutical research. Due to sultam's relevance and growing importance in drug discovery, this review paper aims to consolidate and examine the biological activities of sultam derivatives ranging from 4 to 8-membered ring structures.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 1798-1827"},"PeriodicalIF":3.597,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140837996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chiral hydroxymethyl-1H,3H-pyrrolo[1,2-c]thiazoles: the search for selective p53-activating agents for colorectal cancer therapy†","authors":"Mees M. Hendrikx, Adelino M. R. Pereira, Ana B. Pereira, Carla S. C. Carvalho, João L. P. Ribeiro, Maria I. L. Soares, Lucília Saraiva and Teresa M. V. D. Pinho e Melo","doi":"10.1039/D4MD00076E","DOIUrl":"10.1039/D4MD00076E","url":null,"abstract":"<p >MANIO is an efficient p53-activating anticancer agent with remarkable selectivity to the p53 pathway and promising antitumor activity against colorectal cancer (CRC). Herein, a library of novel MANIO derivatives, including hydroxymethyl- and bis(hydroxymethyl)-1<em>H</em>,3<em>H</em>-pyrrolo[1,2-<em>c</em>]thiazoles, was synthesized by rational structural modulation. The antiproliferative activity of twenty derivatives was evaluated in a panel of human CRC cells with different p53 status. From this library, five compounds with <em>R</em>- and <em>S</em>-configuration and with aromatic or heteroaromatic groups at position 3, including the enantiomer of MANIO, were identified as selective towards p53-expressing cancer cells. On the other hand, two compounds with <em>S</em>-configuration, 6-hydroxymethyl- and 7-hydroxymethyl-5-methyl-3-phenyl-1<em>H</em>,3<em>H</em>-pyrrolo[1,2-<em>c</em>]thiazoles, showed high cytotoxicity against WTp53-expressing HCT116 colon cells but, unlike MANIO, exhibited p53-independent inhibitory activity in CRC. The results described provide relevant structural and pharmacophoric data for the design of new p53-activating agents for precision therapy of CRC or other p53-related cancers harboring both wild-type or mutated p53 forms.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 5","pages":" 1652-1663"},"PeriodicalIF":3.597,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d4md00076e?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140588813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}