MedChemComm最新文献

{"title":"Synthesis and evaluation of HFIP bearing triazolo-amides as amyloid-β aggregation inhibitors and suppressors of aggregation induced neuroinflammation","authors":"Bhaskar Dewangan, Parijat Swain, Srimanta Patra, Praveen Reddy Bodhe, Neeraj Kulkarni and Bichismita Sahu","doi":"10.1039/D5MD00481K","DOIUrl":"10.1039/D5MD00481K","url":null,"abstract":"<p >Alzheimer's disease (AD) is a complex neurodegenerative disease with biological signatures of amyloid beta (Aβ) aggregated plaques and increased levels of bio-metals like copper (Cu), zinc (Zn), and iron (Fe). Aβ-induced lysosomal membrane permeabilization is a key event in neuronal injury in AD. Aβ aggregation also modulates mitochondria membrane potential (MMP), activates interleukin 1β and NLRP3 inflammasome eventually leading to increased reactive oxygen species (ROS) production, neuronal apoptosis and mitochondrial dysfunction. Here, we report a multi-functional compound (<strong>2f</strong>) identified through structure–activity relationship study from a series of polyfluorinated triazole compounds. Compound <strong>2f</strong> suppressed metal induced aggregation, downregulated NLRP3 inflammasome and IL-1β expression. It has maintained the lysosomal acidic pH and restored mitochondrial membrane potential. HFIP bearing triazolo amide (<strong>2f</strong>) was found to chelate with Cu(<small>II</small>) and Zn(<small>II</small>) selectively in the presence of a range of other physiologically relevant metals. Further, a molecular dynamics (MD) simulation study revealed <strong>2f</strong> disrupted the aggregation <em>via</em> interacting with chain A of pentameric Aβ. Therefore the HFIP bearing triazole amides may serve as potential scaffolds for drug development towards the treatment of AD.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 1","pages":" 531-548"},"PeriodicalIF":3.597,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145649079","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":"Evaluating the FEP+ protocol for predicting binding affinity of congeneric ligands towards various soluble proteins","authors":"Shashi Kumar Sampangin Venkatesh, Arpan Das and Naga Rajiv Lakkaniga","doi":"10.1039/D5MD00748H","DOIUrl":"10.1039/D5MD00748H","url":null,"abstract":"<p >Generating libraries of congeneric series of compounds and development of structure–activity relationships (SAR) is a common practice among medicinal chemists. While various computational methods are available to guide scaffold optimization, their reliability in prediction can vary. Ligand free energy perturbation (FEP+) is a rigorous computational program that computes the relative binding free energies between two congeneric ligands against a target, thereby identifying the ligand with greater binding affinity. In this study, we evaluated the FEP+ method to predict the relative binding affinity of two ligands from a congeneric series towards the target proteins. A total of 34 ligand transformations were performed, spanning across 21 soluble proteins. Relative binding free energies were calculated and compared with the experimental value to assess the accuracy of prediction. With a mean unsigned error of 0.46 kcal mol<small>⁻¹</small> and coefficient of determination, <em>R</em><small>²</small> = 0.85, the results of this work suggest that the FEP+ is a reliable tool for the medicinal chemist to predict the relative free energies of binding with good statistical significance, demonstrating its utility in SAR development in drug discovery.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 1","pages":" 606-617"},"PeriodicalIF":3.597,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145701823","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":"Schweinfurthins and their analogues are highly selective cellular probes for oxysterol-binding protein (OSBP)","authors":"Laura Depta, Nianzhe He, Maria Lillevang Madsen, Matilde Lind Hartvig Nielsen, Hogan P. Bryce-Rogers, Samantha C. Waterworth, Jeffrey D. Neighbors, David P. Stockdale, Michael P. Callahan, Nolan R. Mente, David F. Wiemer, John A. Beutler and Luca Laraia","doi":"10.1039/D5MD00625B","DOIUrl":"10.1039/D5MD00625B","url":null,"abstract":"<p >Schweinfurthins (SWs) are natural products isolated from the plant genus <em>Macaranga</em> which display a unique cytotoxicity profile in human cancer cell lines with low nanomolar potency. Their known target is the sterol transport protein (STP) oxysterol-binding protein (OSBP), a key mediator and regulator of lipid transport between the endoplasmic reticulum (ER) and the trans-Golgi network (TGN). However, until now the underlying structure–activity relationships (SAR), as well as the cellular toxicity-target engagement relationships of SWs towards OSBP have not been well-studied. In this study, we present the first comprehensive SAR and selectivity study by characterizing 59 SW analogues utilizing our STP screening panel. Complementary detailed docking studies shine light on the SW-OSBP interactions and unravel amino acid residues critical for potent binding to OSBP. Additionally, we demonstrate cellular target engagement and correlate cancer cell cytotoxicity with Golgi fragmentation as a phenotypic consequence of OSBP inhibition by selected SW analogues. Therefore, this study will pave the way for more focused investigations and therapeutic applications of OSBP inhibitors.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 12","pages":" 6262-6274"},"PeriodicalIF":3.597,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145588715","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":"Design, synthesis, and biological evaluation of sulfonamide-functionalized pyridine carbothioamides as potent tubulin-targeting anticancer agents","authors":"Fatima Younas, Jahan Zaib Arshad, Waqas Ali Shah, Sundas Arshad, Adnan Ashraf, Syed Shoaib Ahmad Shah, Muhammad Asam Raza, Amara Mumtaz, Nasir Shahzad and Tariq Javed","doi":"10.1039/D5MD00693G","DOIUrl":"10.1039/D5MD00693G","url":null,"abstract":"<p >Pyridine carbothioamides (PCAs) are recognized for their gastric mucosal protective effects and low <em>in vivo</em> toxicity, making them attractive scaffolds for anticancer drug development. In this study, a series of <em>N</em>-phenyl 4-substituted and 2,4-disubstituted PCAs (<strong>1–8</strong>) incorporating a sulfonamide pharmacophore were synthesized, fully characterized, and evaluated as tubulin polymerization inhibitors. The compounds were tested against four cancer cell lines (A549, MCF-7, PC-3, HepG2) with colchicine and doxorubicin as reference drugs. Among them, compounds <strong>3</strong> and <strong>5</strong> exhibited potent cytotoxicity, being 2–6-fold more active than colchicine and up to 2.5-fold stronger than doxorubicin in PC-3 cells. Importantly, both showed ∼4-fold lower toxicity toward normal HLMEC cells and displayed higher selectivity towards tested cancer cells than doxorubicin. Tubulin polymerization assays confirmed their activity, with IC<small>₅₀</small> values of 1.1 μM (<strong>3</strong>) and 1.4 μM (<strong>5</strong>), outperforming colchicine (10.6 μM) and CA-4 (2.96 μM). Molecular docking revealed strong binding at the colchicine site, supported by favorable inhibition constants and free binding energies. <em>In silico</em> ADME predictions indicated that the most lipophilic compounds <strong>3</strong> and <strong>5</strong> demonstrated favorable drug-likeness, as expected from computational studies, along with excellent gastrointestinal absorption, favorable bioavailability, and low hemolytic activity. Collectively, these findings highlight compounds <strong>3</strong> and <strong>5</strong> as promising lead candidates for the development of orally active anticancer and antimitotic agents.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 1","pages":" 354-369"},"PeriodicalIF":3.597,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145557762","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":"Targeted protein degradation of HSP90 and associated proteins for cancer therapy via PROTACs and beyond","authors":"Gulshan Kumar, Gouri Tyagi and Vikramdeep Monga","doi":"10.1039/D5MD00369E","DOIUrl":"10.1039/D5MD00369E","url":null,"abstract":"<p >In recent years, heat shock protein 90 (HSP90), a widely expressed molecular chaperone, has emerged as a promising anticancer target due to its crucial role in stabilizing and regulating the functions of numerous client proteins involved in various essential cellular processes, including protein folding, signalling pathways, and activation of tumor-associated proteins. Despite extensive developments, only one HSP90 inhibitor has gained approval, reflecting the complexity of the HSP90 chaperone machinery, associated side effects, and emergence of resistance mechanisms. To overcome these limitations, researchers have focused their attention on developing targeted protein degraders (TPDs), a revolutionary therapeutic approach that selectively eliminates specific dysregulated target proteins. TPDs exploit cellular degradation pathways, including the ubiquitin–proteasome system (UPS), lysosomal pathways, and autophagy to achieve precise protein degradation. Among these strategies, proteolysis-targeting chimeras (PROTACs) as well as HEMTAC/HIM-PROTACs have emerged as prominent UPS-based technologies. PROTACs link targets to E3 ligases for proteasomal removal, where HEMTACs exploit HSP90 to drive client ubiquitination, thereby offering significant potential for cancer therapeutics. Given HSP90's role in tumor progression and considering the potential of TPDs, researchers have designed and developed various HSP90-targeting PROTACs and HEMTAC/HIM-PROTACs, which exhibits remarkable efficacy, selectivity, antiproliferative potency, and the ability to overcome drug resistance. This review highlights the structural and biological functions of HSP90, delineates the mechanistic principles underlying its degradation, and summarizes the structure–activity relationships (SARs) inlcuding the synthetic strategies employed across different HSP90-directed TPD modalities. Furthermore, the challenges and opportunities associated with the utilization of HSP90 and their client proteins in developing TPDs-based therapeutics to tackle the unmet clinical needs in cancer have been discussed.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 12","pages":" 5964-5988"},"PeriodicalIF":3.597,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145346856","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":"Stick to the beads: supercharging medicinal chemistry and methodology development with ChemBeads","authors":"Noah P. Tu and Ying Wang","doi":"10.1039/D5MD00827A","DOIUrl":"10.1039/D5MD00827A","url":null,"abstract":"<p >This perspective explores the development, preparation, and widespread application of ChemBeads, a solid reagent delivery platform designed to overcome longstanding challenges in miniaturized and automated chemical experimentation. Originating from innovation at AbbVie, ChemBeads are formed by dry-coating active reagents onto inert carrier beads, transforming poorly flowing powders into uniform, flowable materials compatible with robotic and manual dispensing. Enabled by resonant acoustic mixing (RAM) or alternative techniques like vortex mixing, ChemBeads have streamlined high-throughput experimentation (HTE) and medicinal chemistry workflows. Their applications span a wide range of transformations including photoredox catalysis, cross-electrophile coupling, C–N and C–H functionalizations and late-stage oxidations. Industrial and academic case studies highlight the critical role of ChemBeads in accelerating the development of new synthetic methodologies that would have otherwise taken significantly longer to accomplish. By solving the long standing problem of material handling at a miniaturized scale with efficiency and generality, ChemBead technology formed the foundation of the AbbVie Discovery HTE platform and positioned us as one of the industry leaders in this field. Over the years, we expanded the technology to make it greatly accessible to academic institutions by making the process economically and operationally friendly. In parallel, we extended this technology in other areas, which ultimately promoted industry–academia collaborations. The technology's expansion into biocatalysis (EnzyBeads), solubility assays, and solid form screening further demonstrates its adaptability.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 1","pages":" 52-64"},"PeriodicalIF":3.597,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145482856","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":"Development of small molecule inhibitors of ECM collagen secretion","authors":"Ross S. Mancini, Pierre-Antoine Bissey, Leonardo Massignan, Vaijinath Mane, Donald F. Weaver, Kenneth W. Yip, Fei-Fei Liu and Mark A. Reed","doi":"10.1039/D5MD00284B","DOIUrl":"10.1039/D5MD00284B","url":null,"abstract":"<p >Tissue fibrosis is a common consequence of many different acute and chronic injuries, which severely impairs the function of affected organs. A significant challenge is the lack of effective strategies to treat fibrotic disorders. The metabolic dysregulation underlying fibrosis may be reversed by the small molecule caffeic acid phenethyl ester (CAPE), but there are limitations which prevent its clinical use. Following the identification of caffeic acid derivative <strong>1</strong> from an in-house library screen, we performed structure–activity relationship studies which led to the discovery of novel small molecule inhibitors of extracellular matrix (ECM) collagen secretion. The small molecules increased PPARG and CD36 expression (markers of fatty acid metabolism), suggesting a mechanism of action involving a metabolic shift from fibrotic-to-normal state. The compounds identified in this study provide a foundation for further development towards a novel, first-in-class therapeutic agent for fibrosis.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 12","pages":" 6010-6019"},"PeriodicalIF":3.597,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145302931","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":"Bacteriophage-mediated antibacterial and photodynamic therapies","authors":"Rui Yu, Guo-Bo Li, Bengui Ye, Jong Seung Kim, Xuechuan Hong, Yuling Xiao and Xiaodong Zeng","doi":"10.1039/D5MD00669D","DOIUrl":"10.1039/D5MD00669D","url":null,"abstract":"<p >Antimicrobial resistance threatens global health, with multidrug-resistant pathogens causing millions of deaths annually. Conventional antibiotics face limitations due to bacterial biofilms, resistance mechanisms, and host toxicity. Bacteriophages, due to their high specificity, hold great potential in antimicrobial therapy, targeted drug delivery. In recent years, advances in chemical biology and nanomaterials science have led to the continuous refinement of surface chemical modification strategies for bacteriophage capsids, providing robust support for their functional expansion. This review summarizes commonly employed bacteriophage surface modification techniques, including both covalent and non-covalent approaches, and categorizes various types of photosensitizers along with their recent progress in antimicrobial applications. Furthermore, it highlights recent studies on bacteriophage–photodynamic synergistic therapy systems in treating bacterial infections and discusses their application prospects and future directions in the field of precision antimicrobial therapy.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 12","pages":" 5873-5885"},"PeriodicalIF":3.597,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145329864","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":"Discovery of indole- and quinolone-based inhibitors of the mTOR/Akt/Pi3K pathway for the potential treatment of autism and certain types of cancer","authors":"Ahmad Elshahary, Hesham Safwan, Ahmad Abdelwaly, Reem K. Arafa and Mohamed A. Helal","doi":"10.1039/D5MD00641D","DOIUrl":"10.1039/D5MD00641D","url":null,"abstract":"<p >Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that belongs to the PI3K-related protein kinase family. It is an integral part of two functionally distinct protein complexes: mTOR complex 1 and mTOR complex 2. Its signaling pathway is linked to cell survival, growth, proliferation, and motility. Deregulation of the mTOR pathway has been reported in many types of cancer. Hence, mTOR is an attractive target for the treatment of certain cancers such as renal cell carcinoma and pancreatic tumors. In addition, hyperactivity in mTOR-mediated signaling is associated with the pathogenesis of autism spectrum disorder (ASD) and Alzheimer's disease. Recently, mTOR inhibitors have been considered as emerging pharmacotherapy for these disorders. In this research, we have used molecular modeling techniques to design three series of compounds, indoles, β-carbolines, and 4-aminoquinolines, targeting the ATP site of the mTOR kinase. Based on insights from molecular docking, we developed twenty eight derivatives of these scaffolds to explore the SAR and optimize their affinities. The prepared compounds were evaluated for their inhibitory activity against mTOR as well as other closely related kinases such as PI3K and AKt. To our delight, twenty compounds have shown sub-micromolar activities towards the mTOR kinase. Compounds <strong>HA-2l</strong> and <strong>HA-2c</strong> showed a superior IC<small>₅₀</small> of 66 and 75 nM, respectively, for mTOR, while being selective against AKt and Pi3K. Upon optimization, these selective inhibitors could be useful for the management of ASD due to their relatively higher safety and, hence, suitability for long-term use. On the other hand, derivatives <strong>HA-1e</strong>, <strong>HA-2g</strong>, and <strong>HA-3d</strong> exhibited high affinities for the three enzymes, suggesting their potential utility as anticancer agents. Also, the cytotoxicity of the most active compounds was assessed using different cell-lines. Compounds <strong>HA-2g</strong>, <strong>HA-2l</strong>, and <strong>HA-3d</strong> showed sub-micromolar inhibition, in the range of 0.610–0.780 μM, against the tested cancer cell lines MDA-MB231 and HCT-116. The discovery of a clinically useful mTOR inhibitor would represent a new hope for patients of two important non-communicable diseases, cancer and ASD.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 1","pages":" 245-262"},"PeriodicalIF":3.597,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145550423","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":"Analysis of two screens reveals a correlation between antiamoebic and anti-tubulin activities of phenothiazine and triphenylethylene derivatives","authors":"Oleg Mediannikov and Philipp O. Tsvetkov","doi":"10.1039/D5MD00715A","DOIUrl":"10.1039/D5MD00715A","url":null,"abstract":"<p > <em>Naegleria fowleri</em> (<em>N.f.</em>), commonly referred to as the “brain-eating amoeba”, is a free-living amoeboflagellate excavate capable to cause primary amoebic meningoencephalitis (PAM)—a rapidly progressing and typically fatal brain infection. Current treatment options are limited, poorly effective, and highly toxic, underscoring the urgent need for novel therapeutics. In this study, we explore the potential of repurposing FDA-approved microtubule-targeting agents (MTAs) for anti-<em>N.f.</em> therapy. By performing a comparative analysis of two large-scale drug screens—one assessing anti-amoebic activity and the other evaluating effects on tubulin polymerization—we identify strong correlations between microtubule disruption and amoebic growth inhibition. Notably, we highlight three major drug families (triphenylethylene, phenothiazine, and miconazole derivatives) and describe how their anti-amoebic effects relate to their MTA activity. In particular, triphenylethylene and phenothiazine compounds demonstrate a high positive correlation between tubulin polymerization inhibition and <em>N.f.</em> suppression, suggesting a shared molecular mechanism. Furthermore, we identify potent MTAs such as ebselen and auranofin—both capable of crossing the blood–brain barrier—as promising candidates for repurposing. These findings demonstrate the value of MTA-based screening in anti-amoebic drug discovery and point toward new therapeutic avenues for treating this devastating disease.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 11","pages":" 5359-5363"},"PeriodicalIF":3.597,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252455","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}