MedChemComm最新文献

{"title":"Donepezil-based rational design of N-substituted quinazolinthioacetamide candidates as potential acetylcholine esterase inhibitors for the treatment of Alzheimer's disease: in vitro and in vivo studies†","authors":"Ahmed A. Al-Karmalawy, Ahmed F. Mohamed, Heba Nasr Shalaby, Ayman Abo Elmaaty, Riham A. El-Shiekh, Mohamed A. Zeidan, Radwan Alnajjar, Abdullah Yahya Abdullah Alzahrani, Mohammed H. AL Mughram, Moataz A. Shaldam and Haytham O. Tawfik","doi":"10.1039/D4MD00778F","DOIUrl":"10.1039/D4MD00778F","url":null,"abstract":"<p >Alzheimer's disease (AD) stands as one of the most outstanding progressive neurodegenerative disorders. Obviously, acetylcholine esterase (AChE) is the primary enzyme responsible for breaking down acetylcholine (ACh) with a much more prominent effect than butyrylcholine esterase (BuChE). Hence, novel quinazoline derivatives (<strong>3a–p</strong>) were designed and synthesized as AChE inhibitors for AD treatment. The newly synthesized quinazoline derivatives (<strong>3a–p</strong>) were pursued for their inhibitory potential towards both AChE and BuChE. Notably, compound <strong>3e</strong> displayed the highest inhibitory potential towards AChE (IC<small>₅₀</small> = 9.26 nM) surpassing donepezil (IC<small>₅₀</small> = 16.43 nM). On the other side, compound <strong>3e</strong> effectively negated the decline in memory acquisition and retention instigated by ICV administration of streptozotocin (STZ) in mice, an effect that was comparable to that produced by donepezil. Moreover, compound <strong>3e</strong>, reduced BACE1 by 51.08% (<em>p</em> &lt; 0.0001), Aβ42 by 52.47% (<em>p</em> &lt; 0.0001), and p(Ser199)-tau by 69.16% (<em>p</em> &lt; 0.0001) compared to STZ mice. Such effects were similar to those of donepezil which reduced all 3 parameters by 57.53%, 58.5%, and 66.78%, respectively, compared to STZ mice. Furthermore, molecular docking studies showed that the superimposition view clarified the similar binding mode of both <strong>3e</strong> and the co-crystallized donepezil at the AChE binding pocket. Moreover, the docked complexes (<strong>3e</strong>-AChE and <strong>3e</strong>-BuChE) were further subject to molecular dynamics simulations for 100 ns. In addition, eligible pharmacokinetic profiles as well as feasible BBB penetration were anticipated for compound <strong>3e</strong> using ADME and BBB permeation prediction studies. Accordingly, the synthesized compounds, in particular compound <strong>3e</strong>, can be treated as promising lead compounds for AD treatment with future further optimization.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 5","pages":" 2078-2097"},"PeriodicalIF":3.597,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143543021","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 in vitro evaluations of new cyclotriphosphazenes as safe drug candidates†","authors":"Elif Yıldız Gül, Büşra Tiryaki, Buse Köse, Nuri Öztürk, Elif Okutan, Burcu Dedeoğlu and Esra Tanrıverdi Eçik","doi":"10.1039/D4MD00885E","DOIUrl":"10.1039/D4MD00885E","url":null,"abstract":"<p >Although it is possible to discover new drug candidate molecules using <em>in silico</em> approaches, chemical synthesis followed by screening of their functions is still at the center of bioactive molecule discovery. While determining the potential effects of compounds on target signaling molecules or pathways, assessing their effects on the circadian rhythm is also very important for determining the efficacy of drug candidates because they control most of the signaling pathways. Herein, new members of the biocompatible cyclotriphosphazene family were prepared, and their <em>in vitro</em> biological activities and effects on circadian rhythm were evaluated for the first time. In particular, new cyclotriphosphazene derivatives carrying morpholine, thiomorpholine and triazole groups were designed and synthesized, and their chemical structures were characterized using appropriate spectroscopic methods. Cellular toxicity analyses of the compounds were performed using different biological methods, such as determination of IC<small>₅₀</small> values, calculation of population doubling times, and colony formation patterns. Subsequently, the effects of the compounds on the cell cycle were analyzed using the flow cytometry technique. Finally, the effects of the synthesized compounds on circadian rhythm were determined using a real-time bioluminescence approach. Based on these studies, it was determined that some compounds demonstrated varying degrees of antiproliferative activity, with the most potent compounds causing G<small>₂</small>/M phase arrest. Additionally, most derivatives had no adverse effects on the circadian rhythm, indicating their potential for safe therapeutic application in targeting cell proliferation. Furthermore, an important pharmacological characteristic of the drug candidate molecules, namely, membrane permeability in terms of log <em>P</em> values, was assessed. In conclusion, these novel cyclotriphosphazene-based compounds are a class of circadian rhythm-safe drug candidate compounds.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 5","pages":" 2061-2077"},"PeriodicalIF":3.597,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542976","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":"Small molecule targeted protein degradation via the UPS: venturing beyond E3 substrate receptors","authors":"Renyu Guo, Fukang Yang and Emily C. Cherney","doi":"10.1039/D4MD00718B","DOIUrl":"10.1039/D4MD00718B","url":null,"abstract":"<p >The ubiquitin proteasome system (UPS) has been successfully hi-jacked by both bifunctional and monovalent small molecules to affect the degradation of proteins that were once considered undruggable. This field has primarily focused on the targeted recruitment of proteins to substrate receptors on E3 ubiquitin ligases, which are only one part of the UPS. More recently, the field has begun to explore recruitment to other types of UPS proteins including E2 ubiquitin-conjugating enzymes, substrate adaptor proteins within the E3 complex, chaperone proteins that associate with E3s, proteasomal subunits, and proteasome-associated proteins. While these approaches are relatively nascent compared to more traditional E3 substrate receptor-based degradation, these approaches are starting to show promise and could offer unique advantages. This review will cover key findings in small molecule UPS-mediated targeted protein degradation (TPD) affected by co-opting proteins beyond traditional E3 substrate receptors.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 5","pages":" 1865-1878"},"PeriodicalIF":3.597,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143415093","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":"Insights from protein frustration analysis of BRD4–cereblon degrader ternary complexes show separation of strong from weak degraders†","authors":"Tianyi Yang, Elizaveta Mukhaleva, Wenyuan Wei, Dahlia Weiss, Ning Ma, Veerabahu Shanmugasundaram and Nagarajan Vaidehi","doi":"10.1039/D4MD00962B","DOIUrl":"10.1039/D4MD00962B","url":null,"abstract":"<p >PROteolysis TArgeting Chimeras (PROTACs), also known as ligand-directed degraders (LDDs), are an innovative class of small molecules that leverage the ubiquitin–proteasome system to induce the degradation of target proteins. Structure based design methods are not readily applicable for designing LDDs due to the dynamic nature of the ternary complexes. This study investigates the dynamic properties of five LDD-mediated BRD4–cereblon complexes, focusing on the challenges of evaluating linker efficiency due to the difficulty in identifying suitable computational metrics that correlate well with the cooperativity or degradation propensity of LDDs. We uncovered that protein frustration, a concept originally developed to understand protein folding, calculated for the residues in the protein–protein interface of the LDD-mediated ternary complexes recapitulate the strength of degradation of the LDDs. Our findings indicated that hydrophobic residues in the interface are among the highly frustrated residues pairs, and they are crucial in distinguishing strong degraders from weak ones. By analyzing frustration patterns, we identified key residues and interactions critical to the effectiveness of the ternary complex. These insights provide practical guidelines for designing and prioritizing more efficient degraders, paving the way for the development of next-generation LDDs with improved therapeutic potential.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 4","pages":" 1818-1828"},"PeriodicalIF":3.597,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515777","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":"Site-specific molecular glues for the 14-3-3/Tau pS214 protein–protein interaction via reversible covalent imine tethering†","authors":"Ansgar Oberheide, Maxime C. M. van den Oetelaar, Jakob J. A. Scheele, Jan Borggräfe, Semmy F. H. Engelen, Michael Sattler, Christian Ottmann, Peter J. Cossar and Luc Brunsveld","doi":"10.1039/D4MD00833B","DOIUrl":"10.1039/D4MD00833B","url":null,"abstract":"<p >Protein–protein interactions (PPIs) are key regulators of various cellular processes. Modulating PPIs with small molecules has gained increasing attention in drug discovery, particularly targeting the 14-3-3 protein family, which interacts with several hundred client proteins and plays a central role in cellular networks. However, targeting a specific PPI of the hub protein 14-3-3, with its plethora of potential client proteins, poses a significant selectivity challenge. This not only involves the selectivity of 14-3-3 PPIs with other client proteins, but also the selective stabilization of a specific 14-3-3 binding site within a protein partner featuring several binding sites. The interaction of 14-3-3 with Tau, characterized by different phospho-site driven binding modes, forms a valuable, disease-relevant, 14-3-3 multivalent model PPI to explore this selectivity issue. This work presents the identification and early-stage optimization of small molecule fragment-like stabilizers for a specific binding site of the 14-3-3/Tau PPI. Using different biophysical assays, the stabilizing potency of the imine-bond forming molecules was mapped and X-ray crystallography studies provided structural data on the binding mode of the ternary complexes. Exploiting the unique topologies and functionalities of the different binding sites enabled the engineering of selectivity for this initial molecular glue matter for the pS214 binding site, over a second 14-3-3 binding site in Tau (pS324). These reversible covalent tool compounds will allow for the further exploration of the role of 14-3-3 in Tau aggregation.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 5","pages":" 2190-2201"},"PeriodicalIF":3.597,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11892739/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143606224","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":"Identification of a novel allosteric binding site on the catalytic domain of NF-κB inducing kinase (NIK)†","authors":"Jared J. Anderson and Daniel A. Harki","doi":"10.1039/D4MD00963K","DOIUrl":"10.1039/D4MD00963K","url":null,"abstract":"<p >NF-κB inducing kinase (NIK) is the central regulatory component of noncanonical NF-κB signalling and has been implicated in a variety of cancers and immune disorders. While NIK has been pursued as a target for such diseases through the design of orthosteric inhibitors, these inhibitors have not resulted in an approved drug. To develop new modalities for NIK-targeting by small molecules, we recently reported a class of chromanol fragments that bind to an unknown allosteric site on the catalytic domain of NIK. Here we report the design of a covalent probe to identify the location of this allosteric binding site. Acrylamide probe <strong>2</strong> (<em>K</em><small>_d</small>: 24.5 μM) was determined to specifically adduct C573 out of 11 total cysteines on the catalytic domain of NIK, thereby identifying the allosteric binding site of our developed ligands.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 4","pages":" 1681-1685"},"PeriodicalIF":3.597,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483518","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":"Recent advancements in the development of next-generation dual-targeting antibacterial agents","authors":"Firdoos Ahmad Sofi, Mayank, Mubashir H. Masoodi and Nahida Tabassum","doi":"10.1039/D4MD00934G","DOIUrl":"10.1039/D4MD00934G","url":null,"abstract":"<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":88,"journal":{"name":"MedChemComm","volume":" 5","pages":" 1891-1922"},"PeriodicalIF":3.597,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143543256","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":"Correction: 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. 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/D5MD90004B","DOIUrl":"10.1039/D5MD90004B","url":null,"abstract":"<p >Correction for ‘Chiral hydroxymethyl-1<em>H</em>,3<em>H</em>-pyrrolo[1,2-<em>c</em>]thiazoles: the search for selective p53-activating agents for colorectal cancer therapy’ by Mees M. Hendrikx <em>et al.</em>, <em>RSC Med. Chem.</em>, 2024, <strong>15</strong>, 1652–1663, https://doi.org/10.1039/D4MD00076E.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 2","pages":" 970-970"},"PeriodicalIF":3.597,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11788826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143190274","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":"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 and Patrick G. Steel","doi":"10.1039/D4MD01004C","DOIUrl":"10.1039/D4MD01004C","url":null,"abstract":"<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 <em>selectivity</em> and show comparable efficacy in a mouse model of <em>Leishmania amazonensis</em> infection.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 4","pages":" 1686-1694"},"PeriodicalIF":3.597,"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":0,"RegionCategory":"","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 and Hongzhe Sun","doi":"10.1039/D4MD00860J","DOIUrl":"10.1039/D4MD00860J","url":null,"abstract":"<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 <em>Helicobacter pylori</em>, 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 <em>Staphylococcus aureus</em> (MRSA). Moreover, the combination of hinokitiol and CBS exhibits anti-biofilm activity by preventing biofilm formation and eliminating <em>S. aureus</em> 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(<small>III</small>)) 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":88,"journal":{"name":"MedChemComm","volume":" 4","pages":" 1829-1841"},"PeriodicalIF":3.597,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143543252","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}