MedChemComm最新文献

{"title":"Investigating the role of cytochrome bd oxidases in the antibacterial activity of madecassic acid and derivatives thereof","authors":"Samantha A. Henry, Geraud N. Sansom, Thao Thi Phuong Tran, Ryan A. Boughton, Guy Joiner, Calum M. Webster, H. Ireshika C. de Silva, Michelle D. Garrett, Christopher J. Serpell, Gary K. Robinson and Mark Shepherd","doi":"10.1039/D5MD01116G","DOIUrl":"10.1039/D5MD01116G","url":null,"abstract":"<p >Natural products are valuable starting points for drug discovery, although individual modes of action are often difficult to pin down. Ursanes such as madecassic acid have been shown to have antibacterial properties, but a variety of mechanisms have been proposed. In this paper, we report previously uninvestigated activity against cytochrome <em>bd</em> oxidases which are only found in prokaryotes and are therefore promising new targets, using madecassic acid and a set of synthetically modified derivatives. Our work shows that madecassic acid and its derivatives can block activity of these enzymes, while phenotypic effects in membrane and whole organism assays are more complex, consistent with modulation of multiple pathways depending upon molecular structure. This provides a new route to ursane-based antibacterial action while highlighting the importance of chemical modifications in fine-tuning biological activity of natural products.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 3","pages":" 1513-1520"},"PeriodicalIF":3.597,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12822377/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030599","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":"Microwave-assisted single-step synthesis of cyclic and acyclic β-aminosulfones and evaluation of their antifungal activity targeting CYP51","authors":"Abigail Bibiana Pinheiro, Soumik Saha, Madhuri Madduri, Utpal Roy, Lakshmi Sudhir Menon, Sumit Biswas, Amrita Chatterjee and Mainak Banerjee","doi":"10.1039/D5MD00907C","DOIUrl":"10.1039/D5MD00907C","url":null,"abstract":"<p >The alarming rise of drug resistance has created an urgent need for novel antifungal agents. On the other hand, growing environmental concerns necessitate the development of sustainable alternatives to conventional synthetic methods for active pharmaceutical ingredients (APIs). β-Aminosulfones represent a potent yet underexplored functionality in biologically active compounds. In this work, a series of β-aminosulfone derivatives, designed as potential antifungal agents, were synthesized <em>via</em> a one-step, reagent-free, catalyst-free double aza-Michael addition of 2-aminobenzothiazoles, biogenic amines, or aromatic amines with different vinyl sulfones. The reactions were carried out in water under microwave irradiation (150 °C, 10 min), affording β-aminosulfones in excellent yields by simple filtration, without the need for further work-up or purification. This cost-effective process makes the production cost comparable to raw materials (<em>e.g.</em>, compound <strong>3d</strong> at $3.43 per g). Molecular docking, performed using the Glide module of the Schrödinger suite, revealed potential inhibitory activity against the fungal target CYP51 (PDB ID: 5V5Z), with reasonably good docking scores ranging from −5.69 to −8.25 kcal mol<small>⁻¹</small> for benzothiazole derivatives and −5.73 to −7.05 kcal mol<small>⁻¹</small> for biogenic amines. <em>In silico</em> ADMET profiling of selected compounds indicated promising drug-like attributes, satisfying Lipinski's rule. β-Aminosulfones were screened for their <em>in vitro</em> antifungal activity against various <em>Candida</em> species, and they exhibited MIC values ranging from 16 to 64 μg mL<small>⁻¹</small>. Notably, one compound (<strong>3d</strong>, 0.051 μM) showed comparable potency to fluconazole (0.052 μM) against <em>Candida glabrata</em>. Through ergosterol depletion assays, the mechanism of antifungal activity could be linked to the CYP51 inhibition pathway. Although these compounds exhibited moderate docking scores against 1KZN for antibacterial activity (−3.96 to −5.63 kcal mol<small>⁻¹</small>), the spot test revealed insignificant inhibition. Cytotoxicity studies with selected molecules revealed that these aza-sulfones are non-toxic to human cells, encouraging further studies with β-aminosulfone scaffolds.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 2","pages":" 1083-1098"},"PeriodicalIF":3.597,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12784295/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145952929","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":"Design and optimization of simplified inhibitors targeting Escherichia coli and Klebsiella pneumoniae IspE","authors":"Danica J. Walsh, Rawia Hamid, Tim Giele, Norbert Reiling, Matthias Rottmann, Mostafa M. Hamed and Anna K. H. Hirsch","doi":"10.1039/D5MD00874C","DOIUrl":"10.1039/D5MD00874C","url":null,"abstract":"<p >The methylerythritol phosphate (MEP) pathway is essential for isoprenoid biosynthesis in many pathogenic bacteria but is absent in humans, making its enzymes attractive antibacterial targets. IspE catalyzes the ATP-dependent phosphorylation of 4-diphosphocytidyl-2-<em>C</em>-methylerythritol, a key step in this pathway. Using a previously identified optimized hit as a starting point, we designed and synthesized a focused library of twelve simplified analogues that retained essential pharmacophoric features while improving synthetic accessibility. Docking studies with <em>Escherichia coli</em> IspE guided the design and predicted binding orientations consistent with known ligand interactions. Biochemical evaluation of the library against <em>E. coli</em> and <em>Klebsiella pneumoniae</em> IspE revealed several low-micromolar inhibitors, confirming the predicted binding interactions. Structure–activity relationships indicated that the hydrophobic pocket adjacent to the cytidine-binding region is a key determinant of potency. Although the compounds showed limited whole-cell activity, these results demonstrate that simplified amide analogues can effectively engage the IspE active site and highlight the importance of the hydrophobic pocket in ligand binding. Overall, this work combines structure-based design, synthesis, and biochemical validation to provide a foundation for further optimization of simplified IspE inhibitors as potential antibacterial leads.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 3","pages":" 1687-1693"},"PeriodicalIF":3.597,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12902931/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146202508","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":"Crystallographic characterisation and development of bi-substrate inhibitors of coronavirus nsp14 methyltransferase","authors":"Irene Georgiou, Colin Robinson, Sean N. O'Byrne, Alex Matsuda, Przemysław Grygier, Craig D. Smith, Sandra O'Neill, Shamshad A. Ahmad, Suzanne Norval, John M. Post, Mirjam Groenewold, Nadya Urakova, Patrick Wanningen, Leanid Kresik, Jacek Plewka, Adrien Delpal, Kexin See, Thomas Eadsforth, Kinga Wierzbicka, Etienne Decroly, Kumar Singh Saikatendu, Edcon Chang, Eric J. Snijder, Krzysztof Pyrć, Anna Czarna, Duncan E. Scott and Ian H. Gilbert","doi":"10.1039/D5MD00896D","DOIUrl":"10.1039/D5MD00896D","url":null,"abstract":"<p >SARS-CoV-2 non-structural protein 14 (nsp14) is essential for viral mRNA cap guanine-N7 methylation and represents a promising but underexplored antiviral target. Herein we describe a structure-guided campaign based on a hit from a focussed SAM mimetic library. Systematic SAR exploration guided by six X-ray co-crystal structures in complex with SARS-CoV-2 led to compound <strong>26</strong>, a bi-substrate inhibitor that bridges the SAM and RNA cap binding sites. Compound <strong>26</strong> achieved nanomolar potency against nsp14 from SARS-CoV-2 (IC<small>₅₀</small> = 53 nM), SARS-CoV-1, and two alphacoronaviruses, with excellent selectivity over human RNMT and flaviviral MTase. In general, the compounds demonstrated favourable metabolic stability, passive permeability, and no HepG2 cytotoxicity. However, cellular antiviral activity was limited, revealing disconnects between enzyme inhibition and phenotypic response. These findings provide a structural framework for optimizing bi-substrate methyltransferase inhibitors against coronaviruses with a view for pan-coronaviral activity.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 2","pages":" 1015-1030"},"PeriodicalIF":3.597,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145918429","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":"Dual COX-2 and EGFR inhibition by pyrazole–ar-turmerone hybrids suppresses colorectal cancer cell proliferation","authors":"Monsin Sangsawat, Nonthaneth Nalinratana, Waraluck Chaichompoo, Opa Vajragupta, Hua Zhu, Yilin Song, Worathat Thitikornpong and Pornchai Rojsitthisak","doi":"10.1039/D5MD00901D","DOIUrl":"10.1039/D5MD00901D","url":null,"abstract":"<p >Colorectal cancer (CRC) progression involves a coordinated interaction between COX-2-mediated inflammation and EGFR-driven proliferation. Current monotherapies often fail due to incomplete pathway suppression and resistance development, highlighting the need for multi-targeted strategies. This study aimed to design and synthesize novel pyrazole–<em>ar</em>-turmerone hybrids capable of simultaneously inhibiting COX-2 and EGFR, thereby achieving enhanced anti-proliferative efficacy in inflammation-associated colorectal cancer. Two hybrid molecules (compounds <strong>1</strong> and <strong>2</strong>) were synthesized and characterized. Their dual-target potential was evaluated <em>in silico</em> using network pharmacology and molecular docking against COX-2 and EGFR crystal structures. <em>In vitro</em> assays in IL-1β-stimulated HT-29 colorectal cancer cells were used to assess anti-proliferative effects by MTT, clonogenic, and CFSE flow cytometry analyses. Mechanistic studies were performed through Western blotting and PGE<small>₂</small> ELISA/rescue experiments to examine inhibition of COX-2 activity and EGFR–ERK1/2 signaling. Both compounds showed high COX-2 selectivity (SI = 14.38 and 23.57) and potent COX-2 inhibition (IC<small>₅₀</small> = 0.63 and 1.04 μM), together with EGFR kinase inhibition (IC<small>₅₀</small> = 37.56 and 57.56 μM). Both hybrids exhibited low cytotoxicity yet significantly suppressed IL-1β-induced HT-29 cell proliferation, with GI<small>₅₀</small> values of 5.85 μM (compound <strong>1</strong>) and 9.57 μM (compound <strong>2</strong>). Mechanistic analysis confirmed reduced PGE<small>₂</small> production, inhibition of EGFR–ERK1/2 activation, and downregulation of cyclin D1 and PCNA expression. The pyrazole–<em>ar</em>-turmerone hybrids function as potent dual COX-2/EGFR inhibitors exhibiting selective anti-proliferative activity in inflammation-driven CRC. These compounds represent promising leads for the development of next-generation dual-target therapeutics against colorectal cancer therapy.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 2","pages":" 1000-1014"},"PeriodicalIF":3.597,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145912801","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 progress of METTL3 inhibitors for cancer therapeutics: design, optimization and potential applications","authors":"Yun Zhang, Mengxiang Quan, Qinlan Chen, Hongdi Han, Xianling Zhang, Xiangwei Xu and Zunyuan Wang","doi":"10.1039/D5MD00867K","DOIUrl":"10.1039/D5MD00867K","url":null,"abstract":"<p >Acute myeloid leukaemia (AML) is a clonal proliferative malignant hematologic disease of hematopoietic stem cells, characterized by the accumulation of immature progenitor cells and the inhibition of hematopoietic function due to blocked differentiation, which is a genetically heterogeneous and dynamic disease and the most common type of leukemia in adults. Studies have shown that methyltransferase-like protein 3 (METTL3) is highly expressed in AML cells, regulating methylation modifications that drive the development of leukemia. This discovery has become a major breakthrough in the treatment of AML, as it is possible to address common issues in current chemotherapy, such as drug resistance, by developing METTL3 inhibitors. This review summarizes the strategies for discovering and optimizing the medicinal chemistry of METTL3 inhibitors, provides a reference for future drug development, and looks forward to the potential application prospects of METTL3 inhibitors in clinical practice.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 3","pages":" 1289-1298"},"PeriodicalIF":3.597,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030675","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":"Novel isoxazolone derivatives as acetylcholinesterase inhibitors: design, synthesis, in silico and in vitro evaluation","authors":"Nitasha Gohar, Adil Saeed, Muzaffar Abbas, Sana Ayaz, Iqra Zulfiqar, Syed Muzzammil Masaud and Humaira Nadeem","doi":"10.1039/D5MD00890E","DOIUrl":"10.1039/D5MD00890E","url":null,"abstract":"<p >Acetylcholinesterase (AChE) plays a pivotal role in Alzheimer's disease by accelerating acetylcholine breakdown, leading to cognitive decline. In this study, a series of novel isoxazolone derivatives were synthesized and structurally characterized using spectroscopic methods. The compounds were evaluated for their AChE inhibitory activity, where several candidates demonstrated stronger inhibition than the standard drug Donepezil. Molecular docking supported these findings, highlighting favorable interactions within the enzyme's active site. Selected compounds also exhibited promising antioxidant properties in the DPPH assay. A developed QSAR model provided insights into structural features contributing to bioactivity. <em>In silico</em> ADMET profiling indicated drug-like behavior, and molecular dynamics simulations confirmed the stability of the top ligand–enzyme complexes. Collectively, the results underscore the potential of isoxazolone-based scaffolds as multifunctional agents for managing Alzheimer's disease. Further biological evaluation is recommended to explore their therapeutic applicability.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 3","pages":" 1600-1618"},"PeriodicalIF":3.597,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146142191","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":"Ferrocenyl ferroptosis inducers as an emerging class of anticancer agents: a mini review","authors":"Mateusz Klarek, Aryan Gautam and Konrad Kowalski","doi":"10.1039/D5MD00935A","DOIUrl":"10.1039/D5MD00935A","url":null,"abstract":"<p >Ferroptosis is one of the regulated cell death pathways. Molecular mechanisms underlying ferroptosis involve iron-dependent lipid peroxidation, which results in cell-deleterious membrane damage. Ferroptosis-inducing agents have been identified as attractive candidates for anticancer drug development as they can bypass drug resistance in cancer cells. Among pro-ferroptotic agents are many organometallic complexes, including ferrocenyl compounds. In this review, we demonstrate that suitably designed ferrocene-containing molecules can induce ferroptosis in different cancer cell types both <em>in vitro</em> and <em>in vivo</em>. Their pro-ferroptotic activity is triggered by diverse initiating factors through different mechanisms (<em>e.g.</em> redox activation, thermal and light activation, and GPX4 inhibition combined with ROS overproduction). Moreover, ferrocenyl bioconjugates are often cancer-cell-selective and trigger ferroptosis in combination with other regulated cell-death pathways, such as apoptosis and immunogenic cell death. Dual or multimodal anticancer activity mechanisms are sought after in modern anticancer therapy approaches as they help to overcome the problem of drug resistance. Research on ferrocene-based ferroptosis inducers, however, is still in the early stage. Hence, more time and effort are needed to fully elucidate the potential of ferrocenes as ferroptosis initiators in cancer therapy.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 3","pages":" 1252-1270"},"PeriodicalIF":3.597,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145998948","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":"Mitochondria-targeting symmetric diiminoguanidines: potent and selective anticancer agents against pancreatic tumors","authors":"Sigrid Lacaille and Andreea R. Schmitzer","doi":"10.1039/D5MD00808E","DOIUrl":"10.1039/D5MD00808E","url":null,"abstract":"<p >Pancreatic cancer remains one of the deadliest malignancies of the 21st century, with a five-year survival rate below 12%. Its growing incidence is strongly linked to modern lifestyles, marked by obesity, diabetes, overnutrition, and physical inactivity. Current chemotherapies offer limited success and are often burdened by severe side effects, highlighting the urgent need for more effective and selective treatments. In response, we have developed a new class of easily synthesized, amphiphilic symmetric diiminoguanidines and evaluated their antiproliferative activity against pancreatic cancer cell lines. Several compounds demonstrated remarkable efficacy and selectivity, positioning them as strong candidates for further <em>in vivo</em> evaluation. Fluorescence microscopy revealed that these molecules rapidly localize into mitochondria. Preliminary mechanistic studies suggest their primary target is the mitochondrial respiratory chain. These findings support the potential of diiminoguanidines as affordable, mitochondria-targeting alternatives to existing pancreatic cancer therapies.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 2","pages":" 1099-1106"},"PeriodicalIF":3.597,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12784416/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145952963","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":"An overview of recent advancements in targeted cancer therapies and their potential clinical impact","authors":"Shujauddin Ahmed, Akash P. Sakla, Kousar Jahan, Naziya Neshat, Mymoona Akhter, Shams Aaghaz and Ahmed Kamal","doi":"10.1039/D5MD00740B","DOIUrl":"10.1039/D5MD00740B","url":null,"abstract":"<p >Recent advances in medicine and drug development have significantly changed how cancer is treated. The success of inhibitors like sotorasib and adagrasib has expanded options for targeting once ‘undruggable’ oncogenic drivers such as KRAS. The emergence of RET and NTRK inhibitors shows the increasing importance of targeted therapies. Recent developments in immunotherapy include new immune checkpoint inhibitors (LAG-3, TIGIT, and TIM-3), which enhance the efforts to combat cancers that evade immune detection. ADCs such as EMRELIS™, Datroway, and ELAHERE™ offer precise targeting along with potent cytotoxic agents. Protein degradation strategies, using the ubiquitin–proteasome system, provide new ways to remove oncogenic proteins through PROTACs and molecular glues. Epigenetic drugs such as IDH and EZH2 inhibitors seek to correct transcriptional dysregulation in cancer. New tactics to overcome resistance, including EGFR C797S inhibitors and combination therapies, aim to improve treatment durability. Cancer vaccine research is progressing with licensed immunoprophylactic drugs, and AI tools like AlphaFold are speeding up drug discovery by enhancing structural biology predictions. This review covers recent cancer therapeutics advancements, including targeted inhibitors, immunotherapies, resistance strategies, epigenetic interventions, combination therapies, vaccines, and AI applications.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 2","pages":" 784-805"},"PeriodicalIF":3.597,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145952982","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}