MedChemComm最新文献

{"title":"Introduction to the themed collection in honour of Professor Christian Leumann","authors":"Marcel Hollenstein and Eugen Stulz","doi":"10.1039/D4MD90039A","DOIUrl":"10.1039/D4MD90039A","url":null,"abstract":"<p >A graphical abstract is available for this content</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 11","pages":" 3636-3638"},"PeriodicalIF":3.597,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142507036","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: computational design, synthesis, and assessment of 3-(4-(4-(1,3,4-oxadiazol-2-yl)-1H-imidazol-2-yl)phenyl)-1,2,4-oxadiazole derivatives as effective epidermal growth factor receptor inhibitors: a prospective strategy for anticancer therapy","authors":"Nilesh Raghunath Khedkar, Milind Sindkhedkar and Alex Joseph","doi":"10.1039/D4MD90040E","DOIUrl":"10.1039/D4MD90040E","url":null,"abstract":"<p >Correction for ‘Computational design, synthesis, and assessment of 3-(4-(4-(1,3,4-oxadiazol-2-yl)-1<em>H</em>-imidazol-2-yl)phenyl)-1,2,4-oxadiazole derivatives as effective epidermal growth factor receptor inhibitors: a prospective strategy for anticancer therapy’ by Nilesh Raghunath Khedkar <em>et al.</em>, <em>RSC Med. Chem.</em>, 2024, <strong>15</strong>, 1626–1639, https://doi.org/10.1039/D4MD00055B.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 11","pages":" 3912-3912"},"PeriodicalIF":3.597,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11474806/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473752","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":"Therapeutic upregulation of DNA repair pathways: strategies and small molecule activators","authors":"Juhyung Song, Cheoljun Park, Francis E. B. Cabanting and Yong Woong Jun","doi":"10.1039/D4MD00673A","DOIUrl":"10.1039/D4MD00673A","url":null,"abstract":"<p >DNA repair activity diminishes with age and genetic mutations, leading to a significantly increased risk of cancer and other diseases. Upregulating the DNA repair system has emerged as a potential strategy to mitigate disease susceptibility while minimizing cytotoxic side effects. However, enhancing DNA repair activity presents significant challenges due to the inherent inefficiency in activator screening processes. Additionally, pinpointing a critical target that can effectively upregulate overall repair processes is complicated as the available information is somewhat sporadic. In this review, we discuss potential therapeutic targets for upregulating DNA repair pathways, along with the chemical structures and properties of reported small-molecule activators. We also elaborate on the diverse mechanisms by which these targets modulate repair activity, highlighting the critical need for a comprehensive understanding to guide the development of more effective therapeutic strategies.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 12","pages":" 3970-3977"},"PeriodicalIF":3.597,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473779","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":"Introduction to the themed collection on ‘AI in Medicinal Chemistry’","authors":"Jian Zhang, Ola Engkvist and Gerhard Hessler","doi":"10.1039/D4MD90035A","DOIUrl":"https://doi.org/10.1039/D4MD90035A","url":null,"abstract":"<p >A graphical abstract is available for this content</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 10","pages":" 3284-3285"},"PeriodicalIF":3.597,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142443210","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":"Pathogenesis of Alzheimer's disease and therapeutic strategies involving traditional Chinese medicine","authors":"Shutang Li and Jinfei Yang","doi":"10.1039/D4MD00660G","DOIUrl":"10.1039/D4MD00660G","url":null,"abstract":"<p >Alzheimer's disease (AD) is a prevalent degenerative disorder affecting the central nervous system of the elderly. Patients primarily manifest cognitive decline and non-cognitive neuro-psychiatric symptoms. Currently, western medications for AD primarily include cholinesterase inhibitors and glutamate receptor inhibitors, which have limited efficacy and accompanied by significant toxic side effects. Given the intricate pathogenesis of AD, the use of single-target inhibitors is limited. In recent years, as research on AD has progressed, traditional Chinese medicine (TCM) and its active ingredients have increasingly played a crucial role in clinical treatment. Numerous studies demonstrate that TCM and its active ingredients can exert anti-Alzheimer's effects by modulating pathological protein production and deposition, inhibiting tau protein hyperphosphorylation, apoptosis, inflammation, and oxidative stress, while enhancing the central cholinergic system, protecting neurons and synapses, and optimizing energy metabolism. This article summarizes extracts from TCM and briefly elucidates their pharmacological mechanisms against AD, aiming to provide a foundation for further research into the specific mechanisms of TCM in the prevention and treatment of the disease, as well as the identification of efficacious active ingredients.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 12","pages":" 3950-3969"},"PeriodicalIF":3.597,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473776","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 a nasal spray steroid, tixocortol, as an inhibitor of SARS-CoV-2 main protease and viral replication†","authors":"David A. Davis, Ashwin Nair, Yana Astter, Emma Treco, Brian Peyser, Rick Gussio, Tam Nguyen, Brett Eaton, Elena Postnikova, Michael Murphy, Prabha Shrestha, Haydar Bulut, Shin-Ichiro Hattorri, Hiroaki Mitsuya and Robert Yarchoan","doi":"10.1039/D4MD00454J","DOIUrl":"10.1039/D4MD00454J","url":null,"abstract":"<p >Coronaviruses rely on the viral-encoded chymotrypsin-like main protease (M<small>^pro</small> or 3CL<small>^pro</small>) for replication and assembly. Our previous research on M<small>^pro</small> of SARS-CoV-2 identified cysteine 300 (Cys300) as a potential allosteric site of M<small>^pro</small> inhibition. Here, we identified tixocortol (TX) as a covalent modifier of Cys300 which inhibits M<small>^pro</small> activity <em>in vitro</em> as well as in a cell-based M<small>^pro</small> expression assay. Most importantly TX inhibited SARS-CoV-2 replication in ACE2 expressing HeLa cells. Biochemical analysis and kinetic assays were consistent with TX acting as a non-competitive inhibitor. By contrast, TX was a weaker inhibitor and modifier of C300S M<small>^pro</small>, confirming a role for Cys300 in inhibition of WT M<small>^pro</small> but also providing evidence for an additional Cys target. TX pivalate (TP), a prodrug for TX that was previously marketed as a nasal spray, also inhibited SARS-CoV-2 replication in HeLa–ACE2 cells at low micromolar IC<small>₅₀</small>s. These studies suggest that TX and/or TP could possibly be repurposed for the prevention and/or treatment of SARS-CoV-2 infection.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 12","pages":" 4193-4205"},"PeriodicalIF":3.597,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381603","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":"Anti-Schistosomal activity and ADMET properties of 1,2,5-oxadiazinane-containing compound synthesized by visible-light photoredox catalysis†","authors":"Kennosuke Itoh, Hiroki Nakahara, Atsushi Takashino, Aya Hara, Akiho Katsuno, Yuriko Abe, Takaaki Mizuguchi, Fumika Karaki, Shigeto Hirayama, Kenichiro Nagai, Reiko Seki, Noriko Sato, Kazuki Okuyama, Masashi Hashimoto, Ken Tokunaga, Hitoshi Ishida, Fusako Mikami, Kofi Dadzie Kwofie, Hayato Kawada, Bangzhong Lin, Kazuto Nunomura, Toshio Kanai, Takeshi Hatta, Naotoshi Tsuji, Junichi Haruta and Hideaki Fujii","doi":"10.1039/D4MD00599F","DOIUrl":"10.1039/D4MD00599F","url":null,"abstract":"<p >The incorporation of saturated nitrogen-containing heterocycle 1,2,5-oxadiazinane into small molecules represents a compelling avenue in drug discovery due to its unexplored behavior within biological systems and incomplete protocols for synthesis. In this study, we present 1,2,5-oxadiazinane, an innovative heterocyclic bioisostere of piperizin-2-one and novel chemotype of the <em>anti</em>-schistosomal drug praziquantel (PZQ), which has been the only clinical drug available for three decades. PZQ is associated with significant drawbacks, including poor solubility, a bitter taste, and low metabolic stability. Therefore, the discovery of a new class of <em>anti</em>-schistosomal agents is imperative. To address this challenge, we introduce a pioneering method for the synthesis of 1,2,5-oxadiazinane derivatives through the cycloaddition of nitrones with <em>N</em>,<em>N</em>,<em>N′</em>,<em>N′</em>-tetraalkyldiaminomethane in the presence of an Ir<small>^III</small> complex photosensitizer. This transformative reaction offers a streamlined route to various kinds of 1,2,5-oxadiazinanes that is characterized by mild reaction conditions and broad substrate scope. Mechanistic investigations suggest that the photoredox pathway underlies the [3 + 3] photocycloaddition process. Thus, based on bioisosteric replacement, we identified a remarkable molecule as a new chemotype of a potent <em>anti</em>-schistosomal compound that not only exhibits superior solubility, but also retains the potent biological activity inherent to PZQ.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 12","pages":" 4001-4010"},"PeriodicalIF":3.597,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11467761/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473750","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":"Exploring 7β-amino-6-nitrocholestens as COVID-19 antivirals: in silico, synthesis, evaluation, and integration of artificial intelligence (AI) in drug design: assessing the cytotoxicity and antioxidant activity of 3β-acetoxynitrocholestane†","authors":"Shahabuddin, Uzma, Mohammad Azam, Mehtab Parveen, Nurul Huda Abd Kadir, Kim Min and Mahboob Alam","doi":"10.1039/D4MD00257A","DOIUrl":"10.1039/D4MD00257A","url":null,"abstract":"<p >In light of the ongoing pandemic caused by SARS-CoV-2, effective and clinically translatable treatments are desperately needed for COVID-19 and its emerging variants. In this study, some derivatives, including 7β-aminocholestene compounds, and 3β-acetoxy-6-nitrocholesta-4,6-diene were synthesized, in quantitative yields from 7β-bromo-6-nitrocholest-5-enes (<strong>1–3</strong>) with a small library of amines. The synthesized steroidal products were then thoroughly characterized using a range of physicochemical techniques, including IR, NMR, UV, MS, and elemental analysis. Next, a virtual screening based on structures using docking studies was conducted to investigate the potential of these synthesized compounds as therapeutic candidates against SARS-CoV-2. Specifically, we evaluated the compounds' binding energy of the reactants and their products with three SARS-CoV-2 functional proteins: the papain-like protease, 3C-like protease or main protease, and RNA-dependent RNA polymerase. Our results indicate that the 7β-aminocholestene derivatives (<strong>4–8</strong>) display intermediate to excellent binding energy, suggesting that they interact strongly with the receptor's active amino acids and may be promising drug candidates for inhibiting SARS-CoV-2. Although the starting steroid derivatives; 7β-bromo-6-nitrocholest-5-enes (<strong>1–3</strong>) and one steroid product; 3β-acetoxy-6-nitrocholesta-4,6-diene (<strong>9</strong>) exhibited strong binding energies with various SARS-CoV-2 receptors, they did not meet the Lipinski Rule and ADMET properties required for drug development. These compounds showed either mutagenic or reproductive/developmental toxicity when assessed using toxicity prediction software. The findings based on structure-based virtual screening, suggest that 7β-aminocholestaines (<strong>4–8</strong>) may be useful for reducing the susceptibility to SARS-CoV-2 infection. The docking pose of compound <strong>4</strong>, which has a high score of −7.4 kcal mol<small>⁻¹</small>, was subjected to AI-assisted deep learning to generate 60 AI-designed molecules for drug design. Molecular docking of these AI molecules was performed to select optimal candidates for further analysis and visualization. The cytotoxicity and antioxidant effects of 3β-acetoxy-6-nitrocholesta-4,6-diene were tested <em>in vitro</em>, showing marked cytotoxicity and antioxidant activity. To elucidate the molecular basis for these effects, steroidal compound 9 was subjected to molecular docking analysis to identify potential binding interactions. The stability of the top-ranked docking pose was subsequently assessed using molecular dynamics simulations.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 11","pages":" 3889-3911"},"PeriodicalIF":3.597,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473770","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":"Synthesis and structure–activity study of the antimicrobial lipopeptide brevibacillin†","authors":"Omar Fliss, Louis-David Guay, Ismail Fliss and Éric Biron","doi":"10.1039/D4MD00612G","DOIUrl":"10.1039/D4MD00612G","url":null,"abstract":"<p >The antimicrobial lipopeptide brevibacillin is a non-ribosomally synthesized peptide produced by <em>Brevibacillus laterosporus</em> with inhibitory activity against several clinically relevant Gram-positive pathogenic bacteria such as <em>Staphylococcus aureus</em>, <em>Listeria monocytogenes</em>, and <em>Clostridium difficile</em>. In this study, we report the total synthesis of brevibacillin and analogues thereof as well as structure–activity relationship and cytotoxicity studies. Several novel synthetic analogues exhibited high inhibitory activities with minimal inhibitory concentration values in the low micromolar range against several bacteria including Gram-positive <em>L. monocytogenes</em>, <em>S. aureus</em>, <em>Enterococcus faecalis</em>, and <em>Clostridium perfringens</em> as well as Gram-negative <em>Campylobacter coli</em> and <em>Pseudomonas aeruginosa</em>. Of particular interest, four analogues showed a broad spectrum of action and greater antimicrobial activity <em>versus</em> cytotoxicity ratios than native brevibacillin. With a more accessible and efficient production process and improved pharmacological properties, these synthetic analogues are promising candidates to prevent and control the proliferation of various pathogens in the food industry as well as veterinary and human medicine.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 12","pages":" 4168-4179"},"PeriodicalIF":3.597,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381608","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":"Understanding the mechanisms of antimicrobial resistance and potential therapeutic approaches against the Gram-negative pathogen Acinetobacter baumannii","authors":"Vishwani Jamwal, Tashi Palmo and Kuljit Singh","doi":"10.1039/D4MD00449C","DOIUrl":"10.1039/D4MD00449C","url":null,"abstract":"<p >Globally, the emergence of anti-microbial resistance in pathogens has become a serious threat to human health and well-being. Infections caused by drug-resistant microorganisms in hospitals are associated with increased morbidity, mortality, and healthcare costs. <em>Acinetobacter baumannii</em> is a Gram-negative bacterium belonging to the ESKAPE group and is widely associated with nosocomial infections. It persists in hospitals and survives antibiotic treatment, prompting acute infections such as urinary tract infections, pneumonia, bacteremia, meningitis, and wound-related infections. An innovation void in drug discovery and the lack of new therapeutic measures against <em>A. baumannii</em> continue to afflict infection control against the rising drug-resistant cases. The emergence of drug-resistant <em>A. baumannii</em> strains has also led to the incessant collapse of newly discovered antibiotics. Therefore exploring novel strategies is requisite to give impetus to <em>A. baumannii</em> drug discovery. The present review discusses the bacterial research community's efforts in the field of <em>A. baumannii</em>, focusing on the strategies adapted to identify potent scaffolds and novel targets to bolster and diversify the chemical space available for drug discovery. Firstly, we have discussed existing chemotherapy and various anti-microbial resistance mechanisms in <em>A. baumannii</em> bacterial strains. Next, we elaborate on multidisciplinary approaches and strategies that may be the way forward to combat the current menace caused by the drug-resistant <em>A. baumannii</em> strains. The review highlights the recent advances in drug discovery, including combinational therapy, high-throughput screening, drug repurposing, nanotechnology, and anti-microbial peptides, which are imperative tools to fight bacterial pathogens in the future.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 12","pages":" 3925-3949"},"PeriodicalIF":3.597,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142392971","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}