RSC medicinal chemistry最新文献

{"title":"Novel rhodanine-thiazole hybrids as potential antidiabetic agents: a structure-based drug design approach.","authors":"Shankar Gharge, Shankar G Alegaon, Shriram D Ranade, Rohini S Kavalapure, B R Prashantha Kumar","doi":"10.1039/d4md00689e","DOIUrl":"10.1039/d4md00689e","url":null,"abstract":"<p><p>New rhodanine-thiazole clubbed compounds (7a-7l) were synthesised and characterised with various spectroscopy methods. The synthesised hybrids underwent <i>in vitro</i> HPA, HLAG inhibition, and peroxisome proliferator-activated receptor-gamma (PPAR-γ) expression assays. Through the biological study, compound 7f showed promising inhibitory activity against HPA with an IC₅₀ value of 27.13 ± 1.02 μM and 7l exhibited better inhibition against HLAG with an IC₅₀ value of 24.21 ± 1.12 μM. In addition, Lineweaver-Burk plot analysis suggested that 7l and 7f behaved as a mixed type of HLAG and HPA inhibitor and further, compound 7f showed significant PPAR-γ expression as compared to controls in a dose dependent manner; the expression can be attributed to its mapped pharmacophoric features with a phase screen score of 1.28 and vector score of 0.62. The proteins modulated by compounds include <i>AMY2A</i>, <i>PPAR</i>, and <i>GAA</i> proteins <i>via MAPK</i>, <i>PPAR</i> signalling pathways identified by cluster analysis and justified by molecular docking studies and MD trajectory analysis to evaluate the binding orientation and stability of the molecules, and the energy profiles of the molecules, both in complex with the protein, were assessed using MM/GBSA and DFT calculations, respectively. Finally, the pharmacokinetic profile was determined using ADMET analysis. Thus, from the above findings, it may demonstrate that rhodanine-thiazole hybrids constitute promising candidates in the pursuit of developing newer oral antidiabetic agents.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11650657/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural peptides and their synthetic congeners acting against <i>Acinetobacter baumannii</i> through the membrane and cell wall: latest progress.","authors":"Gautam Kumar","doi":"10.1039/d4md00745j","DOIUrl":"10.1039/d4md00745j","url":null,"abstract":"<p><p><i>Acinetobacter baumannii</i> is one of the deadliest Gram-negative bacteria (GNB), responsible for 2-10% of hospital-acquired infections. Several antibiotics are used to control the growth of <i>A. baumannii</i>. However, in recent decades, the abuse and misuse of antibiotics to treat non-microbial diseases have led to the emergence of multidrug-resistant <i>A. baumannii</i> strains. <i>A. baumannii</i> possesses a complex cell wall structure. Cell wall-targeting agents remain the center of antibiotic drug discovery. Notably, the antibacterial drug discovery intends to target the membrane of the bacteria, offering several advantages over antibiotics targeting intracellular systems, as membrane-targeting agents do not have to travel through the plasma membrane to reach the cytoplasmic targets. Microorganisms, insects, and mammals produce antimicrobial peptides as their first line of defense to protect themselves from pathogens and predators. Importantly, antimicrobial peptides are considered potential alternatives to antibiotics. This communication summarises the recently identified peptides of natural origin and their synthetic congeners acting against the <i>A. baumannii</i> membrane by cell wall disruption.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11629675/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Strategies of positron emission tomography (PET) tracer development for imaging of tau and α-synuclein in neurodegenerative disorders.","authors":"Shekar Mekala, You Wu, Yue-Ming Li","doi":"10.1039/d4md00576g","DOIUrl":"10.1039/d4md00576g","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a progressive neurodegenerative disorder, characterized by the presence of extracellular amyloid plaques consisting of β-amyloid peptides (Aβ) and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau (pTau) protein in the brain. Genetic and animal studies strongly indicate that Aβ, tau and neuroinflammation play important roles in the pathogenesis of AD. Several staging models showed that NFTs correlated well with the disease progression. Positron emission tomography (PET) imaging has become a widely used non-invasive technique to image NFTs for early diagnosis of AD. Despite the remarkable progress made over the past few years, tau PET imaging is still challenging due to the nature of tau pathology and the technical aspects of PET imaging. Tau pathology often coexists with other proteinopathies, such as Aβ plaques and α-synuclein aggregates. Distinguishing tau-specific signals from other overlapping pathologies is difficult, especially in the context of AD, where multiple protein aggregates are present, as well as the spectrum of different tau isoforms (3R and 4R) and conformations. Moreover, tracers should ideally have optimal pharmacokinetic properties to penetrate the blood-brain barrier (BBB) while maintaining specificity, low toxicity, low non-specific binding, rapid uptake and clearance from the brain, and formation of no radiolabeled metabolites in the brain. On the other hand, Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by the abnormal accumulations of α-synuclein in neurons. Heterogeneity and the unclear pathogenesis of PD hinder early and accurate diagnosis of the disease for therapeutic development in clinical use. In this review, while referring to existing reviews, we focus on the design strategies and current progress in tau (NFTs) targeting new PET tracers for AD; evolution of non-AD tau targeting PET tracers for applications including progressive supranuclear paralysis (PSP) and corticobasal degeneration (CBD); new PET tracer development for α-synuclein aggregate imaging in PD and giving an outlook for future PET tracer development.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638850/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142829597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and biological characterization of a 17β hydroxysteroid dehydrogenase type 10 (17β-HSD10) inhibitor.","authors":"Louise F Dow, Rasangi Pathirage, Helen E Erickson, Edrees Amani, Donald R Ronning, Paul C Trippier","doi":"10.1039/d4md00733f","DOIUrl":"10.1039/d4md00733f","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is estimated to affect over 55 million people across the world. Small molecule treatment options are limited to symptom management with no impact on disease progression. The need for new protein targets and small molecule hit compounds is unmet and urgent. Hydroxysteroid 17-β dehydrogenase type 10 (17β-HSD10) is a mitochondrial enzyme known to bind amyloid beta, a hallmark of AD, and potentiate its toxicity to neurons. Identification of small molecules capable of interacting with 17β-HSD10 may drive drug discovery efforts for AD. The screening compound BCC0100281 (1), was previously identified as an inhibitor of 17β-HSD10. Herein we report the first synthetic access to the hit compound following a convergent pathway starting from simple heterocyclic building blocks. The compound was found to be toxic to 'neuron-like' cells, specifically those of neuroblastoma origin, providing a potential hit compound for cancer drug discovery, wherein the protein is known to be overexpressed. However, assay of synthetic intermediates identified novel scaffolds with effect to rescue amyloid beta-induced cytotoxicity, showcasing the power of organic synthesis and medicinal chemistry to optimize hit compounds.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11605429/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142771814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of diarylpyrimidine derivatives (& other heterocycles) as HIV-1 and WT RT inhibitors.","authors":"Atukuri Dorababu","doi":"10.1039/d4md00697f","DOIUrl":"10.1039/d4md00697f","url":null,"abstract":"<p><p>Reverse transcriptase (RT) is an enzyme encoded by the genetic material of retroviruses. Viruses such as HIV and hepatitis B employ an enzyme reverse transcriptase (RT) to generate complementary DNA from the RNA template during reverse transcription. Thus, viruses replicate their genomes and proliferate within the host genome. In particular, researchers are concerned about the pathogenic viruses that cause numerous diseases through this mechanism. The retroviruses that cause diseases in humans include human immunodeficiency virus (HIV), which causes AIDS, and human T-cell lymphotropic virus I (HTLV-1), which causes leukemia. HIV has been the most devastating health problem for decades. The number of recorded HIV cases was found to be approximately 39 million worldwide in 2022. Acquired immune deficiency syndrome (AIDS), most devastating disease caused by HIV-1 needs potent antiretroviral therapy for treatment. Among the effective treatments for AIDS, NNRTIs are key drugs in highly active antiretroviral therapy (HAART). Heterocyclic small molecules play an important role in drug discovery for treatment of HIV-1 infection. Particularly, diarylpyrimidines class of drugs have shown promising activity. In this review, anti-HIV-1 activity and RT inhibitory activity of heterocycle small molecules focusing mostly on diarylpyrimidines was discussed. Furthermore, structure-activity relationship was discussed emphasizing most potent molecules.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11626402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anticancer potential of copper(i) complexes based on isopropyl ester derivatives of bis(pyrazol-1-yl)acetate ligands.","authors":"Maura Pellei, Carlo Santini, Miriam Caviglia, Jo' Del Gobbo, Chiara Battocchio, Carlo Meneghini, Simone Amatori, Chiara Donati, Eleonora Zampieri, Valentina Gandin, Cristina Marzano","doi":"10.1039/d4md00610k","DOIUrl":"https://doi.org/10.1039/d4md00610k","url":null,"abstract":"<p><p>In this paper, the isopropyl ester derivatives L^OiPr and L^2OiPr of bis(pyrazol-1-yl)acetic acid and bis(3,5-dimethyl-pyrazol-1-yl)acetic acid were used as chelators for the preparation of new Cu(i) phosphane complexes 1-4. They were synthesized by the reaction of [Cu(CH₃CN)₄]PF₆ and triphenylphosphine or 1,3,5-triaza-7-phosphaadamantane with L^OiPr and L^2OiPr ligands, in acetonitrile or acetonitrile/methanol solution. The authenticity of the compounds was confirmed by CHN analysis, ¹H-, ¹³C- and ³¹P-NMR, FT-IR spectroscopy, and electrospray ionization mass spectrometry (ESI-MS). Furthermore, the electronic and molecular structures of the selected Cu(i) coordination compound 3 were investigated by synchrotron radiation-induced X-ray photoelectron spectroscopy (SR-XPS), and the local structure around the copper ion site was studied combining X-ray absorption fine structure (XAFS) spectroscopy techniques and DFT modelling. Triphenylphosphine as a coligand confers to [Cu(L^OiPr)(PPh₃)]PF₆ (1) and [Cu(L^2OiPr)(PPh₃)]PF₆ (3) a significant antitumor activity in 3D spheroidal models of human colon cancer cells. Investigations focused on the mechanism of action evidenced protein disulfide-isomerase (PDI) as an innovative molecular target for this class of phosphane copper(i) complexes. By hampering PDI activity, copper(i) complexes were able to cause an imbalance in cancer cell redox homeostasis thus leading to cancer cell death - a non-apoptotic programmed cell death.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11605304/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142771769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in detecting non-steroidal anti-inflammatory drugs (NSAIDs) using molecular receptors and nanostructured assemblies.","authors":"Avijit Kumar Das","doi":"10.1039/d4md00661e","DOIUrl":"https://doi.org/10.1039/d4md00661e","url":null,"abstract":"<p><p>The detection and quantification of non-steroidal anti-inflammatory drugs (NSAIDs) are crucial due to their widespread use and potential impact on human health and the environment. This review provides a comprehensive survey of the recent advancements in sensing technologies for NSAIDs, focusing on molecular receptors and nanostructured assemblies. Molecular receptors based on different fluorescent molecules such as anthracene, naphthalimide, squaraine, quinoline, BINOL, <i>etc.</i> offer high selectivity and sensitivity for NSAID detection. In parallel, nanostructured assemblies including CdSe/ZnS, Cd/S quantum dots (QDs), carbon dot-containing imprinted polymers, Ag and Au nanoparticles (NPs), hydrogel-embedded chemosensors, <i>etc.</i> were utilized for NSAID detection. This review highlights the different binding pathways with the change of various photophysical properties combining molecular recognition elements with nanomaterials to develop innovative sensors that achieve rapid, sensitive, and selective detection of NSAIDs. The review also discusses current challenges and future prospects in the field and based on reported designed receptors and nanostructured assemblies. To the best of our knowledge, no reviews have been reported on this topic so far. Thus, this review will fruitfully guide researchers to design various new molecular receptors and nanostructured materials to detect NSAIDs.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11605430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142771476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SIGMAP: an explainable artificial intelligence tool for SIGMA-1 receptor affinity prediction.","authors":"Maria Cristina Lomuscio, Nicola Corriero, Vittoria Nanna, Antonio Piccinno, Michele Saviano, Rosa Lanzilotti, Carmen Abate, Domenico Alberga, Giuseppe Felice Mangiatordi","doi":"10.1039/d4md00722k","DOIUrl":"https://doi.org/10.1039/d4md00722k","url":null,"abstract":"<p><p>Developing sigma-1 receptor (S1R) modulators is considered a valuable therapeutic strategy to counteract neurodegeneration, cancer progression, and viral infections, including COVID-19. In this context, <i>in silico</i> tools capable of accurately predicting S1R affinity are highly desirable. Herein, we present a panel of 25 classifiers trained on a curated dataset of high-quality bioactivity data of small molecules, experimentally tested as potential S1R modulators. All data were extracted from ChEMBL v33, and the models were built using five different fingerprints and machine-learning algorithms. Remarkably, most of the developed classifiers demonstrated good predictive performance. The best-performing model, which achieved an AUC of 0.90, was developed using the support vector machine algorithm with Morgan fingerprints. To provide additional, user-friendly information for medicinal chemists in the rational design of S1R modulators, two independent explainable artificial intelligence (XAI) approaches were employed, namely Shapley Additive exPlanations (SHAP) and Contrastive Explanation. The top-performing model is accessible through a user-friendly web platform, SIGMAP (https://www.ba.ic.cnr.it/softwareic/sigmap/), specifically developed for this purpose. With its intuitive interface, robust predictive power, and implemented XAI approaches, SIGMAP serves as a valuable tool for the rational design of new and more effective S1R modulators.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11605305/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142771803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Property-based optimisation of PROTACs.","authors":"James S Scott, Iacovos N Michaelides, Markus Schade","doi":"10.1039/d4md00769g","DOIUrl":"10.1039/d4md00769g","url":null,"abstract":"<p><p>PROTACs are an emerging therapeutic approach towards targeted protein degradation. This article examines the leading examples of this modality that are in clinical development through the prism of their physicochemical properties. In particular, the optimisation of the various components of PROTACs together with the difficulties faced by medicinal chemists seeking to achieve oral bioavailability in this challenging space are outlined. Guidance, opinion and advice based on the authors' own experiences in this area are offered in the hope this may be useful to others working in this fascinating frontier of drug discovery.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561549/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"3-Thio-3,4,5-trisubstituted-1,2,4-triazoles: high affinity somatostatin receptor-4 agonist synthesis and structure-activity relationships.","authors":"A Michael Crider, Audrey Hospital, Karin E Sandoval, William L Neumann, Stephen Kukielski, Lejla Garic, Kristen Ingold, Matthew Dunahoo, Khush N Srabony, Rafael Frare, Olivia Slater, Nathan Peel, Maria Kontoyianni, Ken A Witt","doi":"10.1039/d4md00597j","DOIUrl":"10.1039/d4md00597j","url":null,"abstract":"<p><p>Somatostatin receptor-4 (SST₄) is a therapeutic target for several conditions, including Alzheimer's disease, seizures, neuropsychiatric disorders, and pain. Our previous work on 1,2,4-triazole derivatives led to enhanced SST₄ binding affinity, selectivity, and functional activity. Herein we report the discovery of 3-thio-1,2,4-triazole series as selective and high affinity SST₄ agonists. Thirty-three compounds show <100 nM binding affinity, five of which had sub-nanomolar binding affinity and >300-fold selectivity over other SST subtypes. SST₄ cAMP inhibition assay activity data aligned with the ligand binding affinity. Comparative docking results of the ligands under investigation with the cryo-EM and most recent model-built SST₄ structures suggest similar trends in binding. Amino acids responsible for high and moderate affinity were identified, whereas poorer ligand conformations and limited interactions were observed with the low-affinity compounds. In summary, this study presents a novel series of high affinity SST₄ agonists with corresponding <i>in vitro</i> activity, demonstrating viable therapeutic potential.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11660163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}