Medicinal Chemistry最新文献

{"title":"Nitrogen-fused Heterocycles: Empowering Anticancer Drug Discovery.","authors":"Tanya Biswas, Ravi Kumar Mittal, Vikram Sharma, Kanupriya, Isha Mishra","doi":"10.2174/0115734064278334231211054053","DOIUrl":"10.2174/0115734064278334231211054053","url":null,"abstract":"<p><p>The worldwide impact of cancer is further compounded by the constraints of current anticancer medications, which frequently exhibit a lack of selectivity, raise safety apprehensions, result in significant adverse reactions, and encounter resistance mechanisms. The current situation highlights the pressing need to develop novel and more precise anticancer agents that prioritize safety and target specificity. Remarkably, more than 85% of drugs with physiological activity contain heterocyclic structures or at least one heteroatom. Nitrogen-containing heterocycles hold a significant position among these compounds, emerging as the most prevalent framework within the realm of heterocyclic chemistry. This article explores the medicinal chemistry behind these molecules, highlighting their potential as game-changing possibilities for anticancer medication development. The analysis highlights the inherent structural variety in nitrogen-containing heterocycles, revealing their potential to be customized for creating personalized anticancer medications. It also emphasizes the importance of computational techniques and studies on the relationships between structure and activity, providing a road map for rational medication design and optimization. Nitrogen- containing heterocycles are a promising new area of study in the fight against cancer, and this review summarises the state of the field so far. By utilizing their inherent characteristics and exploiting cooperative scientific investigations, these heterocyclic substances exhibit potential at the forefront of pioneering therapeutic approaches in combating the multifaceted obstacles posed by cancer.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":"369-384"},"PeriodicalIF":1.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139403589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-based Virtual Screening from Natural Products as Inhibitors of SARS-CoV-2 Spike Protein and ACE2 Receptor Binding and their Biological Evaluation <i>In vitro</i>.","authors":"Timoteo Delgado-Maldonado, Luis Donaldo Gonzalez-Morales, Alfredo Juarez-Saldivar, Edgar E Lara-Ramírez, Guadalupe Rojas-Verde, Adriana Moreno-Rodriguez, Debasish Bandyopadhyay, Gildardo Rivera","doi":"10.2174/0115734064279323231206091314","DOIUrl":"10.2174/0115734064279323231206091314","url":null,"abstract":"<p><strong>Background: </strong>In the last years, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused more than 760 million infections and 6.9 million deaths. Currently, remains a public health problem with limited pharmacological treatments. Among the virus drug targets, the SARS-CoV-2 spike protein attracts the development of new anti-SARS-CoV-2 agents.</p><p><strong>Objective: </strong>The aim of this work was to identify new compounds derived from natural products (BIOFACQUIM and Selleckchem databases) as potential inhibitors of the spike receptor binding domain (RBD)-ACE2 binding complex.</p><p><strong>Methods: </strong>Molecular docking, molecular dynamics simulations, and ADME-Tox analysis were performed to screen and select the potential inhibitors. ELISA-based enzyme assay was done to confirm our predictive model.</p><p><strong>Results: </strong>Twenty compounds were identified as potential binders of RBD of the spike protein. <i>In vitro</i> assay showed compound B-8 caused 48% inhibition at 50 μM, and their binding pattern exhibited interactions via hydrogen bonds with the key amino acid residues present on the RBD.</p><p><strong>Conclusion: </strong>Compound B-8 can be used as a scaffold to develop new and more efficient antiviral drugs.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":"546-553"},"PeriodicalIF":1.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139417382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New Thieno[2,3-d]pyrimidines as Anticancer VEGFR-2 Inhibitors with Apoptosis Induction: Design, Synthesis, and Biological and <i>In Silico</i> Studies.","authors":"Eman A Sobh, Mohammed A Dahab, Eslam B Elkaeed, Bshra A Alsfouk, Ibrahim M Ibrahim, Ahmed M Metwaly, Ibrahim H Eissa","doi":"10.2174/0115734064285433240513092047","DOIUrl":"10.2174/0115734064285433240513092047","url":null,"abstract":"<p><strong>Background: </strong>Vascular endothelial growth factor receptor-2 (VEGFR-2) is a critical protein involved in tumor progression, making it an attractive target for cancer therapy.</p><p><strong>Objective: </strong>This study aimed to synthesize and evaluate novel thieno[2,3-d]pyrimidine analogues as potential anticancer VEGFR-2 inhibitors.</p><p><strong>Methods: </strong>The thieno[2,3-<i>d</i>]pyrimidine analogues were synthesized following the pharmacophoric features of VEGFR-2 inhibitors. The anticancer potential was assessed against PC3 and HepG2 cell lines. The VEGFR-2 inhibition was evaluated through IC₅₀ determination. Cell cycle analysis and apoptosis assays were performed to elucidate the mechanisms of action. Molecular docking, molecular dynamics simulations, MM-GBSA, and PLIP studies were conducted to investigate the binding affinities and interactions with VEGFR-2. Additionally, <i>in silico</i> ADMET studies were performed.</p><p><strong>Results: </strong>Compound 8b demonstrated significant anti-proliferative activities with IC₅₀ values of 16.35 μM and 8.24 μM against PC3 and HepG2 cell lines, respectively, surpassing sorafenib and exhibiting enhanced selectivity indices. Furthermore, compound 8b showed an IC₅₀ value of 73 nM for VEGFR-2 inhibition. Cell cycle analysis revealed G2-M phase arrest, while apoptosis assays demonstrated increased apoptosis in HepG2 cells. Molecular docking and dynamic simulations confirmed the binding affinity and interaction of compound 8b with VEGFR-2, supported by MMGBSA and PLIP studies. <i>In silico</i> ADMET studies indicated the drug development potential of the synthesized thieno[2,3-<i>d</i>]pyrimidines.</p><p><strong>Conclusion: </strong>The study highlights compound 8b as a promising VEGFR-2 inhibitor with potent anti-proliferative activities. Its mechanism of action involves cell cycle arrest and induction of apoptosis. Further, molecular docking and dynamic simulations support the strong binding affinity of compound 8b to VEGFR-2.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":"876-899"},"PeriodicalIF":1.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141155352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New 3-Hydroxypyridine-4-one Analogues: Their Synthesis, Antimicrobial Evaluation, Molecular Docking, and <i>In Silico</i> ADME Prediction.","authors":"Sara Sadeghian, Fateme Zare, Lotfollah Saghaie, Afshin Fassihi, Pooria Zare, Razieh Sabet","doi":"10.2174/0115734064307744240523112710","DOIUrl":"10.2174/0115734064307744240523112710","url":null,"abstract":"<p><strong>Introduction: </strong>Drug resistance to existing antimicrobial drugs has become a serious threat to human health, which highlights the need to develop new antimicrobial agents.</p><p><strong>Methods: </strong>In this study, a new set of 3-hydroxypyridine-4-one derivatives (6a-j) was synthesized, and the antimicrobial effects of these derivatives were evaluated against a variety of microorganisms using the microdilution method. The antimicrobial evaluation indicated that compound 6c, with an electron-donating group -OCH₃ at the meta position of the phenyl ring, was the most active compound against <i>S. aureus</i> and <i>E. coli</i> species with an MIC value of 32 μg/mL. Compound 6c was more potent than ampicillin as a reference drug.</p><p><strong>Results: </strong>The <i>in vitro</i> antifungal results showed that the studied derivatives had moderate effects (MIC = 128-512 μg/mL) against <i>C. albicans</i> and <i>A. niger</i> species. The molecular modeling studies revealed the possible mechanism and suitable interactions of these derivatives with the target protein.</p><p><strong>Conclusion: </strong>The obtained biological results offer valuable insights into the design of more effective antimicrobial agents.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":"900-911"},"PeriodicalIF":1.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141262252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent Advances in Nitrogen-Containing Heterocyclic Scaffolds as Antiviral Agents.","authors":"Kanupriya, Ravi Kumar Mittal, Vikram Sharma, Tanya Biswas, Isha Mishra","doi":"10.2174/0115734064280150231212113012","DOIUrl":"10.2174/0115734064280150231212113012","url":null,"abstract":"<p><p>This study aims to provide a thorough analysis of nitrogen-containing heterocycles, focusing on their therapeutic implications for the development of targeted and effective antiviral drugs. To better understand how nitrogen-containing heterocycles can be used to create antiviral drugs, this review adopts a systematic literature review strategy to compile and analyze pertinent research studies. It combines information from various fields to understand better the compounds' mode of action and their therapeutic potential. This review paper summarizes data from multiple sources to highlight the promising potential of heterocycles containing nitrogen as promising possibilities for future antiviral treatments. The capacity to engage selectively and modulate critical pathways bodes well for their use in developing new viral therapies. In conclusion, nitrogen-containing heterocycles are shown to be of utmost importance in the field of medicinal chemistry, as emphasized by the review paper. It emphasizes the central importance of chemical insights and pharmacological potential in developing novel and effective antiviral medicines by bringing them together.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":"487-502"},"PeriodicalIF":1.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139567219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and Evaluation of Novel Substituted N-Aryl 1,4-Dihydropyridines as Antituberculostatic Agents.","authors":"Lisa Seitz, Norbert Reiling, Christopher Vorreiter, Wolfgang Sippl, Sonja Kessler, Andreas Hilgeroth","doi":"10.2174/1573406419666230622121512","DOIUrl":"10.2174/1573406419666230622121512","url":null,"abstract":"<p><strong>Background: </strong>Tuberculosis has been the main cause of mortality of infectious diseases worldwide, with strongly limited therapeutic options. With increasing resistance and missing suitable drugs in those cases, there is a strong need for novel antituberculostatic drugs. We developed novel N-aryl 1,4-dihydropyridines with various substitution patterns to evaluate them as antituberculostatic agents.</p><p><strong>Methods: </strong>1,4-Dihydropyridine derivatives were synthesized and purified by column chromatography or recrystallization. The mycobacterial growth inhibition was determined in a fluorescent mycobacterial growth assay.</p><p><strong>Results: </strong>The compounds were prepared in a simple one-pot reaction under acidic conditions with structurally varied components. The substituent effects on the determined mycobacterial growth inhibitory properties are discussed.</p><p><strong>Conclusion: </strong>Lipophilic diester substituted derivatives show promising activities that were additionally affected by the aromatic substituent functions. Thus, we identified compounds with activities almost reaching that of the used antimycobacterial drug as control.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":"30-39"},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10065091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>In-silico</i> Investigations for the Identification of Novel Inhibitors Targeting Hepatitis C Virus RNA-dependent RNA Polymerase.","authors":"Shailaja Mallya, Raghuvir R S Pissurlenkar","doi":"10.2174/0115734064255683230919071808","DOIUrl":"10.2174/0115734064255683230919071808","url":null,"abstract":"<p><strong>Background: </strong>Hepatitis C is an inflammatory condition of the liver caused by the hepatitis C virus, exhibiting acute and chronic manifestations with severity ranging from mild to severe and lifelong illnesses leading to liver cirrhosis and cancer. According to the World Health Organization's global estimates, a population of about 58 million have chronic hepatitis C virus infection, with around 1.5 million new infections occurring every year.</p><p><strong>Objective: </strong>The present study aimed to identify novel molecules targeting the Hepatitis C viral RNA Dependent RNA polymerases, which play a crucial role in genome replication, mRNA synthesis, etc. Methods: Structure-based virtual screening of chemical libraries of small molecules was done using AutoDock/Vina. The top-ranking pose for every ligand was complexed with the protein and used for further protein-ligand interaction analysis using the Protein-ligand interaction Profiler. Molecules from virtual screening were further assessed using the pkCSM web server. The proteinligand interactions were further subjected to molecular dynamics simulation studies to establish dynamic stability.</p><p><strong>Results: </strong>Molecular docking-based virtual screening of the database of small molecules, followed by screening based on pharmacokinetic and toxicity parameters, yielded eight probable RNA Dependent RNA polymerase inhibitors. The docking scores for the proposed candidates ranged from - 8.04 to -9.10 kcal/mol. The potential stability of the ligands bound to the target protein was demonstrated by molecular dynamics simulation studies.</p><p><strong>Conclusion: </strong>Data from exhaustive computational studies proposed eight molecules as potential anti-viral candidates, targeting Hepatitis C viral RNA Dependent RNA polymerases, which can be further evaluated for their biological potential.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":"52-62"},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41183024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-Activity Relationship Studies on VEGFR2 Tyrosine Kinase Inhibitors for Identification of Potential Natural Anticancer Compounds.","authors":"Meenakshi Verma, Aqib Sarfraz, Inamul Hasan, Prema Gauri Vasudev, Feroz Khan","doi":"10.2174/0115734064247526231129080415","DOIUrl":"10.2174/0115734064247526231129080415","url":null,"abstract":"<p><strong>Background: </strong>Over-expression of Vascular Endothelial Growth Factor Receptors (VEGFRs) leads to the hyperactivation of oncogenes. For inhibition of this hyperactivation, the USA Food Drug Administration (FDA) has approved many drugs that show adverse effects, such as hypertension, hypothyroidism, etc. There is a need to discover potent natural compounds that show minimal side effects. In the present study, we have taken structurally diverse known VEGFR2 inhibitors to develop a Quantitative Structure-Activity Relationship (QSAR) model and used this model to predict the inhibitory activity of natural compounds for VEGFR2.</p><p><strong>Methods: </strong>The QSAR model was developed through the forward stepwise Multiple Linear Regression (MLR) method. A developed QSAR model was used to predict the inhibitory activity of natural compounds. Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) assessment and molecular docking studies were performed. The binding stability of the natural compounds with VEGFR2 was elucidated through Molecular Dynamics (MD) simulation.</p><p><strong>Results: </strong>The developed QSAR model against VEGFR2 showed the regression coefficient of the training dataset (r²) as 0.81 and the external regression coefficient of the test dataset (r2 test) 0.71. Descriptors, viz., electro-topological state of potential hydrogen bonds (maxHBint2, nHBint6), atom types (minssNH), maximum topological distance matrix (SpMAD_Dt), and 2D autocorrelation (ATSC7v), have been identified. Using this model, 14 natural compounds have been selected that have shown inhibitory activity for VEGFR2, of which six natural compounds have been found to possess a strong binding affinity with VEGFR2. In MD simulation, four complexes have shown binding stability up to 50ns.</p><p><strong>Conclusion: </strong>The developed QSAR model has identified 5 conserved activity-inducing physiochemical properties, which have been found to be correlated with the anticancer activity of the nonidentical ligand molecules bound with the VEGFR2 kinase. Lavendustin_A, 3'-O-acetylhamaudol, and arctigenin have been obtained as possible lead natural compounds against the VEGFR2 kinase.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":"646-661"},"PeriodicalIF":1.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139651052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PPARs (Peroxisome Proliferator-activated Receptors) and Their Agonists in Alzheimer's Disease.","authors":"Mohit Kumar, Anita Ashok Sharma, Ashok Kumar Datusalia, Gopal L Khatik","doi":"10.2174/0115734064295063240422100615","DOIUrl":"10.2174/0115734064295063240422100615","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a neurodegenerative disease leading to dementia because of complex phathomechanisms like amyloid β (Aβ) aggregation, tau aggregates, and neurofibrillary tangles. Peroxisome proliferator-activated receptor (PPAR) agonists have been reported recently with neuroprotective and anti-inflammatory properties. PPARs belong to the superfamily of nuclear hormone receptors and function as ligand-activated transcription factors. These have emerged as crucial players in the pathogenesis of AD. This review presented the potential of PPARs and their agonists in treating neurodegenerative diseases like AD. PPARs regulate the expression of specific genes vital for synaptic function and neurotransmitter release. PPAR agonists play a critical role in increasing the clearance of Aβ peptides by lowdensity lipoprotein receptor-related protein 1 (LRP1) in the microvascular endothelial cells of the human brain. Studies have shown that PPAR agonists reduce the level of APoE-mRNA, contributing to the accumulation of Aβ plaques and up-regulation of PPAR. A knockout of miR-128 has been found to inhibit AD-like cognitive decline, amyloid precursor protein (APP) amyloidogenic processing, and inflammatory responses in AD. PPARs are involved in the pathomechanism of AD, and therefore, PPAR agonists could be viable options for controlling the neurodegenerative symptoms and may be useful in treating AD.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":"781-798"},"PeriodicalIF":1.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140898785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and Antibacterial Evaluation of Novel Small-Molecule Antibacterials of a Reduced Acridine Structure in <i>S. aureus</i> Strains Including MRSA.","authors":"Peter Werner, David Kreutzer, Nikoletta Szemeredi, Gabriella Spengler, Andreas Hilgeroth","doi":"10.2174/0115734064302048240424045239","DOIUrl":"10.2174/0115734064302048240424045239","url":null,"abstract":"<p><strong>Background: </strong>The increasing antibacterial drug resistance remains a threat to global health with increasing mortality and morbidity. There is an urgent need to find novel antibacterials and develop alternative strategies to combat the increasing antibacterial drug resistance.</p><p><strong>Objective: </strong>We aimed to synthesize novel small-molecule antibacterials to evaluate the structuredependent antibacterial compound activities against S. aureus and MRSA.</p><p><strong>Methods: </strong>Compounds were synthesized by primary N-alkylation to form alkyl acridinium salts that were further functionalized with substituted phenyl residues and finally purified by column chromatography. The antibacterial growth inhibition activity was determined as MIC value.</p><p><strong>Results: </strong>The substituent effects on the determined antibacterial growth inhibitory properties have been discussed.</p><p><strong>Conclusion: </strong>The best activities have been found for compounds with methoxy functions, exceeding the activities of reported novel antibacterial peptides. The compounds have also shown antibacterial drug-enhancing effects, which have been manifested as a reduction in the MIC values of the used antibiotics.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":"831-838"},"PeriodicalIF":1.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140898787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}