MedChemComm最新文献_第6页

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 更正：3-(4-(4-(1,3,4-恶二唑-2-基)-1H-咪唑-2-基)苯基)-1,2,4-恶二唑衍生物作为有效表皮生长因子受体抑制剂的计算设计、合成和评估：抗癌治疗的前瞻性策略。

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MedChemComm Pub Date : 2024-10-15 DOI: 10.1039/D4MD90040E

Nilesh Raghunath Khedkar, Milind Sindkhedkar and Alex Joseph

引用次数: 0

Ligand-centred phenotype-driven development of potent kinase inhibitors against oesophageal cancer† 以配体为中心，以表型为导向，开发针对食道癌的强效激酶抑制剂。

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MedChemComm Pub Date : 2024-10-15 DOI: 10.1039/D4MD00579A

Cecilia C. Ayala-Aguilera, Yang Ge, Álvaro Lorente-Macías, Benjamin N. Jones, Catherine Adam, Neil O. Carragher and Asier Unciti-Broceta

{"title":"Ligand-centred phenotype-driven development of potent kinase inhibitors against oesophageal cancer†","authors":"Cecilia C. Ayala-Aguilera, Yang Ge, Álvaro Lorente-Macías, Benjamin N. Jones, Catherine Adam, Neil O. Carragher and Asier Unciti-Broceta","doi":"10.1039/D4MD00579A","DOIUrl":"10.1039/D4MD00579A","url":null,"abstract":"Oesophageal cancer (OC) is one of the leading causes of cancer-related deaths worldwide. Due in part to its high heterogeneity, OC prognosis remains poor despite the introduction of targeted and immunotherapy drugs. Although numerous kinases play a significant role in the oncogenesis and progression of OC, targeting kinases have shown so far limited therapeutic success. Based on our understanding of the pharmacological properties of the pyrazolo[3,4-d]pyrimidine scaffold and the complex biology of OC, we implemented a ligand-centred strategy combined with phenotypic screening to develop novel antiproliferative inhibitors against OC. This approach is specifically designed to accelerate the discovery of lead compounds in cancers of high molecular heterogeneity such as OC. In an iterative process driven by structure–antiproliferative activity relationships (SAARs), we synthesised and tested 54 novel pyrazolo[3,4-d]pyrimidine derivatives against OC cell lines. The lead compound 2D7 (a.k.a. eCCA352) induces pan-OC activity and cell cycle arrest in the submicromolar range and was determined to inhibit Aurora kinase A, providing a new starting point to develop anticancer targeted agents against OC.","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 1","pages":" 379-391"},"PeriodicalIF":3.597,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11528321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142570976","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}

引用次数: 0

Natural product-inspired [3 + 2] cycloaddition-based spirooxindoles as dual anticancer agents: synthesis, characterization, and biological evaluation by in vitro and in silico methods† 受天然产物启发的基于 [3 + 2] 环加成的螺氧化吲哚作为双重抗癌剂：通过体外和硅学方法进行合成、表征和生物学评价。

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MedChemComm Pub Date : 2024-10-11 DOI: 10.1039/D4MD00634H

Narayanasamy Nivetha, Jevid Don Hamid, Akshaya Simha N, Devanand Devegowda, Ramith Ramu and Sivan Velmathi

引用次数: 0

Therapeutic upregulation of DNA repair pathways: strategies and small molecule activators DNA 修复途径的治疗性上调：策略和小分子激活剂。

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MedChemComm Pub Date : 2024-10-11 DOI: 10.1039/D4MD00673A

Juhyung Song, Cheoljun Park, Francis E. B. Cabanting and Yong Woong Jun

引用次数: 0

Design, synthesis and mechanistic insights into triclosan derived dimers as potential anti-plasmodials† 三氯生衍生二聚体作为潜在抗疟药物的设计、合成和机理研究。

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MedChemComm Pub Date : 2024-10-11 DOI: 10.1039/D4MD00494A

Shekhar, Shefali Chowdhary, Joel Mosnier, Isabelle Fonta, Bruno Pradines and Vipan Kumar

{"title":"Design, synthesis and mechanistic insights into triclosan derived dimers as potential anti-plasmodials†","authors":"Shekhar, Shefali Chowdhary, Joel Mosnier, Isabelle Fonta, Bruno Pradines and Vipan Kumar","doi":"10.1039/D4MD00494A","DOIUrl":"10.1039/D4MD00494A","url":null,"abstract":"In pursuit of novel anti-plasmodial agents, a library of triclosan-based dimers both with and without a 1H-1,2,3 triazole core were designed and synthesized in order to achieve a multitargeted approach. In vitro assessment against chloroquine-susceptible (3D7) and resistant (W2) P. falciparum strains identified that two of the synthesized dimers containing triazole were the most potent in the series. The most potent of the synthesized compounds exhibited IC50 values of 9.27 and 12.09 μM against the CQ-resistant (W2) and CQ-susceptible (3D7) strains of P. falciparum, with an RI of 0.77, suggesting little or no cross-resistance with CQ. Heme binding and molecular modelling studies revealed the most promising scaffold as a dual inhibitor for hemozoin formation and a P. falciparum chloroquine resistance transporter (PfCRT), respectively. In silico studies of the most potent compound revealed that it shows better binding affinity with PfACP and PfCRT compared to TCS. To the best of our knowledge, this is the first report of triclosan-based compounds demonstrating promising heme-inhibition behaviour, with binding values comparable to those of chloroquine (CQ).","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 2","pages":" 709-720"},"PeriodicalIF":3.597,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142507035","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}

引用次数: 0

A decade of pyridine-containing heterocycles in US FDA approved drugs: a medicinal chemistry-based analysis 美国 FDA 批准药物中含吡啶杂环的十年：基于药物化学的分析。

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MedChemComm Pub Date : 2024-10-10 DOI: 10.1039/D4MD00632A

Ashish Ranjan Dwivedi, Shivani Jaiswal, Deepak Kukkar, Roshan Kumar, Thakur Gurjeet Singh, Mahendra Pratap Singh, Abhay M. Gaidhane, Sorabh Lakhanpal, K. Nagendra Prasad and Bhupinder Kumar

{"title":"A decade of pyridine-containing heterocycles in US FDA approved drugs: a medicinal chemistry-based analysis","authors":"Ashish Ranjan Dwivedi, Shivani Jaiswal, Deepak Kukkar, Roshan Kumar, Thakur Gurjeet Singh, Mahendra Pratap Singh, Abhay M. Gaidhane, Sorabh Lakhanpal, K. Nagendra Prasad and Bhupinder Kumar","doi":"10.1039/D4MD00632A","DOIUrl":"10.1039/D4MD00632A","url":null,"abstract":"Heterocyclic scaffolds, particularly, pyridine-containing azaheterocycles, constitute a major part of the drugs approved in the past decade. In the present review, we explored the pyridine ring part of US FDA-approved small molecules (2014–2023). The analysis of the approved drugs bearing a pyridine ring revealed that a total of 54 drugs were approved. Among them, the significant number comprised the anticancer category (18 drugs, 33%), followed by drugs affecting the CNS system (11 drugs, 20%), which include drugs to treat migraines, Parkinsonism disorders, chemotherapeutic-induced nausea, insomnia, and ADHD or as CNS-acting analgesics or sedatives. Next, six drugs (11%) were also approved to treat rare conditions, followed by five drugs that affect the hematopoietic system. The analysis also revealed that drug approval was granted for antibiotics, antivirals, and antifungals, including drugs for the treatment of tropical and sub-tropical diseases. Primary drug targets explored were kinases, and the major metabolizing enzyme was CYP3A4. Further analysis of formulation types revealed that 50% of the approved drugs were tablets, followed by 17% capsules and 15% injections. Elemental analysis showed that most approved drugs contained sulfur, while fluorine was noted in 32 compounds. Therefore, the present review is a concerted effort to cover drugs bearing pyridine rings approved in the last decade and provide thorough discussion and commentary on their pharmacokinetics and pharmacodynamics aspects. Furthermore, in-depth structural and elemental analyses were explored, thus providing comprehensive guidance for medicinal chemists and scientists working in allied science domains.","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 1","pages":" 12-36"},"PeriodicalIF":3.597,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568074","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}

引用次数: 0

Introduction to the themed collection on ‘AI in Medicinal Chemistry’ 药物化学中的人工智能 "主题文集简介

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MedChemComm Pub Date : 2024-10-09 DOI: 10.1039/D4MD90035A

Jian Zhang, Ola Engkvist and Gerhard Hessler

引用次数: 0

Continuous flow synthesis of N,N-dimethyltryptamine (DMT) analogues with therapeutic potential† 具有治疗潜力的 N,N-二甲基色胺 (DMT) 类似物的连续流合成。

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MedChemComm Pub Date : 2024-10-07 DOI: 10.1039/D4MD00562G

Andreas Simoens, Andreas Dejaegere, Marthe Vandevelde and Christian V. Stevens

引用次数: 0

Novel benzenesulfonamides containing a dual triazole moiety with selective carbonic anhydrase inhibition and anticancer activity† 具有选择性碳酸酐酶抑制和抗癌活性的含有双重三唑分子的新型苯磺酰胺类化合物。

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MedChemComm Pub Date : 2024-10-04 DOI: 10.1039/D4MD00617H

Aida Buza, Cüneyt Türkeş, Mustafa Arslan, Yeliz Demir, Busra Dincer, Arleta Rifati Nixha and Şükrü Beydemir

{"title":"Novel benzenesulfonamides containing a dual triazole moiety with selective carbonic anhydrase inhibition and anticancer activity†","authors":"Aida Buza, Cüneyt Türkeş, Mustafa Arslan, Yeliz Demir, Busra Dincer, Arleta Rifati Nixha and Şükrü Beydemir","doi":"10.1039/D4MD00617H","DOIUrl":"10.1039/D4MD00617H","url":null,"abstract":"A series of sulfonamides incorporating a 1,2,3-triazolyloxime substituted 1,2,3-triazolyl moiety were conceptualized and synthesized as human carbonic anhydrase (hCA) inhibitors. The synthesized small structures, denoted 7a through 7o, exhibited moderate inhibitory effects against the tumor-associated isoforms hCA IX and hCA XII compared to the well-known hCA inhibitor acetazolamide. In contrast, these molecules demonstrated higher potency and a diverse range of selectivity against the cytosolic isoforms hCA I and hCA II. Notably, the 4-hydroxyphenyl derivative (compound 7dversus cytosolic isoforms), the 4-acetylphenyl derivative (compound 7o), and the phenyl derivative (compound 7a) emerged as the most potent and selective inhibitors in this series, with inhibition constants (KI) of 47.1, 35.9, 170.0, and 149.9 nM, respectively, against hCA I, II, IX, and XII. Further cytotoxicity assays of compounds 7a–o against cancer cell lines Hep3B and A549, as well as normal cell line L929, were conducted to assess their selectivity towards malignant cells. Compounds 7d, 7g, and 7k exhibited selective cytotoxicity towards the Hep3B cell line, with reduced selectivity towards A549, whereas compound 7j demonstrated higher selectivity for the A549 cell line. Additionally, molecular docking studies were performed to elucidate the binding modes of these compounds within the active sites of hCAs, revealing crucial interactions that underpin their significant activity and selectivity for the tumor-specific isoforms.","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 1","pages":" 324-345"},"PeriodicalIF":3.597,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568514","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}

引用次数: 0

Pathogenesis of Alzheimer's disease and therapeutic strategies involving traditional Chinese medicine 阿尔茨海默病的发病机理和中医治疗策略。

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MedChemComm Pub Date : 2024-10-03 DOI: 10.1039/D4MD00660G

Shutang Li and Jinfei Yang

{"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":"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.","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}

引用次数: 0