RSC medicinal chemistry最新文献_第10页

Advances in antibacterial agents for Mycobacterium fortuitum† 治疗坚固分枝杆菌的抗菌剂的进展。

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2024-10-18 DOI: 10.1039/D4MD00508B

Carlos Roberto Tavolari Jortieke, Angélica Rocha Joaquim and Fernando Fumagalli

{"title":"Advances in antibacterial agents for Mycobacterium fortuitum†","authors":"Carlos Roberto Tavolari Jortieke, Angélica Rocha Joaquim and Fernando Fumagalli","doi":"10.1039/D4MD00508B","DOIUrl":"10.1039/D4MD00508B","url":null,"abstract":" Mycobacterium fortuitum is an emerging human pathogen, characterized by an increase in prevalence and antibacterial resistance over the years, highlighting the need for the development of new drugs against this rapidly growing nontuberculous mycobacterium (NTM). To support this crusade, this review summarizes findings from the past two decades concerning compounds with antimycobacterial activity against M. fortuitum. It identifies the most promising and effective chemical frameworks to inspire the development of new therapeutic alternatives for infections caused by this microorganism. Most compounds effective against M. fortuitum are synthetic, with macozinone, featuring a 2-piperazine-benzothiazinone framework, standing out as a notable drug candidate. Among natural products, the polyphenolic polyketide clostrubin and the sansanmycin peptide analogs have shown efficacy against this NTM. Some compounds' mechanisms of action on M. fortuitum have been studied, including NITD-916, which acts as an enoyl-acyl carrier protein reductase inhibitor, and TBAJ-5307, which inhibits F-ATP synthase. Moreover, this review discusses the pathogenic molecular mechanisms and potential therapeutic targets within this mycobacterium.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 1","pages":" 37-49"},"PeriodicalIF":4.1,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568297","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}

引用次数: 0

Design, synthesis, and structure–activity relationship studies of 6H-benzo[b]indeno[1,2-d]thiophen-6-one derivatives as DYRK1A/CLK1/CLK4/haspin inhibitors† 作为 DYRK1A/CLK1/CLK4/haspin 抑制剂的 6H-苯并[b]茚并[1,2-d]噻吩-6-酮衍生物的设计、合成和结构-活性关系研究。

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2024-10-17 DOI: 10.1039/D4MD00537F

Abdelfattah Faouzi, Alexandre Arnaud, François Hallé, Jean Roussel, Mandy Aymard, Vincent Denavit, Cong Viet Do, Angélique Mularoni, Mohamed Salah, Ahmed ElHady, Thanh-Nhat Pham, Alexandre Bancet, Marc Le Borgne, Raphaël Terreux, Roland Barret, Matthias Engel and Thierry Lomberget

{"title":"Design, synthesis, and structure–activity relationship studies of 6H-benzo[b]indeno[1,2-d]thiophen-6-one derivatives as DYRK1A/CLK1/CLK4/haspin inhibitors†","authors":"Abdelfattah Faouzi, Alexandre Arnaud, François Hallé, Jean Roussel, Mandy Aymard, Vincent Denavit, Cong Viet Do, Angélique Mularoni, Mohamed Salah, Ahmed ElHady, Thanh-Nhat Pham, Alexandre Bancet, Marc Le Borgne, Raphaël Terreux, Roland Barret, Matthias Engel and Thierry Lomberget","doi":"10.1039/D4MD00537F","DOIUrl":"10.1039/D4MD00537F","url":null,"abstract":"A series of sulfur-containing tetracycles was designed and evaluated for their ability to inhibit protein kinase DYRK1A, a target known to have several potential therapeutic applications including cancers, Down syndrome or Alzheimer's disease. Our medicinal chemistry strategy relied on the design of new compounds using ring contraction/isosteric replacement and constrained analogy of known DYRK1A inhibitors, thus resulting in their DYRK1A inhibitory activity enhancement. Whereas a good inhibitory effect of targeted DYRK1A protein was observed for 5-hydroxy compounds 4i–k (IC50 = 35–116 nM) and the 5-methoxy derivative 4e (IC50 = 52 nM), a fairly good selectivity towards its known DYRK1B off-target was observed for 4k. In addition, the most active compound 4k, having an ATP-competitive mechanism of action, proved to be also a potent inhibitor of CLK1/CLK4 (IC50 = 20 and 26 nM) and, to a lesser extent, of haspin (IC50 = 76 nM) kinases. In silico docking studies within the DYRK1A, CLK1/CLK4 and haspin ATP binding sites were carried out to understand the interactions of our tetracyclic derivatives 4 with these targets. Antiproliferative activities on U87/U373 glioblastoma cell lines of the most potent compound 4k showed a moderate effect (IC50 values between 33 and 46 μM). Microsomal stabilities of the designed compounds 4a–m were also investigated, showing great disparities, depending on benzo[b]thiophene ring 5-substitution.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 1","pages":" 179-199"},"PeriodicalIF":4.1,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11487425/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473768","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}

引用次数: 0

Design, synthesis, and evaluation of benzhydrylpiperazine-based novel dual COX-2/5-LOX inhibitors with anti-inflammatory and anti-cancer activity† 设计、合成和评估具有抗炎和抗癌活性的基于苯甲基哌嗪的新型 COX-2/5-LOX 双重抑制剂。

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2024-10-17 DOI: 10.1039/D4MD00471J

Poorvi Saraf, Bhagwati Bhardwaj, Akash Verma, Mohammad Aquib Siddiqui, Himanshu Verma, Pradeep Kumar, Samridhi Srivastava, Sairam Krishnamurthy, Saripella Srikrishna and Sushant Kumar Shrivastava

{"title":"Design, synthesis, and evaluation of benzhydrylpiperazine-based novel dual COX-2/5-LOX inhibitors with anti-inflammatory and anti-cancer activity†","authors":"Poorvi Saraf, Bhagwati Bhardwaj, Akash Verma, Mohammad Aquib Siddiqui, Himanshu Verma, Pradeep Kumar, Samridhi Srivastava, Sairam Krishnamurthy, Saripella Srikrishna and Sushant Kumar Shrivastava","doi":"10.1039/D4MD00471J","DOIUrl":"10.1039/D4MD00471J","url":null,"abstract":"Piperazine derivatives were screened using the ChEMBL database, paving the way for the design, synthesis, and evaluation of a novel series of dual COX-2/5-LOX inhibitors and identifying their role in mitigating cancer cell proliferation. Compound 9d with 4-Cl substitution at the terminal phenyl ring showed promising inhibition of COX-2 (IC50 = 0.25 ± 0.03 μM) and 5-LOX (IC50 = 7.87 ± 0.33 μM), outperforming the standards celecoxib (IC50 = 0.36 ± 0.023 μM) and zileuton (IC50 = 14.29 ± 0.173 μM), respectively. The two most active derivatives 9d and 9g indicated a significant anti-inflammatory response in a paw edema model by inhibiting PGE2, IL-6, and TNF-α and an increase in IL-10 concentrations. Interestingly, 9d effectively reduced pain by 55.78%, closely comparable to the 59.09% exhibited by the standard indomethacin, and was also devoid of GI, liver, kidney, and cardiac toxicity. Furthermore, 9d demonstrated anti-cancer potential against in vitro A549, COLO-205, and MIA-PA-CA-2 human cancer cell lines and an in vivo Drosophila cancer model. The pharmacokinetic investigations revealed that 9d has good oral absorption characteristics.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 1","pages":" 200-220"},"PeriodicalIF":4.1,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473753","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}

引用次数: 0

Synthesis and anti-tumor activity of new benzofuran-based chalcone derivatives as potent VEGFR-2 inhibitors† 新型苯并呋喃基查尔酮衍生物作为强效 VEGFR-2 抑制剂的合成与抗肿瘤活性。

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2024-10-16 DOI: 10.1039/D4MD00621F

Chunfei Zhang, Yixin Liu, Xiao Zhang, Chunping Wan and Zewei Mao

引用次数: 0

Enhancing the antimycobacterial efficacy of pyridine-4-carbohydrazide: linkage to additional antimicrobial agents via oxocarboxylic acids† 增强吡啶-4-甲酰肼的抗霉菌功效：通过氧羧酸与其他抗菌剂连接。

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2024-10-16 DOI: 10.1039/D4MD00663A

Václav Pflégr, Klára Konečná, Jiřina Stolaříková, Jan Ősterreicher, Ondřej Janďourek and Martin Krátký

{"title":"Enhancing the antimycobacterial efficacy of pyridine-4-carbohydrazide: linkage to additional antimicrobial agents via oxocarboxylic acids†","authors":"Václav Pflégr, Klára Konečná, Jiřina Stolaříková, Jan Ősterreicher, Ondřej Janďourek and Martin Krátký","doi":"10.1039/D4MD00663A","DOIUrl":"10.1039/D4MD00663A","url":null,"abstract":"This study evaluates the antimycobacterial potential of novel “mutual” bioactive amides, combining pyridine-4-carbohydrazide (isoniazid, INH) with various antimicrobial agents (sulphonamides, 4-aminosalicylic acid, thiosemicarbazide, diphenyl (thio)ethers) via oxocarboxylic acids. The aim was to enhance activity against both drug-susceptible and multidrug-resistant (MDR) Mycobacterium tuberculosis and non-tuberculous strains, while overcoming drug resistance through dual-action mechanisms. Many derivatives exhibited potent antimycobacterial activity, with minimum inhibitory concentrations (MICs) as low as ≤0.25 μM, outperforming INH, especially diphenyl (thio)ethers and biphenyl analogues. Additionally, the compounds were effective against M. kansasii (MICs ≤1 μM) and inhibited MDR strains at higher concentrations (≥8 μM). The cytotoxicity assay indicated a favourable safety profile, with no significant haemolysis at 125 μM, and some compounds were even protective. Selectivity for mycobacteria was confirmed by low inhibition of Gram-positive bacteria and inactivity against Gram-negative bacteria or fungi, highlighting the potential for further development as antimycobacterial agents.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 2","pages":" 767-778"},"PeriodicalIF":4.1,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11575622/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142682722","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}

引用次数: 0

Breaking boundaries in diabetic nephropathy treatment: design and synthesis of novel steroidal SGLT2 inhibitors† 打破糖尿病肾病治疗的界限：新型甾体 SGLT2 抑制剂的设计与合成。

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2024-10-15 DOI: 10.1039/D4MD00645C

Geetmani Singh Nongthombam, Semim Akhtar Ahmed, Kangkon Saikia, Sanjib Gogoi and Jagat Chandra Borah

{"title":"Breaking boundaries in diabetic nephropathy treatment: design and synthesis of novel steroidal SGLT2 inhibitors†","authors":"Geetmani Singh Nongthombam, Semim Akhtar Ahmed, Kangkon Saikia, Sanjib Gogoi and Jagat Chandra Borah","doi":"10.1039/D4MD00645C","DOIUrl":"10.1039/D4MD00645C","url":null,"abstract":"The activity of sodium glucose co-transporter 2 (SGLT2) has always been an important parameter influencing chronic kidney disease in type-2 diabetic patients. Herein, we have meticulously designed, synthesized, and evaluated several novel steroidal pyrimidine molecules that possess the capability to successfully bind to the SGLT2 protein and inhibit its activity, thereby remedying kidney-related ailments in diabetic patients. The lead steroidal pyrimidine compounds were selected after virtually screening from a library of probable N-heterocyclic steroidal scaffolds. A nano-catalyzed synthetic route was also explored for the synthesis of the steroidal pyrimidine analogs demonstrating an environmentally benign protocol. Extensive in vitro investigations encompassing SGLT2 screening assays and cell viability assessments were conducted on the synthesized compounds. Among the steroidal pyrimidine derivatives evaluated, compound 9a exhibited the highest SGLT2 inhibition activity and underwent further scrutiny. Western blot analysis was employed to determine the impact of 9a on inflammatory and fibrotic proteins, aiming to elucidate its mechanism of action. Additionally, in silico analyses were performed to illuminate the structural dynamics and molecular interaction mechanism of 9a. The overall investigation is crucial for advancing the development of the next generation of anti-diabetic drugs.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 1","pages":" 296-311"},"PeriodicalIF":4.1,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547111","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}

引用次数: 0

Synthesis and evaluation of tetrahydropyrrolo[1,2-a]quinolin-1(2H)-ones as new tubulin polymerization inhibitors† 四氢吡咯并[1,2-a]喹啉-1(2H)-酮作为新的小管蛋白聚合抑制剂的合成与评估。

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2024-10-15 DOI: 10.1039/D4MD00541D

Mikhail N. Anisimov, Maksim A. Boichenko, Vitaly V. Shorokhov, Julia N. Borzunova, Marina Janibekova, Vadim V. Mustyatsa, Ilya A. Lifshits, Andrey Yu. Plodukhin, Ivan A. Andreev, Nina K. Ratmanova, Sergey S. Zhokhov, Elena A. Tarasenko, Daria A. Ipatova, Alexander R. Pisarev, Ivan A. Vorobjev, Igor V. Trushkov, Olga A. Ivanova and Nikita B. Gudimchuk

{"title":"Synthesis and evaluation of tetrahydropyrrolo[1,2-a]quinolin-1(2H)-ones as new tubulin polymerization inhibitors†","authors":"Mikhail N. Anisimov, Maksim A. Boichenko, Vitaly V. Shorokhov, Julia N. Borzunova, Marina Janibekova, Vadim V. Mustyatsa, Ilya A. Lifshits, Andrey Yu. Plodukhin, Ivan A. Andreev, Nina K. Ratmanova, Sergey S. Zhokhov, Elena A. Tarasenko, Daria A. Ipatova, Alexander R. Pisarev, Ivan A. Vorobjev, Igor V. Trushkov, Olga A. Ivanova and Nikita B. Gudimchuk","doi":"10.1039/D4MD00541D","DOIUrl":"10.1039/D4MD00541D","url":null,"abstract":"Here we explored new 1,5-disubstituted pyrrolidin-2-ones 1, 2 and 5-aryl-3,3a,4,5-tetrahydropyrrolo[1,2-a]quinoline-1(2H)-ones 3 as inhibitors of tubulin polymerization. We evaluated their effects on microtubule dynamics in vitro and on the proliferation of A549 cells, using flow cytometry-based cell cycle analysis. The results were verified with phase-contrast microscopy in three cancer cell lines: A549, HeLa and MCF-7. Guided by molecular modeling of the interactions between tubulin and the most active of the identified compounds, we designed, synthesized, and tested the 3-hydroxyphenyl-substituted compound 3c. This compound was further shown to bind to the colchicine site of tubulin and reduce microtubule growth rates in vitro. Moreover, compound 3c arrested division of the A549 cells in the low micromolar range (IC50 = 5.9 μM) and exhibited cytotoxicity against four different cell lines in the MTT assay for cell proliferation. Our findings demonstrate that 5-aryltetrahydropyrrolo[1,2-a]quinoline-1(2H)-one is a promising scaffold for the development of novel tubulin polymerization inhibitors.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 1","pages":" 274-285"},"PeriodicalIF":4.1,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142507038","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}

引用次数: 0

Modulating polybasic character of galactose-based glycosylated antitumor ether lipids for enhanced cytotoxic response† 调节基于半乳糖的糖基化抗肿瘤醚脂的多基性，以增强细胞毒性反应。

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2024-10-14 DOI: 10.1039/D4MD00662C

Rajat Arora, Ayan Mukherjee, Gilbert Arthur, Mark W. Nachtigal and Frank Schweizer

引用次数: 0

Recent advances from computer-aided drug design to artificial intelligence drug design 从计算机辅助药物设计到人工智能药物设计的最新进展。

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2024-10-11 DOI: 10.1039/D4MD00522H

Keran Wang, Yanwen Huang, Yan Wang, Qidong You and Lei Wang

{"title":"Recent advances from computer-aided drug design to artificial intelligence drug design","authors":"Keran Wang, Yanwen Huang, Yan Wang, Qidong You and Lei Wang","doi":"10.1039/D4MD00522H","DOIUrl":"10.1039/D4MD00522H","url":null,"abstract":"Computer-aided drug design (CADD), a cornerstone of modern drug discovery, can predict how a molecular structure relates to its activity and interacts with its target using structure-based and ligand-based methods. Fueled by ever-increasing data availability and continuous model optimization, artificial intelligence drug design (AIDD), as an enhanced iteration of CADD, has thrived in the past decade. AIDD demonstrates unprecedented opportunities in protein folding, property prediction, and molecular generation. It can also facilitate target identification, high-throughput screening (HTS), and synthetic route prediction. With AIDD involved, the process of drug discovery is greatly accelerated. Notably, AIDD offers the potential to explore uncharted territories of chemical space beyond current knowledge. In this perspective, we began by briefly outlining the main workflows and components of CADD. Then through showcasing exemplary cases driven by AIDD in recent years, we describe the evolving role of artificial intelligence (AI) in drug discovery from three distinct stages, that is, chemical library screening, linker generation, and de novo molecular generation. In this process, we attempted to draw comparisons between the features of CADD and AIDD.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 12","pages":" 3978-4000"},"PeriodicalIF":4.1,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568527","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}

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

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2024-10-09 DOI: 10.1039/D4MD90035A

Jian Zhang, Ola Engkvist and Gerhard Hessler

引用次数: 0