RSC medicinal chemistry最新文献

Property-based optimisation of PROTACs. 基于属性的 PROTACs 优化。

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2024-11-07 DOI: 10.1039/d4md00769g

James S Scott, Iacovos N Michaelides, Markus Schade

引用次数: 0

A practical guide for the assay-dependent characterisation of irreversible inhibitors. 不可逆抑制剂特性测定实用指南。

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2024-11-01 DOI: 10.1039/d4md00707g

Lavleen K Mader, Jessica E Borean, Jeffrey W Keillor

{"title":"A practical guide for the assay-dependent characterisation of irreversible inhibitors.","authors":"Lavleen K Mader, Jessica E Borean, Jeffrey W Keillor","doi":"10.1039/d4md00707g","DOIUrl":"https://doi.org/10.1039/d4md00707g","url":null,"abstract":"Irreversible targeted covalent inhibitors, in the past regarded as inappropriately reactive and toxic, have seen a recent resurgence in clinical interest. This paradigm shift is attributed to the exploitation of the two-step mechanism, in which a high affinity and selectivity (i.e., low K I) scaffold binds the target and only then does a pendant low intrinsic reactivity warhead react with the target (moderate k inact). This highlights the importance of evaluating inhibitors by deriving both their K I and k inact values. The development of methods to evaluate these inhibitors by accounting for their time-dependent nature has been crucial to the discovery of promising clinical candidates. Herein, we report all the practical kinetic methods available to date to derive k inact and K I values. These methods include direct observation of covalent modification, continuous assay (Kitz & Wilson) evaluation, and discontinuous incubation and pre-incubation time-dependent IC50 assays. We also provide practical guidelines and examples for performing these assays, comparison of their utility, and perspectives for their extended applications. This review aims to provide clarity about the use of these methods for reporting complete inhibitor kinetic profiles, guiding irreversible drug development towards increased target affinity and selectivity, while modulating in vivo stability and on-target reactivity.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11544421/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142627395","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

Adjuvant strategies to tackle mcr-mediated polymyxin resistance. 应对 mcr 介导的多粘菌素抗药性的辅助策略。

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2024-11-01 DOI: 10.1039/d4md00654b

Madison R Nuske, Junlang Zhong, Renjie Huang, Vijayalekshmi Sarojini, Jack L Y Chen, Christopher J Squire, Mark A T Blaskovich, Ivanhoe K H Leung

引用次数: 0

Synthesis and antifungal evaluation of new azole derivatives containing 1,2,3-triazole. 含有 1,2,3- 三唑的新型唑衍生物的合成和抗真菌评价。

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2024-10-29 DOI: 10.1039/d4md00724g

Zhengxiao Huang, Hongjie Chen, Xiao Zhang, Ruirui Wang, Chunyan Hu, Zewei Mao

引用次数: 0

Human microbiome derived synthetic antimicrobial peptides with activity against Gram-negative, Gram-positive, and antibiotic resistant bacteria. 人类微生物组衍生的合成抗菌肽对革兰氏阴性菌、革兰氏阳性菌和抗生素耐药菌具有活性。

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2024-10-28 DOI: 10.1039/d4md00383g

Walaa K Mousa, Ashif Y Shaikh, Rose Ghemrawi, Mohammed Aldulaimi, Aya Al Ali, Nour Sammani, Mostafa Khair, Mohamed I Helal, Farah Al-Marzooq, Emilia Oueis

{"title":"Human microbiome derived synthetic antimicrobial peptides with activity against Gram-negative, Gram-positive, and antibiotic resistant bacteria.","authors":"Walaa K Mousa, Ashif Y Shaikh, Rose Ghemrawi, Mohammed Aldulaimi, Aya Al Ali, Nour Sammani, Mostafa Khair, Mohamed I Helal, Farah Al-Marzooq, Emilia Oueis","doi":"10.1039/d4md00383g","DOIUrl":"10.1039/d4md00383g","url":null,"abstract":"The prevalence of antibacterial resistance has become one of the major health threats of modern times, requiring the development of novel antibacterials. Antimicrobial peptides are a promising source of antibiotic candidates, mostly requiring further optimization to enhance druggability. In this study, a series of new antimicrobial peptides derived from lactomodulin, a human microbiome natural peptide, was designed, synthesized, and biologically evaluated. Within the most active region of the parent peptide, linear peptide LM6 with the sequence LSKISGGIGPLVIPV-NH2 and its cyclic derivatives LM13a and LM13b showed strong antibacterial activity against Gram-positive bacteria, including resistant strains, and Gram-negative bacteria. The peptides were found to have a rapid onset of bactericidal activity and transmission electron microscopy clearly shows the disintegration of the cell membrane, suggesting a membrane-targeting mode of action.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11520653/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547112","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

Light enhanced cytotoxicity and antitumoral effect of a ruthenium-based photosensitizer inspired from natural alkaloids. 从天然生物碱中得到启发的钌基光敏剂的光增强细胞毒性和抗肿瘤作用。

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2024-10-25 DOI: 10.1039/d4md00600c

Gennaro Sanità, Maria Laura Alfieri, Barbara Carrese, Serena Damian, Vincenza Mele, Gaetano Calì, Brigida Silvestri, Sebastiano Marra, Susan Mohammadi, Giuseppina Luciani, Paola Manini, Annalisa Lamberti

{"title":"Light enhanced cytotoxicity and antitumoral effect of a ruthenium-based photosensitizer inspired from natural alkaloids.","authors":"Gennaro Sanità, Maria Laura Alfieri, Barbara Carrese, Serena Damian, Vincenza Mele, Gaetano Calì, Brigida Silvestri, Sebastiano Marra, Susan Mohammadi, Giuseppina Luciani, Paola Manini, Annalisa Lamberti","doi":"10.1039/d4md00600c","DOIUrl":"https://doi.org/10.1039/d4md00600c","url":null,"abstract":"In this work, we report on the synthesis and properties of a new sensitizer for photodynamic therapy applications, constituted by a ruthenium(ii) complex (1) featuring a ligand inspired from natural isoquinoline alkaloids. The spectroscopic analysis revealed that 1 is characterized by an intense red emission (λ em = 620 nm, Φ = 0.17) when excited at 550 nm, a low energy radiation warranting for a safe therapeutic approach. The phototoxicity of 1 on human breast cancer (Hs578T) and melanoma (A375) cell lines was assessed after irradiation using a LED lamp (525 nm, total fluence 10 J cm-2). In vitro biological assays indicated that the cytotoxicity of 1 was significantly enhanced by light reaching IC50 values below the micromolar threshold. The cell damage induced by 1 proved to be strictly connected with the overproduction of reactive oxygen species (ROS) responsible for mitochondrial dysfunction leading to the activation of caspases and then to apoptosis, and for DNA photocleavage leading to cell cycle arrest.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11565246/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648594","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

Synthesis, in silico and bio-evaluation studies of new isothiocyanate derivatives with respect to COX inhibition and H₂S release profiles. 关于 COX 抑制和 H2S 释放特征的新异硫氰酸盐衍生物的合成、硅学和生物评估研究。

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2024-10-24 DOI: 10.1039/d4md00495g

Yakup Berkay Yilmaz, Tuğba Güngör, Serhat Dönmez, Hazal Nazlıcan Atalay, Pınar Siyah, Serdar Durdağı, Mehmet Ay, Tugba Boyunegmez Tumer

{"title":"Synthesis, in silico and bio-evaluation studies of new isothiocyanate derivatives with respect to COX inhibition and H2S release profiles.","authors":"Yakup Berkay Yilmaz, Tuğba Güngör, Serhat Dönmez, Hazal Nazlıcan Atalay, Pınar Siyah, Serdar Durdağı, Mehmet Ay, Tugba Boyunegmez Tumer","doi":"10.1039/d4md00495g","DOIUrl":"10.1039/d4md00495g","url":null,"abstract":"The development of H2S-donating derivatives of non-steroidal anti-inflammatory drugs (NSAIDs) is considered important to reduce or overcome their gastrointestinal side effects. Sulforaphane, one of the most extensively studied isothiocyanates (ITCs), effectively releases H2S at a slow rate. Thus, we rationally designed, synthesized, and characterized new ITC derivatives (I1-3 and I1a-e) inspired by the natural compound sulforaphane. The anti-inflammatory properties of these compounds were evaluated by their inhibitory activities against cyclooxygenase targets COX-1 and COX-2. Additionally, the cytotoxicity of the compounds was tested using the MTT assay on LPS-induced RAW 264.7 cells, revealing no cytotoxic effects at low doses. Notably, compounds I1 and fluorine-containing ester derivative I1c emerged as the most potent and selective COX-2 inhibitors, with selectivity indexes of 2611.5 and 2582.4, respectively. The H2S-releasing capacities of ITC derivatives were investigated and compared with that of sulforaphane, showing that while compounds I1-3 exhibit slow and similar H2S release to sulforaphane, the release from compounds I1a-e was not as pronounced as that of the standard. Physics-based molecular modeling studies including molecular docking and molecular dynamics (MD) simulations, binding free energy calculations and absorption, distribution, metabolism, and excretion (ADME) analyses were also conducted. MD simulations analysis underscored the crucial amino acids such as Tyr385, Trp387, Phe518, Val523, and Ser530 in the interactions between I1c hit compound and COX-2. The combined in silico and in vitro findings suggest that compounds I1 and I1c are promising NSAID candidates against selective COX-2 inhibition.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11536671/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590952","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

Correction: Anti-schistosomal activity and ADMET properties of 1,2,5-oxadiazinane-containing compound synthesized by visible-light photoredox catalysis. 更正：利用可见光光氧化催化合成的含 1,2,5-恶二嗪化合物的抗血吸虫活性和 ADMET 特性。

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2024-10-24 DOI: 10.1039/d4md90044h

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, Hideaki Fujii

引用次数: 0

Development, biological evaluation, and molecular modelling of some benzene-sulfonamide derivatives as protein tyrosine phosphatase-1B inhibitors for managing diabetes mellitus and associated metabolic disorders. 一些苯磺酰胺衍生物作为蛋白酪氨酸磷酸酶-1B 抑制剂用于控制糖尿病和相关代谢紊乱的开发、生物评估和分子建模。

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2024-10-23 DOI: 10.1039/d4md00594e

Nagat Ghareb, Khaled M Darwish, Mohamed S Nafie, Ranwa Elrayess, Noha M Abourobe, Shaimaa A Fattah, Reem M Hazem, Eman T Mehanna, Ranza Elrayess

{"title":"Development, biological evaluation, and molecular modelling of some benzene-sulfonamide derivatives as protein tyrosine phosphatase-1B inhibitors for managing diabetes mellitus and associated metabolic disorders.","authors":"Nagat Ghareb, Khaled M Darwish, Mohamed S Nafie, Ranwa Elrayess, Noha M Abourobe, Shaimaa A Fattah, Reem M Hazem, Eman T Mehanna, Ranza Elrayess","doi":"10.1039/d4md00594e","DOIUrl":"10.1039/d4md00594e","url":null,"abstract":"Exploring new inhibitors with good bioavailability and high selectivity for managing type 2 diabetes mellitus (T2DM) and its associated complications is a major challenge for research, academia, and the pharmaceutical industry. Protein tyrosine phosphatase-1B (PTP1B) arose as an important negative regulator in insulin signaling pathways associated with metabolic disorders, including T2DM and obesity. Novel neutral compounds with a benzene-sulfonamide scaffold were designed and synthesized based on structural- and ligand-based drug design strategies for fragment growth. Promising hits against PTP1B were identified through in vitro enzymology inhibition assay. Mechanistic aspects of the compound's different inhibition activities were rigorously investigated through molecular docking coupled with explicit dynamics simulations. Four identified hits, 3c, 8, 10a, and 11, with sub-micromolar PTP-1B IC50 and significant predicted pharmacokinetic and pharmacodynamic parameters, were further biologically evaluated for their anti-diabetic, anti-obesity, anti-inflammatory, and anti-oxidant effects in a high-fat diet (HFD) + streptozotocin (STZ)-induced T2DM rat model. All these hit compounds exhibited a significant anti-diabetic and anti-obesity effect and a significant efficacy in reducing oxidative stress and increasing anti-oxidant enzymes while reducing inflammatory markers. Improving compound potency was further highlighted by improving the pharmacokinetic profile of the most active compound, 10a, through nano formulation. Compound 10a nano formulation showed the most promising anti-diabetic and anti-obesity effects and a remarkable histopathological improvement in all organs studied.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11499946/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142516596","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 biological evaluation of pyrazole-ciprofloxacin hybrids as antibacterial and antibiofilm agents against Staphylococcus aureus. 设计、合成吡唑-环丙沙星混合物并对其进行生物学评价，以作为抗金黄色葡萄球菌的抗菌剂和抗生物膜剂。

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2024-10-22 DOI: 10.1039/d4md00623b

Ojaswitha Ommi, Priyanka Sudhir Dhopat, Shashikanta Sau, Madhu Rekha Estharla, Srinivas Nanduri, Nitin Pal Kalia, Venkata Madhavi Yaddanapudi

{"title":"Design, synthesis, and biological evaluation of pyrazole-ciprofloxacin hybrids as antibacterial and antibiofilm agents against Staphylococcus aureus.","authors":"Ojaswitha Ommi, Priyanka Sudhir Dhopat, Shashikanta Sau, Madhu Rekha Estharla, Srinivas Nanduri, Nitin Pal Kalia, Venkata Madhavi Yaddanapudi","doi":"10.1039/d4md00623b","DOIUrl":"10.1039/d4md00623b","url":null,"abstract":"In our continued efforts to tackle antibiotic resistance, a new series of pyrazole-ciprofloxacin hybrids were designed, synthesized, and evaluated for their antibacterial activity against Staphylococcus aureus (S. aureus), Pseudomonas aeruginosa (P. aeruginosa), and Mycobacterium tuberculosis (Mtb). Most of the compounds exhibited good to excellent activities against S. aureus, and six compounds (7a, 7b, 7d, 7g, 7k, and 7p) exhibited higher or comparable activity (MIC = 0.125-0.5 μg mL-1) to ciprofloxacin (0.125 μg mL-1). Further, these selected compounds were non-toxic (CC50 ≥ 1000 μg mL-1) when evaluated for cell viability test against the Hep-G2 cell line. Three compounds (7a, 7d, and 7g) demonstrated excellent activity against ciprofloxacin-resistant S. aureus with MIC values ranging from 0.125-0.5 μg mL-1 and good antibiofilm activity. Among them, 7g displayed remarkable antibiofilm activity with an MBIC50 value of 0.02 μg mL-1, which is 50 times lower than ciprofloxacin (MBIC50 = 1.06 μg mL-1). A time-kill kinetics study indicated that 7g showed both concentration and time-dependent bactericidal properties. In addition, 7g effectively inhibited DNA-gyrase supercoiling activity at 1 μg mL-1 (8× MIC). Two compounds 7b and 7d exhibited the highest activity against Mtb with a MIC of 0.5 μg mL-1, while 7c showed the highest activity against P. aeruginosa with a MIC value of 2 μg mL-1. Molecular docking studies revealed that 7g formed stable interactions at the DNA active site.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11528910/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568508","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