European Journal of Medicinal Chemistry最新文献_第3页

Progress in the study of anti-Alzheimer's disease activity of pyrimidine-containing bioactive molecules

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-01-01 DOI: 10.1016/j.ejmech.2024.117199

Yu-Lin Liu, Qian Zhang, Bing-Qian Li, Di Zhang, Rui-Hao Chui, Lin-Lin Zhang, Qi Zhang, Li-Ying Ma

{"title":"Progress in the study of anti-Alzheimer's disease activity of pyrimidine-containing bioactive molecules","authors":"Yu-Lin Liu, Qian Zhang, Bing-Qian Li, Di Zhang, Rui-Hao Chui, Lin-Lin Zhang, Qi Zhang, Li-Ying Ma","doi":"10.1016/j.ejmech.2024.117199","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117199","url":null,"abstract":"Pyrimidines are aromatic, heterocyclic organic compounds characterized by a six-membered ring that contains four carbon atoms and two nitrogen atoms. They have been reported to exhibit a variety of biological activities such as antifungal, antiviral, and anti-Parkinsonian effects. Recently, there has been an increased focus on their potential anti-Alzheimer's properties. Several pyrimidine-based drugs and their analogues are currently undergoing various phases of clinical trials, indicating pyrimidine as a promising chemical structure for drug development. Notably, modifications to the pyrimidine structure significantly influence their activity against Alzheimer's disease. For instance, the introduction of heteroatoms into the pyrimidine ring or alternations in the length of the linkage region have been shown to enhance therapeutic efficacy. This review provides a comprehensive overview of pyrimidine derivatives as potential therapeutics for Alzheimer's disease, with a focus on structure-activity relationship (SAR) studies, design strategies, and binding mechanisms. These insights could pave the way for the development of more effective anti-Alzheimer's medications.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"3 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142908662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

An Oxidation-Reduction-Triggered Thiamine Disulfide-Based Prodrug of 10-Hydroxycamptothecin for Selective Tumor Cell Locking and Therapeutic Delivery

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-12-31 DOI: 10.1016/j.ejmech.2024.117233

Chunyan Yang, Peiyun Yu, Jinxia Chen, Runxin Lu, Li Hai, Zhongzhen Yang, Li Guo, Yong Wu

{"title":"An Oxidation-Reduction-Triggered Thiamine Disulfide-Based Prodrug of 10-Hydroxycamptothecin for Selective Tumor Cell Locking and Therapeutic Delivery","authors":"Chunyan Yang, Peiyun Yu, Jinxia Chen, Runxin Lu, Li Hai, Zhongzhen Yang, Li Guo, Yong Wu","doi":"10.1016/j.ejmech.2024.117233","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117233","url":null,"abstract":"Chemotherapy, a primary method of cancer treatment, has been limited in clinical application due to its lack of specificity and tumor multidrug resistance, resulting in numerous undesired side effects. Herein, a small molecule conjugate, TDK-HCPT, was designed and synthesized, which could target tumor cells and prolong the retention of chemotherapy agents within tumor cells. Moreover, a similarly designed control system, TDK-Nap, has been developed as well to enable cancer cell imaging. Two design elements are incorporated into TDK-HCPT: the thiamine disulfide (TDS) and the thioketal subunit (tk). TDS can be reduced in the high glutathione (GSH) conditions within cancer cell to form thiazolium salt, and the resulting enhanced positive charge and lipophobicity make the system difficult to be pumped out of tumor cells, thereby effectively “locking” the chemotherapy drug HCPT inside the tumor cells. Additionally, the tk subunit serves as a ROS trigger, within the tumor cells, the “locked” HCPT were then released and activated by the high ROS conditions, optimizing its targeted potential. This allows TDK-HCPT to serve as a redox-liable molecular platform that targets cancer cells selectively which decreases cancer cell migration, retards tumor growth, and lowers tumorigenesis rates as evidenced by a combination of in vitro and in vivo studies. To the best of our knowledge, this is the first time a cancer cell “lock in” has been shown to prevent tumorigenesis in an animal model.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"69 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142905535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 Pharmacological Evaluation of Natural Product Diphyllin Derivatives against Head and Neck Squamous Cell Carcinoma

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-12-31 DOI: 10.1016/j.ejmech.2024.117215

Yuqi Tang, Xinhua Pan, Fan-Fan Shang, Yang Li, Chaojun Zhang, Hexin Ma, Ao Zhang, Xu Wang, Chunyong Ding, Wantao Chen

{"title":"Synthesis and Pharmacological Evaluation of Natural Product Diphyllin Derivatives against Head and Neck Squamous Cell Carcinoma","authors":"Yuqi Tang, Xinhua Pan, Fan-Fan Shang, Yang Li, Chaojun Zhang, Hexin Ma, Ao Zhang, Xu Wang, Chunyong Ding, Wantao Chen","doi":"10.1016/j.ejmech.2024.117215","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117215","url":null,"abstract":"Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignant tumors, but clinical drug treatments are limited. The natural product diphyllin was identified as a lead compound suppressing the proliferation of HNSCC cells through phenotypic screening of natural product library. However, further developments of diphyllin as an anti-HNSCC agent were restricted by the weak bioactivity and poor metabolic stability. Herein, we designed and synthesized two series of novel diphyllin derivatives that were achieved by introducing various pyranose rings or hydrophilic groups to block the easily metabolic C-4 site with the aim to improve antitumor activity and drug-like properties. Among these compounds, compound A3 showed the most potent inhibitory effects against HNSCC cells with IC50 values ranging from 4.37 to 77.81 nM and much less potent cytotoxicity against normal cells (IC50 > 10 μM). Mechanistically, it effectively inhibited cell proliferation and migration and induced the cell cycle arrest and apoptosis in a concentration-dependent manner. Besides, A3 possessed greatly improved pharmacokinetic properties including over 10-fold higher plasma exposure (AUC0-t: 541 vs 43.6 h*ng/mL) and better oral bioavailability (F: 20.85% vs 2.70%), lower systemic plasma clearance (CL:1897 vs 24523 mL/h/kg), as well as longer half-life (T1/2: 0.530 vs 0.108 h) when compared to diphyllin. In a tumor cell xenograft model, A3 significantly suppressed the CAL27 tumor growth with a TGI of 42.2% without obvious safety concern, which is superior to that of diphyllin (TGI = 23.3%), suggesting great potential for treatment of HNSCC.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"542 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142908661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Discovery of 4,5-dihydro-benzo[g]indazole-based hydroxamic acids as HDAC3/BRD4 dual inhibitors and anti-tumor agents

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-12-30 DOI: 10.1016/j.ejmech.2024.117230

Bo Li, Yibing Chen, Siyuan Wang, Bo Jin, Jinyu Yang, Qun Niu, Guizhou Hao, Ning Wang, Wenchao Zhang, Linxiang Zhao, Jiachen Wen, Dan Liu

{"title":"Discovery of 4,5-dihydro-benzo[g]indazole-based hydroxamic acids as HDAC3/BRD4 dual inhibitors and anti-tumor agents","authors":"Bo Li, Yibing Chen, Siyuan Wang, Bo Jin, Jinyu Yang, Qun Niu, Guizhou Hao, Ning Wang, Wenchao Zhang, Linxiang Zhao, Jiachen Wen, Dan Liu","doi":"10.1016/j.ejmech.2024.117230","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117230","url":null,"abstract":"Concurrent inhibition of HDAC and BRD4, two well-established epigenetic targets for anti-tumor therapy, demonstrates the potential to enhance anti-tumor effects synergistically. The present study involves the development of a series of novel HDAC3/BRD4 dual inhibitors, followed by evaluation of their antitumor efficacy against several tumor models. Guided by scaffold hopping strategy, key pharmacophore of BRD4 inhibitor I-BET-151 was incorporated into an in-house developed HDAC3-selective inhibitor 17h. A set of twenty-two compounds was synthesized and characterized. Most of these compounds demonstrated significant potency in inhibiting HDAC3 and exhibited selectivity over its closely-related isoform, HDAC1. The potent BRD4 inhibition of these compounds has been further confirmed through HTFR and thermal shift assays. Of which, compounds 26b and 26n demonstrated potent dual inhibition against HDAC3 and BRD4. Compound 26n demonstrated potent antiproliferative effects against a panel of cancer cells, with human pancreatic cancer cell line Capan-1 displaying the highest susceptibility. Compound 26n exhibited significant upregulation of Ac-H3 and downregulation of c-Myc at concentrations as low as 1 μM, suggesting proper target engagement in Capan-1 cells. Compound 26n demonstrated significant antitumor efficacy in Capan-1 CDX model, with a tumor growth inhibition rate of 71% under the given dosing regimen. In summary, this research highlights the promising therapeutic potential of benzodihydroindazole derivatives as HDAC3/BRD4 dual inhibitors, warranting further investigation.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"152 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142905538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Discovery of novel capsaicin analogs as TRPV1 inhibitors for the treatment of idiopathic pulmonary fibrosis

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-12-30 DOI: 10.1016/j.ejmech.2024.117229

Yu Cao, Yongju Wen, Zongyuan Zhou, Ruiying Xi, Wen Shuai, Jichao Zhang, Apichart Suksamrarn, Guolin Zhang, Xiao-xia Lu, Fei Wang

{"title":"Discovery of novel capsaicin analogs as TRPV1 inhibitors for the treatment of idiopathic pulmonary fibrosis","authors":"Yu Cao, Yongju Wen, Zongyuan Zhou, Ruiying Xi, Wen Shuai, Jichao Zhang, Apichart Suksamrarn, Guolin Zhang, Xiao-xia Lu, Fei Wang","doi":"10.1016/j.ejmech.2024.117229","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117229","url":null,"abstract":"Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease for which few drugs are available in clinical practice. Here, we identified novel capsaicin analogs by combining in-house chemical library screening and further structural optimization. (E)-1-(3,4-dihydroxyphenyl)-7-phenylhept-1-en-3-one (Compound 14) was found to be the most potent in inhibiting TGF-β-induced collagen accumulation, proliferation and migration in fibroblast cells. Furthermore, compound 14 (IC50 = 0.51 ± 0.06 μM) showed over 100-fold increasing antifibrotic activity compared to capsaicin (IC50 = 53.71 ± 4.78 μM). Notably, compound 14 could target TRPV1, thereby affecting the expression of the fibrosis markers Collagen Ⅰ and α-SMA by inhibiting the TGF-β/Smads and MAPK pathways to exert antifibrotic activity in vitro. Compound 14 significantly inhibited collagen deposition in lung tissues, ameliorated alveolar structures, and increased survival rates in mice with bleomycin-induced pulmonary fibrosis. In addition, compound 14 possessed lower cytotoxicity (compared to nitedanib) and no toxicity in mice. Overall, compound 14 promise as a potential drug candidate for the treatment of IPF.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"9 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142901870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Novel antimalarial 3-substituted quinolones isosteres with improved pharmacokinetic properties

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-12-28 DOI: 10.1016/j.ejmech.2024.117228

Siyuan Ge, Rongchao Jian, Qiwei Xuan, Yingxiang Zhu, Xiaofei Ren, Wenjiao Li, Xiaole Chen, Ruikang Huang, Chi-Sing Lee, Suet C. Leung, Nicoletta Basilico, Silvia Parapini, Donatella Taramelli, Nattapon Pinthong, Svetlana V. Antonyuk, Paul M. O’Neill, Zhaojun Sheng, W. David Hong

{"title":"Novel antimalarial 3-substituted quinolones isosteres with improved pharmacokinetic properties","authors":"Siyuan Ge, Rongchao Jian, Qiwei Xuan, Yingxiang Zhu, Xiaofei Ren, Wenjiao Li, Xiaole Chen, Ruikang Huang, Chi-Sing Lee, Suet C. Leung, Nicoletta Basilico, Silvia Parapini, Donatella Taramelli, Nattapon Pinthong, Svetlana V. Antonyuk, Paul M. O’Neill, Zhaojun Sheng, W. David Hong","doi":"10.1016/j.ejmech.2024.117228","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117228","url":null,"abstract":"Aryl quinolone derivatives can target the cytochrome bc1 complex of Plasmodium falciparum, exhibiting excellent in vitro and in vivo antimalarial activity. However, their clinical development has been hindered due to their poor aqueous solubility profiles. In this study, a series of bioisosteres containing saturated heterocycles fused to a 4-pyridone ring were designed to replace the inherently poorly soluble quinolone core in antimalarial quinolones with the aim to reduce π-π stacking interactions in the crystal packing solid state, and a synthetic route was developed to prepare these alternative core derivatives. One such novel derivate, F14, exhibited significant enhancements in both aqueous solubility (20 μM) and lipophilicity (LogD 2.7), whilst retaining nanomolar antimalarial activity against the W2 strain of P. falciparum (IC50 = 235 nM). The pharmacokinetic studies reported, provide preliminary insights into the in vivo distribution and elimination of F14, while findings from single crystal X-ray diffraction experiment rationalized the enhanced solubility. Protein X-ray crystallography and in silico docking simulations provide insight into the potential mode of action within the cytochrome bc1 complex. These findings demonstrated the viability of this bioisostere replacement strategy and provided support for further exploration of in vivo efficacy in preclinical animal models and valuable insights for new drug design strategies in the fight against malaria.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"151 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142888979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 Strategies and Anti-parasitic Evaluation of Novel Compounds for Chagas Disease: Advancing Drug Discovery through Structure-Activity Relationships

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-12-28 DOI: 10.1016/j.ejmech.2024.117203

Jitendra Chaudhary, Gurdeep Kaur, Iqubal Singh

{"title":"Synthesis Strategies and Anti-parasitic Evaluation of Novel Compounds for Chagas Disease: Advancing Drug Discovery through Structure-Activity Relationships","authors":"Jitendra Chaudhary, Gurdeep Kaur, Iqubal Singh","doi":"10.1016/j.ejmech.2024.117203","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117203","url":null,"abstract":"This study presents a comprehensive exploration of the synthesis of novel compounds targeting Chagas Disease (CD) caused by Trypanosoma cruzi. It is a global health threat with over 6-7 million infections worldwide. Addressing challenges in current treatments, the investigation explores diverse compound classes, including thiazoles, thiazolidinone, imidazole, pyrazole, 1,6-diphenyl-1H-pyrazolo[3,4-b] pyridine, pyrrole, naphthoquinone, neolignan, benzeneacyl hydrazones, and chalcones-based compounds. Highlighting compounds with superior trypanocidal activity compared to standard drugs. The study elucidates structure-activity relationships, emphasizing the impact of substituents, fluorine presence, and substitution patterns. Noteworthy findings include neolignan derivatives demonstrating efficacy against intracellular amastigotes and free-moving trypomastigotes, with unsaturated side chains. Benzeneacylhydrazones and chalcones, as novel classes, showed varied efficacy, with certain compounds surpassing benznidazole. A novel series of triketone compounds exhibited strong anti-parasitic activity, outperforming standard drugs. Docking study revealed that the halogen and methoxy substituted phenyl ring, thiazole, thiazolidine-4-one, quinoline, isoindoline-1,3-dione, pyrrole heterocyclic motifs can play the key role in the designing of effective inhibitors of T. cruzi. Mutually, these insights placed the foundation for the development of innovative and effective treatments for CD, addressing the urgent need for improved therapeutic options.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"20 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142888939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Novel α-mangostin Derivatives as Promising Antiviral Agents: Isolation, Synthesis, and Evaluation Against Chikungunya Virus

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-12-28 DOI: 10.1016/j.ejmech.2024.117227

Telukuntla Sai Priya, Poonam Patil, Bandi Siva, Diya Roy, Radhika Dhote, Deepti Parashar, Kalichamy Alagarasu, Sarah Cherian, K. Suresh Babu

{"title":"Novel α-mangostin Derivatives as Promising Antiviral Agents: Isolation, Synthesis, and Evaluation Against Chikungunya Virus","authors":"Telukuntla Sai Priya, Poonam Patil, Bandi Siva, Diya Roy, Radhika Dhote, Deepti Parashar, Kalichamy Alagarasu, Sarah Cherian, K. Suresh Babu","doi":"10.1016/j.ejmech.2024.117227","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117227","url":null,"abstract":"Investigations into fruit and vegetable processing residues (FVPRs) offer huge opportunities to discover novel therapeutics against many diseases. In this study, detailed investigation of Garcinia mangostana fruit peel extract led to the isolation and identification of ten known compounds (1-10). Further, a new series of α-mangostin derived sulphonamides, aryl alkynes and 1,2,3-triazole derivatives were synthesized using Huisgen 1,3-dipolar cyclo-addition reaction (“click” chemistry). Both isolated compounds and synthetic derivatives were evaluated for their anti-chikungunya activity (CHIKV). Isolated compounds, gartanin (1), mangostenone-F (4), 1-isomangostin (5), mangostenone-D (6), epicatechin (7) and derivatives 14, 15c, 15d, 15e, 15f, 17d, 17f, and 18h exerted anti-CHIKV activity. Compounds 17d, 17f and 18h manifested higher antiviral activity (>2 log reduction in virus titer) with a selectivity index (SI) > 50. The compounds with higher antiviral activity were evaluated further with various assays, time of addition assay, entry and entry bypass assay and were also subjected to molecular docking with viral proteins. The results revealed that 17d, 17f and 18h affect multiple stages of virus life cycle through probable interaction with envelope proteins and nsP3 macrodomain of CHIKV. Overall, this study provides evidence for anti CHIKV activity of natural xanthones from Garcinia mangostana L and their derivatives which could be further investigated for development of therapeutics against chikungunya.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"31 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142888977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Multicationic Ruthenium Phthalocyanines as Photosensitizers for Photodynamic Inactivation of Multiresistant Microbes

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-12-27 DOI: 10.1016/j.ejmech.2024.117214

Ana Belén Domínguez, Daniel Ziental, Jolanta Długaszewska, Lukasz Sobotta, Tomás Torres, M. Salomé Rodríguez-Morgade

{"title":"Multicationic Ruthenium Phthalocyanines as Photosensitizers for Photodynamic Inactivation of Multiresistant Microbes","authors":"Ana Belén Domínguez, Daniel Ziental, Jolanta Długaszewska, Lukasz Sobotta, Tomás Torres, M. Salomé Rodríguez-Morgade","doi":"10.1016/j.ejmech.2024.117214","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117214","url":null,"abstract":"Four photosensitizers PS1a-PS4a consisting in multicationic Ruthenium(II) Phthalocyanines (RuPcs) have been evaluated in photodynamic inactivation (PDI) of multiresistant microorganisms. The RuPcs, bearing from 4 to 12 terminal ammonium salts, have been designed to target the microorganisms cytoplasmic cell membrane and display high singlet oxygen quantum yields. In addition, PS3a and PS4a were conceived to exhibit multi-target localization by endowing them with amphiphilic character, using two different structural approaches. Under low light regimes, the two hydrophilic PS1a and PS2a, as well as the amphiphilic PS3a show much stronger response against gram-positive MRSA than that observed for the typical phthalocyanines designed for PDI, namely zinc(II) and palladium(II) complexes, as well as free-base Pcs. Besides, PS1a, PS2a and PS3a show remarkably high activity against the gram-negative E. coli, although weak fungicidal character against fluconazole-resistant C. albicans. Contrasting, the structurally different, amphiphilic PS4a shows only slight activity for Gram-positive bacteria, despite its ability to cross cell membrane and reach internal organelles. Still, PS4a shows a positive synergistic effect against MRSA when combined with doxycycline, exhibiting an increased activity from about 1.5 to about 4.9 log reduction under the light dose of 30 J/cm2 and the 0.125 mg/L subinhibitory dose of doxycycline.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"64 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142888997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 Functional Screening of Novel Inhibitors Targeting the HDAC6 Zinc Finger Ubiquitin-Binding Domain

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-12-27 DOI: 10.1016/j.ejmech.2024.117208

Silke Geurs, Eleni Staessens, Kato Bredael, Stefaan Borghgraef, Jordy De Ridder, Leentje Persoons, Steven De Jonghe, Dominique Schols, Mandeep K. Mann, Rachel J. Harding, Jorick Franceus, Tom Desmet, Kristof Van Hecke, Dorien Clarisse, Karolien De Bosscher, Matthias D’hooghe

{"title":"Synthesis and Functional Screening of Novel Inhibitors Targeting the HDAC6 Zinc Finger Ubiquitin-Binding Domain","authors":"Silke Geurs, Eleni Staessens, Kato Bredael, Stefaan Borghgraef, Jordy De Ridder, Leentje Persoons, Steven De Jonghe, Dominique Schols, Mandeep K. Mann, Rachel J. Harding, Jorick Franceus, Tom Desmet, Kristof Van Hecke, Dorien Clarisse, Karolien De Bosscher, Matthias D’hooghe","doi":"10.1016/j.ejmech.2024.117208","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117208","url":null,"abstract":"Histone deacetylase 6 (HDAC6) is a promising target for treating neurodegenerative disorders, several cancer types and viral infections. Unique among HDACs, the HDAC6 isoform possesses a zinc finger ubiquitin-binding domain (UBD) crucial for managing misfolded protein aggregates and facilitating viral infection. HDAC6 binds aggregated polyubiquitinated proteins through its UBD, mediating their transport to the aggresome and subsequent removal via autophagy. Despite the importance of the UBD in proteostasis and viral infection, its pharmacological inhibition has been minimally explored thus far, with research largely focused on the deacetylase domain. We synthesized a diverse library of new compounds designed to target the HDAC6-UBD, termed HZUBi, with varied core structures including quinazolinone, oxindole and tetrahydrothiopyrano[4,3-b]indole, aimed at enhancing UBD interaction and extending into the side pocket. New structure-activity relationships were established, computational docking and molecular dynamics studies were performed and the functional impact of selected inhibitors was assessed in the context of multiple myeloma and viral infection. Several new HZUBi could displace a ubiquitin peptide from HDAC6-UBD in a differential manner, although to a lower extent than the literature reference compound HZUBi-3e. Despite exhibiting in vitro target engagement, neither HZUBi-3e nor its ester prodrug HZUBi-1e enhanced proteasome inhibitor-mediated multiple myeloma cell killing. Finally, none of the screened HZUBi triggered anti-viral activity.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"2 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142888940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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