Journal of Enzyme Inhibition and Medicinal Chemistry最新文献_第4页

Design and synthesis of triazolopyridine derivatives as potent JAK/HDAC dual inhibitors with broad-spectrum antiproliferative activity. 设计和合成具有广谱抗增殖活性的强效 JAK/HDAC 双抑制剂三唑吡啶衍生物。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-10-08 DOI: 10.1080/14756366.2024.2409771

Zhengshui Xu, Changchun Ye, Xingjie Wang, Ranran Kong, Zilu Chen, Jing Shi, Xin Chen, Shiyuan Liu

引用次数: 0

New imidazole-2-thiones linked to acenaphythylenone as dual DNA intercalators and topoisomerase II inhibitors: structural optimization, docking, and apoptosis studies. 与苊烯酮相连的新型咪唑-2-硫酮作为双重 DNA 中间体和拓扑异构酶 II 抑制剂：结构优化、对接和细胞凋亡研究。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-03-15 DOI: 10.1080/14756366.2024.2311818

Asmaa H Mohamed, Mohammed B Alshammari, Ashraf A Aly, Kamal U Sadek, Akil Ahmad, Eman A Aziz, Amira F El-Yazbi, Eman J El-Agroudy, Marwa E Abdelaziz

{"title":"New imidazole-2-thiones linked to acenaphythylenone as dual DNA intercalators and topoisomerase II inhibitors: structural optimization, docking, and apoptosis studies.","authors":"Asmaa H Mohamed, Mohammed B Alshammari, Ashraf A Aly, Kamal U Sadek, Akil Ahmad, Eman A Aziz, Amira F El-Yazbi, Eman J El-Agroudy, Marwa E Abdelaziz","doi":"10.1080/14756366.2024.2311818","DOIUrl":"10.1080/14756366.2024.2311818","url":null,"abstract":"In this article, a new series of 2-((3,5-disubstituted-2-thioxo-imidazol-1-yl)imino)acenaphthylen-1(2H)-ones were synthesized. Imidazole-2-thione with acenaphthylen-one gave a hybrid scaffold that integrated key structural elements essential for DNA damage via direct DNA intercalation and inhibition of the topoisomerase II enzyme. All the synthesized compounds were screened to detect their DNA damage using a terbium fluorescent probe. Results demonstrated that 4-phenyl-imidazoles 5b and 5e in addition to 4-(4-chlorophenyl)imidazoles 5h and 5j would induce detectable potent damage in ctDNA. The four most potent compounds as DNA intercalators were further evaluated for their antiproliferative activity against HepG2, MCF-7 and HCT-116 utilizing the MTT assay. The highest anticancer activity was recorded with compounds 5b and 5h against the breast cancer cell line MCF-7 which were 1.5- and 3- folds more active than doxorubicin, respectively. Therefore, imidazole-2-thione tethered acenaphthylenone derivatives can be considered as promising scaffold for the development of effective dual DNA intercalators and topoisomerase II inhibitors.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2311818"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10946275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140131586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Development of a multi-targeted chemotherapeutic approach based on G-quadruplex stabilisation and carbonic anhydrase inhibition. 开发基于 G-四叉链稳定和碳酸酐酶抑制的多靶点化疗方法。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-06-18 DOI: 10.1080/14756366.2024.2366236

Alessio Nocentini, Anna Di Porzio, Alessandro Bonardi, Carla Bazzicalupi, Andrea Petreni, Tarita Biver, Silvia Bua, Simona Marzano, Jussara Amato, Bruno Pagano, Nunzia Iaccarino, Stefano De Tito, Stefano Amente, Claudiu T Supuran, Antonio Randazzo, Paola Gratteri

{"title":"Development of a multi-targeted chemotherapeutic approach based on G-quadruplex stabilisation and carbonic anhydrase inhibition.","authors":"Alessio Nocentini, Anna Di Porzio, Alessandro Bonardi, Carla Bazzicalupi, Andrea Petreni, Tarita Biver, Silvia Bua, Simona Marzano, Jussara Amato, Bruno Pagano, Nunzia Iaccarino, Stefano De Tito, Stefano Amente, Claudiu T Supuran, Antonio Randazzo, Paola Gratteri","doi":"10.1080/14756366.2024.2366236","DOIUrl":"10.1080/14756366.2024.2366236","url":null,"abstract":"A novel class of compounds designed to hit two anti-tumour targets, G-quadruplex structures and human carbonic anhydrases (hCAs) IX and XII is proposed. The induction/stabilisation of G-quadruplex structures by small molecules has emerged as an anticancer strategy, disrupting telomere maintenance and reducing oncogene expression. hCAs IX and XII are well-established anti-tumour targets, upregulated in many hypoxic tumours and contributing to metastasis. The ligands reported feature a berberine G-quadruplex stabiliser scaffold connected to a moiety inhibiting hCAs IX and XII. In vitro experiments showed that our compounds selectively stabilise G-quadruplex structures and inhibit hCAs IX and XII. The crystal structure of a telomeric G-quadruplex in complex with one of these ligands was obtained, shedding light on the ligand/target interaction mode. The most promising ligands showed significant cytotoxicity against CA IX-positive HeLa cancer cells in hypoxia, and the ability to stabilise G-quadruplexes within tumour cells.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2366236"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11195807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141436968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Anilino-1,4-naphthoquinones as potent mushroom tyrosinase inhibitors: in vitro and in silico studies. 作为强效蘑菇酪氨酸酶抑制剂的苯胺基-1,4-萘醌类化合物：体外和硅学研究。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-05-30 DOI: 10.1080/14756366.2024.2357174

Sahachai Sabuakham, Sutita Nasoontorn, Napat Kongtaworn, Thanyada Rungrotmongkol, Atit Silsirivanit, Ratchanok Pingaew, Panupong Mahalapbutr

{"title":"Anilino-1,4-naphthoquinones as potent mushroom tyrosinase inhibitors: in vitro and in silico studies.","authors":"Sahachai Sabuakham, Sutita Nasoontorn, Napat Kongtaworn, Thanyada Rungrotmongkol, Atit Silsirivanit, Ratchanok Pingaew, Panupong Mahalapbutr","doi":"10.1080/14756366.2024.2357174","DOIUrl":"10.1080/14756366.2024.2357174","url":null,"abstract":"Tyrosinase, a pivotal enzyme in melanin synthesis, is a primary target for the development of depigmenting agents. In this work, in vitro and in silico techniques were employed to identify novel tyrosinase inhibitors from a set of 12 anilino-1,4-naphthoquinone derivatives. Results from the mushroom tyrosinase activity assay indicated that, among the 12 derivatives, three compounds (1, 5, and 10) demonstrated the most significant inhibitory activity against mushroom tyrosinase, surpassing the effectiveness of the kojic acid. Molecular docking revealed that all studied derivatives interacted with copper ions and amino acid residues at the enzyme active site. Molecular dynamics simulations provided insights into the stability of enzyme-inhibitor complexes, in which compounds 1, 5, and particularly 10 displayed greater stability, atomic contacts, and structural compactness than kojic acid. Drug likeness prediction further strengthens the potential of anilino-1,4-naphthoquinones as promising candidates for the development of novel tyrosinase inhibitors for the treatment of hyperpigmentation disorders.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2357174"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11141316/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141174642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Discovery of novel 2,4-diarylaminopyrimidine hydrazone derivatives as potent anti-thyroid cancer agents capable of inhibiting FAK. 发现新型 2,4-二芳基氨基嘧啶腙衍生物，作为能够抑制 FAK 的强效抗甲状腺癌药物。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-11-19 DOI: 10.1080/14756366.2024.2423875

Hongting Li, Mei-Qi Jia, Zhao-Long Qin, Changliang Lu, Weili Chu, Ze Zhang, Jinbo Niu, Jian Song, Sai-Yang Zhang, Lijun Fu

{"title":"Discovery of novel 2,4-diarylaminopyrimidine hydrazone derivatives as potent anti-thyroid cancer agents capable of inhibiting FAK.","authors":"Hongting Li, Mei-Qi Jia, Zhao-Long Qin, Changliang Lu, Weili Chu, Ze Zhang, Jinbo Niu, Jian Song, Sai-Yang Zhang, Lijun Fu","doi":"10.1080/14756366.2024.2423875","DOIUrl":"10.1080/14756366.2024.2423875","url":null,"abstract":"In this work, thirty 2,4-diarylaminopyrimidine-based hydrazones were designed, synthesised, and their anti-thyroid cancer activity were explored. The majority of compounds exhibit moderate to excellent cytotoxic activity against FAK overexpressing TPC-1 cells, with IC50 values ranging from 0.113 to 1.460 μM. Among them, compound 14f displayed exceptional anti-proliferative effect against TPC-1 cells (IC50 = 0.113 μM) and potent FAK inhibitory potency (IC50 = 35 nM). In silico studies indicated that compound 14f could well bind to FAK (Focal Adhesion Kinase) and have favourable pharmacokinetic profiles. In addition, compound 14f could inhibit the phosphorylation of FAK at Tyr397, Tyr576/577 and Tyr925, and did not affect the expression level of FAK in TPC-1 cells. Compound 14f was also effective in inhibiting the proliferation and migration of thyroid cancer cells TPC-1. Thus, these novel 4-arylaminopyrimidine hydrazone derivatives exhibited potent anti-thyroid cancer activities through the inhibition of FAK.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2423875"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11578424/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Evaluation of hydrazone and N-acylhydrazone derivatives of vitamin B6 and pyridine-4-carbaldehyde as potential drugs against Alzheimer's disease. 维生素B6和吡啶-4-乙醛的腙和n -酰基腙衍生物作为抗阿尔茨海默病潜在药物的评价。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-12-09 DOI: 10.1080/14756366.2024.2431832

Marija Bartolić, Ana Matošević, Nikola Maraković, Valentina Bušić, Sunčica Roca, Dražen Vikić-Topić, Antonio Sabljić, Anita Bosak, Dajana Gašo-Sokač

{"title":"Evaluation of hydrazone and N-acylhydrazone derivatives of vitamin B6 and pyridine-4-carbaldehyde as potential drugs against Alzheimer's disease.","authors":"Marija Bartolić, Ana Matošević, Nikola Maraković, Valentina Bušić, Sunčica Roca, Dražen Vikić-Topić, Antonio Sabljić, Anita Bosak, Dajana Gašo-Sokač","doi":"10.1080/14756366.2024.2431832","DOIUrl":"10.1080/14756366.2024.2431832","url":null,"abstract":"The growing prevalence of Alzheimer's disease calls for a drug that can simultaneously act towards several targets involved in the pathophysiology of the disease. In our study, we evaluated the potential of hydrazone and N-acylhydrazone derivatives of vitamin B6 and pyridine-4-carbaldehyde to be used as multi-target directed ligands targeting cholinergic system by inhibiting acetyl- and butyrylcholinesterase, lowering the accumulation of β-amyloid plaques by inhibiting both the β-secretase activity and amyloid self-aggregation, and maintaining the biometal balance by chelating certain biometals. Our results showed that all of the tested hydrazones were potent inhibitors of human cholinesterases with inhibition constants (Ki) in micromolar range able to lower the activity of β-secretase, inhibit amyloid aggregation, chelate biometals and act as antioxidants. Also, most of them were estimated to be able to cross the blood-brain barrier by passive transport and to be absorbed in human intestines as well as with moderate metabolic stability in liver microsomes.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2431832"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11633425/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Evaluation of N-alkyl isatins and indoles as acetylcholinesterase and butyrylcholinesterase inhibitors. n -烷基异黄酮和吲哚作为乙酰胆碱酯酶和丁基胆碱酯酶抑制剂的评价。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2023-12-07 DOI: 10.1080/14756366.2023.2286935

Kaitlyn N Alcorn, Isabelle A Oberhauser, Matthew D Politeski, Todd J Eckroat

{"title":"Evaluation of N-alkyl isatins and indoles as acetylcholinesterase and butyrylcholinesterase inhibitors.","authors":"Kaitlyn N Alcorn, Isabelle A Oberhauser, Matthew D Politeski, Todd J Eckroat","doi":"10.1080/14756366.2023.2286935","DOIUrl":"10.1080/14756366.2023.2286935","url":null,"abstract":"Two series of N-alkyl isatins and N-alkyl indoles varying in size of the alkyl group were synthesised and evaluated for inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Among the N-alkyl isatins 4a-j, the addition of the N-alkyl group improved inhibition potency towards AChE and BChE compared to isatin. Selectivity towards inhibition of BChE was observed, and the increase in size of the N-alkyl group positively correlated to improved inhibition potency. The most potent inhibitor for BChE was 4i (IC50 = 3.77 µM, 22-fold selectivity for BChE over AChE). N-alkyl indoles 5a-j showed similar inhibition of AChE, the most potent being 5g (IC50 = 35.0 µM), but 5a-j lost activity towards BChE. This suggests an important role of the 3-oxo group on isatin for BChE inhibition, and molecular docking of 4i with human BChE indicates a key hydrogen bond between this group and Ser198 and His438 of the BChE catalytic triad.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2286935"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11721616/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138498510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Identification of putative allosteric inhibitors of BCKDK via virtual screening and biological evaluation. 通过虚拟筛选和生物学评价鉴定BCKDK的推定变构抑制剂。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2023-12-07 DOI: 10.1080/14756366.2023.2290458

Chunqiong Li, Quanjun Yang, Li Zhang

{"title":"Identification of putative allosteric inhibitors of BCKDK via virtual screening and biological evaluation.","authors":"Chunqiong Li, Quanjun Yang, Li Zhang","doi":"10.1080/14756366.2023.2290458","DOIUrl":"10.1080/14756366.2023.2290458","url":null,"abstract":"Abnormal accumulation of branched-chain amino acids (BCAAs) can lead to metabolic diseases and cancers. Branched-chain α-keto acid dehydrogenase kinase (BCKDK) is a key negative regulator of BCAA catabolism, and targeting BCKDK provides a promising therapeutic approach for diseases caused by BCAA accumulation. Here, we screened PPHN and POAB as novel putative allosteric inhibitors by integrating allosteric binding site prediction, large-scale ligand database virtual screening, and bioactivity evaluation assays. Both of them showed a high binding affinity to BCKDK, with Kd values of 3.9 μM and 1.86 μM, respectively. In vivo experiments, the inhibitors demonstrated superior kinase inhibitory activity and notable antiproliferative and proapoptotic effects on diverse cancer cells. Finally, bulk RNA-seq analysis revealed that PPHN and POAB suppressed cell growth through a range of signalling pathways. Taken together, our findings highlight two novel BCKDK inhibitors as potent therapeutic candidates for metabolic diseases and cancers associated with BCAA dysfunctional metabolism.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2290458"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11721764/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138498511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Expanding the inhibitor space of the WWP1 and WWP2 HECT E3 ligases. 拓展 WWP1 和 WWP2 HECT E3 连接酶的抑制剂空间。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-09-02 DOI: 10.1080/14756366.2024.2394895

Ashley P Dudey, Jake M Rigby, Gregory R Hughes, G Richard Stephenson, Thomas E Storr, Andrew Chantry, Andrew M Hemmings

{"title":"Expanding the inhibitor space of the WWP1 and WWP2 HECT E3 ligases.","authors":"Ashley P Dudey, Jake M Rigby, Gregory R Hughes, G Richard Stephenson, Thomas E Storr, Andrew Chantry, Andrew M Hemmings","doi":"10.1080/14756366.2024.2394895","DOIUrl":"10.1080/14756366.2024.2394895","url":null,"abstract":"The HECT E3 ubiquitin ligases 1 (WWP1) and 2 (WWP2) are responsible for the ubiquitin-mediated degradation of key tumour suppressor proteins and are dysregulated in various cancers and diseases. Here we expand their limited inhibitor space by identification of NSC-217913 displaying a WWP1 IC50 of 158.3 µM (95% CI = 128.7, 195.1 µM). A structure-activity relationship by synthesis approach aided by molecular docking led to compound 11 which displayed increased potency with an IC50 of 32.7 µM (95% CI = 24.6, 44.3 µM) for WWP1 and 269.2 µM (95% CI = 209.4, 347.9 µM) for WWP2. Molecular docking yielded active site-bound poses suggesting that the heterocyclic imidazo[4,5-b]pyrazine scaffold undertakes a π-stacking interaction with the phenolic group of tyrosine, and the ethyl ester enables strong ion-dipole interactions. Given the therapeutic potential of WWP1 and WWP2, we propose that compound 11 may provide a basis for future lead compound development.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2394895"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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, molecular modelling, and biological evaluation of novel quinoxaline derivatives for treating type II diabetes. 用于治疗 II 型糖尿病的新型喹喔啉衍生物的合成、分子建模和生物学评价。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-09-23 DOI: 10.1080/14756366.2024.2395985

Fatmah Ali S Alasmary, Dalal A Abdullah, Vijay H Masand, Abir Ben Bacha, Abdelsattar Mansour Omar Ebeid, Moustafa E El-Araby, Ahmed M Alafeefy

{"title":"Synthesis, molecular modelling, and biological evaluation of novel quinoxaline derivatives for treating type II diabetes.","authors":"Fatmah Ali S Alasmary, Dalal A Abdullah, Vijay H Masand, Abir Ben Bacha, Abdelsattar Mansour Omar Ebeid, Moustafa E El-Araby, Ahmed M Alafeefy","doi":"10.1080/14756366.2024.2395985","DOIUrl":"10.1080/14756366.2024.2395985","url":null,"abstract":"Quinoxalines are benzopyrazine derivatives with significant therapeutic impact in the pharmaceutical industry. They proved to be useful against inflammation, bacterial, fungal, viral infection, diabetes and other applications. Very recently, in January 2024, the FDA approved new quinoxaline containing drug, erdafitinib for treatment of certain carcinomas. Despite the diverse biological activities exhibited by quinoxaline derivatives and the role of secretory phospholipase A2 (sPLA2) in diabetes-related complications, the potential of sPLA2-targeting quinoxaline-based inhibitors to effectively address these complications remains unexplored. Therefore, we designed novel sPLA2- and α-glucosidase-targeting quinoxaline-based heterocyclic inhibitors to regulate elevated post-prandial blood glucose linked to patients with diabetes-related cardiovascular complications. Compounds 5a-d and 6a-d were synthesised by condensing quinoxaline hydrazides with various aryl sulphonyl chlorides. Biological screening revealed compound 6a as a potent sPLA2 inhibitor (IC50 = 0.0475 µM), whereas compound 6c most effectively inhibited α-glucosidase (IC50 = 0.0953 µM), outperforming the positive control acarbose. Moreover, compound 6a was the best inhibitor for both enzymes. Molecular docking revealed pharmacophoric features, highlighting the importance of a sulfonohydrazide moiety in the structural design of these compounds, leading to the development of potent sPLA2 and α-glucosidase inhibitors. Collectively, our findings helped identify promising candidates for developing novel therapeutic agents for treating diabetes mellitus.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2395985"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11421147/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142288899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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