Chemical Biology & Drug Design最新文献

{"title":"Identification of BAY61-3606 Derivatives With Improved Activity in Splicing Modulation That Induces Inclusion of Cassette Exons Similar to the Splicing Factor 3B Subunit 1 Mutation","authors":"Takanori Matsumaru,&nbsp;Toshiki Iwamatsu,&nbsp;Kana Ishigami,&nbsp;Makoto Inai,&nbsp;Wataru Kanto,&nbsp;Ayumi Ishigaki,&nbsp;Atsushi Toyoda,&nbsp;Satoshi Shuto,&nbsp;Katsumi Maenaka,&nbsp;Shinichi Nakagawa,&nbsp;Hiroshi Maita","doi":"10.1111/cbdd.70002","DOIUrl":"10.1111/cbdd.70002","url":null,"abstract":"<div>\u0000 \u0000 <p>Splicing modulation by a small compound offers therapeutic potential for diseases caused by splicing abnormality. However, only a few classes of compounds that can modulate splicing have been identified. We previously identified BAY61-3606, a multiple kinase inhibitor, as a compound that relaxes the splicing fidelity at the 3′ splice site recognition. We have also reported the synthesis of derivatives of BAY61-3606. In this study, we tested those compounds for their splicing modulation capabilities and identified two contrasting compounds. These compounds were further investigated for their effects on the whole transcriptome, and analysis of changes in transcription and splicing revealed that the highly active derivative in the splicing reporter assay also showed significantly higher activity in modulating the splicing of endogenously expressed genes. Particularly, cassette exon inclusion was highly upregulated by this compound, and clustering analysis revealed that these effects resembled those in splicing factor 3b subunit 1 (SF3B1) K700E mutant cells but contrasted with those of the splicing inhibitor H3B-8800. Additionally, a group of serine/arginine-rich (SR) protein genes was identified as representatively affected, likely via modulation of poison exon inclusion. This finding could guide further analysis of the mode of action of these compounds on splicing, which could be valuable for developing drugs for diseases associated with splicing abnormalities.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142514625","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}

{"title":"Directed Design, Screening and Antiglycation Activity for 3-Substituted Thiazolium Derivatives, New Analogs of Alagebrium","authors":"Olga N. Zhukovskaya,&nbsp;Alexandra A. Kolodina,&nbsp;Roman Litvinov,&nbsp;Umida Ibragimova,&nbsp;Nikita Valuisky,&nbsp;Svetlana Sorokina,&nbsp;Xenia Zhukova,&nbsp;Diana Yu. Pobedinskaya,&nbsp;Alexander Borisov,&nbsp;Denis A. Babkov,&nbsp;Alexander A. Spasov","doi":"10.1111/cbdd.14630","DOIUrl":"https://doi.org/10.1111/cbdd.14630","url":null,"abstract":"<div>\u0000 \u0000 <p>Preliminary ab initio calculations led to the synthesis of novel substituted thiazolium salts, analogs of Alagebrium, which were further explored in vitro for their potential as inhibitors of the glycation reaction utilizing three distinct assays: inhibition of fluorescent AGEs formation, anticrosslinking, and deglycation. Despite the unidirectionality of the assays, distinct differences were observed in the mechanisms of interference and activity manifestation by the compounds. The gathered data permitted the formation of hypotheses about the molecular fragments of the studied antiglycators that are of utmost significance in each assay, thereby guiding future design endeavors. Potential mechanisms of actions are discussed therein. The compound 4-meth-yl-3-[2-(4-methylbiphenyl-4-yl)-2-oxoethyl] thiazolium bromide displayed high activity across all three assays, establishing it as a lead compound. The cytotoxicological properties of the compounds were evaluated using LDH and MTT assays. However, the lead compound exhibited cytotoxicity, indicating the need for additional investigations aimed at decreasing toxicity while maintaining activity. The targeted thiazolium salts were synthesized through an <i>N</i>-alkylation reaction between the corresponding thiazoles and phenacyl bromides.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448987","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}

{"title":"Novel Synthesized Benzophenone Thiazole Hybrids Exhibited Ex Vivo and In Silico Anti-Inflammatory Activity","authors":"Luiz Paulo Melchior de Oliveira Leão,&nbsp;Albert Katchborian Neto,&nbsp;Karen de Jesus Nicácio,&nbsp;Stefânia Neiva Lavorato,&nbsp;Fernanda Brito Leite,&nbsp;Karina Camargo Teixeira,&nbsp;Michael Murgu,&nbsp;Ana Cláudia Chagas de Paula,&nbsp;Marisi Gomes Soares,&nbsp;Daniela Aparecida Chagas-Paula,&nbsp;Danielle Ferreira Dias","doi":"10.1111/cbdd.14634","DOIUrl":"https://doi.org/10.1111/cbdd.14634","url":null,"abstract":"<div>\u0000 \u0000 <p>Novel benzophenone–thiazole hybrids with different substituents were synthesized and evaluated for anti-inflammatory activity using an ex vivo human whole-blood assay. All hybrids (<b>3c</b> and <b>5a–h</b>) showed significant anti-inflammatory activity via prostaglandin E2 (PGE2) release inhibition. Moreover, <b>5c</b> (82.8% of PGE2 inhibition), <b>5e</b> (83.1% of PGE2 inhibition), and <b>5h</b> (82.1% of PGE2 inhibition) were comparable to the reference drugs. Molecular docking revealed potential preferable binding to the active sites of cyclooxygenase 2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) enzymes. This study provides the first evidence that benzophenone–thiazole hybrids may also dock in mPGES-1, a new attractive anti-inflammatory drug target, besides providing promising ex vivo anti-inflammatory activity. Thus, the novel hybrids are promising anti-inflammatory lead compounds and highlight the significance of optimal substituent selection in the design of potent PGE2 inhibitors.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451189","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}

{"title":"Tyramine Derivatives as Versatile Pharmacophores With Potent Biological Properties: Sex Hormone–Binding Globulin Inhibition, Colon Cancer Antimigration, and Antimicrobial Activity","authors":"Jovana S. Marjanović,&nbsp;Dejan Arsenijević,&nbsp;Marijana Kosanić,&nbsp;Jovana Matić,&nbsp;Goran A. Bogdanović,&nbsp;Marina D. Kostić,&nbsp;Vera M. Divac","doi":"10.1111/cbdd.70001","DOIUrl":"https://doi.org/10.1111/cbdd.70001","url":null,"abstract":"<div>\u0000 \u0000 <p>Guided by the idea that the presence of a heterocyclic aromatic core and tyramine moiety, under the umbrella of a single molecular scaffold could bring interesting biological properties, herein we present synthesis, characterization, with two crystal structures reported, and biological evaluation of some tyramine derivates. Cytotoxic and antimigratory potential was addressed by using a colorectal cancer cell line as a model system. Although possessing no cytotoxic effects, two compounds have shown strong antimigratory potential in low doses, with no effect on healthy MRC-5 cells. Evaluation of their antimicrobial activities suggested prominent antimicrobial activity, where Compound <b>4</b> outperformed streptomycin against <i>Escherichia coli</i> and <i>Proteus mirabilis</i>. Hormone-dependent types of cancer, such as prostate, ovary, and breast, are highly dependent on human sex hormone–binding globulin (SHBG) blood levels. A molecular docking study has shown that <b>1</b> has high affinity to bind and therefore compete with natural steroids for the SHBG steroid-binding site. DNA-binding study have shown that <b>4</b> interacts with CT-DNA in a groove-binding mode. <i>In silico</i> ADME/T study revealed that all compounds have suitable physicochemical properties for oral bioavailability and druglikeness, while toxicity tests for <b>1</b>, <b>4,</b> and <b>6</b> suggested potential for mutagenicity (<b>4, 6</b>), hepatotoxicity (<b>6</b>), and skin sensation (<b>1</b>).</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142443414","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}

{"title":"Apelin-13's Actions in Controlling Hypertension-Related Cardiac Hypertrophy and the Expressions of Inflammatory Cytokines","authors":"Xiaoliang Wei,&nbsp;Liyun Luo,&nbsp;Huifang Lu,&nbsp;Songbiao Li,&nbsp;Xinlian Deng,&nbsp;Zhihui Li,&nbsp;Dong Gong,&nbsp;Bairong Chen","doi":"10.1111/cbdd.14628","DOIUrl":"https://doi.org/10.1111/cbdd.14628","url":null,"abstract":"<div>\u0000 \u0000 <p>As a key molecule for improving cardiovascular diseases, Apelin-13 was surveyed in this work to explain its actions in controlling inflammation, pyroptosis, and myocardial hypertrophy. First, mouse models with myocardial hypertrophy were established. Then, assessments were made on the pathological variation in the heart of mouse, on the cardiac functions, as well as on the expressions of cardiac hypertrophy markers (β-MHC, ANP, and BNP), inflammatory factors (TNF-α, COX2, IL-6, ICAM-1, and VCAM-1), myocardial cell pyroptosis markers (NLRP3, ASC, c-caspase-1, and GSDMD-N), and Hippo pathway proteins (p-YAP, YAP, LATS1, and p-LATS1) by HE staining, echocardiography scanning, and western blot tests separately. The expressions of such inflammatory factors as in myocardial tissue were acquired by ELISA. After inducing the phenotype of H9c2 cell hypertrophy by noradrenaline, we used CCK-8 kits to know about the activity of H9c2 cells treated with Apelin-13, and performed ɑ-actinin staining to measure the changes in volumes of such cells. As unraveled through this work, Apelin-13 refrained the activation of the Hippo pathway, which in turn attenuated the hypertrophy, inflammation, and pyroptosis of myocardial tissue and H9c2 cells. Hence, Apelin-13 can be considered as a target for hypertension treatment.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142435358","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}

{"title":"Anti-metastatic Effects of Bee Venom and Melittin in Breast Cancer Cells by Upregulation of BRMS1 and DRG1 Genes","authors":"Nur Sena Sivri,&nbsp;Sinan Tetikoğlu,&nbsp;Sevgi Kolayli,&nbsp;Ammad Ahmad Farooqi,&nbsp;Selcen Çelik Uzuner","doi":"10.1111/cbdd.14637","DOIUrl":"https://doi.org/10.1111/cbdd.14637","url":null,"abstract":"<div>\u0000 \u0000 <p>Apitherapy has started to gain tremendous recognition because of extraordinary pharmacological importance of honeybee-related ingredients and their derivatives. There has been a renewed interest in the bee venom–based therapies. Interdisciplinary researchers are studying the chemistry and translational value of venom for effective cancer treatment. Bee venom and its major component, melittin, are cytotoxic in cancer cells. In this study, MTT and scratch assays were performed for analysis of melittin-mediated antimetastatic effects. QPCR was used for expression profiling of metastasis-related genes. Three anti-metastatic genes (<i>BRMS1</i>, <i>DRG1</i>, and <i>KAI1</i>/<i>CD82</i>) were studied for the first time after bee venom and melittin treatment in MDA-MB-231 breast cancer cells compared with normal breast cells, and two prometastatic genes (<i>EGFR</i> and <i>WNT7B</i>) were also examined. KAI1/CD82 and BRMS1 are the negative regulators of EGFR. WNT7B is a negative regulator of KAI1/CD82. Selective cytotoxicity of bee venom and melittin was found to be higher as compared to cisplatin. Melittin induced an increase in the expression of BRMS1 and DRG1, whereas bee venom upregulated DRG1 and KAI1/CD82 expression in breast cancer. <i>WNT7B</i> was downregulated in bee venom–treated breast cancer cells. Results suggested that bee venom/melittin exerted antimetastatic effects primarily through upregulation of <i>BRMS1</i>, <i>DRG1</i>, and <i>KAI1</i>/<i>CD82</i>, and downregulation of <i>WNT7B</i>.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142435359","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}

{"title":"Exploring the Artificial Intelligence and Its Impact in Pharmaceutical Sciences: Insights Toward the Horizons Where Technology Meets Tradition","authors":"Shruti Bharadwaj,&nbsp;Kumari Deepika,&nbsp;Asim Kumar,&nbsp;Shivani Jaiswal,&nbsp;Shaweta Miglani,&nbsp;Damini Singh,&nbsp;Prachi Fartyal,&nbsp;Roshan Kumar,&nbsp;Shareen Singh,&nbsp;Mahendra Pratap Singh,&nbsp;Abhay M. Gaidhane,&nbsp;Bhupinder Kumar,&nbsp;Vibhu Jha","doi":"10.1111/cbdd.14639","DOIUrl":"https://doi.org/10.1111/cbdd.14639","url":null,"abstract":"<p>The technological revolutions in computers and the advancement of high-throughput screening technologies have driven the application of artificial intelligence (AI) for faster discovery of drug molecules with more efficiency, and cost-friendly finding of hit or lead molecules. The ability of software and network frameworks to interpret molecular structures' representations and establish relationships/correlations has enabled various research teams to develop numerous AI platforms for identifying new lead molecules or discovering new targets for already established drug molecules. The prediction of biological activity, ADME properties, and toxicity parameters in early stages have reduced the chances of failure and associated costs in later clinical stages, which was observed at a high rate in the tedious, expensive, and laborious drug discovery process. This review focuses on the different AI and machine learning (ML) techniques with their applications mainly focused on the pharmaceutical industry. The applications of AI frameworks in the identification of molecular target, hit identification/hit-to-lead optimization, analyzing drug–receptor interactions, drug repurposing, polypharmacology, synthetic accessibility, clinical trial design, and pharmaceutical developments are discussed in detail. We have also compiled the details of various startups in AI in this field. This review will provide a comprehensive analysis and outline various state-of-the-art AI/ML techniques to the readers with their framework applications. This review also highlights the challenges in this field, which need to be addressed for further success in pharmaceutical applications.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.14639","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142435360","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}

{"title":"Computational Insights Into the Mechanism of EGCG's Binding and Inhibition of the TDP-43 Aggregation","authors":"Vini D. Meshram,&nbsp;Ramkumar Balaji,&nbsp;Preethi Saravanan,&nbsp;Yashashwini Subbamanda,&nbsp;Waghela Deeksha,&nbsp;Akarsh Bajpai,&nbsp;Himanshu Joshi,&nbsp;Anamika Bhargava,&nbsp;Basant K. Patel","doi":"10.1111/cbdd.14640","DOIUrl":"10.1111/cbdd.14640","url":null,"abstract":"<div>\u0000 \u0000 <p>Misfolding and aggregation of TAR DNA-binding protein, TDP-43, is linked to devastating proteinopathies such as ALS. Therefore, targeting TDP-43's aggregation is significant for therapeutics. Recently, green tea polyphenol, EGCG, was observed to promote non-toxic TDP-43 oligomer formation disallowing TDP-43 aggregation. Here, we investigated if the anti-aggregation effect of EGCG is mediated via EGCG's binding to TDP-43. In silico molecular docking and molecular dynamics (MD) simulation suggest a strong binding of EGCG with TDP-43's aggregation-prone C-terminal domain (CTD). Three replicas, each having 800 ns MD simulation of the EGCG-TDP-43-CTD complex, yielded a high negative binding free energy (Δ<i>G</i>) inferring a stable complex formation. Simulation snapshots show that EGCG forms close and long-lasting contacts with TDP-43's Phe-313 and Ala-341 residues, which were previously identified for monomer recruitment in CTD's aggregation. Notably, stable physical interactions between TDP-43 and EGCG were also detected in vitro using TTC staining and isothermal titration calorimetry which revealed a high-affinity binding site of EGCG on TDP-43 (<i>K</i>_d, 7.8 μM; Δ<i>G</i>, −6.9 kcal/mol). Additionally, TDP-43 co-incubated with EGCG was non-cytotoxic when added to HEK293 cells. In summary, EGCG's binding to TDP-43 and blocking of residues important for aggregation can be a possible mechanism of its anti-aggregation effects on TDP-43.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142395962","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}

{"title":"Recent Advances in Medicinal Chemistry of Memantine Against Alzheimer's Disease","authors":"Yash Pal Singh,&nbsp;Harish Kumar","doi":"10.1111/cbdd.14638","DOIUrl":"10.1111/cbdd.14638","url":null,"abstract":"<div>\u0000 \u0000 <p>Alzheimer's disease (AD) is a chronic progressive, age-related neurodegenerative brain disorder characterized by the irreversible decline of memory and other cognitive functions. It is one of the major health threat of the 21st century, which affects around 60% of the population over the age of 60 years. The problem of this disease is even more major because the existing pharmacotherapies only provide symptomatic relief without addressing the basic factors of the disease. It is characterized by the extracellular deposition of amyloid β (Aβ) to form senile plaques, and the intracellular hyperphosphorylation of tau to form neurofibrillary tangles (NFTs). Due to the complex pathophysiology of this disease, various hypotheses have been proposed, including the cholinergic, Aβ, tau, oxidative stress, and the metal–ion hypothesis. Among these, the cholinergic and Aβ hypotheses are the primary targets for addressing AD. Therefore, continuous advances have been made in developing potential cholinesterase inhibitors and <i>N</i>-methyl-D-aspartate (NMDA) receptor antagonists to delay disease progression and restore cholinergic neurotransmission. In this review article, we tried to comprehensively summarize the recent advancement in NMDA receptor antagonist (memantine) and their hybrid analogs as potential disease-modifying agents for the treatment of AD. Furthermore, we also depicted the design, rationale, and SAR analysis of the memantine-based hybrids used in the last decade for the treatment of AD.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142382760","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}

{"title":"Evaluation of Quinoline-Related Carboxylic Acid Derivatives as Prospective Differentially Antiproliferative, Antioxidative, and Anti-Inflammatory Agents","authors":"Shereen Arabiyat,&nbsp;Ahmad Alzoubi,&nbsp;Hala Al-Daghistani,&nbsp;Yusuf Al-Hiari,&nbsp;Violet Kasabri,&nbsp;Rema Alkhateeb","doi":"10.1111/cbdd.14615","DOIUrl":"10.1111/cbdd.14615","url":null,"abstract":"<div>\u0000 \u0000 <p>The higher prevalence of cancer and the unmet need for antioxidant/anti-inflammatory chemotherapeutic compounds with little side effect are of utmost importance. In addition, the increased likelihood of failure in clinical trials along with increasing development costs may have diminished the range of choices among newer drugs for clinical use. This has dictated the necessity to seek out novel medications by repurposing as it needs less time, effort, and resources to explore new uses of a current or unsuccessful medication. In this study, we examined the biological activity of 10 potential quinoline derivatives. Given the half-maximal inhibitory concentration (IC₅₀ value) in lipopolysaccharide (LPS) induced inflammation of RAW264.7 mouse macrophages, all commercial FQs and selected quinolines (quinoline-4-carboxlic and quinoline-3-carboxylic acids) exerted impressively appreciable anti-inflammation affinities versus classical NSAID indomethacin without related cytotoxicities in inflamed macrophages. Conversely, all 14 tested compounds lacked antioxidative DPPH radical scavenging capacities as compared to ascorbic acid. Gemifloxacin, considerably unlike markets FQs, indomethacin and quinoline derivatives, exerted exceptional and differential antiproliferation propensities in colorectum SW480, HCT116, and CACO2, pancreatic PANC1, prostate PC3, mammary T47D, lung A375, and melanoma A549 adherent monolayers using the sulforhodamine B colorimetric method versus antineoplastic cisplatin. All quinoline derivatives and gemifloxacin alike, but not levofloxacin, ciprofloxacin, or indomethacin, displayed substantially selective viability reduction affinities in prolonged tumor incubations of cervical HELA and mammary MCF7 cells. Specifically kynurenic acid (hydrate), quinoline-2-carboxylic acid, quinoline-4-carboxylic acid, quinoline-3-carboxylic acid, and 1,2-dihydro-2-oxo-4-quinoline carboxylic acids possessed the most remarkable growth inhibition capacities against mammary MCF7 cell line, while quinoline-2-carboxylic acid was the only quinoline derivative with significant cytotoxicity on cervical HELA cancer cells. It is highly speculated that chelation with divalent metals via co-planarity with close proximity of the COOH and the N atom could have the potential molecular mechanism for optimally promising repurposed pharmacologies. Conclusively, this study revealed the considerably profound repurposed duality of cytotoxicity and anti-inflammation pharmacologies of quinoline derivatives. Activity-guided structural modifications of the present nuclear scaffolds can be inherently linked to the betterment and enhancement of their repurposed pharmacologies.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142367867","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}