Bioorganic Chemistry最新文献

{"title":"Unveiling the potential of xanthines, discovery of potential 7-benzyl-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione derivatives with antifibrotic activity for liver injury","authors":"Abdalla R. Mohamed ,&nbsp;Hanan H. Georgey ,&nbsp;Esraa A. Aidy ,&nbsp;Tamer A. Al-Shafie ,&nbsp;Mohamed R. Elnagar ,&nbsp;Mennatallah A. Ali ,&nbsp;Samar S. Elblehi ,&nbsp;Abdullah Y.A. Alzahrani ,&nbsp;Mai H.A. Mousa","doi":"10.1016/j.bioorg.2025.108441","DOIUrl":"10.1016/j.bioorg.2025.108441","url":null,"abstract":"<div><div>A new series of xanthine-based derivatives were designed, synthesized, and investigated to achieve promising antifibrotic and antioxidant agents for management of liver injury. Structure-based optimizations of the methylxanthine-based KMUP-1 (<strong>IX</strong>) were performed for inhibiting NF-κB activation pathway. All the newly designed xanthine derivatives <strong>3, 4, 5, 6a-d, 7a-d</strong>, and <strong>9a-d</strong> were <em>in vitro</em> screened for the antioxidant activity using the DPPH method. Compounds <strong>4</strong> and <strong>5</strong> showed the highest antioxidant activity with an IC₅₀ of 28.02 and 36.02 μM, respectively. Compounds <strong>9c</strong> and <strong>9d</strong> retained a promising interception of the NF-κB activation pathway in molecular docking simulations within I-κB kinase α (IKKα) crystal structure (PDB ID: <span><span>5EBZ</span><svg><path></path></svg></span>). Subsequently, compounds <strong>9c</strong> and <strong>9d</strong> were evaluated for their <em>in vivo</em> antifibrotic and chemoprotective activity using CCl₄-induced hepatic fibrosis rat model. Compounds <strong>9c</strong> and <strong>9d</strong> successfully ameliorated liver fibrosis, as evidenced by the improved liver histopathological examination and liver enzyme activity levels. Compounds <strong>9c</strong> and <strong>9d</strong> were evaluated for their effects on mRNA expression levels of key genes involved in liver fibrosis <em>via</em> real-time PCR assays. Compound <strong>9c</strong> exhibited a greater inhibitory effect on the expression levels of NF-κB and HIF-1α and a more pronounced stimulation of Nrf2 than compound <strong>9d</strong>. Moreover, all the new xanthine derivatives were screened for the cytotoxic activity against the NCI tumor cell lines. Compounds <strong>9c</strong> and <strong>9d</strong> revealed a non-significant cytotoxic activity against all the assayed tumor cell lines, which indicate their selectivity for the antifibrotic activity. While compounds <strong>6a</strong> and <strong>6c</strong> displayed promising selective activity against melanoma SK-MEL-5 cell line (GI = 125.6, 90.3 %, respectively), and breast T-47D cell line (GI =87.8, 80.6 %, respectively). The utilized design approach unveiled the versatility of xanthine scaffold to deliver potential antioxidant, liver antifibrotic and chemoprotective agents, along with anticancer candidates <em>via</em> structure modification and optimization.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"160 ","pages":"Article 108441"},"PeriodicalIF":4.5,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143792812","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}

{"title":"Synthesis of new selective agents with dual anti-inflammatory and SARS-CoV-2 Mpro inhibitory activity: Antipyrine-celecoxib hybrid analogues; COX-2, COVID-19 cytokine storm and replication inhibitory activities.","authors":"Eman K.A. Abdelall ,&nbsp;Heba A.H. Elshemy ,&nbsp;Madlen B. Labib ,&nbsp;John N. Philoppes ,&nbsp;Fares E.M. Ali ,&nbsp;Amira K.M. Ahmed","doi":"10.1016/j.bioorg.2025.108429","DOIUrl":"10.1016/j.bioorg.2025.108429","url":null,"abstract":"<div><div>Herein, a great aim to introduce novel pyrazolone derivatives with multiple activities, including selective COX-2 and cytokine inhibition in addition to SARS-CoV-2 M^pro inhibitory effects. All the synthesized compounds <strong>4a-c</strong>, <strong>5</strong>, <strong>6a,b</strong>, <strong>7a-f</strong>, <strong>8a,b</strong>, <strong>9a,b</strong>, <strong>10a,b</strong> and <strong>11a-f</strong> were evaluated <em>in vitro</em> for investigation of selective COX-2 inhibitory activity. The results introduced the most selective compounds <strong>7a</strong>, <strong>7d</strong>, <strong>7e</strong>, <strong>9a</strong>, and <strong>11</strong> <strong>f</strong> that were further screened <em>in vivo</em> to evaluate their anti-inflammatory activity, safety concerning gastric ulcer and myocardial infarction. Compounds <strong>7e, 9a</strong> and <strong>11</strong> <strong>f</strong> exhibited % edema inhibition (43.87–54.31) compared to celecoxib (54.17 %) at the same time. Histopathological examination of gastric and cardiac tissues proved the safe profiles of compounds <strong>7e</strong> and <strong>11</strong> <strong>f</strong>. The reduction in cardiac biomarkers level (CK-MP, AST, LDH) and the pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β) ensured the cardiac safety of <strong>7e</strong> and <strong>11</strong> <strong>f</strong>. Also, RT-PCR results confirmed the efficacy of compounds <strong>7e</strong> and <strong>11</strong> <strong>f</strong> to inhibit gene expression of cytokines responsible for the overwhelming inflammation in COVID-19 infection, including TNF-α, IL-6, IL-2 and IL-1β. Additionally, SARS-CoV-2 M^pro inhibitory assay revealed the potency of the compound <strong>7e</strong> against M^pro enzyme (IC₅₀ = 13.24 μM). Furthermore, the proper fitting of <strong>7e</strong> inside both COX-2 and M^pro active site through the docking study supported the affinity of <strong>7e</strong> to inhibit both enzymes. Therefore, a belief stated that compound <strong>7e</strong> is a promising lead compound with a safe profile, acting as a selective COX-2 and cytokine inhibitor. Also, <strong>7e</strong> reduces the COVID-19 infection's cytokine storm and inhibits viral replication <em>via</em> targeting the M^pro enzyme.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"160 ","pages":"Article 108429"},"PeriodicalIF":4.5,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143792810","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}

{"title":"Targeting Autotaxin with imidazole- and Triazolyl-based inhibitors: Biological insights from in vitro and in vivo studies in pulmonary fibrosis","authors":"Misu Kim ,&nbsp;Minh Thanh La ,&nbsp;Young Ah. Shin ,&nbsp;Sujae Yang ,&nbsp;Eun Jeong Kim ,&nbsp;Sol Lee ,&nbsp;Hyun Young Jung ,&nbsp;Sanga Na ,&nbsp;Wonhyo Seo ,&nbsp;Bongyong Lee ,&nbsp;Yun-Sil Lee ,&nbsp;Soosung Kang","doi":"10.1016/j.bioorg.2025.108426","DOIUrl":"10.1016/j.bioorg.2025.108426","url":null,"abstract":"<div><div>Autotaxin (ATX) is a key enzyme in producing lysophosphatidic acid (LPA), a lipid involved in fibrosis. This study reports the synthesis and evaluation of novel ATX inhibitors containing zinc-binding imidazole or triazole motif with piperidine spacers. Compound <strong>27a</strong> exhibited strong ATX inhibition (IC₅₀ = 39 nM) in human plasma and demonstrated efficacy in cellular and animal fibrosis models. In vitro ADME/T studies showed favorable liver microsomal stability, minimal hERG binding, and acceptable PK parameters. In vivo, <strong>27a</strong> significantly reduced plasma LPA levels and downregulated fibrosis-related pathways, including p-ERK, p-P38, and p-JNK. It also inhibited cell migration and collagen gel contraction without cytotoxicity in fibrotic cells. In a bleomycin-induced pulmonary fibrosis model, <strong>27a</strong> reduced collagen deposition, LPAR1, and p-ERK expression, while decreasing mRNA levels of α-SMA, Col1A1, and pro-inflammatory markers IL-6, IL-1β, and INFγ. These findings position <strong>27a</strong> as a promising ATX inhibitor with therapeutic potential for fibrosis-related diseases.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"160 ","pages":"Article 108426"},"PeriodicalIF":4.5,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143792809","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}

{"title":"Whiteleg shrimp-derived Cryptides induce mitochondrial-mediated cytotoxicity in human breast Cancer","authors":"Amr Adel Ahmed Abd El-Aal ,&nbsp;Fairen Angelin Jayakumar ,&nbsp;Kuan Onn Tan ,&nbsp;Chandrajit Lahiri ,&nbsp;Felicia Fei-Lei Chung ,&nbsp;Kavita Reginald","doi":"10.1016/j.bioorg.2025.108432","DOIUrl":"10.1016/j.bioorg.2025.108432","url":null,"abstract":"<div><div>Breast cancer remains the most prevalent cancer in females. The triple negative subtype of breast cancer is associated with higher recurrence rates and poorer prognosis, lack of effective targeted therapy options, and frequently becoming unresponsive to chemotherapy. This study investigates the <em>in vitro</em> anti-cancer potential of our previously <em>in silico</em>-discovered cryptides, from <em>Penaeus vannamei</em>, against MCF-7, MCF-7-CR, and MDA-MB-231 cancer cell lines. Five cryptides—AD4, AD7, AD8, AD11, and AD12—were tested using the MTT assay, revealing selective toxicity against cancer cells. The lowest and highest calculated IC₅₀ values were for AD12 against MCF-7-CR (∼4.6 μM) and MDA-MB-231 (∼20 μM), respectively. Mechanistic studies showed that the cytotoxicity mediated by cryptides, AD7 and AD8, induced loss of mitochondrial membrane potential, release of mitochondrial cytochrome C, and cleavage of caspases that were associated with BAX activation in MCF-7 and MDA-MB-231 cells. Furthermore, our results showed that both MCF-7 and MDA-MB-231 cells treated with AD7 or AD8 exhibited nuclei condensation, activation of Caspase 3/7, leading to apoptotic cell death associated with intrinsic apoptotic cell signaling mechanism. However, further investigation showed that both AD7 and AD8 peptides promoted up-regulation of FAS and p53 in MCF-7 cells while down-regulated the expression of both FAS and p53 in MDA-MB-231 cells, suggesting cell-type dependent apoptotic cell signaling mechanisms. Moreover, both AD7 and AD8 demonstrated cytotoxic and disintegration effects in 3D cancer model. This study highlights the anticancer potential of marine-derived cryptides against challenging breast cancer subtypes, including triple-negative breast cancer (TNBC), with selective cytotoxicity and potential to overcome resistance and recurrence.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"160 ","pages":"Article 108432"},"PeriodicalIF":4.5,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143786068","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}

{"title":"Peptidomimetics based on thiacalixarene with L-tyrosine moieties: Antibacterial activity against methicillin-resistant Staphylococcus aureus and degradation induced by binding to α-chymotrypsin","authors":"Olga Terenteva ,&nbsp;Olga Mostovaya ,&nbsp;Mikhail Bukharov ,&nbsp;Timur Mukhametzyanov ,&nbsp;Azamat Bikmukhametov ,&nbsp;Anna Lyubina ,&nbsp;Alexandra Voloshina ,&nbsp;Konstantin Petrov ,&nbsp;Pavel Padnya ,&nbsp;Ivan Stoikov","doi":"10.1016/j.bioorg.2025.108434","DOIUrl":"10.1016/j.bioorg.2025.108434","url":null,"abstract":"<div><div>The design of new antimicrobial agents is an important challenge due to the growing resistance of microorganisms to existing antibiotics. In recent years, the trend towards the development of compounds and materials with (bio)degradable properties has emerged. In this work, we propose and develop a method for the synthesis of new peptidomimetics, i.e., water-soluble macrocyclic quaternary ammonium salts containing <em>L</em>-tyrosine fragments based on <em>p-tert-</em>butylthiacalix[4]arene in various stereoisomeric forms (<em>cone</em>, <em>partial cone,</em> and <em>1,3-alternate</em>). These compounds have low cytotoxicity (IC₅₀ = 80–267 μM) and high antibacterial activity (MIC = 0.5–15.6 μM) against Gram-positive bacterial strains including methicillin-resistant <em>Staphylococcus aureus</em> (MRSA). The obtained peptidomimetics can bind α-chymotrypsin with the formation of supramolecular systems and their subsequent degradation. Our results demonstrate the first example of multi-action thiacalixarene derivatives with antibacterial activity, protein binding ability and degradation induced by binding to α-chymotrypsin. The obtained results open the possibility of creating multi-action peptidomimetic systems with antimicrobial and biodegradable effect.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"160 ","pages":"Article 108434"},"PeriodicalIF":4.5,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776640","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}

{"title":"Recent advances in PROTAC-based antiviral and antibacterial therapeutics","authors":"Can Zhou ,&nbsp;Shiwei Yang ,&nbsp;Jun Wang ,&nbsp;Wei Pan ,&nbsp;Hongliang Yao ,&nbsp;Gang Li ,&nbsp;Minhong Niu","doi":"10.1016/j.bioorg.2025.108437","DOIUrl":"10.1016/j.bioorg.2025.108437","url":null,"abstract":"<div><div>By harnessing the ubiquitin proteasome system, proteolysis targeting chimeras (PROTACs) have emerged as a highly promising strategy in drug design for degrading pathogenic proteins. The extensive benefits of PROTAC technology have facilitated its swift and extensive adoption, resulting in numerous PROTACs advancing to clinical trials, and most of them was used for cancers, neurodegenerative diseases, and immune disorders in clinical trials. A number of antiviral PROTACs and antibacterial PROTACs have been developed, exhibiting encouraging bioactivities against various pathogenic viruses and bacterial. Herein, this review summarizes recent advances in PROTAC technology for antiviral and antibacterial drugs, we also provided an overview of the current state of PROTAC clinical trials and detailed the crystal structures of PROTAC in complex with its target protein. Hopefully, this review will contribute to the development of novel antiviral and antibacterial drugs through the utilization of PROTAC technology.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"160 ","pages":"Article 108437"},"PeriodicalIF":4.5,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143808763","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}

{"title":"Biosynthesis of the quinovosamycin nucleoside antibiotics diverges from that of tunicamycins by additional sugar processing genes","authors":"Felaine Anne Sumang ,&nbsp;Jeff Errington ,&nbsp;Yousef Dashti","doi":"10.1016/j.bioorg.2025.108431","DOIUrl":"10.1016/j.bioorg.2025.108431","url":null,"abstract":"<div><div>Nucleoside antibiotics tunicamycins and quinovosamycins are closely related microbial natural products with significant antibacterial and antifungal properties. In this study, we identify and elucidate the structure of a new quinovosamycin analogue, quinovosamycin Q4 (<strong>4</strong>), which displays potent activity against <em>Cryptococcus neoformans</em> (0.03 μg/mL), <em>Candida albicans</em> (0.5 μg/mL), and <em>Bacillus subtilis</em> (0.125 μg/mL). Bioinformatics analysis of the sequenced genome of the quinovosamycin producing <em>Streptomyces</em> strain PR-3G identified a biosynthetic gene cluster (BGC), encoding all of the enzymes needed for tunicamycin synthesis, as well as several new upstream genes likely responsible for synthesis and incorporation of the alternative <em>N</em>-acetylquinovosamine sugar needed for quinovosamycin production. The role of the upstream genes in quinovosamycins biosynthesis was confirmed by insertional mutagenesis.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"160 ","pages":"Article 108431"},"PeriodicalIF":4.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143817161","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}

{"title":"A comprehensive review on anti-inflammatory, antibacterial, anticancer and antifungal properties of several bivalent transition metal complexes","authors":"Anas AlAli ,&nbsp;Maged Alkanad ,&nbsp;Khaled Alkanad ,&nbsp;Annegowda Venkatappa ,&nbsp;Nischith Sirawase ,&nbsp;Ismail Warad ,&nbsp;Shaukath Ara Khanum","doi":"10.1016/j.bioorg.2025.108422","DOIUrl":"10.1016/j.bioorg.2025.108422","url":null,"abstract":"<div><div>Transition metal complexes have been recognized as possible therapeutic agents, attributed to their special biological actions, including anti-inflammatory, antibacterial, antifungal, and anticancer. The pharmacological perspective connected with Copper (Cu), Cobalt (Co), Nickel (Ni), Manganese (Mn), Palladium (Pd), Zinc (Zn), and Platinum (Pt) metal(II) complexes is comprehensively explored in-depth in this research. The complexes show unique coordination chemistry and modes of action that help interactions with biological targets, including DNA binding, enzyme inhibition, and the formation of reactive oxygen species. All the metal(II) complexes showed notable potential impact in their perspective activity. Conspicuously, Co(II) and Ni(II) complexes show better antibacterial and antifungal action, while Cu(II) and Zn(II) combinations show higher anti-inflammatory activity. While research is constantly investigating alternative metal-based anticancer drugs like Pd(II), which seem to have lowered side effects, Pt(II) complexes especially cisplatin continue to be the benchmark in cancer treatment. Although the possible pharmacological actions are motivating, problems with toxicity and biocompatibility still provide major difficulties, especially in relation to Cd(II) and Hg(II) complexes. Strategies like ligand modification, nanoparticle-based delivery, and prodrug methods are used to increase selectivity and reduce side effects related to metal complexes. This review compiles the most recent developments and continuous research, thereby shedding light on the potential revolutionary power of metal(II) complexes in medical therapy. Understanding their mechanisms and enhancing their safety profiles will help us open the path to creative ideas for addressing some of the most urgent medical issues of today.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"160 ","pages":"Article 108422"},"PeriodicalIF":4.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776643","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}

{"title":"Structure-activity relationship explorations of 2-(isoxazol-5-yl)phenyl-3,4-dihydroxybenzoate derivatives to develop potent Wnt/β-catenin pathway inhibitors for colorectal cancer treatment","authors":"Li Dong ,&nbsp;Tiemei Long ,&nbsp;Shanghui Zhang ,&nbsp;Yongqing Mao ,&nbsp;Mingji Liu ,&nbsp;Fuhui Zhao ,&nbsp;Zhangxiang Yang ,&nbsp;Lei Li ,&nbsp;Shi-Wu Chen ,&nbsp;Shanggao Liao ,&nbsp;Yongxi Dong","doi":"10.1016/j.bioorg.2025.108433","DOIUrl":"10.1016/j.bioorg.2025.108433","url":null,"abstract":"<div><div>In the canonical Wnt/β-catenin pathway, the nucleus translocation of β-catenin and β-catenin/ B-cell lymphoma 9 (BCL9) protein-protein interactions (PPI) promote the expressions of oncoproteins (Cyclin D1 and C-myc), thereby inducing the colorectal cancer. Herein, we report the identification of the highly potent Wnt/β-catenin pathway inhibitor <strong>19</strong> <strong>t</strong> following structure-activity relationship (SAR) exploration of 2-(isoxazol-5-yl)phenyl-3,4-dihydroxybenzoate which was discovered by our previous work. Further mechanism research confirmed that the optimized compound <strong>19</strong> <strong>t</strong> reduced the expressions of oncoproteins (Cyclin D1 and C-myc) through inhibiting the nucleus translocation of β-catenin and disrupting the interaction of β-catenin/BCL9, thereby inducing the apoptosis of SW480 cells. Encouragingly, the results of HCT116-xenograft nude mice demonstrated that the compound <strong>19</strong> <strong>t</strong> with acceptable pharmacokinetic parameters significantly inhibited tumor growth (TGI: 61.85 % at 20 mg/kg and 77.52 % at 40 mg/kg) and did not exhibit objective hepatotoxicity and nephrotoxicity. Consistently, the compound <strong>19</strong> <strong>t</strong> could also inhibit expressions of Cyclin D1 and C-myc <em>in vivo</em>. Collectively, the optimized compound <strong>19</strong> <strong>t</strong> could serve as a promising Wnt/β-catenin pathway inhibitor for colorectal cancer treatment.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"160 ","pages":"Article 108433"},"PeriodicalIF":4.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776642","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}

{"title":"Design, synthesis, and biological evaluation of Schiff-Base Isoxazole hybrids: Exploring novel antimicrobial agents","authors":"Anjali Rani ,&nbsp;Javed Khan ,&nbsp;Mohd Aslam ,&nbsp;Asghar Ali ,&nbsp;Mohan Kamthan ,&nbsp;Garima Pandey ,&nbsp;Bhaskara Nand","doi":"10.1016/j.bioorg.2025.108428","DOIUrl":"10.1016/j.bioorg.2025.108428","url":null,"abstract":"<div><div>The rise of antimicrobial resistance necessitates the development of novel therapeutic agents. This study presents the design, in silico studies, synthesis, and biological evaluation of Schiff-base isoxazole hybrids as potential antimicrobial agents. Computational approaches, including molecular docking, molecular dynamics (MD) simulations, density functional theory (DFT) calculations, and ADMET predictions, guided the design and assessment of these compounds. DFT analysis identified compound <strong>A20</strong> (−0.0919 Hartree) as having the lowest energy gap, suggesting high reactivity. Molecular docking revealed strong binding affinities (−11.3 to −7.00 kcal/mol) comparable to standard antimicrobial drugs, while MD simulations confirmed the stability of protein-ligand interactions. ADMET analysis predicted favorable pharmacokinetic properties. Biological evaluations revealed promising antimicrobial potential of the synthesized compounds. <strong>A20</strong> showed significant antifungal activity (MIC: 64 μg/mL), while <strong>A7</strong> exhibited notable antibacterial activity (MIC: 1024 μg/mL). Further <strong>A20</strong> in combination with standard antifungal drug fluconazole is exhibiting outstanding antifungal potential. Leading towards the possibility of developing a new drug against resistant microbial strains through combination therapy.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108428"},"PeriodicalIF":4.5,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143761043","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}