Bioorganic Chemistry最新文献

{"title":"Discovery of 6-amino pyridine clubbed heterocycles as potent dual GSK-3β/CK-1δ inhibitors for the treatment of Alzheimer's disease","authors":"Vinita Sharma ,&nbsp;Jurnal Reang ,&nbsp;Vivek Yadav ,&nbsp;Prabodh Chander Sharma ,&nbsp;Jaseela Majeed ,&nbsp;Kalicharan Sharma","doi":"10.1016/j.bioorg.2025.108409","DOIUrl":"10.1016/j.bioorg.2025.108409","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a progressive and chronic neurodegenerative disorder progression through various kinases. Glycogen synthase kinase 3<em>β</em> (GSK-3<em>β</em>) and Casein Kinase-1<em>δ</em> (CK-1<em>δ</em>) have gained a lot of attention for its role in tau pathology. Utilizing a multitarget strategy, a series of 6-amino pyridine derivatives were developed as promising dual GSK-3<em>β</em>/CK-1<em>δ</em> inhibitors for the treatment of AD. This study involved the design, synthesis, and evaluation of novel 6-amino pyridine derivatives as dual GSK-3<em>β</em>/CK-1<em>δ</em> inhibitors exhibiting excellent biological activities. The <em>in-vitro</em> results indicated that most of compounds displayed promising activity against GSK-3<em>β</em>/CK-1<em>δ</em>. Among the tested compounds, <strong>8d</strong> exhibited strong inhibitory activity against GSK-3<em>β</em> and CK-1<em>δ</em>, with IC₅₀ values of 0.77 ± 0.01 μM and 0.57 ± 0.12 μM, respectively. Notably, compound <strong>8d</strong> significantly reduced tau hyperphosphorylated aggregates while demonstrating safety in SH-SY5Y neuroblastoma cell lines. ADME prediction results indicated that compound <strong>8d</strong> adhered to Lipinski's rule of five and exhibited potential to permeate the blood-brain barrier (BBB). Molecular docking analysis revealed that this compound fits well within the ATP binding site, forming hydrogen bonds between its 6-amino pyridine ring with key amino acids, including Asp133 and Val135 in the hinge region of GSK-3<em>β</em>, as well as Leu85 of CK-1<em>δ</em>. These findings indicate that 6-amino pyridine derivatives have the potential to be effective dual-target candidates for AD.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108409"},"PeriodicalIF":4.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143704560","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 advance in macrolactams: Structure, bioactivity, and biosynthesis","authors":"Jiawei Qiu ,&nbsp;Ruochang Qin ,&nbsp;Shuai Zhi ,&nbsp;Liwei Liu","doi":"10.1016/j.bioorg.2025.108406","DOIUrl":"10.1016/j.bioorg.2025.108406","url":null,"abstract":"<div><div>Macrolactams have garnered significant attention in recent years due to their diverse structures and remarkable biological activities. Despite the increasing number of new members being reported, a systematic discussion of recent advancements in this family is still lacking, particularly in areas such as structure-activity relationship and newly identified biosynthetic pathways that deviate from the traditional collinear rule. To address this gap, we compiled 105 macrolactams reported between 2004 and 2023, produced by microbial strains isolated from diverse environments, including marine sediments, soil, plants, and animals. This review not only highlights the sources, structures, and biological activities of these macrolactams but also delves into 17 known biosynthetic pathways. We provide an in-depth analysis of the associated biosynthetic gene clusters, the mechanisms of key enzymes, and their roles in the biosynthesis process. By offering these insights, this review serves as a valuable reference for the discovery of novel macrolactams and their sustainable production using synthetic biology approaches in the future.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108406"},"PeriodicalIF":4.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143760934","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":"Capturing and releasing cucurbitacins with α, β-unsaturated group from Cucumis melo based on reversibility of thia-Michael addition reaction","authors":"Tianyu Zhu ,&nbsp;Liangyong Hu ,&nbsp;Hang Hu ,&nbsp;Yujie Li ,&nbsp;Jiangmin Zhu ,&nbsp;Guanzhao Wu ,&nbsp;Defeng Xu","doi":"10.1016/j.bioorg.2025.108404","DOIUrl":"10.1016/j.bioorg.2025.108404","url":null,"abstract":"<div><div>Molecules containing α, β<strong>-</strong>unsaturated carbonyl structure have gained constant attention because of their potential of interacting with nucleophilic amino acid residues and further protein function regulating. However, current methods for finding and isolating such compounds are challenged by lacking of convenience and orientation. Herein we introduce a new strategy for capturing and releasing natural products with α, β<strong>-</strong>unsaturated group by regulating the direction of thia-Michael addition reaction. Target molecules could be separated from various impurities by means of controlling the association and dissociation with hydrophilic small sulfhydryl molecules and consequently change of polarity and solubleness. Our strategy showed effectiveness that natural products containing α, β<strong>-</strong>unsaturated esters and ketones could be successfully released from the adducts with cysteine. Finally, nine cucurbitacins with target functional group from the extract of <em>Cucumis melo</em> were enriched and isolated with high selectivity. This strategy may thus help to isolate natural products with α, β<strong>-</strong>unsaturated group in complex samples.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108404"},"PeriodicalIF":4.5,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143687697","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":"Optimizing ST6GAL1 inhibition and selectivity using lithocholic acid-amino acid conjugates for antimetastatic and antiangiogenic agent development","authors":"Wei-Sheng Chen ,&nbsp;Christian Angelo P. Concio ,&nbsp;Tzu-Ting Chang ,&nbsp;Chia-Ling Chen ,&nbsp;Ser John Lynon P. Perez ,&nbsp;Wen-Shan Li","doi":"10.1016/j.bioorg.2025.108401","DOIUrl":"10.1016/j.bioorg.2025.108401","url":null,"abstract":"<div><div>A series of LCA-aromatic amino acid conjugates were synthesized and tested for their inhibitory effects on N-glycan specific ST6GAL1 and O-glycan specific ST3GAL1. The LCA-amino acid conjugates with phenyl and indole moieties showed enhanced inhibitory activity and selectivity towards the <em>N</em>-glycan-specific ST6GAL1, with the indole-containing compound <strong>4e</strong> exhibiting the highest activity (IC₅₀ = 20.0 ± 0.5 μM). In addition, compound <strong>4e</strong> exhibited the highest antimetastatic potential, effectively inhibiting MDA-MB-231 cell migration at non-cytotoxic concentrations. Compound <strong>4e</strong> also suppressed tumor growth and metastasis in vivo, attributing to its potential to disrupt integrins sialylation. The conjugate has also demonstrated excellent antiangiogenetic properties in vitro and ex vivo, owing to its ability to downregulate the VEGF/VEGFR2/Akt pathway. Taken together, these findings prove the practicality of employing LCA as a scaffold and aromatic amino acid conjugation in the discovery of novel, potent, and selective ST inhibitors necessary to address abnormal cell surface α-2,6-<em>N</em>-sialylation.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108401"},"PeriodicalIF":4.5,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143747117","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":"Development of new genipin derivatives as potential NASH treatments: Design, synthesis and action mechanism","authors":"Zi-Tong Feng,&nbsp;Shi-Ying Fan,&nbsp;Xing-Yu Pan,&nbsp;Ling-Yi Kong,&nbsp;Jian-Guang Luo","doi":"10.1016/j.bioorg.2025.108403","DOIUrl":"10.1016/j.bioorg.2025.108403","url":null,"abstract":"<div><div>Nonalcoholic steatohepatitis (NASH) is a multifaceted liver disease. Endoplasmic reticulum stress (ERS), a key driver in NASH pathogenesis, triggers metabolic irregularities, liver steatosis, and inflammation. Genipin, an iridoid from the traditional Chinese medicine <em>Gardenia jasminoides</em>, has demonstrated significant effects against ERS. In the current work, 33 new genipin derivatives were designed and synthesized to evaluate their potential to treat NASH. Notably, <strong>G15</strong> emerged as the most potent candidate, significantly attenuating lipid accumulation induced by free fatty acids (FFAs) in L-02 cells. Further investigation revealed that <strong>G15</strong>'s mitigation of ERS was primarily achieved by suppressing the levels of inositol-requiring enzyme 1 (IRE1). Western blot analysis confirmed that <strong>G15</strong> effectively down-regulated IRE1 protein expression and decreased the expression levels of its downstream X-box binding protein 1 (XBP1) and signal transducer and activator of transcription 3 (STAT3) proteins, thereby reducing cellular lipid accumulation. In addition, <strong>G15</strong> treatment inhibited FFA-induced nitric oxide (NO) production in a concentration-dependent manner and suppressed the secretion of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α. Collectively, these findings underscore that <strong>G15</strong> has the potential to be a leading candidate for the treatment of NASH by down-regulating the IRE1/XBP1/STAT3 signaling pathway.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108403"},"PeriodicalIF":4.5,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143704561","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":"Nitazoxanide and Umbelliferone improves Imiquimod-induced psoriasis in Balb/C mice","authors":"Japneet Singh Purewal ,&nbsp;Maheshkumar Borkar ,&nbsp;Gaurav M. Doshi","doi":"10.1016/j.bioorg.2025.108397","DOIUrl":"10.1016/j.bioorg.2025.108397","url":null,"abstract":"<div><div>Signal Transducer and Activator of Transcription (STAT) 3 is a significant contributor to the development and pathogenesis of psoriasis (Pso). Research demonstrated STAT3 signalling to be upregulated in Pso. Additionally, Pso results in oxidative stress that activates various signalling pathways like factor nuclear kappa-B (NF-κB). Nitazoxanide (NTZ) is an antiprotozoal drug shown to inhibit the STAT3 pathway. Umbelliferone (UMB) is an antioxidant, and anti-inflammatory and can suppress NF-κB signalling. Therefore, we propose to hypothesize that NTZ and UMB would be effective in treating Pso. Balb/c mice were treated with IMQ to induce Pso. The clinical characteristics of Pso were assessed using the Psoriasis Area and Severity Index (PASI), back skin thickness, spleen length and mass, and histology of the skin sample tissue. In addition, we measured the levels of interleukin-17 (IL-17), tumor necrosis factor-α (TNF-α), STAT3, and NF-κB. Furthermore, to gain the interaction of NTZ and UMB with STAT3, a detailed <em>in-silico</em> study has been performed. The impact of treatment on oxidative stress was evaluated by estimating the activity of superoxide dismutase (SOD) and catalase (CAT). The results demonstrate that mice subjected to IMQ-induced Pso exhibited positive responses to treatment with NTZ and UMB. Additionally, IL-17, TNF-α levels, STAT3, and NF-κB were decreased in NTZ and UMB-treated groups. SOD and CAT levels in NTZ and UMB groups were elevated. Our findings show that NTZ and UMB are potential therapeutic medications for Pso.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108397"},"PeriodicalIF":4.5,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143747116","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":"Exploring Thieno/Furo[2,3-b]pyridines as new scaffolds for potential FAK inhibition: Design, synthesis, biological evaluation and in silico studies","authors":"Azza Ismail ,&nbsp;Nayera W. Hassan ,&nbsp;Manal N. Saudi ,&nbsp;Yasser S. Abdel-Ghany ,&nbsp;Hala F. Labib ,&nbsp;Nehal M. El-Deeb ,&nbsp;Soad A. El-Hawash","doi":"10.1016/j.bioorg.2025.108392","DOIUrl":"10.1016/j.bioorg.2025.108392","url":null,"abstract":"<div><div>Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that plays a vital role in regulating cancer cell survival, proliferation, migration, and angiogenesis. Aiming to explore new potent inhibitors, a series of thieno/furo[2,3-<em>b</em>]pyridine derivatives was designed and synthesized. The newly synthesized compounds were evaluated for their <em>in vitro</em> anti-proliferative activity against human liver (HUH-7), lung (A549) and breast (MCF-7) cancer cell lines, in addition to their cytotoxic activity against normal lung cell line (WI-38) to predict their safety profile. Seven compounds (<strong>4a, 4c, 5</strong>, <strong>6, 10c</strong>, <strong>11</strong> and <strong>12</strong>) displayed significant anti-proliferative activity as well as high selectivity towards the tested cancer cell lines (SI &gt; 2). Among them, two compounds <strong>(4a and 4c)</strong> potently inhibited FAK enzyme with IC₅₀ values of 54.96 and 50.98 nM, respectively. Flow cytometric cell cycle analysis indicated that compounds <strong>4a</strong> and <strong>4c</strong> caused cell cycle arrest at G1 phase. Compound <strong>4c</strong> also exhibited an increase in the expression level of caspase-3 enzyme. Moreover, molecular docking study of the most promising compounds into FAK's active site was performed to elucidate their possible binding modes and to provide a structural basis for the further structural guidance design of FAK inhibitors.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108392"},"PeriodicalIF":4.5,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143687080","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":"Discovery of novel Bis-amide analogue ST12 for the treatment of inflammatory bowel diseases (IBD) by inhibiting NLRP3 inflammasome activation","authors":"Zhiqiang Sun ,&nbsp;Qinru Zang ,&nbsp;Chenglong Xu ,&nbsp;Xuewen Zhang ,&nbsp;Zhenghui Kang ,&nbsp;Yushe Yang ,&nbsp;Ling Li ,&nbsp;Jianjun Chen","doi":"10.1016/j.bioorg.2025.108402","DOIUrl":"10.1016/j.bioorg.2025.108402","url":null,"abstract":"<div><div>Herein, we designed and synthesized a series of novel bis-amide small molecule anti-inflammatory agents, among them, compound <strong>ST12</strong> showed most potent anti-inflammatory activity. <strong>ST12</strong> effectively inhibited the production of nitric oxide (NO) (inhibition rate of 52.67 ± 0.03 % at 10 μM) and downregulated the mRNA levels of proinflammatory cytokines iNOS, IL-6, IL-1β and TNF-α in lipopolysaccharide (LPS) induced RAW264.7 cells. Furthermore, mechanism studies suggest that compound <strong>ST12</strong> exerted anti-inflammatory effects by inhibiting the activation of the NLRP3 inflammasome. Importantly, <strong>ST12</strong> effectively ameliorated DSS-induced colitis in vivo. Taken together, <strong>ST12</strong> is worthy of further investigation as a small molecule anti-inflammatory agent for treatment of inflammatory bowel diseases (IBD).</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108402"},"PeriodicalIF":4.5,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143715880","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":"“From darkness to radiance”: Light-induced type I and II ROS-mediated apoptosis for anticancer effects of dansylpiperazine-bearing squaraine dyes","authors":"Eurico Lima ,&nbsp;Octávio Ferreira ,&nbsp;João M. Oliveira ,&nbsp;Renato E. Boto ,&nbsp;José R. Fernandes ,&nbsp;Paulo Almeida ,&nbsp;Samuel M. Silvestre ,&nbsp;Adriana O. Santos ,&nbsp;Lucinda V. Reis","doi":"10.1016/j.bioorg.2025.108379","DOIUrl":"10.1016/j.bioorg.2025.108379","url":null,"abstract":"<div><div>Photodynamic therapy relies on the generation of cytotoxic effects triggered by the irradiation of a photosensitizer molecule, resulting in the production of reactive oxygen species at concentrations exceeding physiological levels. In this context, squaraine dyes, a prominent family of second-generation photosensitizers, have gained increasing attention for their remarkable properties, with their photobiological characteristics recently emerging as a key focus of in-depth research. Dansylpiperazine-bearing squaraine dyes exhibited strong absorption in the red visible spectral region, excellent photostability, and a predicted ability to interact with human serum albumin, potentially serving as a transport vehicle to target sites. Benzothiazole derivatives excelled in photodynamic activity, demonstrating 7- to 11-fold increased cytotoxicity upon irradiation against prostate adenocarcinoma PC-3 cells and tumor selectivity indices exceeding 10 when compared to normal NHDF cells. In contrast, the introduction of the dansylpiperazino group in indole-derived compounds unexpectedly declined their photodynamic activity. Concerning benzothiazole-based ones, multiple reactive oxygen species were shown to contribute to the photodynamic effects, with singlet oxygen playing a key role. Squaraine internalization was observed in various cytoplasmic organelles, including mitochondria, endoplasmic reticulum, and lysosomes, without clear evidence of preferential localization to any single organelle. Non-genotoxic in the dark, the squaraines induced cell death by apoptosis upon light activation, as evidenced by significant DNA fragmentation and increased caspase 3/7 activation, particularly for the dye with <em>N</em>-ethyl chains, at concentrations below 1.0 μM, underscoring their potency. Checkpoint arrests in G1 and G2/mitosis were observed for non-irradiated and irradiated conditions, respectively, highlighting the antiproliferative effects of these squaraine dyes.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108379"},"PeriodicalIF":4.5,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143747332","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":"Substituted aryl piperazine ligands as new dual 5-hLOX/COX-2 inhibitors. Synthesis, biological and computational studies","authors":"Michelle Muñoz-Osses ,&nbsp;Elizabeth Navarrete ,&nbsp;Pilar Morales ,&nbsp;Javiera Quiroz ,&nbsp;Maite Silva ,&nbsp;Simón Torres-González ,&nbsp;Yesseny Vásquez-Martínez ,&nbsp;Fernando Godoy ,&nbsp;Carolina Mascayano","doi":"10.1016/j.bioorg.2025.108398","DOIUrl":"10.1016/j.bioorg.2025.108398","url":null,"abstract":"<div><div>Two series of cyano (<strong>1a-l</strong>) and amino (<strong>2a-l</strong>) aryl piperazines were synthesized and evaluated for their inhibitory activity against 5-lipoxygenase (5-hLOX) and cyclooxygenase-2 (COX-2). The newly designed derivatives feature diphenyl methyl (<strong>a-d</strong>), phenyl (<strong>e-h</strong>), or methoxyphenyl (<strong>i-l</strong>) groups, respectively, and demonstrated significant inhibition of 5-hLOX. Noteworthy were compounds <strong>1b</strong>, <strong>1</strong> <strong>g</strong>, <strong>1</strong> <strong>k</strong>, <strong>2f</strong>, and <strong>2</strong> <strong>g</strong>, exhibiting IC₅₀ values ranging from 2.2 to 3.3 μM. The most potent inhibitors (<strong>1b</strong>, <strong>1</strong> <strong>g</strong>, <strong>1</strong> <strong>k</strong>, <strong>2c</strong>, and <strong>2f</strong>) were characterized by a competitive inhibition mechanism, with <em>K</em>_<em>i</em> values ranging between 1.77 μM and 9.50 μM. Additionally, compounds <strong>2a</strong>, <strong>2b</strong>, <strong>2</strong> <strong>g</strong>, and <strong>2</strong> <strong>h</strong> displayed promising dual inhibition of 5-hLOX and COX-2, with IC₅₀ values below 15 μM. Cytotoxicity assessments against HEK293 cells revealed that the cyano derivatives (<strong>1a-l</strong>) were non-cytotoxic (CC₅₀ &gt; 200 μM), whereas the amino derivatives (<strong>2a-l</strong>) exhibited moderate cytotoxicity (CC₅₀ &lt; 50 μM). Notably, the most active derivatives against both targets were non-cytotoxic at their respective inhibitory concentrations. Computational studies, including docking and molecular dynamics simulations, indicated that compound <strong>1</strong> <strong>g</strong> demonstrated greater stability within the catalytic site of 5-hLOX compared to compound <strong>2f</strong>, correlating with the higher affinity observed in kinetic assays. Furthermore, quantitative structure-activity relationship (QSAR) analyses revealed strong correlations between theoretical and experimental IC₅₀ values (97 % for <strong>1a-l</strong> and 93 % for <strong>2a-l</strong>). These findings, combined with absorption, distribution, metabolism, and excretion (ADME) predictions, suggest that these derivatives are promising candidates as dual inhibitors of 5-hLOX and COX-2.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108398"},"PeriodicalIF":4.5,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143747115","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}