Bioorganic & Medicinal Chemistry最新文献

{"title":"From pain relief to proliferation arrest: Synthesis and biological evaluation of novel diclofenac-tethered Schiff bases as VEGFR-2 inhibitors and apoptosis inducers, guided by in silico molecular docking and ADME profiling","authors":"Nadia A. Khalil ,&nbsp;Peter A. Halim ,&nbsp;Alaa Magdy ,&nbsp;Eman O. Osman","doi":"10.1016/j.bmc.2026.118586","DOIUrl":"10.1016/j.bmc.2026.118586","url":null,"abstract":"<div><div>This research is principally focused on designing and developing new diclofenac-tethered Schiff base derivatives with anticipated anticancer potentials. The structures of the synthesized compounds were examined by applying diverse spectroscopic techniques. An additional nuclear Overhauser effect spectroscopy (NOESY) technique was applied to analyze the configuration and stereochemistry of the target compounds, which confirmed the presence of the target molecules as a mixture of <em>E</em>-<em>syn</em>-periplanar and <em>E-anti</em>-periplanar isomers. The cytotoxic potential of the synthesized derivatives was evaluated on MCF-7 breast cancer cells and WI-38 lung normal cells, among which compound <strong>5a</strong> has emerged as the most potent candidate with an IC₅₀ value of 48.19 ± 0.19 μM. Selectivity indices (SI) were determined for compounds <strong>5a, 5c, 6a,</strong> and <strong>6b</strong>, revealing a preferential cytotoxic effect against cancer cells over normal cells. Notably, compound <strong>5a</strong> demonstrated the highest selectivity, with an SI value of <strong>4.1</strong>, indicating a favorable safety profile. The most active derivatives <strong>5a</strong>, <strong>5c</strong>, <strong>6a,</strong> and <strong>6b</strong> were further assessed for their potential to inhibit VEGFR-2 kinase activity. The results displayed moderate to high activity with IC₅₀ values ranging from 0.118 ± 0.001 to 0.876 ± 0.012 μM compared to 0.146 ± 0.002 μM for sorafenib. Moreover, compound <strong>5a</strong> demonstrated a significant elevation in Bax (7.79-fold) and caspase-9 (3.49-fold) expression levels, while reducing Bcl-2 expression level by 0.22-fold in MCF-7 breast cancer cells, indicating activation of the intrinsic mitochondrial apoptotic pathway. Additionally, a scratch wound healing assay revealed that compound <strong>5a</strong> considerably hindered cell migration. Additionally, molecular docking experiments were conducted to determine the binding modes between compounds <strong>5a</strong>, <strong>5c</strong>, <strong>6a</strong>, and <strong>6b</strong> and the VEGFR-2 kinase, thereby elucidating their mechanism of action. Finally, <em>in silico</em> studies and toxicity profiles indicated favorable drug-like characteristics.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"136 ","pages":"Article 118586"},"PeriodicalIF":3.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146172128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 olaparib-β-carboline hybrids for treating BRCA-deficient triple negative breast cancer","authors":"Xiaojuan Yang ,&nbsp;Tong Shen ,&nbsp;Liqiang Wu","doi":"10.1016/j.bmc.2026.118585","DOIUrl":"10.1016/j.bmc.2026.118585","url":null,"abstract":"<div><div>PARP inhibitors exert effects synergistically with DNA damage agents; therefore, the present work focused on designing and synthesizing novel olaparib-β-carboline hybrids for the treatment of BRCA-deficient TNBC. Among synthesized compounds, compound <strong>6</strong> substituted with methyl at position 1 of β-carboline had the most potent anti-proliferative activity against BRCA-deficient TNBC cells MDA-MB-436, with an IC₅₀ value of 4.38 ± 0.05 μM. Moreover, compound <strong>6</strong> potently inhibited PARP-1 and PARP-2, with IC₅₀ values of 1.6 ± 0.7 and 0.9 ± 0.2 nM, respectively. Mechanistically, compound <strong>6</strong> could increase DNA damage, induce cell cycle arrest in the G2/M phase, and promote MDA-MB-436 apoptosis. Overall, <strong>6</strong> is a potential hybrid molecule and can be a candidate compound for the treatment of BRCA-deficient TNBC.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"136 ","pages":"Article 118585"},"PeriodicalIF":3.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146116450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The inhibitory mechanisms of PGG, a natural polyphenol enriched with gallate moieties, against Aβ42 amyloid aggregation: A unified experimental and molecular dynamics simulation study","authors":"Rong-zu Nie ,&nbsp;Huo-min Luo ,&nbsp;Hang Wang ,&nbsp;Yue-ran Yang ,&nbsp;Yi-zun Wang ,&nbsp;Shuai-zhengcheng Zhang ,&nbsp;Kun Feng ,&nbsp;Yi-lin Li ,&nbsp;Fei-yang Chen ,&nbsp;Chen-xi Duan ,&nbsp;Jing-yu Chen ,&nbsp;Tong Ma ,&nbsp;Pei-feng Li","doi":"10.1016/j.bmc.2026.118584","DOIUrl":"10.1016/j.bmc.2026.118584","url":null,"abstract":"<div><div>Alzheimer's disease currently affects over 44 million individuals worldwide. Inhibiting Aβ aggregation and preventing the formation of toxic Aβ oligomers were regarded as promising therapeutic approaches. Experimental studies demonstrated that 1,2,3,4,6-Penta-<em>O</em>-galloyl-β-<span>d</span>-glucopyranose (PGG), a natural polyphenol enriched with gallate moieties, significantly inhibited Aβ₄₂ oligomerization and amyloid formation both in vitro and in vivo, underscoring its potential as a promising lead compound for AD therapy. Nevertheless, the detailed molecular mechanisms remained mostly unknown. Herein, we employed relevant biophysical methods to investigate the inhibitory effects of PGG and its analogs on Aβ₄₂ amyloid aggregation, particularly on oligomer formation, providing direct evidence for the influence of gallate moiety number on its inhibitory activity against Aβ₄₂ amyloid aggregation. Moreover, we further conducted 1500 ns all-atom MD simulations to explore how PGG inhibited Aβ amyloid aggregation. The simulations revealed that PGG promoted the adoption of a more loosely packed conformation of the Aβ₄₂ dimer, and completely prevented the helix-to-β-sheet conformational change. Moreover, the binding of PGG molecules to the Aβ₄₂ dimer resulted in the disruption of the inter-peptide interactions, and dramatically weakened the intra-peptide contacts. We observed that, apart from the usual hydrogen bonds and hydrophobic interactions, both π-π and cation-π interactions were also detected between specific residues of the Aβ₄₂ dimer and the gallate moieties of PGG. We believed that these results might provide novel insights into the mechanisms underlying the inhibitory effects of PGG on Aβ₄₂ amyloid aggregation and further support its potential for AD prevention and treatment.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"136 ","pages":"Article 118584"},"PeriodicalIF":3.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146136965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ligand-Based Design of Novel Thiazole-Quinazolinone Hybrids with Dual Antimicrobial and Anti-Virulence Activity Targeting Staphylococcal Sortase A","authors":"Shaymaa G. Hammad ,&nbsp;Dina S. Aboul-Magd ,&nbsp;Mostafa M. Ghorab ,&nbsp;Mai Adel ,&nbsp;Rabah A.T. Serya ,&nbsp;Ebaa M. El-Hossary ,&nbsp;Marwa G. El-Gazzar ,&nbsp;Khaled A.M. Abouzid","doi":"10.1016/j.bmc.2026.118576","DOIUrl":"10.1016/j.bmc.2026.118576","url":null,"abstract":"<div><div>The escalating prevalence of antimicrobial resistance necessitates the pursuit of therapeutic strategies that specifically target bacterial virulence factors. Here, we describe the design, synthesis, and biological evaluation of novel thiazole–quinazolinone hybrid compounds with dual antimicrobial and anti-virulence activities. We initially designed a hybrid scaffold that rationally integrates thiazole and quinazolinone moieties as antimicrobial motifs, using structure-activity relationship (SAR) analysis and ligand-based pharmacophore modeling derived from established staphylococcal sortase A (SrtA) inhibitors. All the synthesized compounds were evaluated for their antimicrobial activity against six clinically relevant pathogens (<em>Staphylococcus aureus</em>, <em>Bacillus subtilis</em>, <em>Acinetobacter baumannii</em>, <em>Klebsiella pneumoniae</em>, <em>Candida albicans</em>, and <em>Aspergillus fumigatus</em>). Notably, compounds <strong>4c</strong> and <strong>4e</strong> were the most potent candidates, with minimum inhibitory concentration (MIC) values ranging from 0.125 to 4 μg/mL and 0.125 to 8 μg/mL, respectively. Compounds <strong>4c</strong> and <strong>4e</strong> also demonstrated anti-virulence activity by inhibiting biofilm formation, reducing preformed biofilm biomass, inhibiting SrtA, and effectively blocking <em>S. aureus</em> adhesion to immobilized fibrinogen. Molecular docking studies further confirmed efficient non-covalent binding within the SrtA catalytic pocket. Moreover, the minimal cytotoxicity of both compounds toward mammalian cells underscored promising safety profiles. The two compounds exhibited chemical stability under the sterilizing doses of gamma irradiation used.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"136 ","pages":"Article 118576"},"PeriodicalIF":3.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146116449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine learning-driven computational drug repurposing to identify new tubulin inhibitors against cancer","authors":"Neelima Neelima ,&nbsp;Hussein Elrewey ,&nbsp;Sneha Smarakan ,&nbsp;Amalia Ruiz ,&nbsp;Muhammad Wahajuddin ,&nbsp;Gaurav Joshi ,&nbsp;Vibhu Jha","doi":"10.1016/j.bmc.2026.118587","DOIUrl":"10.1016/j.bmc.2026.118587","url":null,"abstract":"<div><div>Tubulin is a validated anticancer target, yet the clinical translation of colchicine-binding site inhibitors remains limited by toxicity and resistance. To accelerate the discovery of safer tubulin-targeting agents, we employed a machine learning (ML)-driven drug repurposing strategy integrating computational and experimental validation. Robust AutoQSAR classification models were trained on 279 curated tubulin inhibitors and used to screen 4500 US FDA-approved drugs, predicting 1800 compounds as potential tubulin inhibitors. These candidates were subjected to multistage structure-based virtual screening using Glide HTVS, SP, and XP docking, narrowing the selection from 698 (HTVS) and 350 (SP) to 38 compounds at the XP stage. Binding free-energy calculations (MM-GBSA) and 200 ns molecular dynamics simulations identified four stable colchicine-site binders: omeprazole, podofilox, sulfadoxine, and trimethoprim, exhibiting favourable binding energetics (Glide XP scores −10.06 to −8.12 kcal/mol; ΔG bind ranging from −10.06 to −8.12 kcal/mol; ΔG bind ranging from −64.16 to −38.61 kcal/mol). Biochemical tubulin polymerization assays confirmed tubulin inhibition, while cell-based cytotoxicity studies demonstrated low-micromolar antiproliferative activity of omeprazole and podofilox against melanoma (IC₅₀ = 4.32 ± 0.29 μM and 4.98 ± 0.37 μM, respectively) and colorectal cancer cells (IC₅₀ = 6.22 ± 0.22 μM and 5.76 ± 0.18 μM; <em>n</em> = 3). Overall, this study highlights a ML-guided drug repurposing framework that, unlike prior colchicine binding site–focused virtual screening studies, integrates large-scale ML prioritization with experimental validation to identify novel colchicine-site-targeted anticancer candidates.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"136 ","pages":"Article 118587"},"PeriodicalIF":3.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146172129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A potent novel small molecule GLP-1R agonist identified by rational design and CADD","authors":"Jiayu Chen ,&nbsp;Yuanshan Yao ,&nbsp;Hao Li","doi":"10.1016/j.bmc.2026.118578","DOIUrl":"10.1016/j.bmc.2026.118578","url":null,"abstract":"<div><div>Small molecule glucagon-like peptide-1 receptor (GLP-1R) agonists are pursued intensively in the pharmaceutical industry considering their advantages in outstanding patient adherence, cost and productivity relative to injectable ones. A series of novel small molecules had been made by rationale design with computer aided drug design (CADD) assistance and evaluated in <em>in vitro</em> and <em>in vivo</em> druggability profilings. Among them, compound <strong>6</strong> with unique binding mode with GLP-1R showed robust efficacy in accumulation of cyclic adenosine monophosphate (cAMP) production cell assay. Compound <strong>6</strong> showed good metabolic stability in both human microsomes and hepatocytes and good to excellent drug exposure and bioavailability in four preclinical species in absorption, distribution, metabolism, excretion (ADME) and pharmacokinetics (PK) studies. It had no human ether-à-go-go-related gene (hERG) potassium channel inhibition liability and no time-dependent inhibition (TDI) and cytochrome P450 (CYP450) induction potential in <em>in vitro</em> tests as well. It also exhibited high plasma stability with no glutathione (GSH) trapping risk. In an intraperitoneal glucose tolerance test (IPGTT) study conducted in humanized-GLP-1R mice, compound <strong>6</strong> displayed impressive blood glucose lowering effect. These preclinical characteristics of compound <strong>6</strong> position it as a promising oral anti-diabetes and anti-obesity candidate that differentiate mainstay injectable peptide drugs.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"136 ","pages":"Article 118578"},"PeriodicalIF":3.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146116448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An integrated framework identified potent inhibitors targeting IRE1α","authors":"Subramaniyan Divya ,&nbsp;Priti Talwar ,&nbsp;Palaniyandi Ravanan","doi":"10.1016/j.bmc.2026.118590","DOIUrl":"10.1016/j.bmc.2026.118590","url":null,"abstract":"<div><div>Inositol-requiring enzyme 1 (IRE1α) is one of the key sensors and signaling effectors of the unfolded protein response (UPR), which is essential for preserving endoplasmic reticulum (ER) homeostasis. Dysregulation of IRE1α signaling can lead to several illnesses. Initially, we employed the multidocking approach utilizing AutoDock Vina, AutoDock Wizard, and iGEMDOCK to predict the accurate binding affinities of the flavonoid library against IRE1α and rank them based on their affinities. Subsequently, post-docking approaches were used to refine the hit selection. Finally, the top-ranked flavonoids were selected based on their consistent high binding affinity and exhibited strong binding within the ATP-binding pocket of the kinase active site. <em>In vitro</em> kinase assays revealed that both amentoflavone and glycitein significantly inhibited IRE1α kinase activity, with IC₅₀ values of 16.4 μM and 23.68 μM, respectively. Cell-based studies demonstrated that these flavonoids have anti-inflammatory properties and significantly promote robust activation of XBP1 splicing and IRE1α expression under normal conditions. In contrast, flavonoid pretreatment significantly attenuated LPS-induced IRE1α–XBP1 signaling and reduced inflammatory responses. Overall, our results indicate that both glycitein and amentoflavone exhibit promising modulatory effects on IRE1α. To the best of our knowledge, this is the first study to report the modulatory potential of flavonoids amentoflavone and glycitein to possess both IRE1α kinase inhibitory and RNase-activating properties. This work provides a valuable basis for the development of flavonoid-based IRE1α inhibitors to treat ER stress and associated inflammatory diseases.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"136 ","pages":"Article 118590"},"PeriodicalIF":3.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146163237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"pH-induced structural switch of a parallel duplex to triplex-DNA at a BOLF1 gene segment of the human herpes virus 4 (HH4) genome","authors":"Shikha Kaushik ,&nbsp;Shrikant Kukreti","doi":"10.1016/j.bmc.2026.118574","DOIUrl":"10.1016/j.bmc.2026.118574","url":null,"abstract":"<div><div>Conformational polymorphism exhibited by nucleic acids makes them potential tools in various fields of molecular biology, medicine, nanobiotechnology, and material science. The structural versatility associated with DNA and RNA forms the basis for developing oligonucleotide-based therapeutic strategies. Moreover, DNA's ability to respond to various physicochemical stimuli makes it a suitable candidate for biosensing applications. Naturally, two strands of the B-DNA duplex are oriented antiparallel to each other, stabilized by Watson-Crick hydrogen bonding. However, the formation of non-canonical DNA structures possessing varied base pairing schemes and strand orientation is also possible. Herein, a combination of UV-thermal denaturation, native polyacrylamide gel electrophoresis, and circular dichroism was used to investigate the structures formed by sequence-specific binding of a designed pyrimidine oligonucleotide to the target dodecamer (Pu.Py) segment of the <em>BOLF1</em> gene of human <em>herpesvirus 4 (HH4)</em> genome. Through a curiosity-driven experiment, we report the formation of a parallel-stranded (ps) duplex at neutral pH, which transforms into a three-stranded DNA structure on lowering the pH. While the ps duplex is facilitated by reverse Watson-Crick; the triplex-DNA structure, formed at low pH, is stabilized by reverse Watson-Crick and Hoogsteen hydrogen bonding, resulting in an all-parallel-strand triple-stranded structure. To the best of our knowledge, any oligomeric structure consisting of all three strands (one Pu and two Py) in parallel orientation has not been characterized to date. Such a pH-mediated structural switching by DNA sequences may provide insights into the bioprocesses involving pH changes, both <em>in vitro</em> and <em>in vivo,</em> and towards the development of pH-based biosensors.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"135 ","pages":"Article 118574"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146075111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"QSAR-based drug discovery of 2-((4-Imino-3,4-dihydroquinazolin-2-yl)thio-substituted analogs targeting Mycobacterium tuberculosis","authors":"Carla Caroline Ribeiro de Mendonça ,&nbsp;Walber Fernandes Ferreira Coutinho ,&nbsp;Thiago Lourenco dos Santos ,&nbsp;Mirely Vitória Farias da Silva ,&nbsp;Gisela C. Paulino ,&nbsp;Demétrius A.M. de Araújo ,&nbsp;Igor José dos Santos Nascimento ,&nbsp;João R. Xavier de Araújo-Júnior ,&nbsp;Francisco Jaime Bezerra Mendonça-Junior ,&nbsp;Valnês da Silva Rodrigues-Júnior ,&nbsp;Edeildo Ferreira da Silva-Júnior","doi":"10.1016/j.bmc.2026.118572","DOIUrl":"10.1016/j.bmc.2026.118572","url":null,"abstract":"<div><div>Dihydroquinazolin-4(3<em>H</em>)-imines have emerged as a promising scaffold for developing novel antimycobacterial agents. Here, we integrated QSAR modeling, <em>in vitro</em> screening, molecular dynamics (MD), binding free-energy calculations, and <em>in vivo</em> toxicity assessment to identify potent inhibitors against <em>Mycobacterium tuberculosis</em> (<em>Mtb</em>). Four QSAR models demonstrated strong internal and external reliability (<em>R</em>^<em>2</em> <em>&gt; 0.68; Q</em>^<em>2</em>_<em>LOO</em> <em>&gt; 0.62; R</em>^<em>2</em>_<em>ext</em> <em>up to 0.82</em>). Additional validation parameters met recommended thresholds (Q²<em>-F1/F2/F3 ≥ 0.72; CCC</em>_<em>ext</em> <em>≥ 0.88</em>; <em>r</em>^<em>2</em>_{<em>m aver</em>} <em>≥ 0.72; r</em>^<em>2</em>_{<em>m delta</em>}<em>: 0.04</em>), and Williams plots confirmed that all predictions fell within the applicability domain (<em>h*: 0.286</em>). Biological assays identified 11 active compounds, with MIC values ranging from 25 to 200 μM. Compound <strong>2c</strong> (<em>p</em>-methylphenyl derivative) and <strong>3d</strong> (<em>m, p</em>-dichlorophenyl analog) were the most potent, displaying MIC values of 50 and 25 μM, respectively. MD simulations revealed stable and specific interactions with Eis, an acetyltransferase linked to kanamycin resistance. Compound <strong>2c</strong> exhibited a mean Δ<em>G</em>_{<em>bind</em>} of −52.19 ± 3.21 kcal/mol, while <strong>3d</strong> showed a more favorable Δ<em>G</em>_{<em>bind</em>} of −73.15 ± 3.16 kcal/mol, consistent with its superior <em>in vitro</em> potency. Distinct interaction profiles—especially the engagement of Tyr¹²⁶ and hydrophobic clusters—help explain their differential affinities. Moreover, both leads demonstrated low to moderate <em>in vitro</em> cytotoxicity against HepG2 cells at the concentrations evaluated. <em>In vivo</em> acute toxicity in <em>Zophobas morio</em> indicated LD₅₀ values of 500 mg/kg for <strong>2c</strong> and 100 mg/kg for <strong>3d</strong>, with transient tremors and melanization observed only for <strong>3d</strong>. Since compound <strong>2c</strong> exhibited a safer <em>in vivo</em> toxicity profile, this compound was investigated for its association with antimicrobial drugs. These compounds were validated as promising anti-TB candidates, supported by robust QSAR predictivity, favorable binding energetics, and measurable <em>in vitro</em> and <em>in vivo</em> toxicity profiles, reinforcing their potentials for further optimization.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"135 ","pages":"Article 118572"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146058341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An endoplasmic reticulum-targeted near-infrared fluorescent probe for selective imaging of hypochlorous acid","authors":"Leqin Cheng ,&nbsp;Mengjuan Shi ,&nbsp;Sijie Li ,&nbsp;Li Fan ,&nbsp;Xue Yu","doi":"10.1016/j.bmc.2026.118581","DOIUrl":"10.1016/j.bmc.2026.118581","url":null,"abstract":"<div><div>Hypochlorous acid (HClO), as a key component of endogenous reactive oxygen species, plays a critical role in endoplasmic reticulum (ER) homeostasis regulation. Its dynamic imbalance is closely associated with pathological processes such as neurodegenerative diseases and cancer. This study introduces a “turn-on” near-infrared fluorescent probe, <strong>XB-CTs</strong>, designed for the specific targeting and detection of hypochlorous acid (HClO) within the ER. It uses a dihydroxanthene-hemicyanine dye as the NIR fluorescent base, featuring an <em>N</em>,<em>N</em>-dimethylthiocarbamate group for quick, specific HClO detection, and a p-toluenesulfonamide group for ER targeting. The <strong>XB-CTs</strong> probe performs exceptionally well by emitting NIR fluorescence at 735 nm, avoiding biological autofluorescence interference. It is highly sensitive to HClO with a 0.141 μM detection limit and responds in 1 s. it specifically targets the ER in live cells, providing high signal-to-noise ratio imaging for real-time HClO detection. Additionally, it has been effectively used for stable fluorescence imaging of HClO in mice. This study provides a feasible detection tool for investigating ER oxidative stress processes, and its potential applications in biomedical research warrant further exploration and validation</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"135 ","pages":"Article 118581"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146103326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}