Bioorganic Chemistry最新文献

{"title":"Multi-scale investigation of PQ3-quinoxaline derivatives as selective COX-2 inhibitors: synthesis, structural analysis, DFT, MD simulations, and in silico/in vitro evaluation","authors":"Fares Hezam Al-Ostoot ,&nbsp;P. Akhileshwari ,&nbsp;Vivek H. Kameshwar ,&nbsp;Majed S. Aljohani ,&nbsp;Hussam Y. Alharbi ,&nbsp;Shwetha H. Nanjundappa ,&nbsp;Karim Chkirate ,&nbsp;Luc Van Meervelt ,&nbsp;Nadeem Abad","doi":"10.1016/j.bioorg.2025.108987","DOIUrl":"10.1016/j.bioorg.2025.108987","url":null,"abstract":"<div><div>Quinoxaline has emerged as a promising scaffold in drug discovery, particularly in the development of anti-inflammatory agents, due to its structural versatility and broad pharmacological potential. Its flexible chemical framework permits diverse modifications, enabling the design of derivatives that can target critical molecular pathways implicated in cancer progression. The title compounds of 3-phenylquinoxalin-2(1<em>H</em>)-one (<strong>PQ3a-f</strong>), were synthesized in good yields from 3-phenylquinoxalin-2(1<em>H</em>)-one (<strong>1</strong>) in DMF, with 1-bromoalkanes (<strong>2a-f)</strong>, and tetrabutylammonium bromide (BTBA). The crude products obtained have been recrystallized and elucidated by spectroscopic techniques (¹HNMR, ¹³CNMR and LC-MS), the 3D of <strong>PQ3a</strong> crystal structure was confirmed by single crystal X-ray diffraction (XRD) studies. Hirshfeld surface analysis confirmed the C-H…O intermolecular interactions. 2D fingerprint plot of <strong>PQ3a</strong> shows that the major contribution to the overall Hirshfeld surface area is from H<img>H (72.7 %) contacts. 3D energy-frameworks calculations shows that the majority of dispersion energy over the other energies. DFT calculations are performed to know the <strong>PQ3a</strong> molecular properties at B3LYP/6–31 + G(d,p) basis sets. The energy gap between the HOMO-LUMO is found to be 3.81 eV, indicating the nature of potent biologically active molecule. Among the six synthesized <strong>PQ3a-f</strong> derivatives, <strong>PQ3a</strong> exhibited the most potent COX-2 inhibition (IC₅₀ = 10.24 μM) with moderate COX-1 inhibition (IC₅₀ = 31.67 μM), yielding a selectivity index (SI) of 3.09, indicative of COX-2 selectivity. <strong>PQ3f</strong> showed moderate COX-2 inhibition (IC₅₀ = 25.54 μM) and COX-1 inhibition (IC₅₀ = 46.45 μM), with an SI of 1.82. In contrast, the remaining derivatives (PQ3b-d) demonstrated weak or non-selective COX inhibition compared to the reference drug celecoxib (COX-2 IC₅₀ = 0.54 μM; SI = 21.15). Docking results revealed strong binding affinity, particularly with COX-2, supported by key interactions with Ser530 and Leu531. Molecular dynamics simulations (MDs) confirmed the stability of the <strong>PQ3a</strong>-COX-2 complex over 500 ns, highlighting sustained hydrophobic interactions and a stable hydrogen bond with Ser530. These findings suggest <strong>PQ3a</strong> as a promising selective COX-2 inhibitor for anti-inflammatory therapy.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 108987"},"PeriodicalIF":4.7,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145084660","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":"Harnessing structure-activity relationships to repurpose the FLAP inhibitor BRP-7 into potent and selective sEH inhibitors","authors":"Kübra Çalışkan ,&nbsp;Mehmet Karataş ,&nbsp;Paul M. Jordan ,&nbsp;Burcu Çalışkan ,&nbsp;Oliver Werz ,&nbsp;Erden Banoglu","doi":"10.1016/j.bioorg.2025.108997","DOIUrl":"10.1016/j.bioorg.2025.108997","url":null,"abstract":"<div><div>Soluble epoxide hydrolase (sEH) has emerged as a validated therapeutic target in inflammation-related conditions, particularly in cardiovascular, metabolic, and central nervous system disorders. In this study, we report the rational design, synthesis, and biological evaluation of a new class of benzimidazole-based amide derivatives as potent and selective inhibitors of sEH. These compounds were developed by scaffold optimization of BRP-7, a previously reported FLAP inhibitor, through strategic modifications at the C(2) and C(5) positions of the benzimidazole core, guided by SAR insights. Among the synthesized analogs, <strong>FP30 (BRP-821)</strong> exhibited exceptional sub-nM sEH inhibitory activity (IC₅₀ = 0.4 nM), along with excellent metabolic stability in human liver microsomes (t_1/2 &gt; 184 min, ER &lt; 0.27) and high solubility in simulated intestinal fluid (108 μM). Notably, the lead compounds demonstrated high selectivity over FLAP, distinguishing this new chemotype from dual inhibitors. Collectively, these findings highlight a promising new scaffold for further optimization toward the development of sEH-targeted therapeutics for the treatment of neuropathic pain and inflammatory diseases.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 108997"},"PeriodicalIF":4.7,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145096955","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":"Quinazoline-based fourth-generation EGFR tyrosine kinase inhibitors to overcome C797S-mediated resistance in non-small cell lung Cancer (NSCLC)","authors":"Bhatu R. Patil ,&nbsp;Kisan Pawara ,&nbsp;Matin Shaikh ,&nbsp;Faizan Ahmed ,&nbsp;Chandragouda R. Patil ,&nbsp;Chandrakant S. Gawli ,&nbsp;Chanakya Nath Kundu ,&nbsp;Biswajit Das ,&nbsp;Iqrar Ahmad ,&nbsp;Harun M. Patel","doi":"10.1016/j.bioorg.2025.108991","DOIUrl":"10.1016/j.bioorg.2025.108991","url":null,"abstract":"<div><div>The emergence of resistance mutations, particularly C797S, in epidermal growth factor receptor tyrosine kinase (EGFR-TK) has significantly limited the long-term efficacy of Osimertinib in non-small cell lung cancer (NSCLC). In this study, we designed and evaluated a series of quinazoline derivatives targeting the triple mutant EGFR (L858R/T790M/C797S). Among them, compound <strong>8d</strong> exhibited the highest potency against EGFR L858R/T790M/C797S, with an IC₅₀ of 0.068 μM, demonstrating strong binding affinity and effective suppression of kinase activity compared to Osimertinib. Molecular docking studies revealed key interactions with catalytic Lys745. Molecular dynamics (MD) simulations over 100 ns confirmed ligand stability, with an average root-mean-square deviation (RMSD) below 2.0 Å and a binding free energy of −44 kcal/mol (MM/GBSA). Structure-activity relationship (SAR) analysis highlighted the critical role of a bulkier hydrophobic substituent at the C2 position of the quinazoline ring in combination with a sulfonyl group, which improved affinity and potency. These findings establish quinazoline derivatives, particularly compound <strong>8d</strong>, as promising fourth-generation EGFR inhibitors for overcoming C797S-mediated resistance in NSCLC therapy.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 108991"},"PeriodicalIF":4.7,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145084656","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 and biological evaluation of novel naproxen–phenacetin triazole hybrids as promising anti-inflammatory agents with enhanced gastrointestinal tolerability","authors":"Ahmet Avci ,&nbsp;Hayrünnisa Taşci ,&nbsp;Begüm Nurpelin Sağlık Özkan ,&nbsp;Gokcen Telli ,&nbsp;Nesrin Gökhan-Kelekçi ,&nbsp;Yusuf Özkay ,&nbsp;Birsen Tozkoparan","doi":"10.1016/j.bioorg.2025.109000","DOIUrl":"10.1016/j.bioorg.2025.109000","url":null,"abstract":"<div><div>Traditional nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both COX-1 and COX-2 isoforms with limited selectivity, often resulting in gastrointestinal (GI) side effects. Compounds that preferentially inhibit COX-2 over COX-1 are believed to pose a lower ulcerogenic risk. To develop GI-safer and cost-effective anti-inflammatory agents, we designed hybrid molecules by combining naproxen and phenacetin with a 1,2,4-triazole-5-thione. The structures of synthesized compounds were confirmed <em>via</em> IR, ¹H/¹³C NMR, and HR-ESI-MS analyses. Among the compounds, ten inhibited COX-2 with IC₅₀ ≤ 0.56 μM, and five exhibited high selectivity (SI ≥ 100). Compounds <strong>46</strong> (IC₅₀ = 0.16 μM, SI = 2.36), <strong>55</strong> (0.19 μM, SI = 2.27), and <strong>59</strong> (0.21 μM, SI = 1.65) demonstrated potency comparable to celecoxib. Three selected compounds were further evaluated <em>in vivo</em> using a carrageenan-induced paw oedema model and for acute gastric toxicity in Swiss mouse (<em>n</em> = 6; Ethics No. 2024/11 08). Orally administered compounds <strong>55</strong> and <strong>64</strong> (20 mg/kg) reduced paw oedema by 61 % and 52 %, respectively, similar to indomethacin (52 %), without causing visible gastric lesions (lesion score ∼ 2 <em>vs.</em> 5 for indomethacin). Molecular docking studies of the active compounds revealed the formation of stable hydrogen bonds with His90 and Arg513 within the COX-2 side pocket, similar to the binding pattern observed in selective COX-2 inhibitors. <em>In silico</em> ADME assessments <em>via</em> SwissADME and PreADMET indicated that these compounds meet Lipinski's rule of five criteria, possess optimal polar surface area and Caco-2 permeability, and show minimal risk for local gastric irritation, suggesting promising oral bioavailability. Overall, the 1,2,4-triazole-thione–naproxen/phenacetin hybrids represent promising lead candidates for the development of GI-safer NSAIDs. Compounds <strong>55</strong> and <strong>64</strong>, in particular, merit further optimization and long-term safety evaluation.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 109000"},"PeriodicalIF":4.7,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145155431","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":"Multifunctional nile red-triphenylamine AIEgen for optical waveguides, lipid droplet imaging, and photodynamic therapy","authors":"Mimi Sun ,&nbsp;Yongcan He ,&nbsp;He Dong ,&nbsp;Jie Hua ,&nbsp;Yuan Chai ,&nbsp;Jianan Dai ,&nbsp;Jin Wang ,&nbsp;Laiping Fang","doi":"10.1016/j.bioorg.2025.108995","DOIUrl":"10.1016/j.bioorg.2025.108995","url":null,"abstract":"<div><div>Aggregation-induced emission luminogens (AIEgens) have drawn significant interest as multifunctional materials, owing to their intense fluorescence in the aggregated state. However, developing an AIEgen that can simultaneously achieve optoelectronic and biological applications remains a significant challenge. Here, we design and synthesize a novel AIE-active molecule, NR-TPA, with a D-π-A structure that emits in the deep-red/near-infrared (DR/NIR) region by introducing triphenylamine (TPA) as the electron donor into a Nile Red (NR) scaffold. Benefiting from its photophysical properties, NR-TPA demonstrates outstanding potential in optical waveguide, lipid droplet (LD) imaging, and photodynamic therapy (PDT). NR-TPA self-assembles into red needle-like crystalline microcrystals that function as optical waveguides with a low loss coefficient of 0.222 dB mm⁻¹. Upon self-assembly with DSPE-PEG2000, NR-TPA forms stable nanoparticles (NPs) with bright fluorescence suitable for LD imaging in living cells. Moreover, the NR-TPA NPs can also generate abundant reactive oxygen species (ROS) under white light irradiation, enabling their application in PDT with minimal dark toxicity. This work highlights a versatile molecular design strategy for constructing AIEgens with combined photonic and biomedical functionalities, and demonstrates the promise of NR-based AIEgens for advanced optical and therapeutic applications.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 108995"},"PeriodicalIF":4.7,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145060941","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":"Corrigendum to \"Discovery of novel 1,2,4-triazole schiff bases hybridized with 1,4-naphthoquinones as potent STAT3 inhibitors\" [Bioorg. Chem. 165 (2025) 108936].","authors":"Kai Yin, Yujun Ruan, Mingchen Guo, Quanxin Tang, Fayi Nie, Yuwei Wang, Hui Guo, Ying Wang, Sha Zhou, Dezhen Yang, Yuping Tang, Ruyi Jin, Hong Peng","doi":"10.1016/j.bioorg.2025.108984","DOIUrl":"https://doi.org/10.1016/j.bioorg.2025.108984","url":null,"abstract":"","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":" ","pages":"108984"},"PeriodicalIF":4.7,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068704","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":"Sirenin and bisabolane sesquiterpenoids from two marine isolates of Penicillium chermesinum with anti-osteoporotic activity by modulating NOD-like receptor signaling pathway","authors":"Yi-Wei Liu ,&nbsp;Xin-Jia Li ,&nbsp;Xue-Yi Hu ,&nbsp;Xiao-Ming Li ,&nbsp;Hui Liu ,&nbsp;Sui-Qun Yang ,&nbsp;Hong-Lei Li ,&nbsp;Xiao-Dan Chen ,&nbsp;Meng Jin ,&nbsp;Bin-Gui Wang","doi":"10.1016/j.bioorg.2025.108993","DOIUrl":"10.1016/j.bioorg.2025.108993","url":null,"abstract":"<div><div>Nine unreported (chermesirenins A–I, <strong>1</strong>–<strong>9</strong>) and one known (eupenicisirenin C, <strong>10</strong>) sirenin sesquiterpenoids as well as two unreported bisabolane-type sesquiterpenoids (chermebisabolins A and B, <strong>11</strong> and <strong>12</strong>) were isolated from two isolates of marine-sourced fungal strains <em>Penicillium chermesinum</em> EN-480 and AS-400, which were obtained as endophytic and endozoic fungi from the marine red alga <em>Pterocladiella tenuis</em> and the marine chiton <em>Liolophura japonica</em>, respectively. The sirenin sesquiterpenoids (<strong>1</strong>–<strong>9</strong>) featured with unique 6/3 dicyclic ring system while compounds <strong>8</strong> and <strong>9</strong> are nor-sirenin analogs by degrading the C-12 methyl group. Their structures including stereochemical configurations were confirmed through NMR interpretation, ECD analysis, Mosher's method, X-ray crystallographic diffraction, and quantum chemical calculations. The anti-osteoporotic activity evaluation in the zebrafish osteoporosis model revealed that chermesirenin A (<strong>1</strong>) could significantly alleviate the reduction of bone fluorescence area and fluorescence density in prednisolone-treated zebrafish. Furthermore, compound <strong>1</strong> could down-regulate the expression of the genes associated with prednisolone-induced osteoclastogenesis, <em>ctsk</em> and <em>tnfrsf11b</em>, to improve bone formation status. Exploration on the mechanism through the transcriptomic analysis showed that compound <strong>1</strong> might act on the NOD-like receptor (NLR) signaling pathway involved in inflammatory responses and bone metabolism regulation, which has not been reported among previous investigations on sesquiterpenoids. These results demonstrated that compound <strong>1</strong> deserved further development as a potential candidate towards the therapy of osteoporotic disease.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 108993"},"PeriodicalIF":4.7,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145084586","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 and biological evaluations of 1,3,4-thiadiazole derivatives as dual acting enzyme inhibitors to target inflammation and diabetes","authors":"Waqas Ahmad ,&nbsp;Basharat Ali ,&nbsp;Bibi Hadiqa ,&nbsp;Shujaat Ali ,&nbsp;Naveed Muhammad ,&nbsp;Ubaid Ali ,&nbsp;Muhammad Saeed Jan ,&nbsp;Waqar-un-Nisa ,&nbsp;Abdul Wadood ,&nbsp;Amir Zeb","doi":"10.1016/j.bioorg.2025.108966","DOIUrl":"10.1016/j.bioorg.2025.108966","url":null,"abstract":"<div><div>Inflammation and metabolic disorders like diabetes mellitus share complex pathways that drive disease progression, emphasizing the urgent need for multi-target therapeutics for effective management. In the present study, a series of 1,3,4-thiadiazole derivatives (<strong>14</strong>–<strong>26</strong>) bearing phenyl and benzyl substitutions at fifth position of thiadiazole core were synthesized and characterized with spectroscopic techniques like FT-IR,¹H NMR,¹³C NMR and EI-MS. The biological evaluation revealed promising inhibition of the key inflammatory enzymes (COX-2 and 5-LOX), and metabolic enzymes (<em>α</em>-glucosidase and <em>α</em>-amylase) linked to type 2 diabetes. Among the tested derivatives, compound <strong>16</strong> exhibited the most potent dual action, with IC₅₀ values of 8.78 μg/ml (COX-2), 4.51 μg/ml (5-LOX), 69.41 μg/ml (<em>α</em>-glucosidase), and 50.50 μg/ml (<em>α</em>-amylase), demonstrated moderated activity as compared to the standard inhibitors. Compound <strong>26</strong> also exhibited significant anti-inflammatory, with IC50 values of 2.03 μg/ml (COX-2), 6.03 μg/ml (5-LOX). Molecular docking studies further supported the biological findings, revealing binding interactions of these derivatives with the active sights of targeted enzymes, reinforcing their potential as lead candidates for dual acting anti-inflammatory and anti-diabetic agents. These findings suggest that 1,3,4-thiadiazole derivatives have the potential to develop as multi-functional therapeutics to target inflammation and metabolic dysregulations.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 108966"},"PeriodicalIF":4.7,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145090850","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":"Photoinactivation of Leishmania amazonensis by Soranjidiol and white LED: Unraveling photodynamic and cell death mechanisms","authors":"J.A. Dimmer ,&nbsp;J. Marioni ,&nbsp;C.N. Barrionuevo ,&nbsp;D.A. Velázquez López ,&nbsp;M.S. Lo Presti ,&nbsp;H.W. Rivarola ,&nbsp;S.C. Núñez-Montoya","doi":"10.1016/j.bioorg.2025.108983","DOIUrl":"10.1016/j.bioorg.2025.108983","url":null,"abstract":"<div><div>Cutaneous Leishmaniasis (CL) is part of the group of neglected diseases that pose significant global health challenges. Despite the many years since the discovery of pentavalent antimonials, the development of effective and affordable therapies remains a major obstacle. Antimicrobial photodynamic therapy (aPDT) is a localized treatment that has demonstrated efficacy in eliminating diverse pathogens without inducing resistance. Soranjidiol (Sor), a natural anthraquinone photosensitizer (PS), has shown promising <em>in vitro</em> and <em>in vivo</em> results against <em>Leishmania amazonensis</em>. This study aims to elucidate the photodynamic and cell death mechanisms of Sor by evaluating two different concentrations in the promastigote form and assessing its photoinactivation effects on the amastigote form of <em>L. amazonensis</em>.</div><div>Our results demonstrate that Sor is a versatile and effective PS capable of eliminating promastigotes at low concentrations through the generation of reactive oxygen species and reactive nitrogen intermediates. Although aPDT is believed to generate both singlet oxygen and radicals, our findings indicate that type II reactions (¹O_₂) may be favoured at low Sor concentrations (singlet oxygen generation), leading to apoptosis, whereas type I reactions (superoxide anion) predominate at the highest concentration, resulting in necrosis.</div><div>The amastigote form was also successfully photo-inactivated, resulting in a reduction in the infection index comparable to that of Amphotericin B, a second-line drug for CL treatment. Although complete amastigote elimination was not achieved, the application of serial aPDT sessions could potentially improve therapeutic efficacy under optimized conditions and might represent a promising strategy to promote lesion healing.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 108983"},"PeriodicalIF":4.7,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145118460","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 adamantane-containing small-molecule peptidomimetics with membrane-disrupting activity for combating drug-resistant Bacteria","authors":"Jie Su ,&nbsp;Yuhang He ,&nbsp;Min Li ,&nbsp;Zhiqiang Shen ,&nbsp;Qingxian Ji ,&nbsp;Yixuan Ren ,&nbsp;Muhammad Subaan Fareed ,&nbsp;Kairong Wang","doi":"10.1016/j.bioorg.2025.108990","DOIUrl":"10.1016/j.bioorg.2025.108990","url":null,"abstract":"<div><div>The rising incidence of drug-resistant bacterial infections poses a significant threat to human health and highlights the urgent need for novel antimicrobial agents. In the present study, inspired by cationic antimicrobial peptides (AMPs) we developed a series of amphiphilic small-molecule peptidomimetics by incorporating adamantane as the hydrophobic moiety and alkylamines as hydrophilic moiety into the scaffold of natural amino acids to combat drug-resistant bacteria. Among them, the optimized compound <strong>A13</strong> exhibited broad spectrum antimicrobial activity, especially against various Gram-positive bacteria, including methicillin-resistant <em>Staphylococcus aureus</em> (MRSA) and vancomycin-resistant <em>Enterococcus gallinarum</em>, while maintaining high cell compatibility. <strong>A13</strong> rapidly killed bacteria primarily through membrane disruption, a mechanism that reduces the likelihood of resistance development. Additionally, <strong>A13</strong> demonstrated significant anti-biofilm activity, excellent stability, and effective in vivo therapeutic efficacy in mouse models of MRSA-induced keratitis and pneumonia. Therefore, this study holds promise in providing effective antimicrobial agents or new strategies for the discovery of novel antibiotics to treat drug-resistant bacterial infections.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 108990"},"PeriodicalIF":4.7,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145060945","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}