Pub Date : 2026-01-23DOI: 10.1016/j.bioorg.2026.109519
Vivian Lioret , Constant Gillot , Marie Hologne , Jenny Ha , Dmytro Strilets , Laurent Lubrano Di Scampamorte , Laurent Gillet , Jonathan Douxfils , Stéphane P. Vincent
Anti-adhesion strategies based on multivalent glycosylated molecules have emerged as promising antiviral tools to block early stages of viral infection. Herein, we report the design, synthesis, and evaluation of a series of porphyrin-based glycoclusters bearing sialic acid (SA) or 9-O-acetyl SA units, connected via linkers of varying length, polarity and rigidity. Their ability to inhibit virus-host cell interaction was assessed against wild-type, Alpha, Delta, JN.1 and KP.3 pseudotyped SARS-CoV-2 variants spanning the virus's evolutionary trajectory. The same inhibition pattern was measured with lived SARS-CoV-2 Delta variant. Although a small erosion of the SA affinity for the spike protein could be observed over the variants, all glycoclusters displayed robust and broad-spectrum neutralizing activity, highlighting the conserved role of SA-mediated recognition. Porphyrins bearing 9Ac-SA always displayed slightly better anti-effective properties than their SA counterparts. The engineering of the linkers distributing the SA ligands to the porphyrin central core proved successful as it could decrease the IC50's up to 4 times. The best optimized tetrameric inhibitors displayed a 60-fold enhanced activity compared to their monomers (15-fold per ligand). This work contributes both to the development and the improvement of antiviral agents and to a better understanding of viral evolution that drives SARS-CoV-2 infection.
基于多价糖基化分子的抗粘附策略已成为阻断早期病毒感染的有前途的抗病毒工具。在此，我们报道了一系列含有唾液酸（SA）或9- o -乙酰SA单元的卟啉基糖簇的设计、合成和评价，这些糖簇通过不同长度、极性和刚性的连接物连接。研究人员评估了它们抑制病毒-宿主细胞相互作用的能力，包括野生型、α型、德尔塔型、JN.1型和KP.3型假型SARS-CoV-2变体。用活的SARS-CoV-2 δ变体测量了相同的抑制模式。虽然在变异中可以观察到SA对刺突蛋白亲和力的轻微侵蚀，但所有糖簇都表现出强大的广谱中和活性，突出了SA介导的识别的保守作用。含9Ac-SA的卟啉的抗药效性能总是略好于含SA的卟啉。将SA配体分配到卟啉中心核的连接体工程证明是成功的，它可以将IC50降低4倍。优化后的四聚体抑制剂的活性是其单体的60倍（每个配体15倍）。这项工作有助于开发和改进抗病毒药物，并有助于更好地了解驱动SARS-CoV-2感染的病毒进化。
{"title":"Sialylated porphyrins optimized as anti-infective agents against SARS-CoV-2 variants","authors":"Vivian Lioret , Constant Gillot , Marie Hologne , Jenny Ha , Dmytro Strilets , Laurent Lubrano Di Scampamorte , Laurent Gillet , Jonathan Douxfils , Stéphane P. Vincent","doi":"10.1016/j.bioorg.2026.109519","DOIUrl":"10.1016/j.bioorg.2026.109519","url":null,"abstract":"<div><div>Anti-adhesion strategies based on multivalent glycosylated molecules have emerged as promising antiviral tools to block early stages of viral infection. Herein, we report the design, synthesis, and evaluation of a series of porphyrin-based glycoclusters bearing sialic acid (SA) or 9-<em>O</em>-acetyl SA units, connected via linkers of varying length, polarity and rigidity. Their ability to inhibit virus-host cell interaction was assessed against wild-type, Alpha, Delta, JN.1 and KP.3 pseudotyped SARS-CoV-2 variants spanning the virus's evolutionary trajectory. The same inhibition pattern was measured with lived SARS-CoV-2 Delta variant. Although a small erosion of the SA affinity for the spike protein could be observed over the variants, all glycoclusters displayed robust and broad-spectrum neutralizing activity, highlighting the conserved role of SA-mediated recognition. Porphyrins bearing 9Ac-SA always displayed slightly better anti-effective properties than their SA counterparts. The engineering of the linkers distributing the SA ligands to the porphyrin central core proved successful as it could decrease the IC<sub>50</sub>'s up to 4 times. The best optimized tetrameric inhibitors displayed a 60-fold enhanced activity compared to their monomers (15-fold per ligand). This work contributes both to the development and the improvement of antiviral agents and to a better understanding of viral evolution that drives SARS-CoV-2 infection.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109519"},"PeriodicalIF":4.7,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073893","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}
Isocitrate lyase (ICL), a pivotal enzyme of the glyoxylate shunt pathway in Mycobacterium tuberculosis (Mtb), represents an attractive target for the development of new anti-tuberculosis (TB) therapeutics. In this study, we identified 2-methoxy-4-((nitrosooxy)methyl)phenyl 2-(2-fluoro-[1,1′-biphenyl]-4-yl)propanoate (IDD-AN-A1) as a potent inhibitor of Mtb ICL. The compound exhibited strong activity against Mtb, with a minimum inhibitory concentration of 6.25 μg/mL, and demonstrated potent inhibition in enzyme-based assays targeting ICL. Molecular docking studies further supported Mtb ICL as the potential molecular target of this compound. Cytotoxicity and hemolytic assays revealed a favorable safety profile for the compound with selectivity index >10. In combination studies, it exhibited additive and synergistic activity with the frontline drug Rifampicin and Delamanid respectively. Additionally, ex vivo assays simulating the intracellular environment of the pathogen demonstrated strong inhibitory potency. In vitro inhibition studies further confirmed the bacteriostatic nature of the compound across different concentrations. Collectively, these findings demonstrate that this molecule possesses promising anti-tuberculosis activity by targeting the ICL enzyme in Mtb.
{"title":"Elucidating the potential of novel class biphenyl-phenyl acetate, IDD-AN-A1, an inhibitor targeting Isocitrate Lyase in Mycobacterium tuberculosis: A target to lead approach","authors":"Anjali Negi , Summaya Perveen , Harpreet Kour , Sanghapal D. Sawant , Rashmi Sharma","doi":"10.1016/j.bioorg.2026.109557","DOIUrl":"10.1016/j.bioorg.2026.109557","url":null,"abstract":"<div><div>Isocitrate lyase (ICL), a pivotal enzyme of the glyoxylate shunt pathway in <em>Mycobacterium tuberculosis (Mtb</em>), represents an attractive target for the development of new anti-tuberculosis (TB) therapeutics. In this study, we identified <strong>2-methoxy-4-((nitrosooxy)methyl)phenyl 2-(2-fluoro-[1,1′-biphenyl]-4-yl)propanoate</strong> (<strong>IDD-AN-A1</strong>) as a potent inhibitor of <em>Mtb</em> ICL. The compound exhibited strong activity against <em>Mtb</em>, with a minimum inhibitory concentration of 6.25 μg/mL, and demonstrated potent inhibition in enzyme-based assays targeting ICL. Molecular docking studies further supported <em>Mtb</em> ICL as the potential molecular target of this compound. Cytotoxicity and hemolytic assays revealed a favorable safety profile for the compound with selectivity index >10. In combination studies, it exhibited additive and synergistic activity with the frontline drug Rifampicin and Delamanid respectively. Additionally, <em>ex vivo</em> assays simulating the intracellular environment of the pathogen demonstrated strong inhibitory potency. <em>In vitro</em> inhibition studies further confirmed the bacteriostatic nature of the compound across different concentrations. Collectively, these findings demonstrate that this molecule possesses promising anti-tuberculosis activity by targeting the ICL enzyme in <em>Mtb.</em></div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109557"},"PeriodicalIF":4.7,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146058338","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}
Pub Date : 2026-01-23DOI: 10.1016/j.bioorg.2026.109531
Ji-Long Zou , Da-Yu Shi , Yi-Zhou Xiang , Li Zhang , Ping Tian , Qing-Hua Li
A biomimetic carbocation-trapping reaction of (−)-β-caryophyllene with heteroaryl thiols, aryl thiols, and aryl sulfinates has been developed, enabling the efficient construction of a series of epicaryolane-based thioether and sulfone derivatives with fully determined absolute configurations. The reaction proceeds rapidly under mild and operationally straightforward conditions. The synthesized derivatives were evaluated for farnesoid X receptor (FXR) agonist activity and hepatoprotective effects, with the 2-benzoyl-substituted thioether exhibiting the strongest FXR activation (EC₅₀ = 2.2 μM). Subsequent oxidation afforded the corresponding epicaryolane sulfones, thereby enhancing hydrophilicity while retaining bioactivity. These sulfones could be further converted into epicaryolane sulfonyl fluoride covalent warheads and diversified through multiple functionalization reactions, demonstrating their potential as versatile pharmacologically active scaffolds. This study highlights a concise and efficient strategy for the synthesis and diversification of sulfur-containing epicaryolane derivatives with promising therapeutic potential.
{"title":"Design, synthesis and biological evaluation of sulfur-containing epicaryolane derivatives as FXR agonists","authors":"Ji-Long Zou , Da-Yu Shi , Yi-Zhou Xiang , Li Zhang , Ping Tian , Qing-Hua Li","doi":"10.1016/j.bioorg.2026.109531","DOIUrl":"10.1016/j.bioorg.2026.109531","url":null,"abstract":"<div><div>A biomimetic carbocation-trapping reaction of (−)-β-caryophyllene with heteroaryl thiols, aryl thiols, and aryl sulfinates has been developed, enabling the efficient construction of a series of epicaryolane-based thioether and sulfone derivatives with fully determined absolute configurations. The reaction proceeds rapidly under mild and operationally straightforward conditions. The synthesized derivatives were evaluated for farnesoid X receptor (FXR) agonist activity and hepatoprotective effects, with the 2-benzoyl-substituted thioether exhibiting the strongest FXR activation (EC₅₀ = 2.2 μM). Subsequent oxidation afforded the corresponding epicaryolane sulfones, thereby enhancing hydrophilicity while retaining bioactivity. These sulfones could be further converted into epicaryolane sulfonyl fluoride covalent warheads and diversified through multiple functionalization reactions, demonstrating their potential as versatile pharmacologically active scaffolds. This study highlights a concise and efficient strategy for the synthesis and diversification of sulfur-containing epicaryolane derivatives with promising therapeutic potential.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109531"},"PeriodicalIF":4.7,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073899","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}
Pub Date : 2026-01-23DOI: 10.1016/j.bioorg.2026.109520
Yuxin Chen , Enqiang Liu , Xingchun Ding , Chong Qin , Yuqi Jiang , Xiaoyang Li
Acute myeloid leukemia (AML) is a heterogeneous hematopoietic neoplasm driven in part by aberrant epigenetic mechanisms such as histone deacetylation, with HDAC3 playing an important role in its pathogenesis. In this study, we designed a series of novel HDAC3 PROTACs based on our previously designed HDAC3 inhibitor as the POI ligand. Among these, representative compound B22 potently degraded HDAC3, with a DC50 of 30.73 nM and a Dmax of 82%. B22 synergized with the clinically approved AML agent Venetoclax, demonstrating potent anti-proliferative effects and significantly promoting apoptosis in MV4–11 cells. Mechanistically, the combination of B22 and Venetoclax synergistically induces DNA damage and downregulates the anti-apoptotic proteins Mcl-1 and Bcl-xL. In conclusion, this study provided insights into novel HDAC3-directed PROTACs development and proposed their therapeutic potential against AML.
{"title":"Design, synthesis, and biological evaluation of novel HDAC3 PROTACs for combined therapy with Venetoclax in acute myeloid leukemia","authors":"Yuxin Chen , Enqiang Liu , Xingchun Ding , Chong Qin , Yuqi Jiang , Xiaoyang Li","doi":"10.1016/j.bioorg.2026.109520","DOIUrl":"10.1016/j.bioorg.2026.109520","url":null,"abstract":"<div><div>Acute myeloid leukemia (AML) is a heterogeneous hematopoietic neoplasm driven in part by aberrant epigenetic mechanisms such as histone deacetylation, with HDAC3 playing an important role in its pathogenesis. In this study, we designed a series of novel HDAC3 PROTACs based on our previously designed HDAC3 inhibitor as the POI ligand. Among these, representative compound <strong>B22</strong> potently degraded HDAC3, with a DC<sub>50</sub> of 30.73 nM and a D<sub>max</sub> of 82%. <strong>B22</strong> synergized with the clinically approved AML agent Venetoclax, demonstrating potent anti-proliferative effects and significantly promoting apoptosis in MV4–11 cells. Mechanistically, the combination of <strong>B22</strong> and Venetoclax synergistically induces DNA damage and downregulates the anti-apoptotic proteins Mcl-1 and Bcl-xL. In conclusion, this study provided insights into novel HDAC3-directed PROTACs development and proposed their therapeutic potential against AML.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109520"},"PeriodicalIF":4.7,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073894","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}
Pub Date : 2026-01-23DOI: 10.1016/j.bioorg.2026.109544
Mengzhi Zhang , Xing-Jie Dai , Binbin Huang , Shuxian Zheng , Hong-Min Liu , Lijuan Zhao , Pengran Liu , Ya Gao
Interleukin-4-induced protein 1 (IL4I1) is a secreted L-amino acid oxidase primarily produced by antigen-presenting cells and aberrantly expressed in tumors and tumor-associated immune cells. It catalyzes the oxidative deamination of aromatic amino acids (L-phenylalanine, tryptophan, and tyrosine), generating hydrogen peroxide, ammonia, keto acids, and immunomodulatory indole derivatives such as indole-3-pyruvate, which activate the aryl hydrocarbon receptor (AHR). Through its enzymatic activity and metabolites, IL4I1 suppresses T-cell proliferation and effector functions, promotes regulatory T cell (Treg) differentiation, and negatively regulates B-cell (BCR) and T-cell receptor (TCR) signaling. These mechanisms facilitate tumor immune escape, promoting cancer progression, metastasis, and resistance to immunotherapy. Beyond oncology, IL4I1 is implicated in autoimmune, infectious, and inflammatory diseases, underscoring its role as a critical metabolic immune checkpoint. Consequently, IL4I1 emerges as a significant prognostic biomarker and a promising therapeutic target, driving ongoing development of targeted inhibitors. This review comprehensively synthesizes the structural, functional, and clinical landscape of IL4I1, highlighting its therapeutic potential.
{"title":"Decoding IL4I1: The Core role of metabolism-driven immune regulation and new perspectives on disease targeting","authors":"Mengzhi Zhang , Xing-Jie Dai , Binbin Huang , Shuxian Zheng , Hong-Min Liu , Lijuan Zhao , Pengran Liu , Ya Gao","doi":"10.1016/j.bioorg.2026.109544","DOIUrl":"10.1016/j.bioorg.2026.109544","url":null,"abstract":"<div><div>Interleukin-4-induced protein 1 (IL4I1) is a secreted L-amino acid oxidase primarily produced by antigen-presenting cells and aberrantly expressed in tumors and tumor-associated immune cells. It catalyzes the oxidative deamination of aromatic amino acids (<em>L</em>-phenylalanine, tryptophan, and tyrosine), generating hydrogen peroxide, ammonia, keto acids, and immunomodulatory indole derivatives such as indole-3-pyruvate, which activate the aryl hydrocarbon receptor (AHR). Through its enzymatic activity and metabolites, IL4I1 suppresses T-cell proliferation and effector functions, promotes regulatory T cell (Treg) differentiation, and negatively regulates B-cell (BCR) and T-cell receptor (TCR) signaling. These mechanisms facilitate tumor immune escape, promoting cancer progression, metastasis, and resistance to immunotherapy. Beyond oncology, IL4I1 is implicated in autoimmune, infectious, and inflammatory diseases, underscoring its role as a critical metabolic immune checkpoint. Consequently, IL4I1 emerges as a significant prognostic biomarker and a promising therapeutic target, driving ongoing development of targeted inhibitors. This review comprehensively synthesizes the structural, functional, and clinical landscape of IL4I1, highlighting its therapeutic potential.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"171 ","pages":"Article 109544"},"PeriodicalIF":4.7,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146057318","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}
Pub Date : 2026-01-23DOI: 10.1016/j.bioorg.2026.109558
Wei Su , Jiayin Chen , Chenxiang Lin , Jun-An Xiao , Peiyuan Li
Multidrug-resistant bacterial infections, such as methicillin-resistant Staphylococcus aureus (MRSA), pose a severe global health threat exacerbated by the limitations of conventional antibiotics and the hypoxic microenvironment of infections. To address this, we developed a novel supramolecular photosensitizer, TAPc@TMAP, via electrostatic self-assembly of anionic 2,3,9,10,16,17,23,24-octacarboxyphthalocyanine (TAPc) and cationic 5,10,15,20-tetrakis(4-trimethylammoniophenyl) porphyrin tetraiodide (TMAP). This nanocomposite exhibits exceptional near-infrared (NIR) responsiveness at 808 nm, enabling synergistic type-I photodynamic therapy (PDT) and photothermal therapy (PTT). Under NIR irradiation, TAPc@TMAP generated superoxide radicals (O2•−) with 55% efficiency retention under hypoxic conditions, significantly outperforming individual components (TAPc and TMAP), and achieved a photothermal conversion efficiency of 31.9% with negligible degradation over five cycles. In vitro, TAPc@TMAP eradicated 99.69% of MRSA at 30 μM concentration under 808 nm laser radiation (0.5 W/cm2, 30 min), inducing bacterial membrane rupture as confirmed by scanning electron microscopy. In a murine model of MRSA-infected wounds, TAPc@TMAP-mediated phototherapy reduced the residual wound area to 14.19 ± 1.9% within 12 days (vs. 33.11 ± 14% in controls) and decreased bacterial burden by 95.96% at day 8. Histological and immunohistochemical analyses revealed attenuated inflammation (22.65% reduction in TNF-α expression, p < 0.001), enhanced angiogenesis (5.06% increase in CD31-positive microvessels, p < 0.001), and organized collagen deposition. This study demonstrates the robust antibacterial efficacy and wound healing promotion of TAPc@TMAP via oxygen-independent type-I PDT/PTT synergy, offering a promising strategy for combating multidrug-resistant bacterial infections.
{"title":"NIR-triggered synergistic Photothermal therapy and type I photodynamic therapy using supramolecular porphyrin-Phthalocyanine assemblies for the treatment of multidrug-resistant bacterial infections","authors":"Wei Su , Jiayin Chen , Chenxiang Lin , Jun-An Xiao , Peiyuan Li","doi":"10.1016/j.bioorg.2026.109558","DOIUrl":"10.1016/j.bioorg.2026.109558","url":null,"abstract":"<div><div>Multidrug-resistant bacterial infections, such as methicillin-resistant <em>Staphylococcus aureus</em> (MRSA), pose a severe global health threat exacerbated by the limitations of conventional antibiotics and the hypoxic microenvironment of infections. To address this, we developed a novel supramolecular photosensitizer, TAPc@TMAP, via electrostatic self-assembly of anionic 2,3,9,10,16,17,23,24-octacarboxyphthalocyanine (TAPc) and cationic 5,10,15,20-tetrakis(4-trimethylammoniophenyl) porphyrin tetraiodide (TMAP). This nanocomposite exhibits exceptional near-infrared (NIR) responsiveness at 808 nm, enabling synergistic type-I photodynamic therapy (PDT) and photothermal therapy (PTT). Under NIR irradiation, TAPc@TMAP generated superoxide radicals (O<sub>2</sub><sup>•−</sup>) with 55% efficiency retention under hypoxic conditions, significantly outperforming individual components (TAPc and TMAP), and achieved a photothermal conversion efficiency of 31.9% with negligible degradation over five cycles. In vitro, TAPc@TMAP eradicated 99.69% of MRSA at 30 μM concentration under 808 nm laser radiation (0.5 W/cm<sup>2</sup>, 30 min), inducing bacterial membrane rupture as confirmed by scanning electron microscopy. In a murine model of MRSA-infected wounds, TAPc@TMAP-mediated phototherapy reduced the residual wound area to 14.19 ± 1.9% within 12 days (vs. 33.11 ± 14% in controls) and decreased bacterial burden by 95.96% at day 8. Histological and immunohistochemical analyses revealed attenuated inflammation (22.65% reduction in TNF-α expression, <em>p</em> < 0.001), enhanced angiogenesis (5.06% increase in CD31-positive microvessels, p < 0.001), and organized collagen deposition. This study demonstrates the robust antibacterial efficacy and wound healing promotion of TAPc@TMAP via oxygen-independent type-I PDT/PTT synergy, offering a promising strategy for combating multidrug-resistant bacterial infections.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"171 ","pages":"Article 109558"},"PeriodicalIF":4.7,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146057333","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}
Pub Date : 2026-01-23DOI: 10.1016/j.bioorg.2026.109524
Vojtech Varecka , Karolina Seligova , Alena Hofrova , Karin Ravaszova , Petr Mokry , Miroslava Bittova , Jozef Hritz , Eva Havrankova
This study presents the design, synthesis, and biological evaluation of a new series of 1,3,5-triazinyl benzenesulfonamide derivatives incorporating substituted piperazines, aminobenzenes, or adamantane moieties. The compounds were tested for inhibitory activity against human carbonic anhydrase isoenzymes II and IX, aiming for selectivity towards the latter, cancer associated isoenzyme IX, on the basis of an initial molecular docking screening. Several compounds showed inhibitory activity and selectivity exceeding that of the clinical benchmark acetazolamide. Among the most effective compounds were derivatives 9 (KI = 7.4 nM, selectivity ratio = 3.4) and 38 (KI = 9.4 nM, selectivity ratio = 3.9). This activity trend was related to structural rigidity and hydrophobicity based on structure-activity analysis and molecular docking. The compound's inhibition constants were determined using stopped-flow spectrophotometry in an updated approach, which enables accurate KI determination with higher throughput. The methodology framework is described in detail to facilitate reproducibility in the field.
{"title":"Triazinyl-benzenesulfonamide derivatives as hCA IX inhibitors: Design, synthesis, and activity determination using an optimized stop-flow methodology","authors":"Vojtech Varecka , Karolina Seligova , Alena Hofrova , Karin Ravaszova , Petr Mokry , Miroslava Bittova , Jozef Hritz , Eva Havrankova","doi":"10.1016/j.bioorg.2026.109524","DOIUrl":"10.1016/j.bioorg.2026.109524","url":null,"abstract":"<div><div>This study presents the design, synthesis, and biological evaluation of a new series of 1,3,5-triazinyl benzenesulfonamide derivatives incorporating substituted piperazines, aminobenzenes, or adamantane moieties. The compounds were tested for inhibitory activity against human carbonic anhydrase isoenzymes II and IX, aiming for selectivity towards the latter, cancer associated isoenzyme IX, on the basis of an initial molecular docking screening. Several compounds showed inhibitory activity and selectivity exceeding that of the clinical benchmark acetazolamide. Among the most effective compounds were derivatives <strong>9</strong> (K<sub>I</sub> = 7.4 nM, selectivity ratio = 3.4) and <strong>38</strong> (K<sub>I</sub> = 9.4 nM, selectivity ratio = 3.9). This activity trend was related to structural rigidity and hydrophobicity based on structure-activity analysis and molecular docking. The compound's inhibition constants were determined using stopped-flow spectrophotometry in an updated approach, which enables accurate K<sub>I</sub> determination with higher throughput. The methodology framework is described in detail to facilitate reproducibility in the field.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109524"},"PeriodicalIF":4.7,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146058430","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}
Pub Date : 2026-01-22DOI: 10.1016/j.bioorg.2026.109551
Carlos J. Bethencourt-Estrella , Atteneri López-Arencibia , Raquel Diana-Rivero , Ines Sifaoui , Isabel M. Calero-Docina , David Tejedor , Jacob Lorenzo-Morales , José E. Piñero
Chagas disease, caused by the protozoan Trypanosoma cruzi, remains a serious public health concern, particularly in Latin America, due to its high prevalence and the limited efficacy and safety of current treatments. To identify new potential therapeutic options, a library of 40 synthetic indole derivatives was screened for antiparasitic activity. The compounds were tested against both epimastigote and intracellular amastigote forms of T. cruzi using in vitro assays. While most of the molecules showed low or no activity, ten compounds exhibited promising effects with IC₅₀ values below 200 μM. The most active derivatives were further evaluated for cytotoxicity on mammalian cells. Among them, the compound I – 7b stood out with a selectivity index of 19.8 and was selected for further characterization. Subsequent assays revealed that this compound induced several cellular effects in the parasite, including ATP depletion, chromatin condensation, plasma membrane damage, reactive oxygen species (ROS) accumulation, and disruption of mitochondrial membrane potential (ΔΨm). These findings suggest that certain indole-based compounds may serve as promising scaffolds for the development of novel therapies against T. cruzi, contributing to the advancement of global health efforts targeting neglected tropical diseases.
{"title":"Targeting Trypanosoma cruzi with indoles: mechanistic insights and implications for human health and Chagas disease therapy","authors":"Carlos J. Bethencourt-Estrella , Atteneri López-Arencibia , Raquel Diana-Rivero , Ines Sifaoui , Isabel M. Calero-Docina , David Tejedor , Jacob Lorenzo-Morales , José E. Piñero","doi":"10.1016/j.bioorg.2026.109551","DOIUrl":"10.1016/j.bioorg.2026.109551","url":null,"abstract":"<div><div>Chagas disease, caused by the protozoan <em>Trypanosoma cruzi</em>, remains a serious public health concern, particularly in Latin America, due to its high prevalence and the limited efficacy and safety of current treatments. To identify new potential therapeutic options, a library of 40 synthetic indole derivatives was screened for antiparasitic activity. The compounds were tested against both epimastigote and intracellular amastigote forms of <em>T. cruzi</em> using in vitro assays. While most of the molecules showed low or no activity, ten compounds exhibited promising effects with IC₅₀ values below 200 μM. The most active derivatives were further evaluated for cytotoxicity on mammalian cells. Among them, the compound I – 7b stood out with a selectivity index of 19.8 and was selected for further characterization. Subsequent assays revealed that this compound induced several cellular effects in the parasite, including ATP depletion, chromatin condensation, plasma membrane damage, reactive oxygen species (ROS) accumulation, and disruption of mitochondrial membrane potential (ΔΨm). These findings suggest that certain indole-based compounds may serve as promising scaffolds for the development of novel therapies against <em>T. cruzi</em>, contributing to the advancement of global health efforts targeting neglected tropical diseases.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"171 ","pages":"Article 109551"},"PeriodicalIF":4.7,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076746","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}
Pub Date : 2026-01-22DOI: 10.1016/j.bioorg.2026.109529
Joydeep Chatterjee, Shivkanya M Bhujbal, Gaurav Joshi, Uttam Kumar Mishra, Ashoke Sharon, Muskan, Shivam Singh, Muhammad Wahajuddin, Prasad V Bharatam, Rajdeep Dalal, Raj Kumar
A green, catalyst-free synthesis of seventeen new 2,9-disubstituted purine-6-carboxamides (5 and 6) designed as EGFR inhibitors in high yields (85-93%) was accomplished. DFT analysis revealed the formation of an energetically favorable oxazolidine transition state with a lower activation barrier compared to alternative pathways, supporting the experimentally observed selectivity. In vitro anticancer activity against A549 lung cancer cells demonstrated dose-dependent growth inhibition, with IC₅₀ values ranging from 4.35 to 22.1 μM, and compound 6E emerged as the most potent derivative. It exhibited superior activity compared to the reference drug erlotinib, with a cellular IC₅₀ of 4.35 μM vs 11.83 μM and an EGFR enzymatic IC₅₀ of 105.96 nM vs 218.47 nM, indicating approximately 2-fold enhanced potency. Flow cytometric analysis demonstrated that compound 6E significantly reduced p-PI3K levels, comparably to erlotinib, indicating effective suppression of EGFR-AKT downstream signaling at the cellular level. Mechanistic investigations demonstrated that 6E increased ROS generation, induced mitochondrial depolarisation, and promoted apoptotic cell death. Further, molecular docking and MD simulations of the 6E-EGFR complex highlighted key amino acid interactions, corroborating the observed in vitro EGFR inhibition.
绿色，无催化剂合成了17种新的2,9-二取代嘌呤-6-羧酰胺（5和6），设计为EGFR抑制剂，产率高（85-93%）。DFT分析显示，与其他途径相比，形成了一个能量有利的恶唑烷过渡态，其激活势垒较低，支持实验观察到的选择性。对A549肺癌细胞的体外抗癌活性显示出剂量依赖性的生长抑制，IC₅0值范围为4.35至22.1 μM，化合物6E成为最有效的衍生物。与参比药物厄洛替尼相比，它具有优越的活性，细胞IC₅₀为4.35 μM vs 11.83 μM， EGFR酶IC₅₀为105.96 nM vs 218.47 nM，表明效力提高了约2倍。流式细胞分析显示，与厄洛替尼相比，化合物6E显著降低了p-PI3K水平，表明在细胞水平上有效抑制了EGFR-AKT下游信号传导。机制研究表明，6E增加ROS生成，诱导线粒体去极化，促进凋亡细胞死亡。此外，6E-EGFR复合物的分子对接和MD模拟突出了关键氨基酸的相互作用，证实了体外观察到的EGFR抑制作用。
{"title":"Design, catalyst-free synthesis, DFT study and anticancer assessment of new 2,9-disubstituted purine-6-carboxamides.","authors":"Joydeep Chatterjee, Shivkanya M Bhujbal, Gaurav Joshi, Uttam Kumar Mishra, Ashoke Sharon, Muskan, Shivam Singh, Muhammad Wahajuddin, Prasad V Bharatam, Rajdeep Dalal, Raj Kumar","doi":"10.1016/j.bioorg.2026.109529","DOIUrl":"https://doi.org/10.1016/j.bioorg.2026.109529","url":null,"abstract":"<p><p>A green, catalyst-free synthesis of seventeen new 2,9-disubstituted purine-6-carboxamides (5 and 6) designed as EGFR inhibitors in high yields (85-93%) was accomplished. DFT analysis revealed the formation of an energetically favorable oxazolidine transition state with a lower activation barrier compared to alternative pathways, supporting the experimentally observed selectivity. In vitro anticancer activity against A549 lung cancer cells demonstrated dose-dependent growth inhibition, with IC₅₀ values ranging from 4.35 to 22.1 μM, and compound 6E emerged as the most potent derivative. It exhibited superior activity compared to the reference drug erlotinib, with a cellular IC₅₀ of 4.35 μM vs 11.83 μM and an EGFR enzymatic IC₅₀ of 105.96 nM vs 218.47 nM, indicating approximately 2-fold enhanced potency. Flow cytometric analysis demonstrated that compound 6E significantly reduced p-PI3K levels, comparably to erlotinib, indicating effective suppression of EGFR-AKT downstream signaling at the cellular level. Mechanistic investigations demonstrated that 6E increased ROS generation, induced mitochondrial depolarisation, and promoted apoptotic cell death. Further, molecular docking and MD simulations of the 6E-EGFR complex highlighted key amino acid interactions, corroborating the observed in vitro EGFR inhibition.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"172 ","pages":"109529"},"PeriodicalIF":4.7,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146123180","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}
Pub Date : 2026-01-22DOI: 10.1016/j.bioorg.2026.109532
Mohsen Mohammadgholi , Seyed Jalal Hosseinimehr
Advanced imaging technologies, such as single photon emission computed tomography (SPECT) and positron emission tomography (PET), have greatly improved our understanding of psychiatric disorders. These imaging modalities not only help us delve deeper into the neurobiology and underlying mechanisms of these disorders, but they also play a crucial role in enhancing clinical diagnosis, leading to better care for affected individuals. Research utilizing PET and SPECT has provided insights into the neurobiological underpinnings of schizophrenia, allowing for the visualization of brain activity and the assessment of neurotransmitter systems, particularly dopamine, which is often implicated in the pathophysiology of the disorder. Furthermore, radiotracers used in dopaminergic system imaging can help in comprehending how antipsychotic medications affect brain function and assist in evaluating treatment responses. Overall, PET and SPECT contribute valuable information to the understanding of schizophrenia, aiding both research and clinical settings.
{"title":"Radiotracers for imaging of schizophrenia","authors":"Mohsen Mohammadgholi , Seyed Jalal Hosseinimehr","doi":"10.1016/j.bioorg.2026.109532","DOIUrl":"10.1016/j.bioorg.2026.109532","url":null,"abstract":"<div><div>Advanced imaging technologies, such as single photon emission computed tomography (SPECT) and positron emission tomography (PET), have greatly improved our understanding of psychiatric disorders. These imaging modalities not only help us delve deeper into the neurobiology and underlying mechanisms of these disorders, but they also play a crucial role in enhancing clinical diagnosis, leading to better care for affected individuals. Research utilizing PET and SPECT has provided insights into the neurobiological underpinnings of schizophrenia, allowing for the visualization of brain activity and the assessment of neurotransmitter systems, particularly dopamine, which is often implicated in the pathophysiology of the disorder. Furthermore, radiotracers used in dopaminergic system imaging can help in comprehending how antipsychotic medications affect brain function and assist in evaluating treatment responses. Overall, PET and SPECT contribute valuable information to the understanding of schizophrenia, aiding both research and clinical settings.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109532"},"PeriodicalIF":4.7,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146058396","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}
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