Pub Date : 2026-02-01Epub Date: 2025-12-02DOI: 10.1016/j.bmc.2025.118503
Juan Zhang , Wen-Jing Gao , Yu-Xi Zheng , Jia-Dong Shao , Nai-Yu Zhang , Wei Guo , Shuai Wang , Qing Zhao , Kongkai Zhu , Ming Gao , Jin-Hai Yu , Ning Meng , Cheng-Shi Jiang
Indoleamine 2,3-dioxygenase-1 (IDO1) has emerged as a promising therapeutic target for antidepressant development. The present study performed scaffold hopping-based structural optimization of a known benzimidazole-derived IDO1 inhibitor C-0 (20.20 ± 2.27 nM), which yielded a series of novel indole-based IDO1 inhibitors. Among these, the 6-fluoroindole/indole-2-carboxamide hybrid 9f and the 6-fluoroindole/4-bromopyrrole-2-carboxamide hybrid 10f exhibited the most improved IDO1 inhibitory activity, achieving IC₅₀ values of 9.18 ± 0.84 and 6.57 ± 0.61 nM, respectively. In addition, compound 10f demonstrated anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. Further study revealed that compounds 9f and 10f had improved in vitro and in vivo pharmacokinetic properties compared to the controls, and rescued LPS-induced depressive-like behavior in mice. The present study provides indole-based IDO1 inhibitors as a promising lead compound for the development of novel and effective IDO1-targeted antidepressants.
{"title":"Novel indole-based indoleamine 2,3-dioxygenase-1 (IDO1) inhibitors: design, synthesis, and antidepressant evaluation","authors":"Juan Zhang , Wen-Jing Gao , Yu-Xi Zheng , Jia-Dong Shao , Nai-Yu Zhang , Wei Guo , Shuai Wang , Qing Zhao , Kongkai Zhu , Ming Gao , Jin-Hai Yu , Ning Meng , Cheng-Shi Jiang","doi":"10.1016/j.bmc.2025.118503","DOIUrl":"10.1016/j.bmc.2025.118503","url":null,"abstract":"<div><div>Indoleamine 2,3-dioxygenase-1 (IDO1) has emerged as a promising therapeutic target for antidepressant development. The present study performed scaffold hopping-based structural optimization of a known benzimidazole-derived IDO1 inhibitor <strong>C-0</strong> (20.20 ± 2.27 nM), which yielded a series of novel indole-based IDO1 inhibitors. Among these, the 6-fluoroindole/indole-2-carboxamide hybrid <strong>9f</strong> and the 6-fluoroindole/4-bromopyrrole-2-carboxamide hybrid <strong>10f</strong> exhibited the most improved IDO1 inhibitory activity, achieving IC₅₀ values of 9.18 ± 0.84 and 6.57 ± 0.61 nM, respectively. In addition, compound <strong>10f</strong> demonstrated anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. Further study revealed that compounds <strong>9f</strong> and <strong>10f</strong> had improved <em>in vitro</em> and <em>in vivo</em> pharmacokinetic properties compared to the controls, and rescued LPS-induced depressive-like behavior in mice. The present study provides indole-based IDO1 inhibitors as a promising lead compound for the development of novel and effective IDO1-targeted antidepressants.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118503"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145686619","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}
Antimicrobial peptides (AMPs) are a prominent weapon that can expand human beings' arsenal against antimicrobial resistance. However, microorganisms can equip themselves against the antimicrobial effects of AMPs. Increasing daily dosing of AMPs to dispel resistance may lead to severe side effects or toxicity. In addition, some poor properties of AMPs, such as rapid degradation and low water solubility, make it difficult to achieve the right therapeutic dose at the target site. To provide more potent and less toxic AMPs, structural modification is one of the promising approaches. This review focuses on five representative AMPs: daptomycin, pexiganan (MSI-78), murepavadin (POL7080), iseganan (IB-367), and omiganan (MBI-226), and involves an analysis of their clinical development, mechanisms of resistance, toxicity profiles, and resultant outcomes. By investigating these specific cases, we derive critical insights into the factors influencing the emergence of resistance, the challenges posed by toxicity, and the structural limitations that have impeded the translation of AMPs into clinical applications. Furthermore, we discuss prospective peptide design strategies that may effectively address these challenges. Notably, we underscore the potential of structure-based strategies, including amino acid substitutions and conjugation with diverse molecular entities (such as small functional groups, synthetic polymers, peptides, and antibiotics), as promising pathways to mitigate these barriers and advance the development of clinically viable AMP therapeutics.
{"title":"Peptide-based antibiotics: structure-driven strategies to tackle toxicity and resistance of antimicrobial peptides","authors":"Maryam Tabarzad , Maryam Torshabi , Azadeh Haeri , Fariba Fathi , Seyedeh Maryam Mortazavi","doi":"10.1016/j.bmc.2025.118486","DOIUrl":"10.1016/j.bmc.2025.118486","url":null,"abstract":"<div><div>Antimicrobial peptides (AMPs) are a prominent weapon that can expand human beings' arsenal against antimicrobial resistance. However, microorganisms can equip themselves against the antimicrobial effects of AMPs. Increasing daily dosing of AMPs to dispel resistance may lead to severe side effects or toxicity. In addition, some poor properties of AMPs, such as rapid degradation and low water solubility, make it difficult to achieve the right therapeutic dose at the target site. To provide more potent and less toxic AMPs, structural modification is one of the promising approaches. This review focuses on five representative AMPs: daptomycin, pexiganan (MSI-78), murepavadin (POL7080), iseganan (IB-367), and omiganan (MBI-226), and involves an analysis of their clinical development, mechanisms of resistance, toxicity profiles, and resultant outcomes. By investigating these specific cases, we derive critical insights into the factors influencing the emergence of resistance, the challenges posed by toxicity, and the structural limitations that have impeded the translation of AMPs into clinical applications. Furthermore, we discuss prospective peptide design strategies that may effectively address these challenges. Notably, we underscore the potential of structure-based strategies, including amino acid substitutions and conjugation with diverse molecular entities (such as small functional groups, synthetic polymers, peptides, and antibiotics), as promising pathways to mitigate these barriers and advance the development of clinically viable AMP therapeutics.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118486"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145578653","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}
Pub Date : 2026-02-01Epub Date: 2025-12-05DOI: 10.1016/j.bmc.2025.118516
Wei Cheng , Peng Wen , Pei-Yin Song , Yang Zhang , Jin-Bu Xu , Steven De Jonghe , Dominique Schols , Feng Gao
Constructing structural diverse compound libraries based on naturally scarce skeletons is a key challenge in natural product medicinal chemistry research. In this study, structural diversification of three classes of naturally scarce Euphorbia diterpenoids (including 5/7/7/4 eupholathones, 6/11/3 lathyranones, and 5/11 integerrimenes) was achieved via a biomimetic skeleton conversion strategy yielding a library of 72 rare Euphorbia diterpenoid analogues, that was investigated as potential inhibitors of HIV replication. The eupholathone type esters exhibited the most potent anti-HIV activity, emerging as a promising class of anti-HIV agents within the Euphorbia diterpenoids family. Analysis of the structure-activity relationship revealed that the hydroxyl group at C6 of the eupholathone scaffold is a critical position for enhancing anti-HIV potency, with aromatic esters on being particularly favorable. Specifically, the eupholathone ester 2t showed the best anti-HIV-1 activity, with an EC50 of 1.51 μM and a selectivity index of more than 66.2, suggesting its potential as a candidate for further antiviral drug development.
{"title":"Biomimetic semi-synthesis, structural optimization and anti-HIV activity of naturally scarce eupholathone-, lathyranone- and integerrimine-type Euphorbia diterpenoids","authors":"Wei Cheng , Peng Wen , Pei-Yin Song , Yang Zhang , Jin-Bu Xu , Steven De Jonghe , Dominique Schols , Feng Gao","doi":"10.1016/j.bmc.2025.118516","DOIUrl":"10.1016/j.bmc.2025.118516","url":null,"abstract":"<div><div>Constructing structural diverse compound libraries based on naturally scarce skeletons is a key challenge in natural product medicinal chemistry research. In this study, structural diversification of three classes of naturally scarce <em>Euphorbia</em> diterpenoids (including 5/7/7/4 eupholathones, 6/11/3 lathyranones, and 5/11 integerrimenes) was achieved via a biomimetic skeleton conversion strategy yielding a library of 72 rare <em>Euphorbia</em> diterpenoid analogues, that was investigated as potential inhibitors of HIV replication. The eupholathone type esters exhibited the most potent anti-HIV activity, emerging as a promising class of anti-HIV agents within the <em>Euphorbia</em> diterpenoids family. Analysis of the structure-activity relationship revealed that the hydroxyl group at C6 of the eupholathone scaffold is a critical position for enhancing anti-HIV potency, with aromatic esters on being particularly favorable. Specifically, the eupholathone ester <strong>2t</strong> showed the best anti-HIV-1 activity, with an EC<sub>50</sub> of 1.51 μM and a selectivity index of more than 66.2, suggesting its potential as a candidate for further antiviral drug development.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118516"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145733233","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}
Pub Date : 2026-02-01Epub Date: 2025-11-20DOI: 10.1016/j.bmc.2025.118495
Amanda Tsang , Cassandra Yuan , Manuel Berumen , Leah Duong , Karen Gomez , Shelby Seely , Alex Salgado , Adim Rai , Jo Vistosa , Edith Morales Munoz , Marcos E. Ortega , Christophe Morisseau , Bruce D. Hammock , Jake E. Zuckerman , Joseph Yount , Davin G. Piercey , Ram Kandasamy , Stevan Pecic
Both soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH) are involved in degradation of anti-inflammatory and antinociceptive lipids, thus inhibition of these enzymatic pathways represents a novel strategy in the discovery of non-opioid drugs for treating inflammatory pain. We previously discovered several multi-targeted designed ligands and described a pharmacophore necessary for inhibition of both sEH and FAAH. The potential for optimization on the left side of the pharmacophore led us to exploration of different heterocyclic moieties with the hope to keep strong inhibition potencies, but to increase the metabolic stability and solubility of new analogs. Eighteen analogs containing various substituted and unsubstituted pyrimidinyl-, quinoxalinyl- and tetrazolyl- rings are synthesized and tested for inhibition potency in human FAAH, and human, rat and mouse sEH. The structure-activity relationship study revealed quinoxalinyl- analog 4 m, the most potent dual inhibitor reported to date, with IC50 values of 2.9 nM in human FAAH and 0.7 nM, 39.1 nM and 0.3 nM in human, mouse and rat sEH, respectively. 4 m showed no binding to opioid and most serotonin receptors and was tested in the human, mouse and rat liver microsomes stability assays where it exhibited good and/or moderate clearance rates. Lastly, we evaluated 4 m in vivo in a wheel running assay to determine its effects on voluntary locomotor behavior. Both 4 m and the traditional opioid morphine exhibited significant depression of wheel running after intraperitoneal administration indicating that 4 m may produce undesirable behavioral effects, which will be the basis for future studies.
{"title":"Polynitrogen-containing compounds as multi-target sEH/FAAH inhibitors: Structure-activity relationship and pharmacological studies","authors":"Amanda Tsang , Cassandra Yuan , Manuel Berumen , Leah Duong , Karen Gomez , Shelby Seely , Alex Salgado , Adim Rai , Jo Vistosa , Edith Morales Munoz , Marcos E. Ortega , Christophe Morisseau , Bruce D. Hammock , Jake E. Zuckerman , Joseph Yount , Davin G. Piercey , Ram Kandasamy , Stevan Pecic","doi":"10.1016/j.bmc.2025.118495","DOIUrl":"10.1016/j.bmc.2025.118495","url":null,"abstract":"<div><div>Both soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH) are involved in degradation of anti-inflammatory and antinociceptive lipids, thus inhibition of these enzymatic pathways represents a novel strategy in the discovery of non-opioid drugs for treating inflammatory pain. We previously discovered several multi-targeted designed ligands and described a pharmacophore necessary for inhibition of both sEH and FAAH. The potential for optimization on the left side of the pharmacophore led us to exploration of different heterocyclic moieties with the hope to keep strong inhibition potencies, but to increase the metabolic stability and solubility of new analogs. Eighteen analogs containing various substituted and unsubstituted pyrimidinyl-, quinoxalinyl- and tetrazolyl- rings are synthesized and tested for inhibition potency in human FAAH, and human, rat and mouse sEH. The structure-activity relationship study revealed quinoxalinyl- analog <strong>4 m</strong>, the most potent dual inhibitor reported to date, with IC<sub>50</sub> values of 2.9 nM in human FAAH and 0.7 nM, 39.1 nM and 0.3 nM in human, mouse and rat sEH, respectively. <strong>4 m</strong> showed no binding to opioid and most serotonin receptors and was tested in the human, mouse and rat liver microsomes stability assays where it exhibited good and/or moderate clearance rates. Lastly, we evaluated <strong>4 m</strong> in vivo in a wheel running assay to determine its effects on voluntary locomotor behavior. Both <strong>4 m</strong> and the traditional opioid morphine exhibited significant depression of wheel running after intraperitoneal administration indicating that <strong>4 m</strong> may produce undesirable behavioral effects, which will be the basis for future studies.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118495"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145601646","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}
Pub Date : 2026-02-01Epub Date: 2025-12-05DOI: 10.1016/j.bmc.2025.118518
Min Chen , Huifang Jiao , Dandan Lu , Wenhuan Chen , Zhen Yang , Xue Liang , Pengcheng Wei , Kunpeng Liu
Influenza viruses generate new strains or subtypes through antigenic drift and antigenic shift, leading to the failure of existing antiviral drugs and potentially causing widespread viral infection and influenza epidemics. However, during evolution, certain influenza virus proteins remain unchanged or undergo only minor mutations. Therefore, drugs targeting these evolutionarily conserved viral protein regions may exhibit broad-spectrum antiviral activity across subtypes and against mutations. The purpose of this study is to target the evolutionarily conserved domain of influenza A virus M2 protein and screen for drugs with cross-strain, mutation-resistant, and broad-spectrum antiviral activity. This study used AlphaFold3 to predict the M2 conserved domain structure and employed AutoDock to perform virtual screening of the NMPA database, identifying seven potential candidate drugs. Molecular dynamics simulations indicated that pamiparib exhibits strong affinity for the M2 conserved domain. It demonstrates excellent physiological activity in vitro in inhibiting the replication of H1N1 replication, while showing no effect on other viruses. CETSA experiments confirmed that pamiparib has the potential to bind to the M2 proteins of various influenza virus subtypes. In addition, pamiparib suppresses effectively viral infection in vivo. Ultimately, this study verifies that antiviral drugs designed to target the evolutionarily conserved regions of the influenza virus M2 protein indeed possess broad-spectrum antiviral activity across different strains.
{"title":"Broad-spectrum anti-influenza activity of the NMPA-approved drug Pamiparib is uncovered by virtual docking to the evolutionarily conserved domain of IAV-M2 protein","authors":"Min Chen , Huifang Jiao , Dandan Lu , Wenhuan Chen , Zhen Yang , Xue Liang , Pengcheng Wei , Kunpeng Liu","doi":"10.1016/j.bmc.2025.118518","DOIUrl":"10.1016/j.bmc.2025.118518","url":null,"abstract":"<div><div>Influenza viruses generate new strains or subtypes through antigenic drift and antigenic shift, leading to the failure of existing antiviral drugs and potentially causing widespread viral infection and influenza epidemics. However, during evolution, certain influenza virus proteins remain unchanged or undergo only minor mutations. Therefore, drugs targeting these evolutionarily conserved viral protein regions may exhibit broad-spectrum antiviral activity across subtypes and against mutations. The purpose of this study is to target the evolutionarily conserved domain of influenza A virus M2 protein and screen for drugs with cross-strain, mutation-resistant, and broad-spectrum antiviral activity. This study used AlphaFold3 to predict the M2 conserved domain structure and employed AutoDock to perform virtual screening of the NMPA database, identifying seven potential candidate drugs. Molecular dynamics simulations indicated that pamiparib exhibits strong affinity for the M2 conserved domain. It demonstrates excellent physiological activity in vitro in inhibiting the replication of H1N1 replication, while showing no effect on other viruses. CETSA experiments confirmed that pamiparib has the potential to bind to the M2 proteins of various influenza virus subtypes. In addition, pamiparib suppresses effectively viral infection in vivo. Ultimately, this study verifies that antiviral drugs designed to target the evolutionarily conserved regions of the influenza virus M2 protein indeed possess broad-spectrum antiviral activity across different strains.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118518"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145733231","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}
Pub Date : 2026-02-01Epub Date: 2025-11-24DOI: 10.1016/j.bmc.2025.118498
Yinxu Zhao , Liman Hou , Shuang Tian , Mengxin Zhu , Jiale Wu , Yukun Ma , Ming Bu , Yu Lin
Lupeol is a natural pentacyclic triterpenoid compound and exhibits great potential as a lead compound for the development of novel antitumor drugs. To further enhance its antitumor activity and targeting ability, two series of new lupeol derivatives were designed and synthesized in this study, and their antiproliferative activities against three human cancer cell lines (A549, HepG2, and MCF-7) were evaluated. Among these derivatives, compound 5l exhibited more potent in vitro antiproliferative activity against A549 cells, with a half-maximal inhibitory concentration (IC50) of 1.84 ± 0.53 μmol/L and a selectivity index (SI; IC50 of human embryonic lung fibroblast MRC-5 cells/IC50 of A549 cells) of 15.39. Mechanistic studies further revealed that compound 5l is a novel tubulin inhibitor: it can specifically bind to the colchicine-binding site of β-tubulin with a binding energy of −13.40 kcal/mol, effectively inhibit tubulin polymerization, arrest the cell cycle at the G2/M phase, and simultaneously trigger a series of apoptosis-related responses, thereby significantly inducing apoptosis of tumour cells. In the mouse lung cancer model, compound 5l demonstrated significant antitumor activity and a favorable safety profile. Based on these results, compound 5l holds promise as a new tubulin inhibitor for the treatment of non-small cell lung cancer (NSCLC).
{"title":"Development of lupeol derivatives based on tubulin-targeting strategy: structural modification and correlation analysis of antitumor activity","authors":"Yinxu Zhao , Liman Hou , Shuang Tian , Mengxin Zhu , Jiale Wu , Yukun Ma , Ming Bu , Yu Lin","doi":"10.1016/j.bmc.2025.118498","DOIUrl":"10.1016/j.bmc.2025.118498","url":null,"abstract":"<div><div>Lupeol is a natural pentacyclic triterpenoid compound and exhibits great potential as a lead compound for the development of novel antitumor drugs. To further enhance its antitumor activity and targeting ability, two series of new lupeol derivatives were designed and synthesized in this study, and their antiproliferative activities against three human cancer cell lines (A549, HepG2, and MCF-7) were evaluated. Among these derivatives, compound <strong>5l</strong> exhibited more potent in vitro antiproliferative activity against A549 cells, with a half-maximal inhibitory concentration (IC<sub>50</sub>) of 1.84 ± 0.53 μmol/L and a selectivity index (SI; IC<sub>50</sub> of human embryonic lung fibroblast MRC-5 cells/IC<sub>50</sub> of A549 cells) of 15.39. Mechanistic studies further revealed that compound <strong>5l</strong> is a novel tubulin inhibitor: it can specifically bind to the colchicine-binding site of β-tubulin with a binding energy of −13.40 kcal/mol, effectively inhibit tubulin polymerization, arrest the cell cycle at the G2/M phase, and simultaneously trigger a series of apoptosis-related responses, thereby significantly inducing apoptosis of tumour cells. In the mouse lung cancer model, compound <strong>5l</strong> demonstrated significant antitumor activity and a favorable safety profile. Based on these results, compound <strong>5l</strong> holds promise as a new tubulin inhibitor for the treatment of non-small cell lung cancer (NSCLC).</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118498"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145622398","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}
Pub Date : 2026-02-01Epub Date: 2025-11-19DOI: 10.1016/j.bmc.2025.118489
Ida Amalie Nystad Reierth , Yngve Guttormsen , Jeanette H. Andersen , Espen H. Hansen , Ahmed Mossad Abdelhady , Manuel K. Langer , Bengt Erik Haug , Annette Bayer , Guillaume A. Petit
Histone deacetylases (HDACs) are enzymes that remove acyl groups from histones and other proteins. This process leads to condensation of DNA and subsequent downregulation in expression of specific genes altering the activity of essential cellular pathways and changing the cell's behaviour. As a result, HDACs have emerged as potential therapeutic targets to treat different forms of cancer. In this study we synthesized and investigated compounds built around a phorbazole scaffold to characterize their histone deacetylase inhibitor (HDACi) activity. Eighteen phorbazole analogues were tested against class I and II HDACs in cell lysate, seven showed moderate activity, of which, three had IC50 values below 50 μM. The five best candidates were evaluated more extensively against HDAC1-11 (except for HDAC10). The best candidate, compound 9, initially appeared to reduce the activity of HDAC9 and HDAC11 by more than 50 % at 10 μM concentration. The binding mode of compound 9 to HDACs was explored via computational docking, where two poses stood out. These were explored further by molecular dynamic simulation. We found that 9 likely binds HDAC9 with the pyrrole group buried in the active site and forming H-bonds with the backbone oxygen of one of the glycine residues lining the cavity. But neither of the poses explored offered convincing arguments to describe the mode of action of the phorbazole, especially when comparing 9 to other analogues tested in this study. Additional experiments found that 9 interfered with the cell lysate assays by inhibiting luciferase in a dose-dependent manner (IC50 < 1 μM) and by exhibiting autofluorescence when tested on purified HDAC proteins, thereby confounding the obtained results during both the pan-HDAC screening and the single point HDAC inhibition assay. To address this, we employed fluorophores with excitation and emission wavelengths outside of the emission range of 9 and found that the HDAC inhibition potential of 9 was weaker than first observed. Finally, Compound 9 was found to be very soluble in water (418 μM) and membrane permeable (>48 % flux). This study highlights the need for rigorous validation of results. In our case, two orthogonal testing methods were not sufficient to catch all the confounding factors involved in measurement of HDAC inhibition, and a third approach was required to identify the actual inhibition of 9 against HDAC9 and 11.
{"title":"Investigation of the histone deacetylase inhibitor potential of phorbazole analogues","authors":"Ida Amalie Nystad Reierth , Yngve Guttormsen , Jeanette H. Andersen , Espen H. Hansen , Ahmed Mossad Abdelhady , Manuel K. Langer , Bengt Erik Haug , Annette Bayer , Guillaume A. Petit","doi":"10.1016/j.bmc.2025.118489","DOIUrl":"10.1016/j.bmc.2025.118489","url":null,"abstract":"<div><div>Histone deacetylases (HDACs) are enzymes that remove acyl groups from histones and other proteins. This process leads to condensation of DNA and subsequent downregulation in expression of specific genes altering the activity of essential cellular pathways and changing the cell's behaviour. As a result, HDACs have emerged as potential therapeutic targets to treat different forms of cancer. In this study we synthesized and investigated compounds built around a phorbazole scaffold to characterize their histone deacetylase inhibitor (HDACi) activity. Eighteen phorbazole analogues were tested against class I and II HDACs in cell lysate, seven showed moderate activity, of which, three had IC<sub>50</sub> values below 50 μM. The five best candidates were evaluated more extensively against HDAC1-11 (except for HDAC10). The best candidate, compound <strong>9</strong>, initially appeared to reduce the activity of HDAC9 and HDAC11 by more than 50 % at 10 μM concentration. The binding mode of compound <strong>9</strong> to HDACs was explored via computational docking, where two poses stood out. These were explored further by molecular dynamic simulation. We found that <strong>9</strong> likely binds HDAC9 with the pyrrole group buried in the active site and forming H-bonds with the backbone oxygen of one of the glycine residues lining the cavity. But neither of the poses explored offered convincing arguments to describe the mode of action of the phorbazole, especially when comparing <strong>9</strong> to other analogues tested in this study. Additional experiments found that <strong>9</strong> interfered with the cell lysate assays by inhibiting luciferase in a dose-dependent manner (IC<sub>50</sub> < 1 μM) and by exhibiting autofluorescence when tested on purified HDAC proteins, thereby confounding the obtained results during both the pan-HDAC screening and the single point HDAC inhibition assay. To address this, we employed fluorophores with excitation and emission wavelengths outside of the emission range of <strong>9</strong> and found that the HDAC inhibition potential of <strong>9</strong> was weaker than first observed. Finally, Compound <strong>9</strong> was found to be very soluble in water (418 μM) and membrane permeable (>48 % flux). This study highlights the need for rigorous validation of results. In our case, two orthogonal testing methods were not sufficient to catch all the confounding factors involved in measurement of HDAC inhibition, and a third approach was required to identify the actual inhibition of <strong>9</strong> against HDAC9 and 11.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118489"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145622400","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}
Pub Date : 2026-02-01Epub Date: 2025-11-20DOI: 10.1016/j.bmc.2025.118488
Kumar Rohit, Bibekananda Sarkar
The microtubules are known to possess inimitable characteristics termed ‘exquisite dynamic behavior,’ which allows cells to maintain their shape and assist in cellular division. This exquisite dynamicity is lost in the case of cancer, and considering their pivotal role, they are considered as central drug targets in cancer chemotherapy. To target them, microtubule-targeting agents (MTAs) are unique small molecules that inhibit one of the seven unique druggable pockets of microtubules, impacting their dynamicity and leading to cell cycle arrest and apoptosis. In the present work, we employ a drug repurposing strategy to identify plausible leads targeting the colchicine binding site (CBS) from a pool of 2787 FDA-approved drugs. CBS is a unique and flexible druggable pocket site in microtubules that has been targeted for both cancer and non-cancer diseases. Additionally, the inhibition of this site is reported to reverse drug resistance and exhibit synergistic anti-inflammatory and anti-angiogenic properties, further enhancing the anticancer effects. The cumulative analysis led to the identification of Tafenoquine, a well-known antimalarial FDA-approved molecule, as a potential tubulin-targeting agent with predicted binding to the colchicine site. The in-silico analysis was further corroborated using in vitro investigation on breast (MCF-7 and MDA-MB-231), lung (A549), and colon (HCT-116) cancer cells. Tafenoquine was found to exert broad-spectrum antiproliferative effects, with greatest potency against MDA-MB-231 cells (IC₅₀ = 4.75 ± 0.18 μM), a model for aggressive and treatment-resistant triple-negative breast cancer (TNBC). Considering the tubulin polymerization assay, the identified hit was found to inhibit microtubule assembly (low Vmax) in a manner similar to colchicine, and exhibited a similar G2/M arrest, indicating a mode of inhibition similar to that of colchicine.
{"title":"Repurposing the USFDA-approved small molecules for their affinity against the colchicine binding site (CBS) in the tubulin: Corroborating the in-silico findings through biological assessment","authors":"Kumar Rohit, Bibekananda Sarkar","doi":"10.1016/j.bmc.2025.118488","DOIUrl":"10.1016/j.bmc.2025.118488","url":null,"abstract":"<div><div>The microtubules are known to possess inimitable characteristics termed ‘exquisite dynamic behavior,’ which allows cells to maintain their shape and assist in cellular division. This exquisite dynamicity is lost in the case of cancer, and considering their pivotal role, they are considered as central drug targets in cancer chemotherapy. To target them, microtubule-targeting agents (MTAs) are unique small molecules that inhibit one of the seven unique druggable pockets of microtubules, impacting their dynamicity and leading to cell cycle arrest and apoptosis. In the present work, we employ a drug repurposing strategy to identify plausible leads targeting the colchicine binding site (CBS) from a pool of 2787 FDA-approved drugs. CBS is a unique and flexible druggable pocket site in microtubules that has been targeted for both cancer and non-cancer diseases. Additionally, the inhibition of this site is reported to reverse drug resistance and exhibit synergistic anti-inflammatory and anti-angiogenic properties, further enhancing the anticancer effects. The cumulative analysis led to the identification of Tafenoquine, a well-known antimalarial FDA-approved molecule, as a potential tubulin-targeting agent with predicted binding to the colchicine site. The in-silico analysis was further corroborated using in vitro investigation on breast (MCF-7 and MDA-MB-231), lung (A549), and colon (HCT-116) cancer cells. Tafenoquine was found to exert broad-spectrum antiproliferative effects, with greatest potency against MDA-MB-231 cells (IC₅₀ = 4.75 ± 0.18 μM), a model for aggressive and treatment-resistant triple-negative breast cancer (TNBC). Considering the tubulin polymerization assay, the identified hit was found to inhibit microtubule assembly (low Vmax) in a manner similar to colchicine, and exhibited a similar G2/M arrest, indicating a mode of inhibition similar to that of colchicine.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118488"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145675992","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}
Pub Date : 2026-02-01Epub Date: 2025-11-26DOI: 10.1016/j.bmc.2025.118500
Phoebe R. Rubio , Gavin A. Clausen , Zachary D. Ruighaver , Abigail F. Dalton, John P. Blobe, Amanda L. Moore, Christopher R. Shugrue
We report the development of a new benzothiazole sulfone (BTS) tool for peptide modification and cleavage. Benzothiazole sulfones are electrophiles that rapidly react with thiols in nucleophilic aromatic substitution (SNAr) reactions. Alkyne-containing BTS compounds were incorporated onto azidolysine-containing peptides through copper-catalyzed azide-alkyne cycloadditions (CuAACs). BTS-containing peptides were found to react rapidly with two equivalents of thiol nucleophiles at room temperature in 30 min or less. BTS-containing peptides were conjugated to a variety of different compounds, including small molecules, fluorophores, and peptides. Alternatively, a BTS-based cleavable linker could also be synthesized with small molecule cargo, such as biotin, and attached to peptides through CuAAC. This linker enabled the capture and release of a peptide with immobilized streptavidin. The BTS motif is a versatile tool for various applications in peptide science.
{"title":"Benzothiazole sulfones as a tool for peptide modification and cleavage","authors":"Phoebe R. Rubio , Gavin A. Clausen , Zachary D. Ruighaver , Abigail F. Dalton, John P. Blobe, Amanda L. Moore, Christopher R. Shugrue","doi":"10.1016/j.bmc.2025.118500","DOIUrl":"10.1016/j.bmc.2025.118500","url":null,"abstract":"<div><div>We report the development of a new benzothiazole sulfone (BTS) tool for peptide modification and cleavage. Benzothiazole sulfones are electrophiles that rapidly react with thiols in nucleophilic aromatic substitution (S<sub><em>N</em></sub>Ar) reactions. Alkyne-containing BTS compounds were incorporated onto azidolysine-containing peptides through copper-catalyzed azide-alkyne cycloadditions (CuAACs). BTS-containing peptides were found to react rapidly with two equivalents of thiol nucleophiles at room temperature in 30 min or less. BTS-containing peptides were conjugated to a variety of different compounds, including small molecules, fluorophores, and peptides. Alternatively, a BTS-based cleavable linker could also be synthesized with small molecule cargo, such as biotin, and attached to peptides through CuAAC. This linker enabled the capture and release of a peptide with immobilized streptavidin. The BTS motif is a versatile tool for various applications in peptide science.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118500"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145666512","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}
Mitochondrial dysfunction is not only a known cause of mitochondrial disease but has also been implicated in diabetes and neurodegenerative diseases. Therefore, modulating mitochondrial function may provide new insights into the treatment of these diseases. In this study, we used a cancer cell-based energy metabolism restriction model with a glycolytic inhibitor and screened a natural product library and a fungal extract library to identify natural products that improve mitochondrial function. Seven compounds, including quillaic acid (1) and 20-deoxyingenol (2), were identified as mitochondrial function modulators from the Selleck natural product library. Furthermore, an extract of a fungus, Trichoderma sp., from an in-house fungal extract library suppressed 2-deoxy-d-glucose-induced cell death. Bioassay-guided fractionation of the extract afforded seven known sorbicillinoids. Among them, bisvertinol (8) did not directly affect cellular energy metabolism but appeared to protect mitochondria from oxidative stress through its antioxidant properties.
{"title":"Natural products that suppress 2-deoxy-d-glucose-induced cell death as potential drug seeds for mitochondrial diseases","authors":"Koyo Honda , Yuki Hitora , Yusaku Sadahiro , Masahiro Wato , Yuriko Nagano , Sachiko Tsukamoto","doi":"10.1016/j.bmc.2025.118478","DOIUrl":"10.1016/j.bmc.2025.118478","url":null,"abstract":"<div><div>Mitochondrial dysfunction is not only a known cause of mitochondrial disease but has also been implicated in diabetes and neurodegenerative diseases. Therefore, modulating mitochondrial function may provide new insights into the treatment of these diseases. In this study, we used a cancer cell-based energy metabolism restriction model with a glycolytic inhibitor and screened a natural product library and a fungal extract library to identify natural products that improve mitochondrial function. Seven compounds, including quillaic acid (<strong>1</strong>) and 20-deoxyingenol (<strong>2</strong>), were identified as mitochondrial function modulators from the Selleck natural product library. Furthermore, an extract of a fungus, <em>Trichoderma</em> sp., from an in-house fungal extract library suppressed 2-deoxy-<span>d</span>-glucose-induced cell death. Bioassay-guided fractionation of the extract afforded seven known sorbicillinoids. Among them, bisvertinol (<strong>8</strong>) did not directly affect cellular energy metabolism but appeared to protect mitochondria from oxidative stress through its antioxidant properties.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118478"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145450276","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}
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