Pub Date : 2025-02-14DOI: 10.1016/j.bioorg.2025.108266
Qingyuan Yi , Chunxiao Pu , Xiao Tang , Min Liu , Xia Lin , Weisen Lan , Xinyu Zhang , Man Yang , Mian Wang , Jianyi Wang
In this work, a novel near-infrared fluorescent probe of benzopyranonitrile toward β-Gal was developed with high selectivity and low detection limits. DCM-Mor-Gal could effectively distinguish hepatocellular cells (HepG2) from SGC7901, HeLa, A549, and human normal liver cells (HL-7702) under the mediation of the galactose group, and effectively aggregate in the lysosomes under the acidity-alkalinity attraction, showing a notable dual-targeting potential of hepatocytes and lysosomes. The zebrafish experiments confirmed the utility of DCM-Mor-Gal in detecting β-Gal in vivo, which is expected to be an effective tool for the clinical detection of related diseases.
{"title":"A near-infrared fluorescent probe toward β-Gal with dual-targeting potential of hepatocytes and lysosomes: Design, synthesis, and evaluation","authors":"Qingyuan Yi , Chunxiao Pu , Xiao Tang , Min Liu , Xia Lin , Weisen Lan , Xinyu Zhang , Man Yang , Mian Wang , Jianyi Wang","doi":"10.1016/j.bioorg.2025.108266","DOIUrl":"10.1016/j.bioorg.2025.108266","url":null,"abstract":"<div><div>In this work, a novel near-infrared fluorescent probe of benzopyranonitrile toward β-Gal was developed with high selectivity and low detection limits. <strong>DCM-Mor-Gal</strong> could effectively distinguish hepatocellular cells (HepG2) from SGC7901, HeLa, A549, and human normal liver cells (HL-7702) under the mediation of the galactose group, and effectively aggregate in the lysosomes under the acidity-alkalinity attraction, showing a notable dual-targeting potential of hepatocytes and lysosomes. The zebrafish experiments confirmed the utility of <strong>DCM-Mor-Gal</strong> in detecting β-Gal in vivo, which is expected to be an effective tool for the clinical detection of related diseases.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108266"},"PeriodicalIF":4.5,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143445247","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}
The poor prognosis and inefficiency of the therapeutic agents in treating triple negative breast cancer (TNBC) have raised significant concerns, driving the quest for designing novel and potent chemotherapeutic compounds. In this regard, inducing programmed cell death (PCD) has emerged as a promising approach for breast cancer therapy. Accordingly, a series of hybrid molecules comprising hydrazone and oxamide moieties (5a-5q) were designed, synthesized, and assessed for their anticancer activity against various cancer cells. Among these synthesized hybrids, compound 5q was selected as the lead compound with remarkable ability to disrupt MDA-MB-231 cell growth, achieving an IC50-72h of 9.79 μM, while exhibiting lower toxicity in normal human cells. The in vitro experiments revealed that this compound triggers neither apoptosis nor autophagy in TNBC cells. Furthermore, the in vivo outcomes corroborated the in vitro results, showing a significant delay in tumor growth at a dose of 1 mg/kg/day following three weeks of treatment in the 4T1 mouse model of TNBC. The findings of this study suggested that compound 5q acts through necroptosis by overexpression of P-RIPK3 and phosphorylation of its downstream effector, MLKL. Compound 5q holds promise as a potential candidate for the development of anti-TNBC drugs.
{"title":"Discovery of a new hydrazone-oxamide hybrid capable of inducing necroptotic cell death in triple negative breast cancer cells","authors":"Romina Akhavan , Sanaz Jabari Harsini , Samira Shafiee , Mahya Eftekhari , Raheleh Tahmasvand , Fereshteh Taghipour , Zahra Kooshafar , Hiva Mohammadmirzaeizarandi , Misha Salimi , Ali Almasirad , Mona Salimi","doi":"10.1016/j.bioorg.2025.108267","DOIUrl":"10.1016/j.bioorg.2025.108267","url":null,"abstract":"<div><div>The poor prognosis and inefficiency of the therapeutic agents in treating triple negative breast cancer (TNBC) have raised significant concerns, driving the quest for designing novel and potent chemotherapeutic compounds. In this regard, inducing programmed cell death (PCD) has emerged as a promising approach for breast cancer therapy. Accordingly, a series of hybrid molecules comprising hydrazone and oxamide moieties (<strong>5a-5q</strong>) were designed, synthesized, and assessed for their anticancer activity against various cancer cells. Among these synthesized hybrids, compound <strong>5q</strong> was selected as the lead compound with remarkable ability to disrupt MDA-MB-231 cell growth, achieving an IC<sub>50-72h</sub> of 9.79 μM, while exhibiting lower toxicity in normal human cells. The <em>in vitro</em> experiments revealed that this compound triggers neither apoptosis nor autophagy in TNBC cells. Furthermore, the <em>in vivo</em> outcomes corroborated the <em>in vitro</em> results, showing a significant delay in tumor growth at a dose of 1 mg/kg/day following three weeks of treatment in the 4T1 mouse model of TNBC. The findings of this study suggested that compound <strong>5q</strong> acts through necroptosis by overexpression of P-RIPK3 and phosphorylation of its downstream effector, MLKL. Compound <strong>5q</strong> holds promise as a potential candidate for the development of anti-TNBC drugs.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108267"},"PeriodicalIF":4.5,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143453213","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}
Diabetes mellitus is characterized by the progressive loss of pancreatic β-cells. Owing to the adverse side effects of conventional antidiabetic, ethnopharmacological agents have emerged as adjunct therapies for their management. The present study aims to validate the antidiabetic activity of an aqueous polyherbal extract (APE) via in silico, in vitro, and in vivo models.
UHPLC–Q-TOF-MS and HPLC analysis of APE were performed to identify bioactive secondary plant metabolites. In silico approaches implemented to predict the binding efficacy of the active phytoconstituents. Biochemical estimation, antioxidant activity, and in vitro and in vivo antidiabetic activities of APE were performed. Histomorphological and immunohistological studies of the pancreatic islets were carried out in diabetic animals for microarchitectural study.
UHPLC-Q-TOF-MS identified a total of 60 compounds in APE, of which 39 were reported to have antidiabetic activity, and 16 marker compounds were identified via high-performance liquid chromatography (HPLC). An in silico study revealed a strong interaction of verbacoside B with the target proteins. APE is characterized by high flavonoid and phenolic contents with strong antioxidant properties. In an in vitro enzymatic assay, APE significantly inhibited α-amylase and α-glucosidase enzymes, with calculated IC50 values of 54.26 ± 0.14 and 26.47 ± 0.12 μg/ml, respectively. An in vitro glucose uptake assay revealed increased uptake with APE treatment in a dose-dependent manner. APE significantly decreased blood glucose and HbA1c levels and had no side effects on liver or kidney function, as measured from blood parameters. Immunohistological observation revealed 47% regeneration of pancreatic β-cells with APE treatment in diabetic animals.
{"title":"Elucidating the therapeutic efficacy of polyherbal formulation for the management of diabetes through endogenous pancreatic β-cell regeneration","authors":"Abhijit Sahu , Pravash Ranjan Mishra , Pratyush Pragyandipta , Srichandan Rath , Ashirbad Nanda , Satish Kanhar , Dibya Ranjan Sahoo , Eeshara Naik , Deepali Naik , Pradeep K. Naik","doi":"10.1016/j.bioorg.2025.108270","DOIUrl":"10.1016/j.bioorg.2025.108270","url":null,"abstract":"<div><div>Diabetes mellitus is characterized by the progressive loss of pancreatic β-cells. Owing to the adverse side effects of conventional antidiabetic, ethnopharmacological agents have emerged as adjunct therapies for their management. The present study aims to validate the antidiabetic activity of an aqueous polyherbal extract (APE) via <em>in silico</em>, <em>in vitro</em>, and <em>in vivo</em> models.</div><div>UHPLC–Q-TOF-MS and HPLC analysis of APE were performed to identify bioactive secondary plant metabolites. <em>In silico</em> approaches implemented to predict the binding efficacy of the active phytoconstituents. Biochemical estimation, antioxidant activity, and <em>in vitro</em> and <em>in vivo</em> antidiabetic activities of APE were performed. Histomorphological and immunohistological studies of the pancreatic islets were carried out in diabetic animals for microarchitectural study.</div><div>UHPLC-Q-TOF-MS identified a total of 60 compounds in APE, of which 39 were reported to have antidiabetic activity, and 16 marker compounds were identified via high-performance liquid chromatography (HPLC). An <em>in silico</em> study revealed a strong interaction of verbacoside B with the target proteins. APE is characterized by high flavonoid and phenolic contents with strong antioxidant properties. In <em>an</em> in vitro enzymatic assay, APE significantly inhibited α-amylase and α-glucosidase enzymes, with calculated IC<sub>50</sub> values of 54.26 ± 0.14 and 26.47 ± 0.12 μg/ml, respectively. An <em>in vitro</em> glucose uptake assay revealed increased uptake with APE treatment in a dose-dependent manner. APE significantly decreased blood glucose and HbA1c levels and had no side effects on liver or kidney function, as measured from blood parameters. Immunohistological observation revealed 47% regeneration of pancreatic β-cells with APE treatment in diabetic animals.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108270"},"PeriodicalIF":4.5,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143437045","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 : 2025-02-14DOI: 10.1016/j.bioorg.2025.108281
Xiaoquan Xu , Xuemei Tang , Wenmin Wu , Min Liu , Junqing Zeng
Nasopharyngeal carcinoma (NPC) is a prevalent malignant epithelial tumor and epidemic in East and Southeast Asia. The pathology of NPC was characterized by local infiltration early, regional nodal involvement and distant metastases. The specialty of pathological sites makes it hard to early diagnosis, which relies on multiple imaging techniques (MRI, CT scans, and endoscopy) and biopsy. Precise staging of NPC and targeted therapies are vital to the therapeutic efficacy and prognosis. Noninvasive and high-resolution imaging techniques are urgently needed for NPC. Radiopharmaceuticals and imaging equipment (single-photon emission computed tomography (SPECT) and positron emission tomography (PET)) are rapidly developed and applied in the diagnosis of NPC. In this review, we summarized the radiopharmaceuticals in NPC. Reviewing the radiopharmaceuticals in NPC would greatly help further optimize the radioligands and discover novel targets.
{"title":"Radiopharmaceuticals in Nasopharyngeal Cancer","authors":"Xiaoquan Xu , Xuemei Tang , Wenmin Wu , Min Liu , Junqing Zeng","doi":"10.1016/j.bioorg.2025.108281","DOIUrl":"10.1016/j.bioorg.2025.108281","url":null,"abstract":"<div><div>Nasopharyngeal carcinoma (NPC) is a prevalent malignant epithelial tumor and epidemic in East and Southeast Asia. The pathology of NPC was characterized by local infiltration early, regional nodal involvement and distant metastases. The specialty of pathological sites makes it hard to early diagnosis, which relies on multiple imaging techniques (MRI, CT scans, and endoscopy) and biopsy. Precise staging of NPC and targeted therapies are vital to the therapeutic efficacy and prognosis. Noninvasive and high-resolution imaging techniques are urgently needed for NPC. Radiopharmaceuticals and imaging equipment (single-photon emission computed tomography (SPECT) and positron emission tomography (PET)) are rapidly developed and applied in the diagnosis of NPC. In this review, we summarized the radiopharmaceuticals in NPC. Reviewing the radiopharmaceuticals in NPC would greatly help further optimize the radioligands and discover novel targets.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108281"},"PeriodicalIF":4.5,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143509025","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 : 2025-02-13DOI: 10.1016/j.bioorg.2025.108274
Miguel V. Rodrigues , António Ferreira , Maria Ramirez-Montoya , Rita A. Oliveira , Raphaël Defaix , Peter Kis , Vitor Cabral , M. Rosário Bronze , Karina B. Xavier , M. Rita Ventura
Quorum Sensing is a signalling mechanism used by bacteria to regulate gene expression as a function of population density, enabling them to engage in group behaviours. Autoinducer-2 (AI-2) is the most ubiquitously produced quorum sensing signal among bacterial species and it is unique in its capability of fostering cell-cell signalling across species from different phyla in multispecies communities. Alterations of AI-2 levels in the mouse gut can change the composition of the major gut microbiota phyla, but given the chemical instability of this signal, its quantification in intestinal samples and in vivo manipulation are challenging. Here, we optimised a Gas Chromatography – Mass Spectrometry (GC–MS) method to detect and quantify AI-2 in intestinal samples. Using a newly synthesised deuterated AI-2 molecule as the internal standard for AI-2 quantification, we quantified the levels of AI-2 in the cecum of conventionally raised mice with a complex microbiota. Moreover, we used a commensal Klebsiella sp. with probiotic potential to manipulate AI-2 levels in the mouse gut. We showed that mice colonised with mutants of this commensal Klebsiella sp. can be used to manipulate the levels of AI-2 in the mouse gut in both mono-colonised animals and those with a complex microbiota following recovery from antibiotic treatment. Overall, our results show that the analytical approach proposed here allows for robust and specific direct measurements of AI-2 in mouse caecal samples and can also be applied to other complex biological samples containing AI-2 aiming to study the role of quorum sensing signalling in microbiota communities.
{"title":"Manipulation and quantification of the levels of Autoinducer-2 quorum sensing signal in the mouse gut","authors":"Miguel V. Rodrigues , António Ferreira , Maria Ramirez-Montoya , Rita A. Oliveira , Raphaël Defaix , Peter Kis , Vitor Cabral , M. Rosário Bronze , Karina B. Xavier , M. Rita Ventura","doi":"10.1016/j.bioorg.2025.108274","DOIUrl":"10.1016/j.bioorg.2025.108274","url":null,"abstract":"<div><div>Quorum Sensing is a signalling mechanism used by bacteria to regulate gene expression as a function of population density, enabling them to engage in group behaviours. Autoinducer-2 (AI-2) is the most ubiquitously produced quorum sensing signal among bacterial species and it is unique in its capability of fostering cell-cell signalling across species from different phyla in multispecies communities. Alterations of AI-2 levels in the mouse gut can change the composition of the major gut microbiota phyla, but given the chemical instability of this signal, its quantification in intestinal samples and in vivo manipulation are challenging. Here, we optimised a Gas Chromatography – Mass Spectrometry (GC–MS) method to detect and quantify AI-2 in intestinal samples. Using a newly synthesised deuterated AI-2 molecule as the internal standard for AI-2 quantification, we quantified the levels of AI-2 in the cecum of conventionally raised mice with a complex microbiota. Moreover, we used a commensal <em>Klebsiella</em> sp. with probiotic potential to manipulate AI-2 levels in the mouse gut. We showed that mice colonised with mutants of this commensal <em>Klebsiella</em> sp. can be used to manipulate the levels of AI-2 in the mouse gut in both mono-colonised animals and those with a complex microbiota following recovery from antibiotic treatment. Overall, our results show that the analytical approach proposed here allows for robust and specific direct measurements of AI-2 in mouse caecal samples and can also be applied to other complex biological samples containing AI-2 aiming to study the role of quorum sensing signalling in microbiota communities.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108274"},"PeriodicalIF":4.5,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143453217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-13DOI: 10.1016/j.bioorg.2025.108276
Jun Wu , Yun Han , Ruixin Liu , Wenqing Yang , Zhengwei Gu , Zhixin Tang
The early stage of atherosclerosis (AS) is characterized by explosion of reactive oxygen species (ROS) in mitochondria and inflammatory reaction, and then abundant ROS further promote the progress of AS. As an endogenous signal biomolecule with antioxidant properties, carbon monoxide (CO) is enriched in mitochondria to combat oxidative stress, thereby significantly increasing during the pathogenesis of AS. However, there is currently no mitochondria-targeted near-infrared fluorescence probe for detecting CO in atherosclerosis. In this paper, we use a mitochondrion-targeting metal-free near-infrared fluorescence probe, AS-CO, for investigating AS via detecting and mapping the fluctuations of CO with enhanced sensitivity and selectivity. In addition, probe AS-CO can be positioned at mitochondria. It has also proven effective in detecting both internally and externally sourced CO in HUVEC cells. More importantly, using AS-CO, for the first time, we provided the visualization evidence of endogenous CO generation in the aorta of mice that induced AS by high-fat diet (HFD) and further investigated the protective effects of (−)-epicatechin gallate (ECG) against HFD-induced AS. The results demonstrated the feasibility of AS-CO for monitoring and evaluating personalized treatment of AS.
{"title":"A novel mitochondria-targeted near-infrared metal-free fluorescence probe for detecting carbon monoxide in atherosclerosis","authors":"Jun Wu , Yun Han , Ruixin Liu , Wenqing Yang , Zhengwei Gu , Zhixin Tang","doi":"10.1016/j.bioorg.2025.108276","DOIUrl":"10.1016/j.bioorg.2025.108276","url":null,"abstract":"<div><div>The early stage of atherosclerosis (AS) is characterized by explosion of reactive oxygen species (ROS) in mitochondria and inflammatory reaction, and then abundant ROS further promote the progress of AS. As an endogenous signal biomolecule with antioxidant properties, carbon monoxide (CO) is enriched in mitochondria to combat oxidative stress, thereby significantly increasing during the pathogenesis of AS. However, there is currently no mitochondria-targeted near-infrared fluorescence probe for detecting CO in atherosclerosis. In this paper, we use a mitochondrion-targeting metal-free near-infrared fluorescence probe, <strong>AS-CO</strong>, for investigating AS <em>via</em> detecting and mapping the fluctuations of CO with enhanced sensitivity and selectivity. In addition, probe <strong>AS-CO</strong> can be positioned at mitochondria. It has also proven effective in detecting both internally and externally sourced CO in HUVEC cells. More importantly, using <strong>AS-CO</strong>, for the first time, we provided the visualization evidence of endogenous CO generation in the aorta of mice that induced AS by high-fat diet (HFD) and further investigated the protective effects of (−)-epicatechin gallate (ECG) against HFD-induced AS. The results demonstrated the feasibility of <strong>AS-CO</strong> for monitoring and evaluating personalized treatment of AS.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108276"},"PeriodicalIF":4.5,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143437043","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 : 2025-02-13DOI: 10.1016/j.bioorg.2025.108279
Muhammad Waleed Iqbal , Syed Zeeshan Haider , Muhammad Zohaib Nawaz , Muhammad Irfan , Khalid A. Al-Ghanim , Xinxiao Sun , Qipeng Yuan
Overexpression of the antioxidant enzyme glutathione peroxidase-1 (GPx1) is associated with different cancer types. Inhibitors of GPx1, including mercaptosuccinic acid and pentathiepins derivatives, have been proposed previously and investigated as potent drugs to combat cancer. However, these compounds often lack specificity and demonstrate off-target effects, which necessitates the need for more targeted, non-toxic, and effective GPx1 inhibitors. This study utilized molecular docking and dynamic simulations based computational pipeline to repurpose drugs, approved by The Food and Drug Administration [1], as potent GPx1 inhibitors from a library containing 1615 synthetic compounds. The drug suitability and stability of the selected compounds were further investigated using ADMET, bioactivity probability, Molecular Mechanics-Generalized Born Surface Area (MM-GBSA), and Molecular Mechanics-Poisson-Boltzmann Surface Area (MM-PBSA) analyses. Initially, 13 compounds were virtually screened based on the Triangle Matcher algorithm, docking modules, and GBVI/WSA dG scoring function. Of these 13 screened compounds, three compounds, including dronedarone, nilotinib, and thonzonium, were rigorously selected based on their ADMET profiles, physicochemical properties, drug suitability, and stability and were subjected to Molecular Dynamic (MD) simulations. MD simulations further validated the stability of the dronedarone, nilotinib, and thonzonium complexes with GPx1 and provided further insights into the mechanism of their interaction. The in-silico approaches used herein revealed thonzonium, dronedarone, and nilotinib as potent GPx1 inhibitors.
{"title":"Molecular simulations guided drugs repurposing to inhibit human GPx1 enzyme for cancer therapy","authors":"Muhammad Waleed Iqbal , Syed Zeeshan Haider , Muhammad Zohaib Nawaz , Muhammad Irfan , Khalid A. Al-Ghanim , Xinxiao Sun , Qipeng Yuan","doi":"10.1016/j.bioorg.2025.108279","DOIUrl":"10.1016/j.bioorg.2025.108279","url":null,"abstract":"<div><div>Overexpression of the antioxidant enzyme glutathione peroxidase-1 (<em>GPx1</em>) is associated with different cancer types. Inhibitors of <em>GPx1,</em> including mercaptosuccinic acid and pentathiepins derivatives, have been proposed previously and investigated as potent drugs to combat cancer. However, these compounds often lack specificity and demonstrate off-target effects, which necessitates the need for more targeted, non-toxic, and effective <em>GPx1</em> inhibitors. This study utilized molecular docking and dynamic simulations based computational pipeline to repurpose drugs, approved by The Food and Drug Administration [<span><span>1</span></span>], as potent <em>GPx1</em> inhibitors from a library containing 1615 synthetic compounds. The drug suitability and stability of the selected compounds were further investigated using ADMET, bioactivity probability, Molecular Mechanics-Generalized Born Surface Area (MM-GBSA), and Molecular Mechanics-Poisson-Boltzmann Surface Area (MM-PBSA) analyses. Initially, 13 compounds were virtually screened based on the Triangle Matcher algorithm, docking modules, and GBVI/WSA dG scoring function. Of these 13 screened compounds, three compounds, including dronedarone, nilotinib, and thonzonium, were rigorously selected based on their ADMET profiles, physicochemical properties, drug suitability, and stability and were subjected to Molecular Dynamic (MD) simulations. MD simulations further validated the stability of the dronedarone, nilotinib, and thonzonium complexes with <em>GPx1</em> and provided further insights into the mechanism of their interaction. The <em>in-silico</em> approaches used herein revealed thonzonium, dronedarone, and nilotinib as potent <em>GPx1</em> inhibitors.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108279"},"PeriodicalIF":4.5,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143445246","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 : 2025-02-12DOI: 10.1016/j.bioorg.2025.108243
İrfan Çapan , Mohammed Hawash , Mohammed T. Qaoud , Nidal Jaradat
Diabetes mellitus remains a global health challenge, demanding innovative therapeutic solutions. Herein, we present the design, synthesis, and pharmacological evaluation of a novel series of carbazole-thiadiazole hybrids targeting key enzymes in carbohydrate metabolism. Among the synthesized compounds, 5l emerged as the most potent inhibitor of α-amylase, with an IC50 value of 0.68 µM—far surpassing the efficacy of the standard drug acarbose (IC50: 5.19 µM). Similarly, 5r exhibited exceptional dual activity against both α-amylase and α-glucosidase, with IC50 values of 1.63 µM and 0.14 µM, respectively, highlighting its dual inhibitory potential. Biological assays demonstrated the compounds’ low cytotoxicity on hepatic stellate (LX-2) cells, affirming their safety for therapeutic use. Molecular docking studies provided mechanistic insights into their binding interactions, revealing strong hydrogen bonding and hydrophobic interactions with key active site residues. Density functional theory (DFT) and electrostatic potential (ESP) analyses further elucidated their electronic properties, offering a deeper understanding of their structure–activity relationships. Pharmacokinetic profiling via the BOILED-Egg model confirmed these derivatives’ excellent oral bioavailability and drug-likeness. Collectively, these findings establish carbazole-thiadiazole hybrids as promising candidates for next-generation antidiabetic therapies, warranting further investigation in preclinical and clinical settings.
{"title":"Novel carbazole-thiadiazole derivatives as α-amylase and α-glucosidase inhibitors: Design, biological evaluation, and computational insights","authors":"İrfan Çapan , Mohammed Hawash , Mohammed T. Qaoud , Nidal Jaradat","doi":"10.1016/j.bioorg.2025.108243","DOIUrl":"10.1016/j.bioorg.2025.108243","url":null,"abstract":"<div><div>Diabetes mellitus remains a global health challenge, demanding innovative therapeutic solutions. Herein, we present the design, synthesis, and pharmacological evaluation of a novel series of carbazole-thiadiazole hybrids targeting key enzymes in carbohydrate metabolism. Among the synthesized compounds, <strong>5l</strong> emerged as the most potent inhibitor of α-amylase, with an IC<sub>50</sub> value of 0.68 µM—far surpassing the efficacy of the standard drug acarbose (IC<sub>50</sub>: 5.19 µM). Similarly, <strong>5r</strong> exhibited exceptional dual activity against both α-amylase and α-glucosidase, with IC<sub>50</sub> values of 1.63 µM and 0.14 µM, respectively, highlighting its dual inhibitory potential. Biological assays demonstrated the compounds’ low cytotoxicity on hepatic stellate (LX-2) cells, affirming their safety for therapeutic use. Molecular docking studies provided mechanistic insights into their binding interactions, revealing strong hydrogen bonding and hydrophobic interactions with key active site residues. Density functional theory (DFT) and electrostatic potential (ESP) analyses further elucidated their electronic properties, offering a deeper understanding of their structure–activity relationships. Pharmacokinetic profiling via the BOILED-Egg model confirmed these derivatives’ excellent oral bioavailability and drug-likeness. Collectively, these findings establish carbazole-thiadiazole hybrids as promising candidates for next-generation antidiabetic therapies, warranting further investigation in preclinical and clinical settings.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108243"},"PeriodicalIF":4.5,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143420080","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 : 2025-02-10DOI: 10.1016/j.bioorg.2025.108265
Iveta Zůvalová , Barbora Vyhlídalová , Karolína Ondrová , Petr Nádvorník , Jiří Hrubý , Peter Illés , Miroslav Soural , Marek Šebela , Lenka Šindlerová , Lukáš Kubala , Sridhar Mani , Zdeněk Dvořák
Monocyclic monoterpenoids carvones have been recently identified as atypical negative allosteric modulators of aryl hydrocarbon receptor (AhR). In the current work, we performed AhR antagonist activity screening of 100 natural and synthetic monoterpenoids, and their analogues. Using SAR approach, structural determinants of AhR antagonist activity were assigned, including CO presence/position, planarity, and C3/C5-alkylation. Applying pyramidal selection criteria, including absence of residual agonist activity, no cytotoxicity, strong antagonist potency, and pan-antagonism against diverse AhR agonists, we distilled four lead AhR antagonists (carvacrol, o-cresol, 3-methyl-S-carvone, EN-2). Whereas 3-methyl-S-carvone and EN-2 were non-competitive AhR pan-antagonists, carvacrol and o-cresol were ligand-selective AhR antagonists acting by unclear mechanism. We characterized in detail the effects of lead compounds at cellular functions of AhR, including AhR nuclear translocation, AhR dimerization with ARNT, and the expression of AhR-regulated genes. As a proof of concept, effects of monoterpenoids in the murine macrophages were investigated.
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