Aliakbar Khalili Yazdi, Sumera Perveen, Cheng Dong, Xiaosheng Song, Aiping Dong, Magdalena M. Szewczyk, Matthew F. Calabrese, Agustin Casimiro-Garcia, Subramanyam Chakrapani, Matthew S. Dowling, Emel Ficici, Jisun Lee, Justin I. Montgomery, Thomas N. O'Connell, Grzegorz J. Skrzypek, Tuan P. Tran, Matthew D. Troutman, Feng Wang, Jennifer A. Young, Jinrong Min, Dalia Barsyte-Lovejoy, Peter J. Brown, Vijayaratnam Santhakumar, Cheryl H. Arrowsmith, Masoud Vedadi and Dafydd R. Owen
We have developed a novel chemical handle (PFI-E3H1) and a chemical probe (PFI-7) as ligands for the Gid4 subunit of the human E3 ligase CTLH degradation complex. Through an efficient initial hit-ID campaign, structure-based drug design (SBDD) and leveraging the sizeable Pfizer compound library, we identified a 500 nM ligand for this E3 ligase through file screening alone. Further exploration identified a vector that is tolerant to addition of a linker for future chimeric molecule design. The chemotype was subsequently optimized to sub-100 nM Gid4 binding affinity for a chemical probe. These novel tools, alongside the suitable negative control also identified, should enable the interrogation of this complex human E3 ligase macromolecular assembly.
{"title":"Chemical tools for the Gid4 subunit of the human E3 ligase C-terminal to LisH (CTLH) degradation complex†","authors":"Aliakbar Khalili Yazdi, Sumera Perveen, Cheng Dong, Xiaosheng Song, Aiping Dong, Magdalena M. Szewczyk, Matthew F. Calabrese, Agustin Casimiro-Garcia, Subramanyam Chakrapani, Matthew S. Dowling, Emel Ficici, Jisun Lee, Justin I. Montgomery, Thomas N. O'Connell, Grzegorz J. Skrzypek, Tuan P. Tran, Matthew D. Troutman, Feng Wang, Jennifer A. Young, Jinrong Min, Dalia Barsyte-Lovejoy, Peter J. Brown, Vijayaratnam Santhakumar, Cheryl H. Arrowsmith, Masoud Vedadi and Dafydd R. Owen","doi":"10.1039/D3MD00633F","DOIUrl":"10.1039/D3MD00633F","url":null,"abstract":"<p >We have developed a novel chemical handle (PFI-E3H1) and a chemical probe (PFI-7) as ligands for the Gid4 subunit of the human E3 ligase CTLH degradation complex. Through an efficient initial hit-ID campaign, structure-based drug design (SBDD) and leveraging the sizeable Pfizer compound library, we identified a 500 nM ligand for this E3 ligase through file screening alone. Further exploration identified a vector that is tolerant to addition of a linker for future chimeric molecule design. The chemotype was subsequently optimized to sub-100 nM Gid4 binding affinity for a chemical probe. These novel tools, alongside the suitable negative control also identified, should enable the interrogation of this complex human E3 ligase macromolecular assembly.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":null,"pages":null},"PeriodicalIF":3.597,"publicationDate":"2024-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140034918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jindan Xu, Yuanfang Kong, Pengbo Zhu, Mingyan Du, Xuan Liang, Yan Tong, Xiaofei Li and Chunhong Dong
PD-L1 is a transmembrane protein overexpressed by tumor cells. It binds to PD-1 on the surface of T-cells, suppresses T-cell activity and hinders the immune response against cancer. Clinically, several monoclonal antibodies targeting PD-1/PD-L1 have achieved significant success in cancer immunotherapy. Nevertheless, their disadvantages, such as unchecked immune responses, high cost and long half-life, stimulated pharmacologists to develop small-molecule inhibitors targeting PD-1/PD-L1. After a batch of excellent inhibitors with a biphenyl core structure were firstly reported by BMS, more and more researchers focused on small-molecule inhibitors targeting PD-L1 rather than PD-1. Numerous small-molecule inhibitors were extensively designed and synthesized in the past few years. In this paper, the structural characteristics of PD-L1 and complexes of PD-L1 with its inhibitors are elaborated and small molecule inhibitors developed in the last decade are summarized as well. This paper aims to provide insights into further designing and synthesis of small molecule inhibitors targeting PD-L1.
{"title":"Progress in small-molecule inhibitors targeting PD-L1","authors":"Jindan Xu, Yuanfang Kong, Pengbo Zhu, Mingyan Du, Xuan Liang, Yan Tong, Xiaofei Li and Chunhong Dong","doi":"10.1039/D3MD00655G","DOIUrl":"10.1039/D3MD00655G","url":null,"abstract":"<p >PD-L1 is a transmembrane protein overexpressed by tumor cells. It binds to PD-1 on the surface of T-cells, suppresses T-cell activity and hinders the immune response against cancer. Clinically, several monoclonal antibodies targeting PD-1/PD-L1 have achieved significant success in cancer immunotherapy. Nevertheless, their disadvantages, such as unchecked immune responses, high cost and long half-life, stimulated pharmacologists to develop small-molecule inhibitors targeting PD-1/PD-L1. After a batch of excellent inhibitors with a biphenyl core structure were firstly reported by BMS, more and more researchers focused on small-molecule inhibitors targeting PD-L1 rather than PD-1. Numerous small-molecule inhibitors were extensively designed and synthesized in the past few years. In this paper, the structural characteristics of PD-L1 and complexes of PD-L1 with its inhibitors are elaborated and small molecule inhibitors developed in the last decade are summarized as well. This paper aims to provide insights into further designing and synthesis of small molecule inhibitors targeting PD-L1.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":null,"pages":null},"PeriodicalIF":3.597,"publicationDate":"2024-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140154489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jason Muller, Luca Marchisio, Rym Attia, Andy Zedet, Robin Maradan, Maxence Vallet, Alison Aebischer, Dominique Harakat, François Senejoux, Christophe Ramseyer, Sarah Foley, Bruno Cardey, Corine Girard and Marc Pudlo
Arginase, a difficult-to-target metalloenzyme, is implicated in a wide range of diseases, including cancer, infectious, and cardiovascular diseases. Despite the medical need, existing inhibitors have limited structural diversity, consisting predominantly of amino acids and their derivatives. The search for innovative arginase inhibitors has now extended to screening approaches. Due to the small and narrow active site of arginase, screening must meet the criteria of fragment-based screening. However, the limited binding capacity of fragments requires working at high concentrations, which increases the risk of interference and false positives. In this study, we investigated three colorimetric assays and selected one based on interference for screening under these challenging conditions. The subsequent adaptation and application to the screening a library of metal chelator fragments resulted in the identification of four compounds with moderate activity. The synthesis and evaluation of a series of compounds from one of the hits led to compound 21a with an IC50 value of 91.1 μM close to the reference compound piceatannol. Finally, molecular modelling supports the potential binding of aurones and chalcones to the active site of arginase, suggesting them as new candidates for the development of novel arginase inhibitors.
{"title":"A colorimetric assay adapted to fragment screening revealing aurones and chalcones as new arginase inhibitors†","authors":"Jason Muller, Luca Marchisio, Rym Attia, Andy Zedet, Robin Maradan, Maxence Vallet, Alison Aebischer, Dominique Harakat, François Senejoux, Christophe Ramseyer, Sarah Foley, Bruno Cardey, Corine Girard and Marc Pudlo","doi":"10.1039/D3MD00713H","DOIUrl":"10.1039/D3MD00713H","url":null,"abstract":"<p >Arginase, a difficult-to-target metalloenzyme, is implicated in a wide range of diseases, including cancer, infectious, and cardiovascular diseases. Despite the medical need, existing inhibitors have limited structural diversity, consisting predominantly of amino acids and their derivatives. The search for innovative arginase inhibitors has now extended to screening approaches. Due to the small and narrow active site of arginase, screening must meet the criteria of fragment-based screening. However, the limited binding capacity of fragments requires working at high concentrations, which increases the risk of interference and false positives. In this study, we investigated three colorimetric assays and selected one based on interference for screening under these challenging conditions. The subsequent adaptation and application to the screening a library of metal chelator fragments resulted in the identification of four compounds with moderate activity. The synthesis and evaluation of a series of compounds from one of the hits led to compound <strong>21a</strong> with an IC<small><sub>50</sub></small> value of 91.1 μM close to the reference compound piceatannol. Finally, molecular modelling supports the potential binding of aurones and chalcones to the active site of arginase, suggesting them as new candidates for the development of novel arginase inhibitors.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":null,"pages":null},"PeriodicalIF":3.597,"publicationDate":"2024-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140589215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Joana R. L. Ribeiro, Nikoletta Szemerédi, Bruno M. F. Gonçalves, Gabriella Spengler, Carlos A. M. Afonso and Maria-José U. Ferreira
Multidrug resistance (MDR) remains a challenging issue in cancer treatment. Aiming at finding anticancer agents to overcome MDR, the triacetyl derivative (2) of the labdane diterpenoid lactone andrographolide (1) underwent the Michael-type addition reaction followed by elimination, yielding twenty-three new derivatives, bearing nitrogen-containing substituents (3–25). Their structures were assigned, mainly, by 1D and 2D NMR experiments. The MDR reversal potential of compounds 1–25 was assessed, by functional and chemosensitivity assays, using resistant human ABCB1-gene transfected L5178Y mouse lymphoma cells as a model. Several derivatives exhibited remarkable P-glycoprotein (P-gp) inhibitory ability. Compounds 13 and 20, bearing thiosemicarbazide moieties, were the most active exhibiting a strong MDR reversal effect at 2 μM. Some compounds showed selectivity towards the resistant cells, with compound 5 exhibiting a collateral sensitivity effect associated with significant antiproliferative activity (IC50 = 5.47 ± 0.22 μM). Moreover, all selected compounds displayed synergistic interaction with doxorubicin, with compound 3 being the most active. In the ATPase assay, selected compounds exhibited characteristics of P-gp inhibitors.
{"title":"Nitrogen-containing andrographolide derivatives with multidrug resistance reversal effects in cancer cells†","authors":"Joana R. L. Ribeiro, Nikoletta Szemerédi, Bruno M. F. Gonçalves, Gabriella Spengler, Carlos A. M. Afonso and Maria-José U. Ferreira","doi":"10.1039/D3MD00711A","DOIUrl":"10.1039/D3MD00711A","url":null,"abstract":"<p >Multidrug resistance (MDR) remains a challenging issue in cancer treatment. Aiming at finding anticancer agents to overcome MDR, the triacetyl derivative (<strong>2</strong>) of the labdane diterpenoid lactone andrographolide (<strong>1</strong>) underwent the Michael-type addition reaction followed by elimination, yielding twenty-three new derivatives, bearing nitrogen-containing substituents (<strong>3–25</strong>). Their structures were assigned, mainly, by 1D and 2D NMR experiments. The MDR reversal potential of compounds <strong>1–25</strong> was assessed, by functional and chemosensitivity assays, using resistant human <em>ABCB1</em>-gene transfected L5178Y mouse lymphoma cells as a model. Several derivatives exhibited remarkable P-glycoprotein (P-gp) inhibitory ability. Compounds <strong>13</strong> and <strong>20</strong>, bearing thiosemicarbazide moieties, were the most active exhibiting a strong MDR reversal effect at 2 μM. Some compounds showed selectivity towards the resistant cells, with compound <strong>5</strong> exhibiting a collateral sensitivity effect associated with significant antiproliferative activity (IC<small><sub>50</sub></small> = 5.47 ± 0.22 μM). Moreover, all selected compounds displayed synergistic interaction with doxorubicin, with compound <strong>3</strong> being the most active. In the ATPase assay, selected compounds exhibited characteristics of P-gp inhibitors.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":null,"pages":null},"PeriodicalIF":3.597,"publicationDate":"2024-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d3md00711a?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140154514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marthe Vandevelde, Andreas Simoens, Bavo Vandekerckhove and Christian Stevens
Psilocybin analogues have been synthesized comprising a non-hydrolysable P–C bond to evaluate the biological activity and the selectivity towards 5-HT2AR, 5-HT2BR and the TNAP receptor. No activity was observed towards the phosphatase, however all compounds showed good binding affinity for 5-HT2AR and 5-HT2BR and one compound showed a higher selectivity towards 5-HT2AR than psilocin.
{"title":"Synthesis and bioactivity of psilocybin analogues containing a stable carbon–phosphorus bond†","authors":"Marthe Vandevelde, Andreas Simoens, Bavo Vandekerckhove and Christian Stevens","doi":"10.1039/D4MD00043A","DOIUrl":"10.1039/D4MD00043A","url":null,"abstract":"<p >Psilocybin analogues have been synthesized comprising a non-hydrolysable P–C bond to evaluate the biological activity and the selectivity towards 5-HT<small><sub>2A</sub></small>R, 5-HT<small><sub>2B</sub></small>R and the TNAP receptor. No activity was observed towards the phosphatase, however all compounds showed good binding affinity for 5-HT<small><sub>2A</sub></small>R and 5-HT<small><sub>2B</sub></small>R and one compound showed a higher selectivity towards 5-HT<small><sub>2A</sub></small>R than psilocin.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":null,"pages":null},"PeriodicalIF":3.597,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d4md00043a?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140046150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mihaela-Liliana Ţînţaş, Ludovic Peauger, Anaïs Barré, Cyril Papamicaël, Thierry Besson, Jana Sopkovà-de Oliveira Santos, Vincent Gembus and Vincent Levacher
Based on a multitarget approach implementing rivastigmine-INDY hybrids 1, we identified a set of pseudo-irreversible carbamate-type inhibitors of eqBuChE that, after carbamate transfer at the active site serine residue, released the corresponding INDY analogues 2 endowed with hDYRK1A/hCLK1 kinases inhibitory properties. A SAR study and molecular docking investigation of both series of compounds 1 and 2 revealed that appropriate structural modifications at the carbamate moiety and at the N-appendage of the benzothiazole core led to potent and selective eqBuChE inhibitors with IC50 up to 27 nM and potent hDYRK1A and hCLK1 inhibitors with IC50 up to 106 nM and 17 nM respectively. Pleasingly, identification of the matched pair of compounds 1b/2b with a good balance between inhibition of eqBuChE and hDYRK1A/hCLK1 kinases (IC50 = 68 nM and IC50 = 529/54 nM, respectively) further validated our multitarget approach based on a sequential mechanism of action. In addition, target compound 1b exhibited a suitable ADMET profile, including good brain permeability and high stability in PBS, encouraging further biological investigation as a drug candidate.
{"title":"Design, synthesis and preliminary biological evaluation of rivastigmine-INDY hybrids as multitarget ligands against Alzheimer's disease by targeting butyrylcholinesterase and DYRK1A/CLK1 kinases†","authors":"Mihaela-Liliana Ţînţaş, Ludovic Peauger, Anaïs Barré, Cyril Papamicaël, Thierry Besson, Jana Sopkovà-de Oliveira Santos, Vincent Gembus and Vincent Levacher","doi":"10.1039/D3MD00708A","DOIUrl":"10.1039/D3MD00708A","url":null,"abstract":"<p >Based on a multitarget approach implementing rivastigmine-INDY hybrids <strong>1</strong>, we identified a set of pseudo-irreversible carbamate-type inhibitors of <em>eq</em>BuChE that, after carbamate transfer at the active site serine residue, released the corresponding INDY analogues <strong>2</strong> endowed with <em>h</em>DYRK1A/<em>h</em>CLK1 kinases inhibitory properties. A SAR study and molecular docking investigation of both series of compounds <strong>1</strong> and <strong>2</strong> revealed that appropriate structural modifications at the carbamate moiety and at the <em>N</em>-appendage of the benzothiazole core led to potent and selective <em>eq</em>BuChE inhibitors with IC<small><sub>50</sub></small> up to 27 nM and potent <em>h</em>DYRK1A and <em>h</em>CLK1 inhibitors with IC<small><sub>50</sub></small> up to 106 nM and 17 nM respectively. Pleasingly, identification of the matched pair of compounds <strong>1b</strong>/<strong>2b</strong> with a good balance between inhibition of <em>eq</em>BuChE and <em>h</em>DYRK1A/<em>h</em>CLK1 kinases (IC<small><sub>50</sub></small> = 68 nM and IC<small><sub>50</sub></small> = 529/54 nM, respectively) further validated our multitarget approach based on a sequential mechanism of action. In addition, target compound <strong>1b</strong> exhibited a suitable ADMET profile, including good brain permeability and high stability in PBS, encouraging further biological investigation as a drug candidate.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":null,"pages":null},"PeriodicalIF":3.597,"publicationDate":"2024-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140008645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zein Alabdeen Khdar, Tam Minh Le, Zsuzsanna Schelz, István Zupkó and Zsolt Szakonyi
A new library of allo-gibberic acid-based aminoalcohol regioisomers was synthesised stereoselectively starting from commercially available gibberellic acid, which yields allo-gibberic acid under mild acidic conditions. The successful formation of hydroxymethyl ketone derivative 5, by acid-mediated rearrangement of previously prepared epoxide, paved the way to obtain the desired 1,3-aminoalcohols through Schiff base formation. To obtain the desired regioisomers, the primary alcohol functionality of 5 was subjected to mesylation, then replaced with either primary amine or sodium azide. The formed azide derivative was subjected to either CuAAC reaction to obtain 1,2,3-triazoles or underwent Pd-catalysed hydrogenolysis to obtain primary aminoalcohol, which was further transformed into 1,3-aminoalcohols by reductive alkylation. All prepared aminoalcohols were identified in a satisfactory manner using modern spectroscopic techniques and assessed for their antiproliferative activity against a panel of human cancer cell lines. The antiproliferative effects of the prepared compounds were assayed by in vitro MTT method against a panel of human cancer cell lines (HeLa, SiHa, A2780, MCF-7 and MDA-MB-231). A significant difference was observed in the antiproliferative activity between the regioisomers. Some compounds exerted outstanding activities against the malignant cells with limited action on fibroblasts, indicating considerable cancer selectivity.
{"title":"Stereoselective synthesis and antiproliferative activity of allo-gibberic acid-based 1,3-aminoalcohol regioisomers†","authors":"Zein Alabdeen Khdar, Tam Minh Le, Zsuzsanna Schelz, István Zupkó and Zsolt Szakonyi","doi":"10.1039/D3MD00665D","DOIUrl":"10.1039/D3MD00665D","url":null,"abstract":"<p >A new library of <em>allo</em>-gibberic acid-based aminoalcohol regioisomers was synthesised stereoselectively starting from commercially available gibberellic acid, which yields <em>allo</em>-gibberic acid under mild acidic conditions. The successful formation of hydroxymethyl ketone derivative <strong>5</strong>, by acid-mediated rearrangement of previously prepared epoxide, paved the way to obtain the desired 1,3-aminoalcohols through Schiff base formation. To obtain the desired regioisomers, the primary alcohol functionality of <strong>5</strong> was subjected to mesylation, then replaced with either primary amine or sodium azide. The formed azide derivative was subjected to either CuAAC reaction to obtain 1,2,3-triazoles or underwent Pd-catalysed hydrogenolysis to obtain primary aminoalcohol, which was further transformed into 1,3-aminoalcohols by reductive alkylation. All prepared aminoalcohols were identified in a satisfactory manner using modern spectroscopic techniques and assessed for their antiproliferative activity against a panel of human cancer cell lines. The antiproliferative effects of the prepared compounds were assayed by <em>in vitro</em> MTT method against a panel of human cancer cell lines (HeLa, SiHa, A2780, MCF-7 and MDA-MB-231). A significant difference was observed in the antiproliferative activity between the regioisomers. Some compounds exerted outstanding activities against the malignant cells with limited action on fibroblasts, indicating considerable cancer selectivity.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":null,"pages":null},"PeriodicalIF":3.597,"publicationDate":"2024-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d3md00665d?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139902147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fernanda A. Rosa, Davana S. Gonçalves, Karlos E. Pianoski, Michael J. V. da Silva, Franciele Q. Ames, Rafael P. Aguiar, Hélito Volpato, Danielle Lazarin-Bidóia, Celso V. Nakamura and Ciomar A. Bersani-Amado
In this paper, we present the design and synthesis of a novel series of pyrido[2,3-d]pyridazine-2,8-dione derivatives via the annulation of the 2-pyridone pattern. The synthesized derivatives were evaluated for in vivo anti-inflammatory activity using an ear edema model. Compound 7c, which showed a greater inhibition of ear edema (82%), was further tested for its in vitro COX-1/COX-2 inhibitory activity. Compound 7c showed similar inhibitory activities against COX-1 and COX-2 isoenzymes. The structural features that ensure the dual inhibition of COX-1 and COX-2 were elucidated using molecular docking studies. Overall, the ring closing of 2-pyridone pattern I transformed this highly selective COX-2 inhibitor into a dual COX inhibitor (7c), which could serve as a model for determining selectivity for COX-2.
{"title":"Discovery of a new pyrido[2,3-d]pyridazine-2,8-dione derivative as a potential anti-inflammatory agent through COX-1/COX-2 dual inhibition†","authors":"Fernanda A. Rosa, Davana S. Gonçalves, Karlos E. Pianoski, Michael J. V. da Silva, Franciele Q. Ames, Rafael P. Aguiar, Hélito Volpato, Danielle Lazarin-Bidóia, Celso V. Nakamura and Ciomar A. Bersani-Amado","doi":"10.1039/D3MD00604B","DOIUrl":"10.1039/D3MD00604B","url":null,"abstract":"<p >In this paper, we present the design and synthesis of a novel series of pyrido[2,3-<em>d</em>]pyridazine-2,8-dione derivatives <em>via</em> the annulation of the 2-pyridone pattern. The synthesized derivatives were evaluated for <em>in vivo</em> anti-inflammatory activity using an ear edema model. Compound <strong>7c</strong>, which showed a greater inhibition of ear edema (82%), was further tested for its <em>in vitro</em> COX-1/COX-2 inhibitory activity. Compound <strong>7c</strong> showed similar inhibitory activities against COX-1 and COX-2 isoenzymes. The structural features that ensure the dual inhibition of COX-1 and COX-2 were elucidated using molecular docking studies. Overall, the ring closing of 2-pyridone pattern <strong>I</strong> transformed this highly selective COX-2 inhibitor into a dual COX inhibitor (<strong>7c</strong>), which could serve as a model for determining selectivity for COX-2.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":null,"pages":null},"PeriodicalIF":3.597,"publicationDate":"2024-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139948157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hari Madhav, G. Srinivas Reddy, Zeba Rizvi, Ehtesham Jameel, Tarosh S. Patel, Abdur Rahman, Vikas Yadav, Sadaf Fatima, Fatima Heyat, Kavita Pal, Amisha Minju-OP, Naidu Subbarao, Souvik Bhattacharjee, Bharat C. Dixit, Puran Singh Sijwali and Nasimul Hoda
Malaria eradication is still a global challenge due to the lack of a broadly effective vaccine and the emergence of drug resistance to most of the currently available drugs as part of the mainline artemisinin-based combination therapy. A variety of experimental approaches are quite successful in identifying and synthesizing new promising pharmacophore hybrids with distinct mechanisms of action. Based on our recent findings, the current study demonstrates the reinvestigation of a series of diphenylmethylpiperazine and pyrazine-derived molecular hybrids. Pyrazine-derived molecular hybrids were screened to investigate the antiplasmodial activity on drug-susceptible Pf3D7 and drug-resistant PfW2 strains. The selected compounds were shown to be potent dual inhibitors of cysteine protease PfFP2 and PfFP3. Time-course parasitic development study demonstrated that compounds were able to arrest the growth of the parasite at the early trophozoite stage. The compounds did not show hemolysis of red blood cells and showed selectivity to the parasite compared with the mammalian Vero and A5489 cell lines. The study underlined HR5 and HR15 as a new class of Plasmodial falcipain inhibitors with an IC50 of 6.2 μM and 5.9 μM for PfFP2 and 6.8 μM and 6.4 μM for PfFP3, respectively. Both compounds have antimalarial efficacy with IC50 values of 3.05 μM and 2.80 μM for the Pf3D7 strain, and 4.35 μM and 3.39 μM for the PfW2 strain, respectively. Further structural optimization may turn them into potential Plasmodial falcipain inhibitors for malaria therapeutics.
{"title":"Reinvestigation of diphenylmethylpiperazine analogues of pyrazine as new class of Plasmodial cysteine protease inhibitors for the treatment of malaria†","authors":"Hari Madhav, G. Srinivas Reddy, Zeba Rizvi, Ehtesham Jameel, Tarosh S. Patel, Abdur Rahman, Vikas Yadav, Sadaf Fatima, Fatima Heyat, Kavita Pal, Amisha Minju-OP, Naidu Subbarao, Souvik Bhattacharjee, Bharat C. Dixit, Puran Singh Sijwali and Nasimul Hoda","doi":"10.1039/D3MD00490B","DOIUrl":"10.1039/D3MD00490B","url":null,"abstract":"<p >Malaria eradication is still a global challenge due to the lack of a broadly effective vaccine and the emergence of drug resistance to most of the currently available drugs as part of the mainline artemisinin-based combination therapy. A variety of experimental approaches are quite successful in identifying and synthesizing new promising pharmacophore hybrids with distinct mechanisms of action. Based on our recent findings, the current study demonstrates the reinvestigation of a series of diphenylmethylpiperazine and pyrazine-derived molecular hybrids. Pyrazine-derived molecular hybrids were screened to investigate the antiplasmodial activity on drug-susceptible <em>Pf</em>3D7 and drug-resistant <em>Pf</em>W2 strains. The selected compounds were shown to be potent dual inhibitors of cysteine protease <em>Pf</em>FP2 and <em>Pf</em>FP3. Time-course parasitic development study demonstrated that compounds were able to arrest the growth of the parasite at the early trophozoite stage. The compounds did not show hemolysis of red blood cells and showed selectivity to the parasite compared with the mammalian Vero and A5489 cell lines. The study underlined <strong>HR5</strong> and <strong>HR15</strong> as a new class of <em>Plasmodial falcipain</em> inhibitors with an IC<small><sub>50</sub></small> of 6.2 μM and 5.9 μM for <em>Pf</em>FP2 and 6.8 μM and 6.4 μM for <em>Pf</em>FP3, respectively. Both compounds have antimalarial efficacy with IC<small><sub>50</sub></small> values of 3.05 μM and 2.80 μM for the <em>Pf</em>3D7 strain, and 4.35 μM and 3.39 μM for the <em>Pf</em>W2 strain, respectively. Further structural optimization may turn them into potential <em>Plasmodial falcipain</em> inhibitors for malaria therapeutics.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":null,"pages":null},"PeriodicalIF":3.597,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139751546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ghadeer A. R. Y. Suaifan, Bayan Alkhawaja, Mayadah B. Shehadeh, Mridula Sharmaa, Chan Hor Kuan and Patrick Nwabueze Okechukwu
Normally, skeletal muscle accounts for 70–80% of insulin-stimulated glucose uptake in the postprandial hyperglycemia state. Consequently, abnormalities in glucose uptake by skeletal muscle or insulin resistance (IR) are deemed as initial metabolic defects in the pathogenesis of type 2 diabetes mellitus (T2DM). Globally, T2DM is growing in exponential proportion. The majority of T2DM patients are treated with sulfonylureas in combination with other drugs to improve insulin sensitivity. Glycosylated sulfonylureas (sulfonylurea–glucosamine analogues) are modified analogues of sulfonylurea that have been previously reported to possess antidiabetic activity. The aim of this study was to evaluate the impact of glycosylated sulfonylureas on the insulin signalling pathway at the molecular level using L6 skeletal muscle cell (in vitro) and extracted soleus muscle (ex vivo) models. To create an in vitro model, insulin resistance was established utilizing a high insulin–glucose approach in differentiated L6 muscle cells from Rattus norvegicus. Additionally, for the ex vivo model, extracted soleus muscles, adult Sprague-Dawley rats were subjected to a solution containing 25 mmol L−1 glucose and 100 mmol L−1 insulin for 24 hours to induce insulin resistance. After insulin resistance, compounds under investigation and standard medicines (metformin and glimepiride) were tested. The differential expression of PI3K, IRS-1, PKC, AKT2, and GLUT4 genes involved in the insulin signaling pathway was evaluated using qPCR. The evaluated glycosylated sulfonylurea analogues exhibited a significant increase in the gene expression of insulin-dependent pathways both in vitro and ex vivo, confirming the rejuvenation of the impaired insulin signaling pathway genes. Altogether, glycosylated sulfonylurea analogues described in this study represent potential therapeutic anti-diabetic drugs.
{"title":"Glucosamine substituted sulfonylureas: IRS–PI3K–PKC–AKT–GLUT4 insulin signalling pathway intriguing agent","authors":"Ghadeer A. R. Y. Suaifan, Bayan Alkhawaja, Mayadah B. Shehadeh, Mridula Sharmaa, Chan Hor Kuan and Patrick Nwabueze Okechukwu","doi":"10.1039/D3MD00647F","DOIUrl":"10.1039/D3MD00647F","url":null,"abstract":"<p >Normally, skeletal muscle accounts for 70–80% of insulin-stimulated glucose uptake in the postprandial hyperglycemia state. Consequently, abnormalities in glucose uptake by skeletal muscle or insulin resistance (IR) are deemed as initial metabolic defects in the pathogenesis of type 2 diabetes mellitus (T2DM). Globally, T2DM is growing in exponential proportion. The majority of T2DM patients are treated with sulfonylureas in combination with other drugs to improve insulin sensitivity. Glycosylated sulfonylureas (sulfonylurea–glucosamine analogues) are modified analogues of sulfonylurea that have been previously reported to possess antidiabetic activity. The aim of this study was to evaluate the impact of glycosylated sulfonylureas on the insulin signalling pathway at the molecular level using L6 skeletal muscle cell (<em>in vitro</em>) and extracted soleus muscle (<em>ex vivo</em>) models. To create an <em>in vitro</em> model, insulin resistance was established utilizing a high insulin–glucose approach in differentiated L6 muscle cells from <em>Rattus norvegicus</em>. Additionally, for the <em>ex vivo</em> model, extracted soleus muscles, adult Sprague-Dawley rats were subjected to a solution containing 25 mmol L<small><sup>−1</sup></small> glucose and 100 mmol L<small><sup>−1</sup></small> insulin for 24 hours to induce insulin resistance. After insulin resistance, compounds under investigation and standard medicines (metformin and glimepiride) were tested. The differential expression of PI3K, IRS-1, PKC, AKT2, and GLUT4 genes involved in the insulin signaling pathway was evaluated using qPCR. The evaluated glycosylated sulfonylurea analogues exhibited a significant increase in the gene expression of insulin-dependent pathways both <em>in vitro</em> and <em>ex vivo</em>, confirming the rejuvenation of the impaired insulin signaling pathway genes. Altogether, glycosylated sulfonylurea analogues described in this study represent potential therapeutic anti-diabetic drugs.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":null,"pages":null},"PeriodicalIF":3.597,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139657192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}