Nina Reßing, Daniel Stopper, Thomas Martin Schäfer, Lais Pessanha de Carvalho, Elizabeth A. Winzeler, Jana Held, Finn K. Hansen
{"title":"基于氟化肽的组蛋白去乙酰化酶抑制剂作为双期抗疟原虫药物的探索","authors":"Nina Reßing, Daniel Stopper, Thomas Martin Schäfer, Lais Pessanha de Carvalho, Elizabeth A. Winzeler, Jana Held, Finn K. Hansen","doi":"10.1002/ardp.70071","DOIUrl":null,"url":null,"abstract":"<p>The antiplasmodial properties of a series of fluorinated peptoid-capped histone deacetylase inhibitors (HDACi) were investigated against asexual blood stages of the drug-sensitive 3D7 and drug-resistant Dd2 strains of <i>Plasmodium falciparum</i>, as well as the exo-erythrocytic liver stages and mature gametocytes. Among the series, compound <b>1h</b> emerged as the most potent derivative, showing strong activity against both <i>P. falciparum</i> strains (<i>Pf</i> 3D7 and Dd2 IC<sub>50</sub>: 0.010 μM) and <i>Plasmodium berghei</i> liver stages (<i>Pb</i> EEF IC<sub>50</sub>: 0.74 μM), while lacking activity against mature gametocytes. Compound <b>1b</b> was identified as a second hit compound with slightly lower activity against asexual blood and liver stages (<i>Pf</i> 3D7 IC<sub>50</sub>: 0.019 μM; <i>Pf</i> Dd2 IC<sub>50</sub>: 0.023 μM; <i>Pb</i> EEF IC<sub>50</sub>: 2.25 μM) but showed excellent parasite selectivity (SI<sup>HepG2/3D7</sup>: 2389; SI<sup>HepG2/Dd2</sup>: 1973) and low single-digit micromolar activity against mature gametocytes (IC<sub>50</sub>: 1.70 μM). Compared to our previous hit compound MAHA-022, both <b>1b</b> and <b>1h</b> exhibited improved activity against asexual blood stages and enhanced parasite selectivity, albeit with reduced activity against liver stage parasites. Taken together, compounds <b>1b</b> and <b>1h</b> represent promising multi-stage antiplasmodial HDACi scaffolds for further development and optimization.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 8","pages":""},"PeriodicalIF":3.6000,"publicationDate":"2025-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.70071","citationCount":"0","resultStr":"{\"title\":\"Exploration of Fluorinated Peptoid-Based Histone Deacetylase Inhibitors as Dual-Stage Antiplasmodial Agents\",\"authors\":\"Nina Reßing, Daniel Stopper, Thomas Martin Schäfer, Lais Pessanha de Carvalho, Elizabeth A. Winzeler, Jana Held, Finn K. Hansen\",\"doi\":\"10.1002/ardp.70071\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>The antiplasmodial properties of a series of fluorinated peptoid-capped histone deacetylase inhibitors (HDACi) were investigated against asexual blood stages of the drug-sensitive 3D7 and drug-resistant Dd2 strains of <i>Plasmodium falciparum</i>, as well as the exo-erythrocytic liver stages and mature gametocytes. Among the series, compound <b>1h</b> emerged as the most potent derivative, showing strong activity against both <i>P. falciparum</i> strains (<i>Pf</i> 3D7 and Dd2 IC<sub>50</sub>: 0.010 μM) and <i>Plasmodium berghei</i> liver stages (<i>Pb</i> EEF IC<sub>50</sub>: 0.74 μM), while lacking activity against mature gametocytes. Compound <b>1b</b> was identified as a second hit compound with slightly lower activity against asexual blood and liver stages (<i>Pf</i> 3D7 IC<sub>50</sub>: 0.019 μM; <i>Pf</i> Dd2 IC<sub>50</sub>: 0.023 μM; <i>Pb</i> EEF IC<sub>50</sub>: 2.25 μM) but showed excellent parasite selectivity (SI<sup>HepG2/3D7</sup>: 2389; SI<sup>HepG2/Dd2</sup>: 1973) and low single-digit micromolar activity against mature gametocytes (IC<sub>50</sub>: 1.70 μM). Compared to our previous hit compound MAHA-022, both <b>1b</b> and <b>1h</b> exhibited improved activity against asexual blood stages and enhanced parasite selectivity, albeit with reduced activity against liver stage parasites. Taken together, compounds <b>1b</b> and <b>1h</b> represent promising multi-stage antiplasmodial HDACi scaffolds for further development and optimization.</p>\",\"PeriodicalId\":128,\"journal\":{\"name\":\"Archiv der Pharmazie\",\"volume\":\"358 8\",\"pages\":\"\"},\"PeriodicalIF\":3.6000,\"publicationDate\":\"2025-08-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.70071\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Archiv der Pharmazie\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/ardp.70071\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Archiv der Pharmazie","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/ardp.70071","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Exploration of Fluorinated Peptoid-Based Histone Deacetylase Inhibitors as Dual-Stage Antiplasmodial Agents
The antiplasmodial properties of a series of fluorinated peptoid-capped histone deacetylase inhibitors (HDACi) were investigated against asexual blood stages of the drug-sensitive 3D7 and drug-resistant Dd2 strains of Plasmodium falciparum, as well as the exo-erythrocytic liver stages and mature gametocytes. Among the series, compound 1h emerged as the most potent derivative, showing strong activity against both P. falciparum strains (Pf 3D7 and Dd2 IC50: 0.010 μM) and Plasmodium berghei liver stages (Pb EEF IC50: 0.74 μM), while lacking activity against mature gametocytes. Compound 1b was identified as a second hit compound with slightly lower activity against asexual blood and liver stages (Pf 3D7 IC50: 0.019 μM; Pf Dd2 IC50: 0.023 μM; Pb EEF IC50: 2.25 μM) but showed excellent parasite selectivity (SIHepG2/3D7: 2389; SIHepG2/Dd2: 1973) and low single-digit micromolar activity against mature gametocytes (IC50: 1.70 μM). Compared to our previous hit compound MAHA-022, both 1b and 1h exhibited improved activity against asexual blood stages and enhanced parasite selectivity, albeit with reduced activity against liver stage parasites. Taken together, compounds 1b and 1h represent promising multi-stage antiplasmodial HDACi scaffolds for further development and optimization.
期刊介绍:
Archiv der Pharmazie - Chemistry in Life Sciences is an international journal devoted to research and development in all fields of pharmaceutical and medicinal chemistry. Emphasis is put on papers combining synthetic organic chemistry, structural biology, molecular modelling, bioorganic chemistry, natural products chemistry, biochemistry or analytical methods with pharmaceutical or medicinal aspects such as biological activity. The focus of this journal is put on original research papers, but other scientifically valuable contributions (e.g. reviews, minireviews, highlights, symposia contributions, discussions, and essays) are also welcome.