Mercedes Rubio-Hernández, Verónica Alcolea, Elany Barbosa da Silva, Miriam A. Giardini, Thaís H. M Fernandes, Nuria Martínez-Sáez, Anthony J. O’Donoghue, Jair L. Siqueira-Neto, Silvia Pérez-Silanes
{"title":"新型查耳酮半咔唑酮(S,Se)及其偶氮唑衍生物的合成及其对南美锥虫病的生物学评价","authors":"Mercedes Rubio-Hernández, Verónica Alcolea, Elany Barbosa da Silva, Miriam A. Giardini, Thaís H. M Fernandes, Nuria Martínez-Sáez, Anthony J. O’Donoghue, Jair L. Siqueira-Neto, Silvia Pérez-Silanes","doi":"10.1021/acs.jmedchem.4c01535","DOIUrl":null,"url":null,"abstract":"Chagas disease is caused by the eukaryote parasite <i>Trypanosoma cruzi</i>. Current treatment exhibits limited efficacy and selenium-based compounds emerged as promising candidates for new therapies which is surpassing its bioisoster, sulfur. We designed new thiosemicarbazones, thiazoles, selenosemicarbazones and selenazoles, using isosteric substitution. We synthesized 57 new chalcogen compounds which were evaluated against <i>T. cruzi</i>, C2C12 cells and cruzain, the main target of this parasite. Additionally, human cathepsin L, was tested for selectivity. Three compounds were selected, based on their activity against the intracellular amastigotes (EC<sub>50</sub> < 1 μM, SI > 10) and cruzain (IC<sub>50</sub> < 100 nM, SI > 5.55) which compared favorably with the approved drug, Benznidazole, and the well-established cruzain inhibitor K777. Seleno-compounds demonstrated enhanced activity and selenazoles showed a decrease in selenium-associated toxicity. Compound 4-methyl-2-(2-(1-(3-nitrophenyl)ethylidene)hydrazineyl)-1,3-selenazole (<i><b>Se</b></i><b>2h</b>) emerged as a promising candidate, and its binding to cruzain was investigated. Pharmacokinetic assessment was conducted, showing a favorable profile for subsequent <i>in vivo</i> assays.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"87 1","pages":""},"PeriodicalIF":6.8000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Synthesis and Biological Evaluation of New Chalcogen Semicarbazone (S, Se) and Their Azole Derivatives against Chagas Disease\",\"authors\":\"Mercedes Rubio-Hernández, Verónica Alcolea, Elany Barbosa da Silva, Miriam A. Giardini, Thaís H. M Fernandes, Nuria Martínez-Sáez, Anthony J. O’Donoghue, Jair L. Siqueira-Neto, Silvia Pérez-Silanes\",\"doi\":\"10.1021/acs.jmedchem.4c01535\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Chagas disease is caused by the eukaryote parasite <i>Trypanosoma cruzi</i>. Current treatment exhibits limited efficacy and selenium-based compounds emerged as promising candidates for new therapies which is surpassing its bioisoster, sulfur. We designed new thiosemicarbazones, thiazoles, selenosemicarbazones and selenazoles, using isosteric substitution. We synthesized 57 new chalcogen compounds which were evaluated against <i>T. cruzi</i>, C2C12 cells and cruzain, the main target of this parasite. Additionally, human cathepsin L, was tested for selectivity. Three compounds were selected, based on their activity against the intracellular amastigotes (EC<sub>50</sub> < 1 μM, SI > 10) and cruzain (IC<sub>50</sub> < 100 nM, SI > 5.55) which compared favorably with the approved drug, Benznidazole, and the well-established cruzain inhibitor K777. Seleno-compounds demonstrated enhanced activity and selenazoles showed a decrease in selenium-associated toxicity. Compound 4-methyl-2-(2-(1-(3-nitrophenyl)ethylidene)hydrazineyl)-1,3-selenazole (<i><b>Se</b></i><b>2h</b>) emerged as a promising candidate, and its binding to cruzain was investigated. Pharmacokinetic assessment was conducted, showing a favorable profile for subsequent <i>in vivo</i> assays.\",\"PeriodicalId\":46,\"journal\":{\"name\":\"Journal of Medicinal Chemistry\",\"volume\":\"87 1\",\"pages\":\"\"},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2024-11-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1021/acs.jmedchem.4c01535\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acs.jmedchem.4c01535","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Synthesis and Biological Evaluation of New Chalcogen Semicarbazone (S, Se) and Their Azole Derivatives against Chagas Disease
Chagas disease is caused by the eukaryote parasite Trypanosoma cruzi. Current treatment exhibits limited efficacy and selenium-based compounds emerged as promising candidates for new therapies which is surpassing its bioisoster, sulfur. We designed new thiosemicarbazones, thiazoles, selenosemicarbazones and selenazoles, using isosteric substitution. We synthesized 57 new chalcogen compounds which were evaluated against T. cruzi, C2C12 cells and cruzain, the main target of this parasite. Additionally, human cathepsin L, was tested for selectivity. Three compounds were selected, based on their activity against the intracellular amastigotes (EC50 < 1 μM, SI > 10) and cruzain (IC50 < 100 nM, SI > 5.55) which compared favorably with the approved drug, Benznidazole, and the well-established cruzain inhibitor K777. Seleno-compounds demonstrated enhanced activity and selenazoles showed a decrease in selenium-associated toxicity. Compound 4-methyl-2-(2-(1-(3-nitrophenyl)ethylidene)hydrazineyl)-1,3-selenazole (Se2h) emerged as a promising candidate, and its binding to cruzain was investigated. Pharmacokinetic assessment was conducted, showing a favorable profile for subsequent in vivo assays.
期刊介绍:
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.