Safaa I. Elewa , Ibrahim F. Nassar , Ahmed F. El-Farargy , Yaseen A.M.M. Elshaier , Omnia Kutkat , Asmaa M. Elfiky , Ahmed A. El-Rashedy , Eman Mansour
{"title":"在分子动力学模拟的辅助下,简化奥希替尼的结构,开发出具有抗增殖和抗SARS-CoV-2活性的新型吲哚基嘧啶-5-甲腈衍生物","authors":"Safaa I. Elewa , Ibrahim F. Nassar , Ahmed F. El-Farargy , Yaseen A.M.M. Elshaier , Omnia Kutkat , Asmaa M. Elfiky , Ahmed A. El-Rashedy , Eman Mansour","doi":"10.1016/j.tet.2024.134272","DOIUrl":null,"url":null,"abstract":"<div><div>Based on the simplicity and modification of the medication osimertinib, two new series of indolyle-pyrimidine-5-carbonitrile scaffolds were created and synthesized with dual action as anti-SARS-Cov-2 and anticancer. The newly created heterocyclic compounds' chemical structures were effectively characterized. With IC50 values of 18.52, 20.89, and 19.85, respectively, compounds <strong>9b, 10</strong>, and <strong>15</strong> had inhibitory actions against SARS-CoV-2 when compared to remdesivir and chloroquine, which served as pharmacological controls and had IC50 values of 3.38 μM and 24.9 μM, respectively.</div><div>Furthermore, compounds <strong>9a</strong> and <strong>13</strong> showed anti-proliferative activity against HepG2 cell lines with IC<sub>50s</sub> of 5.63 μM and 3.06 μM, respectively, in comparison to doxorubicin's IC<sub>50</sub> of 7.4 μM. qRT-PCR revealed that HepG2 cells treated with compounds <strong>9a</strong> and <strong>13</strong> showed increased p53 expression levels and decreased CDK1 and PI3K expression levels in comparison to doxorubicin. Molecular dynamics simulations of 20 ns duration were performed with PI3Kα, PI3Kγ, and CDK and active compound complexes. The results confirm that compound <strong>13</strong> has the potential to be a therapeutic candidate for additional preclinical and clinical research, as indicated by the molecular docking data.</div></div>","PeriodicalId":437,"journal":{"name":"Tetrahedron","volume":null,"pages":null},"PeriodicalIF":2.1000,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Structural simplification of Osimertinib to elaborate new indolyle-pyrimidine-5-carbonitrile derivatives with Anti-proliferative and Anti-SARS-CoV-2 activities assisted by molecular dynamic simulation\",\"authors\":\"Safaa I. Elewa , Ibrahim F. Nassar , Ahmed F. El-Farargy , Yaseen A.M.M. Elshaier , Omnia Kutkat , Asmaa M. Elfiky , Ahmed A. El-Rashedy , Eman Mansour\",\"doi\":\"10.1016/j.tet.2024.134272\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Based on the simplicity and modification of the medication osimertinib, two new series of indolyle-pyrimidine-5-carbonitrile scaffolds were created and synthesized with dual action as anti-SARS-Cov-2 and anticancer. The newly created heterocyclic compounds' chemical structures were effectively characterized. With IC50 values of 18.52, 20.89, and 19.85, respectively, compounds <strong>9b, 10</strong>, and <strong>15</strong> had inhibitory actions against SARS-CoV-2 when compared to remdesivir and chloroquine, which served as pharmacological controls and had IC50 values of 3.38 μM and 24.9 μM, respectively.</div><div>Furthermore, compounds <strong>9a</strong> and <strong>13</strong> showed anti-proliferative activity against HepG2 cell lines with IC<sub>50s</sub> of 5.63 μM and 3.06 μM, respectively, in comparison to doxorubicin's IC<sub>50</sub> of 7.4 μM. qRT-PCR revealed that HepG2 cells treated with compounds <strong>9a</strong> and <strong>13</strong> showed increased p53 expression levels and decreased CDK1 and PI3K expression levels in comparison to doxorubicin. Molecular dynamics simulations of 20 ns duration were performed with PI3Kα, PI3Kγ, and CDK and active compound complexes. The results confirm that compound <strong>13</strong> has the potential to be a therapeutic candidate for additional preclinical and clinical research, as indicated by the molecular docking data.</div></div>\",\"PeriodicalId\":437,\"journal\":{\"name\":\"Tetrahedron\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.1000,\"publicationDate\":\"2024-09-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Tetrahedron\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0040402024004538\",\"RegionNum\":3,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, ORGANIC\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Tetrahedron","FirstCategoryId":"92","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0040402024004538","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, ORGANIC","Score":null,"Total":0}
Structural simplification of Osimertinib to elaborate new indolyle-pyrimidine-5-carbonitrile derivatives with Anti-proliferative and Anti-SARS-CoV-2 activities assisted by molecular dynamic simulation
Based on the simplicity and modification of the medication osimertinib, two new series of indolyle-pyrimidine-5-carbonitrile scaffolds were created and synthesized with dual action as anti-SARS-Cov-2 and anticancer. The newly created heterocyclic compounds' chemical structures were effectively characterized. With IC50 values of 18.52, 20.89, and 19.85, respectively, compounds 9b, 10, and 15 had inhibitory actions against SARS-CoV-2 when compared to remdesivir and chloroquine, which served as pharmacological controls and had IC50 values of 3.38 μM and 24.9 μM, respectively.
Furthermore, compounds 9a and 13 showed anti-proliferative activity against HepG2 cell lines with IC50s of 5.63 μM and 3.06 μM, respectively, in comparison to doxorubicin's IC50 of 7.4 μM. qRT-PCR revealed that HepG2 cells treated with compounds 9a and 13 showed increased p53 expression levels and decreased CDK1 and PI3K expression levels in comparison to doxorubicin. Molecular dynamics simulations of 20 ns duration were performed with PI3Kα, PI3Kγ, and CDK and active compound complexes. The results confirm that compound 13 has the potential to be a therapeutic candidate for additional preclinical and clinical research, as indicated by the molecular docking data.
期刊介绍:
Tetrahedron publishes full accounts of research having outstanding significance in the broad field of organic chemistry and its related disciplines, such as organic materials and bio-organic chemistry.
Regular papers in Tetrahedron are expected to represent detailed accounts of an original study having substantially greater scope and details than that found in a communication, as published in Tetrahedron Letters.
Tetrahedron also publishes thematic collections of papers as special issues and ''Reports'', commissioned in-depth reviews providing a comprehensive overview of a research area.