Hina Aftab, Saeed Ullah, Ajmal Khan, Mariya al-Rashida, Talha Islam, Abdulrahman Alshammari, Norah A. Albekairi, Parham Taslimi, Ahmed Al-Harrasi, Zahid Shafiq and Saeed Alghamdi
{"title":"作为二氢叶酸还原酶抑制剂的新型吡咯烷衍生硫代氨基甲酸盐的合成、体外生物学评价和硅学研究。","authors":"Hina Aftab, Saeed Ullah, Ajmal Khan, Mariya al-Rashida, Talha Islam, Abdulrahman Alshammari, Norah A. Albekairi, Parham Taslimi, Ahmed Al-Harrasi, Zahid Shafiq and Saeed Alghamdi","doi":"10.1039/D4RA05071A","DOIUrl":null,"url":null,"abstract":"<p >Dihydrofolate reductase (DHFR) is a crucial enzyme involved in folate metabolism and serves as a prime target for anticancer and antimicrobial therapies. In this study, a series of 4-pyrrolidine-based thiosemicarbazones were synthesized and evaluated for their DHFR inhibitory activity. The synthesis involved a multistep procedure starting from readily available starting materials, leading to the formation of diverse thiosemicarbazone <strong>5(a–r)</strong> derivatives. These compounds were then subjected to <em>in vitro</em> assays to evaluate their inhibitory potential against DHFR enzyme. The synthesized compounds <strong>5(a–r)</strong> exhibited potent inhibition with IC<small><sub>50</sub></small> values in the range of 12.37 ± 0.48 μM to 54.10 ± 0.72 μM. Among all the derivatives <strong>5d</strong> displayed highest inhibitory activity. Furthermore, molecular docking and ADME studies were performed to understand the binding interactions between the synthesized compounds and the active site of DHFR. The <em>in vitro</em> and <em>in silico</em> data were correlated to identify compounds with promising inhibitory activity and favorable binding modes. This comprehensive study provides insights into the structure–activity relationships of 4-pyrrolidine-based thiosemicarbazones as DHFR inhibitors, offering potential candidates for further optimization towards the development of novel therapeutic agents.</p>","PeriodicalId":102,"journal":{"name":"RSC Advances","volume":null,"pages":null},"PeriodicalIF":3.9000,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11460214/pdf/","citationCount":"0","resultStr":"{\"title\":\"Synthesis, in vitro biological evaluation and in silico studies of novel pyrrolidine derived thiosemicarbazones as dihydrofolate reductase inhibitors†\",\"authors\":\"Hina Aftab, Saeed Ullah, Ajmal Khan, Mariya al-Rashida, Talha Islam, Abdulrahman Alshammari, Norah A. Albekairi, Parham Taslimi, Ahmed Al-Harrasi, Zahid Shafiq and Saeed Alghamdi\",\"doi\":\"10.1039/D4RA05071A\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Dihydrofolate reductase (DHFR) is a crucial enzyme involved in folate metabolism and serves as a prime target for anticancer and antimicrobial therapies. In this study, a series of 4-pyrrolidine-based thiosemicarbazones were synthesized and evaluated for their DHFR inhibitory activity. The synthesis involved a multistep procedure starting from readily available starting materials, leading to the formation of diverse thiosemicarbazone <strong>5(a–r)</strong> derivatives. These compounds were then subjected to <em>in vitro</em> assays to evaluate their inhibitory potential against DHFR enzyme. The synthesized compounds <strong>5(a–r)</strong> exhibited potent inhibition with IC<small><sub>50</sub></small> values in the range of 12.37 ± 0.48 μM to 54.10 ± 0.72 μM. Among all the derivatives <strong>5d</strong> displayed highest inhibitory activity. Furthermore, molecular docking and ADME studies were performed to understand the binding interactions between the synthesized compounds and the active site of DHFR. The <em>in vitro</em> and <em>in silico</em> data were correlated to identify compounds with promising inhibitory activity and favorable binding modes. This comprehensive study provides insights into the structure–activity relationships of 4-pyrrolidine-based thiosemicarbazones as DHFR inhibitors, offering potential candidates for further optimization towards the development of novel therapeutic agents.</p>\",\"PeriodicalId\":102,\"journal\":{\"name\":\"RSC Advances\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.9000,\"publicationDate\":\"2024-10-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11460214/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"RSC Advances\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://pubs.rsc.org/en/content/articlelanding/2024/ra/d4ra05071a\",\"RegionNum\":3,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"RSC Advances","FirstCategoryId":"92","ListUrlMain":"https://pubs.rsc.org/en/content/articlelanding/2024/ra/d4ra05071a","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
Synthesis, in vitro biological evaluation and in silico studies of novel pyrrolidine derived thiosemicarbazones as dihydrofolate reductase inhibitors†
Dihydrofolate reductase (DHFR) is a crucial enzyme involved in folate metabolism and serves as a prime target for anticancer and antimicrobial therapies. In this study, a series of 4-pyrrolidine-based thiosemicarbazones were synthesized and evaluated for their DHFR inhibitory activity. The synthesis involved a multistep procedure starting from readily available starting materials, leading to the formation of diverse thiosemicarbazone 5(a–r) derivatives. These compounds were then subjected to in vitro assays to evaluate their inhibitory potential against DHFR enzyme. The synthesized compounds 5(a–r) exhibited potent inhibition with IC50 values in the range of 12.37 ± 0.48 μM to 54.10 ± 0.72 μM. Among all the derivatives 5d displayed highest inhibitory activity. Furthermore, molecular docking and ADME studies were performed to understand the binding interactions between the synthesized compounds and the active site of DHFR. The in vitro and in silico data were correlated to identify compounds with promising inhibitory activity and favorable binding modes. This comprehensive study provides insights into the structure–activity relationships of 4-pyrrolidine-based thiosemicarbazones as DHFR inhibitors, offering potential candidates for further optimization towards the development of novel therapeutic agents.
期刊介绍:
An international, peer-reviewed journal covering all of the chemical sciences, including multidisciplinary and emerging areas. RSC Advances is a gold open access journal allowing researchers free access to research articles, and offering an affordable open access publishing option for authors around the world.