{"title":"Applications of Bridgehead Heterocycles in Drug Design and Medicinal Chemistry","authors":"Simona Di Martino, Pietro Amico, Maria De Rosa","doi":"10.1007/s41061-025-00502-2","DOIUrl":null,"url":null,"abstract":"<div><p>Bridged heterocycles are highly relevant in medicinal chemistry and drug discovery due to the unique features associated with their three-dimensional configuration that ensures great scaffold complexity. In general, inserting bridged systems into a chemical structure positively influences the pharmacokinetic (PK) profile of leads, reducing lipophilicity and enhancing metabolic stability. Several optimization studies show that bridged systems often promoted a significant improvement of the small molecule–enzyme binding interaction due to conformational changes within the biological target active site. To date, many drugs including bridged cores are available in the market to cure several diseases. Given the broad range of biological activities of naturally occurring and (semi)-synthetic bridgehead heterocycles, here, we have thoroughly reviewed the rational design and the structure–activity relationship (SAR) studies of the most remarkable bridged compounds developed during the past decade, to highlight both the chemical and biological roles of these motifs.</p><h3>Graphical Abstract</h3>\n<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":802,"journal":{"name":"Topics in Current Chemistry","volume":"383 2","pages":""},"PeriodicalIF":8.6000,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Topics in Current Chemistry","FirstCategoryId":"92","ListUrlMain":"https://link.springer.com/article/10.1007/s41061-025-00502-2","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"Chemistry","Score":null,"Total":0}
引用次数: 0
Abstract
Bridged heterocycles are highly relevant in medicinal chemistry and drug discovery due to the unique features associated with their three-dimensional configuration that ensures great scaffold complexity. In general, inserting bridged systems into a chemical structure positively influences the pharmacokinetic (PK) profile of leads, reducing lipophilicity and enhancing metabolic stability. Several optimization studies show that bridged systems often promoted a significant improvement of the small molecule–enzyme binding interaction due to conformational changes within the biological target active site. To date, many drugs including bridged cores are available in the market to cure several diseases. Given the broad range of biological activities of naturally occurring and (semi)-synthetic bridgehead heterocycles, here, we have thoroughly reviewed the rational design and the structure–activity relationship (SAR) studies of the most remarkable bridged compounds developed during the past decade, to highlight both the chemical and biological roles of these motifs.
期刊介绍：
Topics in Current Chemistry provides in-depth analyses and forward-thinking perspectives on the latest advancements in chemical research. This renowned journal encompasses various domains within chemical science and their intersections with biology, medicine, physics, and materials science.
Each collection within the journal aims to offer a comprehensive understanding, accessible to both academic and industrial readers, of emerging research in an area that captivates a broader scientific community.
In essence, Topics in Current Chemistry illuminates cutting-edge chemical research, fosters interdisciplinary collaboration, and facilitates knowledge-sharing among diverse scientific audiences.
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