The Role of Hydrogen Bond Donors and Intramolecular Hydrogen Bonding in Modulating Blood–Brain Barrier Permeability: Implications for CNS Drug Design

The blood-brain barrier (BBB) represents a major challenge in central nervous system (CNS) drug development due to its selective permeability. Multiple molecular properties such as lipophilicity, molecular size, and hydrogen-bonding potential critically influence a compound's ability to cross the BBB. In particular, the presence of hydrogen bond donors (HBDs) and the ability to form intramolecular hydrogen bonds (IMHBs) play a crucial role in modulating brain penetration. This review discusses the mechanistic impact of HBDs and IMHBs on BBB permeability, highlighting key physicochemical parameters and case studies that demonstrate the utility of IMHBs in CNS drug design. Strategies to mask polar functionalities through IMHB formation are emphasized as promising tools to optimize brain delivery without compromising pharmacological activities. The literature reviewed in this work was collected through comprehensive searches of scientific databases, including SciFinder, PubMed, Web of Science, and Scopus, complemented by manual search of reference lists from relevant publications.