Fused Indole-Diazepines with a Bridgehead Nitrogen Atom: Synthesis and Pharmaceutical Significance

Mengyang Zhou,1 Xiaohong Yang,2 Shutao Wang3 1Department of Pharmacy, China-Japan Union Hospital of Jilin University, Changchun, 130033, People’s Republic of China; 2School of Pharmaceutical Sciences, Jilin University, Changchun, 130021, People’s Republic of China; 3Department of Pharmacy, The Second Hospital of Jilin University, Changchun, 130041, People’s Republic of ChinaCorrespondence: Shutao Wang, Department of Pharmacy, The Second Hospital of Jilin University, Changchun, 130041, People’s Republic of China, Email [email protected]: Indole-fused diazepines with a bridgehead nitrogen atom represent a unique and privileged scaffold in medicinal chemistry, offering considerable potential for the development of novel pharmaceuticals. The bridgehead nitrogen atom acts as a key pharmacophoric element. It rigidifies the molecular conformation, modulates electronic properties, and participates in target binding via hydrogen bonding or electrostatic interactions. These features significantly influence biological activity, target selectivity, and pharmacokinetic profiles. This review comprehensively summarizes the synthesis, biological activities, and therapeutic potential of indole-fused diazepines, with emphasis on their structural diversity and pharmacological properties. We highlight recent advances in synthetic methodologies as well as important historical studies. We also discuss their implications for drug discovery, provide insights into structure-activity relationships (SAR), and propose future research directions for this class of compounds. Keywords: indole-fused diazepines, synthetic methodologies, biological activities, structure-activity relationships