Next-Generation Rigid Scaffolds: Lessons from Prismane and Twistane

Abstract

Valery M. Dembitsky* and Alexander O. Terentev

Rigid polycyclic hydrocarbons represent a unique class of molecular scaffolds whose constrained three-dimensional architectures offer distinct advantages for chemical biology and drug design. Among these, prismane and twistane occupy an exceptional position due to their extreme rigidity, high geometric strain, and well-defined topological features. In contrast to classical rigid frameworks such as adamantane, prismane and twistane remain largely unexplored in biomedical research, despite their potential to access novel regions of pharmacological space.This review provides a comprehensive analysis of prismane- and twistane-based model compounds bearing diverse functional groups and halogen substituents, with a particular focus on their predicted biological activities evaluated using the Prediction of Activity Spectra for Substances (PASS) algorithm. By systematically comparing these scaffolds to the clinically validated adamantane framework, we elucidate how differences in topology, symmetry, chirality, and strain influence biological activity profiles. PASS-based structure–activity analysis reveals that selected prismane derivatives exhibit strong predicted antiprotozoal, anti-inflammatory, and neuroactive properties, while specific twistane derivatives demonstrate notable potential as DNA intercalators, neuroprotective agents, and stroke-related therapeutics. Mechanistic hypotheses are discussed in the context of rigid-scaffold interactions with ion channels, redox-sensitive pathways, neuro–immune– inflammatory signaling, and nucleic acid targets. Overall, this review positions prismane and twistane as promising next-generation rigid scaffolds for in silico-guided drug discovery. The findings highlight their value as model systems for exploring structure–activity relationships driven by molecular topology and rigidity, and underscore their potential relevance in the development of new therapeutics for neurodegenerative, inflammatory, infectious, and oncological diseases.

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