In vitro estimation of human skin permeability and retention and quantitative structure-property analysis of selected chalcones

This study aimed to evaluate the in vitro skin permeability and retention of 21 selected chalcone derivatives using the parallel artificial membrane permeability assay (PAMPA), and to develop quantitative structure–property relationship (QSPR) models to identify structural features influencing these properties. All compounds exhibited low skin permeation (CA(t)/CD(0) ≤ 5.27%), with several ones showing high membrane retention (R > 30%), making them suitable for topical application. CH20 emerged as the most promising compound due to its high retention (66.10%) and low permeation. The most reliable QSPR models (OLS and PLS) revealed that permeability decreases with the addition of electronegative substituents, especially in meta and para positions, and that retention is positively influenced by molecular features such as lower polarizability and the presence of non-voluminous substituents. These findings support the potential of chalcones as topical agents and provide a framework for rational design of future compounds with optimized dermal delivery characteristics.