Exploring the N1 Position of Biginelli Compounds: New Insights and Trends for Chemical Diversity Generation of Bioactive Derivatives

: Dihydropyrimidinones (DHPMs) are heterocycles obtained by the multicomponent Biginelli reaction. Recently, new synthetic protocols have allowed us to explore functionalisation at less explored positions of DHPMs, such as the N1 position. In this context, we have performed a full literature survey of N1-substituted DHPMs. We analysed 27 papers and identified 379 compounds with substituents at the N1 position, most of them with alkyl groups, and of 28% with aromatic substituents attached at the N1 position. N1-substituted DHPMs are explored mainly due to their effects on cancer cell proliferation via numerous targets, such as kinesin Eg5, heat shock protein 70, heat shock protein 90 and the epidermal growth factor receptor. Similarity analyses were performed using the data of 379 DHPMs from different cheminformatic approaches, i.e. chemical property correlations, principal component analysis, similarity networks and compound clustering.