Diversity-oriented synthesis of novel heterocyclic compounds and their preliminary evaluation as antimalarial agents

Push-pull alkenes refer to substituted alkenes bearing one or two electron-donating groups at one end of the double bond and one or two electron-accepting groups at the other end. These chemical properties make push-pull alkenes particularly reactive with electrophilic and nucleophilic species and therefore they have been widely used as building blocks in organic synthesis, especially for the preparation of heterocycle derivatives. In particular, ketene N,S- and S,S-acetals are the most representative class of push-pull alkenes used in organic synthesis. Recently, we reported a stepwise synthetic procedure through ketene N,S-acetal intermediates for the preparation of novel 5-anilinopyrazoles 1 endowed with antimalarial activities. To further extend the SARs of this class of compounds, we designed and synthesized a new series of 5-aminopyrazoles and 4-aminopyrimidines (derivatives 2 and 3) bearing all the structural determinants for the antimalarial activity. The unreported molecules were synthesized trough a versatile synthetic procedure which involved subsequent isolation of ketene S,S-acetals A and N,S-acetals B that were then cyclized with hydrazine or guanidine to afford the desired compounds. All the new isolated derivatives were screened against D10 and W2 Plasmodium strains and their cytotoxicity was evaluated on normal fibroblast cells by MTT assay.