Structure-Activity and Structure-Toxicity Relationships of Peptoid-Based Histone Deacetylase Inhibitors with Dual-Stage Antiplasmodial Activity.

摘要: Novel malaria intervention strategies are of great importance, given the development drug resistance in malaria-endemic countries. In this regard, histone deacetylases (HDACs) have emerged as new and promising targets. work, we present design, synthesis, biological evaluation 20 novel HDAC inhibitors with antiplasmodial activity. Based on a previously discovered peptoid-based hit compound, modified all regions peptoid scaffold by using one-pot multicomponent pathway submonomer routes to gain deeper understanding structure–activity structure–toxicity relationships. Most compounds displayed potent activity against asexual blood-stage P. falciparum parasites, IC 50 values range 0.0052–0.25 μm selectivity over mammalian cells (SI Pf3D7/HepG2 : 170–1483). addition, several showed encouraging sub-micromolar berghei exo-erythrocytic forms (PbEEF). Our study led discovery compound N-(2-(benzylamino)-2-oxoethyl)-N-(4-(hydroxycarbamoyl)benzyl)-4-isopropylbenzamide (2 h) parasite-specific dual-stage inhibitor (IC Pf3D7=0.0052 μm, PbEEF=0.016 μm).