Synthesis, and biological validation of selected pyrimidinones for the inhibition of propagation of the malaria parasite, Plasmodium falciparum

ORGN 648

Bettina Quade, beq1@pitt.edu1, Shuli Mao1, Peter Wipf1, and Jeffrey Brodsky2. (1) Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260, (2) Department of Biological Sciences, University of Pittsburgh, 274A Crawford Hall, 4249 Fifth Avenue, Pittsburgh, PA 15260
Plasmodium falciparum, the Apicomplexan parasite that is responsible for the most lethal forms of human malaria, is exposed to radically different environments and stress factors during its complex lifecycle. In any organism, Hsp70 chaperones are typically associated with tolerance to stress. Accordingly, there is a considerable interest in the inhibition of P. falciparum Hsp70 chaperones to adversely affect parasite homeostasis. Based on earlier efforts towards the inhibition of P. falciparum growth, the synthesis of a library of modified pyrimidinones and the biological effects of these Biginelli and Ugi multicomponent condensation products will be described.