CHEMICAL DETERMINANTS OF ANTIMALARIAL ACTIVITY OF REVERSED SIDEROPHORES

Reversed siderophores (RSFs) are artificial hydroxamate-based iron che lators designed after the natural siderophore ferrichrome. The modular molecular design of RSF derivatives allowed the synthesis of various congeners with controlled iron-binding capacities and partition coeffi cients. These two physicochemical properties were assessed by a novel fluorescent method and were found to be the major determinants of RSF permeation across erythrocyte membranes and scavenging of compartmenta lized iron. The partition coefficient apparently conferred upon RSFs t wo major features: (i) the ability to rapidly access iron pools of in vitro-grown Plasmodium falciparum at all developmental stages and to m obilize intracellular iron and transfer it to the medium and (ii) the ability to suppress parasite growth at all developmental stages. These features of RSFs were assessed by quantitative determination of the s tructure-activity relationships of the biological activities and parti tion coefficients spanning a wide range of values. The most effective RSF containing the aromatic group of phenylalanine (RSFm2phe) showed 5 0% inhibitory concentration of 0.60 +/- 0.03 nmol/ml in a 48-h test an d a 2-h onset of inhibition of ring development at 5 nmol/ml. The lipo philic compound RSFm2phe and the lipophilic and esterase-cleavable com pound RSFm2pee inhibited parasite growth at all developmental stages w hether inhibition was assessed in a continuous mode or after discontin uing drug administration. The antimalarial effects of RSFm2phe and cle avable RSFm2pee were potentiated in the presence of desferrioxamine (D FO) at concentrations at which DFO alone had no effect on parasite gro wth. These studies provide experimental evidence indicating that the e ffective and persistent antimalarial actions of RSFs are associated wi th drug access to infected cells and scavenging of iron from intracell ular parasites. Moreover, the optimal antimalarial actions of RSFs are apparently also determined by improved accessibility to critical iron pools or by specific interactions with critical parasite targets.