ABSTRACT
New antimalarial agents that exhibit multistage activities against drug-resistant strains of malaria parasites represent good starting points for developing next-generation antimalarial therapies. To facilitate the progression of such agents into the development phase, we developed an image-based parasitological screening method for defining drug effects on different asexual life cycle stages of Plasmodium falciparum. High-throughput screening of a newly assembled diversity-oriented synthetic library using this approach led to the identification of carbohybrid-based 2-aminopyrimidine compounds with fast-acting growth inhibitory activities against three laboratory strains of multidrug-resistant P. falciparum. Our structure-activity relationship study led to the identification of two derivatives (8aA and 11aA) as the most promising antimalarial candidates (mean EC50 of 0.130 and 0.096 µM against all three P. falciparum strains, selectivity indices >600, microsomal stabilities >80%, and mouse malaria ED50 values of 0.32 and 0.12 mg/kg/day, respectively), targeting all major blood stages of multidrug-resistant P. falciparum parasites.
Subject(s)
Antimalarials/pharmacology , Life Cycle Stages/drug effects , Plasmodium falciparum/drug effects , Pyrimidines/pharmacology , Animals , Antimalarials/chemistry , Antimalarials/pharmacokinetics , Area Under Curve , Cell Line, Tumor , Cell Survival/drug effects , Drug Discovery , Drug Evaluation, Preclinical , Hep G2 Cells , Host-Parasite Interactions/drug effects , Humans , Malaria/parasitology , Malaria/prevention & control , Male , Metabolic Clearance Rate , Mice , Mice, Inbred BALB C , Models, Chemical , Molecular Structure , Plasmodium chabaudi/drug effects , Plasmodium chabaudi/physiology , Plasmodium falciparum/growth & development , Pyrimidines/chemistry , Pyrimidines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
In this report we describe the identification of novel pyrazole analogs as potent hepatitis C virus (HCV) entry inhibitor. The pyrazoles were identified by our phenotypic high-throughput screening using infectious HCV. A series of pyrazole derivatives was synthesized and evaluated for inhibitory activity against HCV in the infectious cell culture system. Through evaluation of selected compounds we observed that the pyrazoles did not interfere with HCV RNA replication but with viral entry as shown by experiments with HCV replicons and HCV pseudo particles, respectively.
