Discovery of 1,3,4-oxadiazoles with slow-action activity againstPlasmodium falciparummalaria parasites

Abstract

ABSTRACTTo achieve malaria eradication, new preventative agents that act differently to front-line treatment drugs are needed. To identify potential chemoprevention starting points we screened a sub-set of the CSIRO Australia Compound Collection for compounds with slow-actionin vitroactivity againstPlasmodium falciparum. This work identifiedN,N-dialkyl-5-alkylsulfonyl-1,3,4-oxadiazol-2-amines as a new antiplas-modial chemotype (e.g.,196 h IC50550 nM) with a different action to delayed-death slow-action drugs. Structure activity relationship analysis of analogues identified multiple compounds with potent and selectivein vitroactivity against drug-sensitive and multi-drug resistantPlasmodiumparasites (e.g.,31and3296 h IC50<40 nM; SI >2,500). However subsequent studies in mice with lead compound1, which had the best microsomal stability of the compounds assessed, demonstrated rapid clearance (T1/2<1.6 h) and poor oralin vivoefficacy. This indicates that improvements in the pharmacokinetic profile ofN,N-dialkyl-5-alkylsulfonyl-1,3,4-oxadiazol-2-amines would be needed for the development of this chemotype for malaria chemoprophylaxis.