ABSTRACT
We report here the parallel synthesis of 200 compounds based on squaric acid template. These compounds are obtained via a one-step solution-phase procedure starting from three squaric acid N-hydroxylamide esters precursors. The set of diverse reagents qualified (amines, anilines, amino-alcohols and amino-esters) makes this strategy suitable for the search of biologically active compounds. The library was screened on the zinc metalloenzyme ADAMTS-5 and hits with IC(50) in the range of 1-50 microM were identified.
Subject(s)
ADAM Proteins/metabolism , Amides/chemical synthesis , Combinatorial Chemistry Techniques , Cyclobutanes/chemical synthesis , Zinc/metabolism , ADAMTS5 Protein , Amides/chemistry , Cyclobutanes/chemistry , Humans , Inhibitory Concentration 50 , Molecular Structure , Structure-Activity RelationshipABSTRACT
Proteases that are expressed during the erythocytic stage of Plasmodium falciparum are newly explored drug targets for the treatment of malaria. We report here the discovery of potent inhibitors of PfA-M1, a metallo-aminopeptidase of the parasite. These compounds are based on a malonic hydroxamic template and present a very good selectivity toward neutral aminopeptidase (APN-CD13), a related protease in mammals. Structure-activity relationships in these series are described. Further optimization of the best inhibitor yielded a nanomolar, selective inhibitor of PfA-M1. This inhibitor displays good physicochemical and pharmacokinetic properties and a promising antimalarial activity.
Subject(s)
Aminopeptidases/antagonists & inhibitors , Antimalarials/chemical synthesis , Hydroxamic Acids/chemical synthesis , Malonates/chemical synthesis , Metalloproteases/antagonists & inhibitors , Plasmodium falciparum/enzymology , Zinc , Aminopeptidases/chemistry , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Cells, Cultured , Erythrocytes/drug effects , Erythrocytes/parasitology , Humans , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Malonates/chemistry , Malonates/pharmacology , Metalloproteases/chemistry , Plasmodium falciparum/drug effects , Quantitative Structure-Activity Relationship , SolubilityABSTRACT
We report here the design and parallel synthesis of 217 compounds based on a malonic-hydroxamic acid template. These compounds are obtained via a two-step solution-phase procedure. The set of diverse building-blocks used makes this strategy suitable for the search of inhibitors of various metallo-proteases and for the investigation of the biological role of new metallo-proteases. As a proof of concept, we screened this library on Neutral Aminopeptidase (APN; EC 3.4.11.2), the prototypal enzyme of the M1 family. Several submicromolar inhibitors were identified.
