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
A method to access totally new analogues of tadalafil was explored. The Buchwald reaction was adapted and used to replace the methyl group of tadalafil by various aryl groups. Inhibition potencies on PDE5 of these analogues were determined and proved to be comparable to the one of tadalafil. Using the same route, compounds with the same level of activity but improved water solubility were produced by introducing a pyridine or a pyrimidine ring. This original route also opens access to new unpatented compounds.
Subject(s)
3',5'-Cyclic-GMP Phosphodiesterases/antagonists & inhibitors , Carbolines/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Catalysis , Copper , Cyclic Nucleotide Phosphodiesterases, Type 5 , Fluorescence Resonance Energy Transfer , Indicators and Reagents , Isomerism , Molecular Conformation , Structure-Activity Relationship , TadalafilABSTRACT
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.
Subject(s)
Aminopeptidases/antagonists & inhibitors , Combinatorial Chemistry Techniques/methods , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Aminopeptidases/chemistry , Animals , Drug Design , Drug Evaluation, Preclinical , Enzyme Activation/drug effects , Hydroxamic Acids/chemistry , Kidney/enzymology , Microsomes/enzymology , Molecular Structure , Protease Inhibitors/chemistry , Stereoisomerism , Structure-Activity Relationship , Swine , Zinc/chemistryABSTRACT
The synthesis of a new polymer-supported coupling reagent derived from 1-hydroxybenzotriazole is described. An aminomethylated polystyrene was functionalized by reaction with 3-nitro-4-chlorobenzenesulfonyl chloride (2) followed by treatement with hydrazine hydrate, to give the polymeric N-benzyl-1-hydroxybenzotriazole-6-sulfonamide (4).The polymeric reagent 4 was shown to be highly efficient for the synthesis of amides. The efficiency of 4 could be attributed to its high acidity, conferred by the sulfonyl moiety. The procedure for amide synthesis involves the formation of an activated ester on the derivatized polymer followed, in a second step, by treatment with an amine to generate the amide in solution. Simple filtration allows the separation of the product from the polymeric reagent which in this case plays the role of leaving group. An optimization study of this two-step procedure was performed. As amides are obtained in solution free of reaction byproducts, this method can be used in an automated procedure to recover them directly into a 96 well plate, ready to be used in high throughput screening assays. Thus 4 was shown to be particularly suitable for the high throughput parallel synthesis of amides libraries.
