Generation of bis-cationic heterocyclic inhibitors of Bacillus subtilis HPr kinase/phosphatase from a ditopic dynamic combinatorial library.
Ditopic dynamic combinatorial libraries were generated and screened toward inhibition of the bifunctional enzyme HPr kinase/phosphatase from Bacillus subtilis. The libraries were composed of all possible combinations resulting from the dynamic interconversion of 16 hydrazides and five monoaldehyde or dialdehyde building blocks, resulting in libraries containing up to 440 different constituents. Of all possible acyl hydrazones formed, active compounds containing two terminal cationic heterocyclic recognition groups separated by a spacer of appropriate structure could be rapidly identified using a dynamic deconvolution procedure. Thus, parallel testing of sublibraries where one specific component was excluded basically revealed all the essential components. A potent ditopic inhibitor, based on 2-aminobenzimidazole, was identified from the process.
Bunyapaiboonsri
Taridaporn
T
Laboratoire de Chimie Supramoléculaire, ISIS-Université Louis Pasteur, 4 rue Blaise Pascal, F-67000 Strasbourg, France.
Ramström
Helena
H
Ramström
Olof
O
Haiech
Jacques
J
Lehn
Jean-Marie
JM
D000447:Aldehydes / Q000737:chemistry; D001426:Bacterial Proteins; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques; D006834:Hydrazines / Q000737:chemistry; D010731:Phosphoenolpyruvate Sugar Phosphotransferase System / Q000037:antagonists & inhibitors* / Q000737:chemistry; D010749:Phosphoprotein Phosphatases / Q000737:chemistry*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship
D000447:Aldehydes; D001426:Bacterial Proteins; D001562:Benzimidazoles; D006834:Hydrazines; D010731:Phosphoenolpyruvate Sugar Phosphotransferase System; C030182:phosphocarrier protein HPr; C110847:HPr kinase; D017346:Protein Serine-Threonine Kinases; D010749:Phosphoprotein Phosphatases