title: 1,4-bis(3-aminopropyl)piperazine libraries: from the discovery of classical chloroquine-like antimalarials to the identification of new targets.
abstract: The purpose of this review is to provide an update on our work based on the 1,4-bis(3-aminopropyl)piperazine skeleton and how it allowed our group to validate a new target. After a brief introduction where we will relate the way this substructure was introduced in our 4-aminoquinolinyl derivatives, we will present first the different libraries synthesized around this moiety: (1) libraries of sulfonamides, amides and amines derived from 4-aminoquinolines and, (2) libraries where the 4-aminoquinoline nucleus is replaced. High throughput evaluation of biological activity and physicochemical parameters will be presented. The evaluation of the anti-malarial activity of the compounds will be discussed in the light of a chloroquine-like mechanism (accumulation in the acidic food vacuole and inhibition of beta-hematin formation). In a second part we will present active 1,4-bis(3-aminopropyl)piperazine as tools for identification and/or validation of new antimalarial targets. Fluorescence assays on some derivatives show that they are surprisingly localized outside the food vacuole, suggesting the existence of other target(s). Secondly, we will present a library of 1,4-bis(3-aminopropyl)piperazine as inhibitors of the cytosolic aminopeptidase Pfa-M1, a new potential target for antimalarials.
authors.affiliation: Laboratoire de Chimie Générale et Bioinorganique, UMR CNRS 8525, Institut Pasteur de Lille et Faculté des Sciences Pharmaceutiques et Biologiques, 3 rue du Professeur Laguesse, F-59006 LILLE Cedex France. rpoulain@pharma.univ-lille2.fr
authors.forename: Rébecca
authors.initials: R
authors.lastname: Deprez-Poulain
authors.forename: Patricia
authors.initials: P
authors.lastname: Melnyk
mesh_terms: D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D010879:Piperazines; C486841:1,4-bis(3-aminopropyl)piperazine