1,4-Bis(3-Aminopropyl)Piperazine Libraries: From the Discovery of Classical Chloroquine-Like Antimalarials to the Identification of New Targets

Title: 1,4-Bis(3-Aminopropyl)Piperazine Libraries: From the Discovery of Classical Chloroquine-Like Antimalarials to the Identification of New Targets

Volume: 8 Issue: 1

Author(s): Rebecca Deprez-Poulain and Patricia Melnyk

Affiliation:

Keywords: antimalarials, piperazine, 4-aminoquinoline, benzimidazole, chemogenomics, pfa-m1

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 β-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.

Cite this article as:

Deprez-Poulain Rebecca and Melnyk Patricia, 1,4-Bis(3-Aminopropyl)Piperazine Libraries: From the Discovery of Classical Chloroquine-Like Antimalarials to the Identification of New Targets, Combinatorial Chemistry & High Throughput Screening 2005; 8 (1) . https://dx.doi.org/10.2174/1386207053328165