Structure activity refinement of phenylsulfonyl piperazines as antimalarials that block erythrocytic invasion

The emerging resistance to combination therapies comprised of artemisinin derivatives has driven a need to identify new antimalarials with novel mechanisms of action. Central to the survival and proliferation of the malaria parasite is the invasion of red blood cells by Plasmodium merozoites, provid...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:European journal of medicinal chemistry 2021-03, Vol.214, p.113253, Article 113253
Hauptverfasser: Nguyen, William, Dans, Madeline G., Ngo, Anna, Gancheva, Maria R., Romeo, Ornella, Duffy, Sandra, de Koning-Ward, Tania F., Lowes, Kym N., Sabroux, Helene Jousset, Avery, Vicky M., Wilson, Danny W., Gilson, Paul R., Sleebs, Brad E.
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung:The emerging resistance to combination therapies comprised of artemisinin derivatives has driven a need to identify new antimalarials with novel mechanisms of action. Central to the survival and proliferation of the malaria parasite is the invasion of red blood cells by Plasmodium merozoites, providing an attractive target for novel therapeutics. A screen of the Medicines for Malaria Venture Pathogen Box employing transgenic P. falciparum parasites expressing the nanoluciferase bioluminescent reporter identified the phenylsulfonyl piperazine class as a specific inhibitor of erythrocyte invasion. Here, we describe the optimization and further characterization of the phenylsulfonyl piperazine class. During the optimization process we defined the functionality required for P. falciparum asexual stage activity and determined the alpha-carbonyl S-methyl isomer was important for antimalarial potency. The optimized compounds also possessed comparable activity against multidrug resistant strains of P. falciparum and displayed weak activity against sexual stage gametocytes. We determined that the optimized compounds blocked erythrocyte invasion consistent with the asexual activity observed and therefore the phenylsulfonyl piperazine analogues described could serve as useful tools for studying Plasmodium erythrocyte invasion. [Display omitted] •Key structural motifs necessary for asexual parasite potency were identified.•Analogues exhibit potent P. knowlesi and P. falciparum multi-drug resistant potency.•Phenylsulfonyl piperazine class has a unique erythrocyte invasion phenotype.•Optimized analogues are useful tools for studying Plasmodium erythrocyte invasion.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2021.113253