Structure activity refinement of phenylsulfonyl piperazines as antimalarials that block erythrocytic invasion
File version
Author(s)
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
Griffith University Author(s)
Primary Supervisor
Other Supervisors
Editor(s)
Date
Size
File type(s)
Location
License
Abstract
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.
Journal Title
European Journal of Medicinal Chemistry
Conference Title
Book Title
Edition
Volume
214
Issue
Thesis Type
Degree Program
School
Publisher link
Patent number
Funder(s)
Grant identifier(s)
Rights Statement
Rights Statement
Item Access Status
Note
Access the data
Related item(s)
Subject
Medicinal and biomolecular chemistry
Organic chemistry
Pharmacology and pharmaceutical sciences
Antimalarial
Erythrocyte invasion
Malaria
Phenylsulfonyl piperazine
Plasmodium
Persistent link to this record
Citation
Nguyen, W; Dans, MG; Ngo, A; Gancheva, MR; Romeo, O; Duffy, S; de Koning-Ward, TF; Lowes, KN; Sabroux, HJ; Avery, VM; Wilson, DW; Gilson, PR; Sleebs, BE, Structure activity refinement of phenylsulfonyl piperazines as antimalarials that block erythrocytic invasion., European Journal of Medicinal Chemistry, 2021, 214