Open AccessStructure–Activity Relationship Studies Reveal New Astemizole Analogues Active against Plasmodium falciparum In Vitro
Author(s) -
Dickson Mambwe,
Malkeet Kumar,
Richard Ferger,
Dale Taylor,
Mathew Njoroge,
Dina Coertzen,
Janette Reader,
Mariëtte van der Watt,
Lyn-Marié Birkholtz,
Kelly Chibale
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.1c00328
Subject(s) - astemizole , gametocyte , chinese hamster ovary cell , plasmodium falciparum , herg , ic50 , chemistry , cytotoxicity , context (archaeology) , in vitro , stereochemistry , pharmacology , malaria , potassium channel , biology , biochemistry , biophysics , receptor , paleontology , immunology
In the context of drug repositioning and expanding the existing structure-activity relationship around astemizole (AST), a new series of analogues were designed, synthesized, and evaluated for their antiplasmodium activity. Among 46 analogues tested, compounds 21 , 30 , and 33 displayed high activities against asexual blood stage parasites ( Pf NF54 IC 50 = 0.025-0.043 μM), whereas amide compound 46 additionally showed activity against late-stage gametocytes (stage IV/V; Pf LG IC 50 = 0.6 ± 0.1 μM) and 860-fold higher selectivity over hERG ( 46 , SI = 43) compared to AST. Several analogues displaying high solubility (Sol > 100 μM) and low cytoxicity in the Chinese hamster ovary (SI > 148) cell line have also been identified.