Astemizole analogues with reduced hERG inhibition as potent antimalarial compounds

Junjun Tian; Leen Vandermosten; Steve Peigneur; Lien Moreels; Jef Rozenski; Jan Tytgat; Piet Herdewijn; Philippe E Van den Steen; Steven De Jonghe

doi:10.1016/j.bmc.2017.10.004

Astemizole analogues with reduced hERG inhibition as potent antimalarial compounds

Bioorg Med Chem. 2017 Dec 15;25(24):6332-6344. doi: 10.1016/j.bmc.2017.10.004. Epub 2017 Oct 7.

Authors

Junjun Tian¹, Leen Vandermosten², Steve Peigneur³, Lien Moreels³, Jef Rozenski¹, Jan Tytgat³, Piet Herdewijn¹, Philippe E Van den Steen², Steven De Jonghe⁴

Affiliations

¹ Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
² Immunobiology, Rega Institute for Medical Research, Department of Microbiology and Immunology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
³ KU Leuven, Toxicology and Pharmacology, Campus Gasthuisberg, Onderwijs en Navorsing 2, Herestraat 49, PO Box 922, 3000 Leuven, Belgium.
⁴ Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Herestraat 49, 3000 Leuven, Belgium. Electronic address: steven.dejonghe@kuleuven.be.

PMID: 29042223
DOI: 10.1016/j.bmc.2017.10.004

Abstract

Astemizole is a H₁-antagonist endowed with antimalarial activity, but has hERG liabilities. Systematic structural modifications of astemizole led to the discovery of analogues that display very potent activity as inhibitors of the growth of the Plasmodium parasite, but show a decreased hERG inhibition, when compared to astemizole. These compounds can be used as starting point for the development of a new class of antimalarials.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antimalarials / chemical synthesis
Antimalarials / chemistry
Antimalarials / pharmacology*
Astemizole / chemical synthesis
Astemizole / chemistry
Astemizole / pharmacology*
Dose-Response Relationship, Drug
Humans
Molecular Structure
Parasitic Sensitivity Tests
Plasmodium falciparum / drug effects*
Plasmodium falciparum / growth & development
Structure-Activity Relationship
Transcriptional Regulator ERG / antagonists & inhibitors
Transcriptional Regulator ERG / metabolism

Substances

Antimalarials
ERG protein, human
Transcriptional Regulator ERG
Astemizole