Malaria is one of the most important parasitic infectious diseases as far as human suffering is concerned, with its burden being felt worldwide as seen by the huge numbers of deaths recorded each year. This is in part due to the unfortunate spread of resistance to most of the drugs that were once effective and safe. It is therefore crucial to invest research efforts into novel and structurally diverse antimalarials with different modes of action, that are not only able to circumvent resistance but are also efficacious at the different life cycle stages of the parasite in order to contribute to the disease eradication. A high-throughput screening of marketed drugs led to the identification of Astemizole as an antimalarial agent with activity in vitro and in vivo against both chloroquine-sensitive (CQ-S) and multi-drug resistant (MDR) strains of the human malaria parasite Plasmodium falciparum. Unfortunately, astemizole also possesses a serious cardiotoxicity risk due to its ability to potently block the hERG (human ether-a-go-go-related gene) potassium channel. Structure-activity relationship (SAR) studies have been conducted to employ different strategies aimed at countering hERG and improve intrinsic solubility while maintaining antimalarial activity. We have identified a series of ester bioisostere analogues of astemizole with in vitro asexual blood stage antiplasmodium potency in the nanomolar range, with some analogues also showing moderate in vitro gametocytocidal activity at both early and late gametocyte stages. Although hERG activity and solubility remain a concern within the series, the study has revealed critical molecular features that create a basis for further optimization.

Ester bioisostere analogues of Astemizole as potential antiplasmodium agents

2019 Fall National Meeting

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