Spirocyclic Chromanes Exhibit Antiplasmodial Activities And Inhibit All Intraerythrocytic Life Cycle Stages

Keywords

Antimalarials; Antiplasmodials; Natural-product-like compounds; Novel mechanism of action; Spirocyclic chromane

Abstract

We screened a collection of synthetic compounds consisting of natural-product-like substructural motifs to identify a spirocyclic chromane as a novel antiplasmodial pharmacophore using an unbiased cell-based assay. The most active spirocyclic compound UCF 201 exhibits a 50% effective concentration (EC50) of 350 nM against the chloroquine-resistant Dd2 strain and a selectivity over 50 using human liver HepG2 cells. Our analyses of physicochemical properties of UCF 201 showed that it is in compliance with Lipinski's parameters and has an acceptable physicochemical profile. We have performed a limited structure-activity-relationship study with commercially available chromanes preserving the spirocyclic motif. Our evaluation of stage specificities of UCF 201 indicated that the compound is early-acting in blocking parasite development at ring, trophozoite and schizont stages of development as well as merozoite invasion. SPC is an attractive lead candidate scaffold because of its ability to act on all stages of parasite's aexual life cycle unlike current antimalarials.

Publication Date

4-1-2016

Publication Title

International Journal for Parasitology: Drugs and Drug Resistance

Volume

6

Issue

1

Number of Pages

85-92

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1016/j.ijpddr.2016.02.004

Socpus ID

84959234138 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/84959234138

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