Spirofused tetrahydroisoquinoline-oxindole hybrids as a novel class of fast acting antimalarial agents with multiple modes of action

Noella M Efange,Simon M N Efange,Lawrence Ayong,Rodrigue Keumoe,Maloba M M Lobe

doi:10.1038/s41598-020-74824-0

Noella M Efange, Simon M N Efange + Show 3 more

Open Access

https://doi.org/10.1038/s41598-020-74824-0

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Journal: Scientific Reports	Publication Date: Oct 21, 2020
Citations: 7	License type: open-access

Affiliation: University of Buea, Centre Pasteur du Cameroun

Abstract

Molecular hybridization of privileged scaffolds may generate novel antiplasmodial chemotypes that display superior biological activity and delay drug resistance. In the present study, we describe the in vitro activities and mode of action of 3′,4′-dihydro-2′H-spiro[indoline-3,1′-isoquinolin]-2-ones, a novel class of spirofused tetrahydroisoquinoline–oxindole hybrids, as novel antimalarial agents. Whole cell phenotypic screening of these compounds identified (14b), subsequently named (±)-moxiquindole, as the most potent compound in the current series with equipotent antiplasmodial activity against both chloroquine sensitive and multidrug resistant parasite strains with good selectivity. The compound was active against all asexual stages of the parasite including inhibition of merozoite egress. Additionally, (±)-moxiquindole exhibited significant inhibitory effects on hemoglobin degradation, and disrupted vacuolar lipid dynamics. Taken together, our data confirm the antiplasmodial activity of (±)-moxiquindole, and identify 3′4′-dihydro-2′H-spiro[indoline-3,1′-isoquinolin]-2-ones as a novel class of antimalarial agents with multiple modes of action.

Highlights

Molecular hybridization of privileged scaffolds may generate novel antiplasmodial chemotypes that display superior biological activity and delay drug resistance
In our search for novel antimalarial scaffolds, we chose to study the recently described 3′,4′-dihydro-2′H-spiro[indoline3,1′-isoquinolin]-2-ones (DSIIQs) which had been designed as molecular hybrids of two privileged scaffolds, tetrahydroisoquinoline (THIQ) and oxindole (OX)
(2) DSIIQs are structurally related to the naphthylisoquinolines (NIQs), a class of structurally diverse plant secondary metabolites characterized by the presence of a THIQ scaffold substituted with a naphthyl group

Summary

Introduction

Molecular hybridization of privileged scaffolds may generate novel antiplasmodial chemotypes that display superior biological activity and delay drug resistance. In our search for novel antimalarial scaffolds, we chose to study the recently described 3′,4′-dihydro-2′H-spiro[indoline3,1′-isoquinolin]-2-ones (DSIIQs) which had been designed as molecular hybrids of two privileged scaffolds, tetrahydroisoquinoline (THIQ) and oxindole (OX). These molecular hybrids offered a attractive target for investigation because they combine privileged scaffolds that occur separately in mechanistically disparate groups of antimalarial agents, spiroindolones and naphthylisoquinolines, as revealed below: Scientific Reports | (2020) 10:17932. The antimalarial activity appears to reside in the THIQ fragment and the mode of action of the NIQs appears to be primarily inhibition of hemoglobin degradation[17]

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