In vitro anti-malarial efficacy of chalcones: cytotoxicity profile, mechanism of action and their effect on erythrocytes

Shweta Sinha,Rakesh Sehgal,Ashish Bhalla,Daniela I Batovska,Nadezhda Markova,B D Radotra,Bikash Medhi

doi:10.1186/s12936-019-3060-z

Abstract

BackgroundMalaria extensively leads to mortality and morbidity in endemic regions, and the emergence of drug resistant parasites is alarming. Plant derived synthetic pharmaceutical compounds are found to be a foremost research to obtain diverse range of potent leads. Amongst them, the chalcone scaffold is a functional template for drug discovery. The present study involves synthesis of ten chalcones with various substitution pattern in rings A and B and assessment of their anti-malarial efficacy against chloroquine sensitive and chloroquine resistant strains as well as of their cytotoxicity and effect on haemozoin production.MethodsThe chalcones were synthesized by Claisen-Schmidt condensation between equimolar quantities of substituted acetophenones and aryl benzaldehydes (or indole-3-carboxaldehyde) and were screened for anti-malarial activity by WHO Mark III schizont maturation inhibition assay. The cytotoxicity profile of a HeLa cell line was evaluated through MTT viability assay and the selectivity index (SI) was calculated. Haemozoin inhibition assay was performed to illustrate mode of action on a Plasmodium falciparum strain.ResultsThe IC50 values of all compounds were in the range 0.10–0.40 μg/mL for MRC-2 (a chloroquine sensitive strain) and 0.14–0.55 μg/mL for RKL-9 (a chloroquine resistant strain) of P. falciparum. All the chalcones showed low cellular toxicity with minimal haemolysis. The statistically significant reduction (p < 0.05) in the haemozoin production suggests a similar mechanism than that of chloroquine.ConclusionsOut of ten chalcones, number 7 was found to be a lead compound with the highest potency (IC50 = 0.11 µg/mL), as compared to licochalcone (IC50 = 1.43 µg/mL) and with high selectivity index of 85.05.

Highlights

Malaria extensively leads to mortality and morbidity in endemic regions, and the emergence of drug resistant parasites is alarming
The test cultures were centrifuged for 5–10 min at 1300 rpm to dispose of the culture medium
Anti‐malarial activity The chloroquine sensitive (MRC-2) and chloroquine resistant (RKL-9) strains of P. falciparum were cultured in vitro under sufficient gaseous mixture in RPMI1640 medium and the culture was synchronized by treating with 5% d-sorbitol to acquire mainly ring stage Plasmodium as depicted in Fig. 3a, b

Summary

Introduction

Malaria extensively leads to mortality and morbidity in endemic regions, and the emergence of drug resistant parasites is alarming. The present study involves synthesis of ten chalcones with various substitution pattern in rings A and B and assessment of their anti-malarial efficacy against chloroquine sensitive and chloroquine resistant strains as well as of their cytotoxicity and effect on haemozoin production. Malaria control programmes are threatened due to a rapid expansion of resistance to distinct anti-malarial drugs. To combat drug resistant Plasmodium, artemisinin and its derivatives have been widely implicated all over in endemic regions, but appearance of artemisinin resistance, first in Cambodia in 2007 [2] and later its rapid spread to the south-east Asian region [3,4,5,6,7] has threatened all the previous success incurred by malaria control strategies.

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