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

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.

Ultrastructural alterations in Plasmodium falciparum induced by chalcone derivatives

“…antigens which benefit in parasite sequestration, therefore the absence of these knobs leads in poor cytoadhesion [17]. Also, the food vacuole was intact but in condensed form in case of CQ-treated parasite, however, chalcone-treated parasites showed disintegrated food vacuole in mostly both CQsensitive and CQ-resistant strain, that suggest food vacuole may be the optimum target for chalcones 6 which is further supported by our previous finding on significant reduction in hemozoin formation after chalcone treatment [11].…”

“…The three chalcone derivatives 2, 6 and 7 were synthesized as described previously by our group [11]. Chloroquine phosphate was obtained from Sigma Aldrich and artemisinin from IPCA.…”

“…Chalcones (1,3-diaryl-2-propen-1-ones), a plant secondary metabolites is well known for its diverse pharmacological activity [7][8][9], including antimalarial activity [10]. It can also offer a huge repository of bioactive compounds with enormous molecular targets [11]. Earlier our group has reported three potent chalcone derivatives 2, 6 and 7 with antimalarial activity, screened from a series of recently synthesized chalcone derivatives under in vitro conditions on both chloroquine-sensitive and chloroquine-resistant strain of Plasmodium.…”

“…The study revealed even minor structural changes can increase the activity of a particular pharmacophore. Additionally, these derivatives act on the haeme degradation pathway of the malaria parasite, i.e., in a similar way as chloroquine does [11]. However, to better understand the effect and the mechanism by which these derivatives act on P. falciparum, an ultrastructure study was performed using the in vitro culture system.…”

Synthesis, Structure and In Vitro Anti-Trypanosomal Activity of Non-Toxic Arylpyrrole-Based Chalcone Derivatives

“…More importantly, chalcones are appealing as key synthetic intermediates and frameworks in the design of therapeutic tools for the treatment of various ailments including antimicrobial, antibacterial, antimalarial, anticancer, anti-inflammatory, anti-HIV, anti-Alzheimer's, etc. [24][25][26][27][28][29][30][31][32]. The structural modification of chalcones where the B-ring ( Figure 2) is substituted with other bioactive fragments or units is a contemporary strategy that has been extensively utilized by various research groups involved in designing bioactive compounds for the treatment of different diseases [33].…”