Facile synthesis of vanillin-based novel bischalcones identifies one that induces apoptosis and displays synergy with Artemisinin in killing chloroquine resistant Plasmodium falciparum

摘要

The inherent affinity of natural compounds for biological receptors has been comprehensively exploited with great success for the development of many drugs, including antimalarials. Here the natural flavoring compound vanillin has been used as an economical precursor for the synthesis of a series of novel bischalcones whosein?vitroantiplasmodial activities have been evaluated against erythrocytic stages ofPlasmodium falciparum.Bischalcones9,11and13showed promising antiplasmodial activity {Chloroquine (CQ) sensitivePf3D7 IC50(μM): 2.0, 1.5 and 2.5 respectively}but only13displayed potent activities also against CQ resistantPfDd2 andPfIndo strains exhibiting resistance indices of 1.4 and 1.5 respectively. IC90(8?μM) of13showed killing activity against ring, trophozoite and schizont stages. Further,13initiated the cascade of reactions that culminates in programmed cell death of parasites including translocation of phosphatidylserine from inner to outer membrane leaflet, loss of mitochondrial membrane potential, activation of caspase like enzyme, DNA fragmentation and chromatin condensation. The combinations of13?+?Artemisinin (ART) exhibited strong synergy (ΣFIC50:0.46 to 0.58) while13?+?CQexhibited mild synergy(ΣFIC50: 0.7 to 0.98) to mild antagonism(ΣFIC50: 1.08 to 1.23) againstPfIndo. In contrast, both combinations showed marked antagonism againstPf3D7(ΣFIC50: 1.33 to 3.34). These features of apoptosis and strong synergy with Artemisinin suggest that bischalcones possess promising antimalarial drug-like properties and may also act as a good partner drugs for artemisinin based combination therapies (ACTs) against Chloroquine resistantP.?falciparum.