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Facile synthesis of vanillin-based novel bischalcones identifies one that induces apoptosis and displays synergy with Artemisinin in killing chloroquine resistant Plasmodium falciparum
- Source :
- European journal of medicinal chemistry. 155
- Publication Year :
- 2018
-
Abstract
- 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 whose in vitro antiplasmodial activities have been evaluated against erythrocytic stages of Plasmodium falciparum. Bischalcones 9, 11 and 13 showed promising antiplasmodial activity {Chloroquine (CQ) sensitive Pf3D7 IC50 (μM): 2.0, 1.5 and 2.5 respectively}but only 13 displayed potent activities also against CQ resistant PfDd2 and PfIndo strains exhibiting resistance indices of 1.4 and 1.5 respectively. IC90 (8 μM) of 13 showed killing activity against ring, trophozoite and schizont stages. Further, 13 initiated 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 of 13 + Artemisinin (ART) exhibited strong synergy (ΣFIC50:0.46 to 0.58) while 13 + CQ exhibited mild synergy (ΣFIC50: 0.7 to 0.98) to mild antagonism (ΣFIC50: 1.08 to 1.23) against PfIndo. In contrast, both combinations showed marked antagonism against Pf3D7(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 resistant P. falciparum.
- Subjects :
- 0301 basic medicine
Programmed cell death
Cell Survival
Plasmodium falciparum
Drug Resistance
Apoptosis
01 natural sciences
03 medical and health sciences
Antimalarials
Structure-Activity Relationship
Chalcones
Parasitic Sensitivity Tests
Chloroquine
Cell Line, Tumor
Drug Discovery
medicine
Structure–activity relationship
Humans
Artemisinin
Pharmacology
biology
Dose-Response Relationship, Drug
Molecular Structure
010405 organic chemistry
Chemistry
Organic Chemistry
General Medicine
biology.organism_classification
Artemisinins
0104 chemical sciences
030104 developmental biology
Biochemistry
Benzaldehydes
DNA fragmentation
Antagonism
medicine.drug
HeLa Cells
Subjects
Details
- ISSN :
- 17683254
- Volume :
- 155
- Database :
- OpenAIRE
- Journal :
- European journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....964e402834afb2449cd8081c06bdb3fa