| Abstrak/Abstract |
Objective: To synthesize chalcone derivatives and investigate their antimalarial activity toward
chloroquine-sensitive Plasmodium falciparum 3D7 (Pf3D7) strain; to develop quantitative structureactivity
relationships (QSAR) model to estimate IC50 values for biological activity of antimalarial
and compared to experimental measurement; and to determine the binding interactions of the most
active compounds with targeting P. falciparum dihydrofolate reductase-thymidylate synthase using
molecular docking simulation.
Methods: Seven chalcone derivatives have been synthesized from substituted acetophenone and
substituted benzaldehyde in ethanol with the presence of bases catalysis at reflux condition. The
QSAR analysis was conducted by using Gaussian 09 software to predict IC50 value for antimalarial
activity. The in vitro test was evaluated against the chloroquine-sensitive Pf3D7 strain. Finally, the
docking studies were performed with the CDOCKER protocol under the receptor-ligand interaction
section in Discovery Studio® 3.1 (Accelrys, Inc., San Diego, USA).
Results: Among the synthesized chalcone, a prenylated chalcone 5c and an allylated chalcones
10a showed the best IC50 values of 1.08 and 1.73 ?g/mL respectively against Pf3D7 strain (1.37
and 2.33 ?g/mL based on QSAR analysis). Comparison between the prediction of IC50 value
generated from the QSAR and the outcome from an in vitro assay showed a similar result as
seen from the r
2
value (r
2
= 0.99). The most active compound 5c was employed in the docking
simulation to determine the potential binding interactions with active sites of P. falciparum
dihydrofolate reductase-thymidylate synthase (protein data bank ID: 1J3I). The docking simulation
study showed 5c bind well with Ala16, Ser108, Ile164, Trp48, and Phe58 which are the crucial
interactions that could possibly interrupt the sequential catalysis reactions in the thymidylate cycle
and subsequently prevent deoxythymidine monophosphate production and DNA synthesis. The
formed binding interaction (H-bond) toward residues of Ala16, Ser108, and Ile164 also indicate
the activity of 5c against chloroquine-resistance P. falciparum strain.
Conclusions: We have successfully determined the effects of some chalcone derivatives on
antimalarial activity against the chloroquine-sensitive Pf3D7 strain. Compound 5c and 10a were
described a good antiplasmodial compounds. Interestingly, these in vitro results relevance with IC50
predicted QSAR studies. Moreover, molecular docking simulation provided insight into the binding
modes of 5c into the anti-folate resistance from malarial P. falciparum |
