Synthesis, biological evaluation, QSAR analysis, and molecular docking of chalcone derivatives for antimalarial activity

Jufrizal Syahri, Kamal Rullah, Ria Armunanto, Emmy Yuanita, Beta Achromi Nurohmah, Mohd Fadhlizil Fasihi Mohd Aluwi, Kok Wai Lam, Bambang Purwono

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 μg/mL respectively against Pf3D7 strain (1.37 and 2.33 μg/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 r2 value (r2 = 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.

Original languageEnglish
Pages (from-to)8-13
Number of pages6
JournalAsian Pacific Journal of Tropical Disease
Volume7
Issue number1
DOIs
Publication statusPublished - 2017

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Molecular Docking Simulation
Chalcone
Antimalarials
Plasmodium falciparum
Inhibitory Concentration 50
Chloroquine
Catalysis
Chalcones
Folic Acid
Thymidine
Catalytic Domain
Ethanol
Software
Databases
Ligands

ASJC Scopus subject areas

  • Microbiology (medical)
  • Infectious Diseases

Cite this

Synthesis, biological evaluation, QSAR analysis, and molecular docking of chalcone derivatives for antimalarial activity. / Syahri, Jufrizal; Rullah, Kamal; Armunanto, Ria; Yuanita, Emmy; Nurohmah, Beta Achromi; Fasihi Mohd Aluwi, Mohd Fadhlizil; Lam, Kok Wai; Purwono, Bambang.

In: Asian Pacific Journal of Tropical Disease, Vol. 7, No. 1, 2017, p. 8-13.

Research output: Contribution to journalArticle

Syahri, Jufrizal ; Rullah, Kamal ; Armunanto, Ria ; Yuanita, Emmy ; Nurohmah, Beta Achromi ; Fasihi Mohd Aluwi, Mohd Fadhlizil ; Lam, Kok Wai ; Purwono, Bambang. / Synthesis, biological evaluation, QSAR analysis, and molecular docking of chalcone derivatives for antimalarial activity. In: Asian Pacific Journal of Tropical Disease. 2017 ; Vol. 7, No. 1. pp. 8-13.
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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 μg/mL respectively against Pf3D7 strain (1.37 and 2.33 μg/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 r2 value (r2 = 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.",
author = "Jufrizal Syahri and Kamal Rullah and Ria Armunanto and Emmy Yuanita and Nurohmah, {Beta Achromi} and {Fasihi Mohd Aluwi}, {Mohd Fadhlizil} and Lam, {Kok Wai} and Bambang Purwono",
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T1 - Synthesis, biological evaluation, QSAR analysis, and molecular docking of chalcone derivatives for antimalarial activity

AU - Syahri, Jufrizal

AU - Rullah, Kamal

AU - Armunanto, Ria

AU - Yuanita, Emmy

AU - Nurohmah, Beta Achromi

AU - Fasihi Mohd Aluwi, Mohd Fadhlizil

AU - Lam, Kok Wai

AU - Purwono, Bambang

PY - 2017

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N2 - 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 μg/mL respectively against Pf3D7 strain (1.37 and 2.33 μg/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 r2 value (r2 = 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.

AB - 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 μg/mL respectively against Pf3D7 strain (1.37 and 2.33 μg/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 r2 value (r2 = 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.

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