Sintesis kalkon dari benzaldehida dan turunan kloroasetofenon menggunakan metode microwave-asissted organic syinthesis serta uji aktivitas antiplasmodium falciparum secara in vitro dan in silico

ISTIQOMAH, Dr. Deni Pranowo, S.Si., M.Si. ; Dr. Winarto Haryadi, S.Si., M.Si.

2023 | Tesis | S2 Ilmu Kimia

Resistensi plasmodium terhadap obat malaria secara signifikan berkontribusi terhadap penurunan angka kesembuhan penderita malaria. Salah satu senyawa yang memiliki bioaktivitas sebagai antiplasmodium yakni kalkon dapat disintesis menggunakan metode Microwave-Assisted Organic Synthesis (MAOS) yang meningkatkan rendemen serta mengurangi waktu reaksi dibandingkan dengan metode konvensional. Sintesis 2-klorokalkon (Senyawa A), 3-klorokalkon (senyawa B) dan 4-klorokalkon (senyawa C) melalui reaksi kondensasi aldol Claisen-Schmidt menggunakan metode MAOS, uji aktivitas antiplasmodium serta penambatan molekul telah dilakukan. Kakon A, B dan C disintesis dari benzaldehida dan turunan kloroasetofenon (2-kloroasetofenon, 3-kloroasetofenon dan 4-kloroasetofenon) dengan katalis basa NaOH 40% (b/v). Optimasi waktu, daya dan suhu dilakukan terhadap reaksi sintesis menggunakan oven microwave. Hasil reaksi diidentifikasi menggunakan GC-MS, FTIR, 1H-NMR dan 13C-NMR. Uji aktivitas antiplasmodium dilakukan secara in vitro terhadap P. falciparum strain FCR3 dan 3D7. Penambatan molekul dilakukan secara in silico menggunakan perangkat lunak Autodock Vina terhadap reseptor PfLDH (PDB ID: 1CET) dan PfENR (PDB ID: 1NHG) serta prediksi profil farmakokinetik melalui analisis ADMET berbasis web. Hasil penelitian menunjukkan bahwa kalon A, B dan C telah berhasil disintesis menggunakan metode MAOS pada kondisi optimum waktu 10 menit, daya 640 Watt dan suhu 70oC, dengan rendemen berturut-turut 98,63%; 98,63%; dan 95,89%. Hasil aktivitas antiplasmodiium secara in vitro menujukkan bahwa kalkon A, B, dan C memiliki aktivitas antiplasmodium serta nilai indeks resistensi yang baik. Kalkon A, B dan C memiliki nilai IC50 berturut-turut 4,99; 2,71; dan 4,74 mikroM terhadap P. falciparum FCR3, serta memiliki nilai IC50 berturut-turut 2,55; 2,39; dan 2,48 mikroM terhadap P. falciparum 3D7. Penambatan molekul kalkon A, B dan C terhadap protein PfLDH dan PfENR menunjukkan bahwa kalkon A, B dan C beriteraksi dengan residu asam aino spesifik Phe52, Val26, Ile54, Ile119, dan Ala98 pada sisi aktif protein PfLDH, residu asam amino Tyr267, Tyr277, Gly313, Ile323, Phe368, Ile369, Ala372, dan Lys285 pada sisi aktif protein PfENR serta memiliki nilai afinitas ikatan yang rendah (negatif). Profil farmakokinetik menunjukkan senyawa hasil sintesis berpotensi dikembangkan menjadi kandidat obat malaria.

Plasmodium resistance to malaria drugs significantly contributes to the reduction in the cure rate for malaria sufferers. One of the compounds that has bioactivity as antiplasmodium, namely chalcone, can be synthesized using the Microwave-Assisted Organic Synthesis (MAOS) method which increases the yield and reduces reaction time compared to conventional methods. Synthesis of  E-1-(2-chlorophenyl)-3-phenylprop-2-en-1-one (chalcone A), E-1-(3-chlorophenyl)-3-phenylprop-2-en-1-one (chalcone B), and E-1-(4-chlorophenyl)-3-phenylprop-2-en-1-one (chalcone C) by Claisen-Schmidt aldol condensation reaction using the MAOS method, testing antiplasmodium activity and molecular docking were carried out. Chalcones A, B, and C were synthesized from benzaldehyde and chloroacetophenone derivatives (2-chloroacetophenone, 3-chloroacetophenone, and 4-chloroacetophenone) using 40% (w/v) NaOH as base catalyst. Optimization of time, power and temperature was carried out for the synthesis reaction using a microwave oven. The reaction products were identified using GC-MS, FTIR, 1H-NMR and 13C-NMR. Antiplasmodium activity test was carried out in vitro against P. falciparum strains FCR3 and 3D7. Molecular docking was performed in silico using Autodock Vina software against PfLDH (PDB ID:1CET) and PfENR (PDB ID:1NHG) receptors and prediction of pharmacokinetic profiles through web based ADMET analysis. The results showed that chalcones A, B, and C had been successfully synthesized using the MAOS method at an optimum condition of 10 minutes, 640 Watts of power and 70oC of temperature, with successive yields of 98.63%; 98.63%; and 95.89%. In vitro antiplamodium activity test showed that chalcones A, B, and C had good antimalarial activity and resistance index values. Chalcones A, B, and C have IC50 values of 4.99; 2.71; and 4.74 microM respectively against P. falciparum FCR3 and has an IC50 value of 2.55; 2.39; and 2.48 microM respectively against P. falciparum 3D7. Molecular docking of chalcones A, B, and C to the PfLDH and PfENR proteins shows that the chalcones A, B, and C which interacted with specific amino acid residues Phe52, Val26, Ile54, Ile119, and Ala98 on the active site of PfLDH protein, the amino acid residues Tyr267, Tyr277, Gly313, Ile323, Phe368, Ile369, Ala372, and Lys285 on the active site of PfENR protein and have a low (negative) bond affinity value. The pharmacokinetic profile shows that the synthesized compounds have the potential to be developed as malaria drug candidates.

Kata Kunci : 2-klorokalkon, 3-klorokalkon dan 4-klorokalkon, MAOS, aktivitas antiplasmodium, penambatan molekul