AKTIVITAS ANTIMALARIA ANALOG KURKUMIN HASIL SINTESIS SINAMALDEHIDA DENGAN VARIASI KETON DAN STUDI IN SILICO TERHADAP ENZIM Plasmodium falciparum LACTATE DEHYDROGENASE (PfLDH)

PRATISTA ARGYANTI A, Dr. Endang Astuti, M.Si.; Prof. Dr.rer.nat. Harno Dwi Pranowo, M.Si.

2021 | Skripsi | S1 KIMIA

Telah dilakukan sintesis dan uji aktivitas antimalaria senyawa analog kurkumin berbahan dasar sinamaldehida dengan variasi keton berupa sikloheksanon (analog kurkumin A), siklopentanon (analog kurkumin B), dan aseton (analog kurkumin C) dan studi in silico terhadap enzim Plasmodium falciparum Lactate Dehydrogenase (PfLDH). Penelitian ini bertujuan untuk melakukan sintesis senyawa analog kurkumin melalui reaksi kondensasi aldol Claisen-Schmidt, melakukan uji antiplasmodium terhadap P. falciparum strain FCR-3, dan menentukan jenis interaksi antara senyawa analog kurkumin dengan reseptor enzim dengan studi in silico menggunakan teknik penambatan molekul. Sintesis dilakukan dengan mereaksikan sinamaldehida dengan variasi keton menggunakan katalis HCl 37% pada pengadukan di suhu ruang selama 24 jam. Reaksi dipantau dengan uji KLT setiap 30 menit dengan campuran eluen n-heksana:etil asetat (7:3). Reaksi kemudian dinetralkan dengan NaOH 40% (w/w) dan direkritalisasi dengan etanol. Karakterisasi senyawa hasil sintesis dilakukan dengan analisis elemental, FTIR, DI-MS, 1H-NMR dan 13C-NMR. Aktivitas antimalaria diuji secara in vitro terhadap P. falciparum strain FCR-3 dengan inkubasi 72 jam. Studi in silico dilakukan terhadap protein dari enzim PfLDH (PDB ID: 1U4O) dengan metode penambatan molekul menggunakan software AutoDock4. Senyawa analog kurkumin 2,5-bis(3-fenilalilidin)sikloheksanon (A); 2,5-bis(3-fenilalilidin)siklopentanon (B); dan 1,9-difenilnona-1,3,6,8-tetraen-5-on (C) berhasil disintesis dengan menghasilkan rendemen secara berurutan sebesar 69,9%; 75,6%; dan 54,5%. Uji in vitro terhadap P. falciparum strain FCR-3 senyawa analog kurkumin A, B, C memiliki aktivitas yang sangat aktif dengan nilai IC50 secara berurutan sebesar 2,27; 3,42; 3,85 µg/mL, sedangkan kurkumin memiliki aktivitas yang aktif dengan nilai IC50 5,11 µg/mL. Studi in silico analog kurkumin A, B, C, dan kurkumin dengan penambatan molekul menghasilkan nilai energi ikatan secara berurutan sebesar -6,12; -5,79; -5,16; dan -5,02 kkal mol-1 yang menunjukkan adanya afinitas ikatan yang tinggi dalam berikatan dengan sisi aktif enzim PfLDH sebagai antimalaria.

Curcumin analogue compounds based on cinnamaldehyde with variations of ketones in the form of cyclohexanone (analogue curcumin A), cyclopentanone (analogue curcumin B), and acetone (analogue curcumin C) were synthesized and tested for antimalarial activity, as well as in silico study of the Plasmodium falciparum Lactate Dehydrogenase (PfLDH) enzyme. The goal of this research were to synthesize curcumin analogue compounds using the Claisen-Schmidt aldol condensation method, to perform antiplasmodium tests on P. falciparum strain FCR-3, and to evaluate the bond energy of interaction between curcumin analogue compounds and enzyme receptors using in silico study by the molecular docking technique. The synthesis was carried out by reacting cinnamaldehyde with a variety of ketones with HCl 37% as a catalyst at room temperature for 24 hours while stirring. TLC tests with a mixture of eluent N-hexane:ethyl acetate (7:3) were performed every 30 minutes to monitor the reaction. The reaction was then recrystalized with ethanol after being neutralized with NaOH 40% (w/w). The characterization of the synthesized compounds was carried out by elemental analysis, FTIR, DI-MS, 1H-NMR and 13C-NMR. The antimalarial activity was assessed in vitro against the P. falciparum strain FCR-3 with a 72-hour incubation period. The protein of the PfLDH enzyme (PDB ID: 1U4O) was studied by in silico using tilizing the molecular docking method with AutoDock4 software. Analogue curcumin compounds 2,5-bis (3-phenylalilidine) cyclohexanone (A); 2,5-bis (3-phenylalilidine) cyclopentanone (B); 1,9-diphenylnona-1,3,6,8-tetraen-5-on (C) were successfully synthesized by producing 69.9%; 75.6%; and 54.5% yield. In vitro test against P. falciparum strain FCR-3 of analogue curcumin compounds A, B, C remarked good activity as antimalarial with its IC50 values were 2.27; 3.42; 3.85 µg/mL respectively than curcumin that was remarked moderately active and its IC50 was 5.11 µg/mL. In silico studies of analogue curcumin A, B, C, and curcumin control with molecular docking yielded bond energy values of -6.12; -5.79; -5.16; and -5.02 kcal mol-1 that showed its high bond affinity for bonding with the active site of the PfLDH enzyme as antimalarial.

Kata Kunci : antimalaria, kurkumin, penambatan molekul, PfLDH, Plasmodium falciparum