SENYAWA ANALOG KURKUMIN MONOKETON BERBAHAN DASAR 4-KLOROBENZALDEHIDA SEBAGAI KANDIDAT ANTIMALARIA: PENAMBATAN MOLEKUL, SINTESIS DAN UJI AKTIVITAS ANTIMALARIA SECARA IN VITRO

FAUZAN SETIAWAN, Dr. Endang Astuti, M.Si.; Prof. Drs. Bambang Purwono, M.Sc., Ph.D.

2022 | Tesis | MAGISTER KIMIA

Studi penambatan molekul telah dilakukan terhadap senyawa analog kurkumin monoketon (1E,4E)-1,5-bis(4-klorofenil)-1,4-pentadien-3-on (AK A), (2E,5E)-2,5-bis(4-klorobenziliden)siklopentanon (AK B), (2E,6E)-2,6-bis(4-klorobenziliden)sikloheksanon (AK C), (3E,5E)-3,5-bis(4-klorobenziliden)-4-piperidon (AK D), (3E,5E)-3,5-bis(4-klorobenziliden)-1-metil-piperidin-4-on (AK E), dan (3E,5E)-3,5-bis(4-klorobenziliden)-1-benzil-piperidin-4-on (AK F) dengan protein PfLDH, PfENR dan PfATP6. Tiga senyawa analog kurkumin terbaik berdasarkan interaksi dengan residu asam amino spesifik dan nilai afinitas ikatan terendah hasil penambatan molekul disintesis melalui reaksi kondensasi Claisen-Schmidt dari 4-klorobenzaldehida dengan variasi keton. Hasil reaksi diidentifikasi menggunakan TLC scanner, FTIR, MS/MS, 1H-NMR dan 13C-NMR, diuji aktivitasnya sebagai kandidat antimalaria secara in vitro terhadap P. falciparum strain FCR3 dan 3D7, serta dievaluasi terhadap profil ADMET. Hasil penelitian diperoleh tiga senyawa analog kurkumin terbaik yaitu senyawa AK C, E, dan F yang berinteraksi dengan residu asam amino spesifik Ile54, Ala98, Ile119, Phe52, Val26 pada sisi aktif protein PfLDH. Senyawa AK C, E, dan F juga berinteraksi dengan residu asam amino spesifik Tyr267, Pro314, Phe368, Ile369, dan Lys285 pada sisi aktif protein PfENR, serta dengan residu asam amino spesifik Leu268 pada sisi aktif protein PfATP6. Ketiga senyawa analog kurkumin memiliki interaksi dengan residu asam amino spesifik dan nilai afinitas ikatan terendah terhadap protein PfLDH, PfENR dan PfATP6 dibandingkan dengan kurkumin. Sintesis senyawa AK C, E, dan F diperoleh rendemen masing-masing 56,51%; 56,52%; dan 30,39%. Uji aktivitas antimalaria secara in vitro menunjukkan senyawa AK C, E, dan F memiliki aktivitas antimalaria serta nilai indeks resistensi yang lebih baik dibandingkan kurkumin. Senyawa AK C, E, dan F memiliki nilai IC50 berturut-turut 0,173; 0,447; dan 0,018 μM terhadap P. falciparum strain FCR3, serta memiliki nilai IC50 berturut-turut 0,924; 2,268; dan 0,336 μM terhadap P. falciparum strain 3D7. Senyawa AK C, E, dan F memiliki nilai indeks resistensi yang lebih rendah dan memiliki profil ADMET yang lebih baik dari kurkumin sehingga berpotensi dikembangkan menjadi kandidat obat antimalaria.

Molecular docking studies have been carried out by the monoketone curcumin analogues compound of (1E,4E)-1,5-bis(4-chlorophenyl)-1,4-pentadiene-3-one (AK A), (2E,5E)-2,5-bis(4-chlorobenzyliden)cyclopentanone (AK B), (2E-6E)-2,6-bis(4-chlorobenzyliden)cyclohexanone (AK C), (3E,5E)-3.5-bis(4-chlorobenzyliden)-4-piperidone (AK D), (3E,5E)-3,5-bis(4-chlorobenzyliden)-1-methyl-piperidine-4-one (AK E), and (3E,5E)-3,5-bis(4-chlorobenzyliden)-1-benzyl-piperidine-4-one (AK F) with PfLDH, PfENR and PfATP6 proteins. The three best curcumin analog compounds are based on interactions with specific amino acid residues and the lowest molecular affinity value, synthesized through the condensation reaction of claisen-schmidt from 4-chlorobenzaldehyde with ketone variations. The reaction results were identified using TLC scanner, FTIR, MS/MS, 1H-NMR, and 13C-NMR, tested for their in vitro activity as antimalarial candidates against P. falciparum strains FCR3 and 3D7, and evaluated their ADMET profile. The results showed that the three best curcumin analogues were compounds AK C, E, and F which interacted with specific amino acid residues Ile54, Ala98, Ile119, Phe52, Val26 on the active site of PfLDH protein. Compounds AK C, E, and F also interacted with specific amino acid residues Tyr267, Pro314, Phe368, Ile369, and Lys285 on the active site of PfENR protein, as well as with specific amino acid residues of Leu268 on the active site of PfATP6 protein. The three curcumin analogue compounds have interactions with specific amino acid residues and the lowest binding affinity for PfLDH, PfENR and PfATP6 proteins compared to curcumin. Synthesis of AK C, E, and F was obtained in yields of 56.51%; 56.62%; and 30.39%, respectively. In vitro antimalarial activity test showed that AK C, E, and F had better antimalarial activity than curcumin. The IC50 of AK C, E, and F was 0.173; 0.447; and 0.018 μM, respectively against P. falciparum strain FCR3, and 0.924, 2.268, and 0.336 μM, respectively against P. falciparum strain 3D7. AK C, E, and F compounds have lower resistance index and have a good ADMET profile than curcumin so that they have the potential to be developed as antimalarial drug candidates

Kata Kunci : 4-klorobenzaldehida, analog kurkumin, penambatan molekul, aktivitas antimalaria.