TURUNAN PIRAZOLINA TERKONJUGASI DAN DIBENZALSIKLOHEKSANON SEBAGAI ANTIMALARIA: MOLECULAR DOCKING, SINTESIS DAN UJI AKTIVITAS SECARA IN VITRO

MUZDALIFAH WALEULU, Prof. Drs. Bambang Purwono, M.Sc., Ph.D.; Dr. Muhammad Idham Darussalam Mardjan, S.Si., M.Sc.

2022 | Tesis | MAGISTER KIMIA

Molecular docking, sintesis dan uji bioaktivitas antimalaria senyawa dibenzalsikloheksanon (2,6-bis(E)-benzilidin)sikloheksanon (DS 1); 2,6-bis(E)-4-metoksibenzilidin)sikloheksanon (DS 2); 2,6-bis(E)-3,4-metoksibenzilidin)sikloheksanon (DS 3); serta (E)-7-benzilidin-2,3-difenil-3,3a,4,5,6,7-heksahidro-2H-indazol (PT 1); (E)-7-(4-metoksibenzilidin)-3-(4-metoksifenil)-3,3a,4,5,6,7-heksahidro-2H-indazol (PT 2); dan (E)-7-(4-metoksibenzilidin)-3-(3,4-dimetoksifenil)-3,3a,4,5,6,7-heksahidro-2H-indazol (PT 3) telah dilakukan. Molecular docking dilakukan terhadap protein PfLDH. Sintesis senyawa dibenzalsikloheksanon DS 1-3 dilakukan melalui reaksi kondensasi Claisen Schmidt antara sikloheksanon dan turunan aldehida aromatik benzaldehida, p-anisaldehida, dan veratraldehida terkatalisis basa NaOH. Sintesis senyawa pirazolina terkonjugasi PT 1-3 dilakukan dengan mereaksikan senyawa dibenzalsikloheksanon hasil sintesis dengan fenilhidrazin dengan NaOH sebagai katalis menggunakan metode refluks. Elusidasi struktur senyawa sintesis dilakukan menggunakan spektrometer FTIR, GC-MS, MS-MS, 1H-NMR dan 13C-NMR. Senyawa hasil sintesis diuji bioaktivitasnya sebagai antimalaria secara in vitro terhadap Plasmodium falciparum strain 3D7. Hasil penelitian molecular docking senyawa DS 1, DS 2, dan DS 3, serta PT 1, PT 2, dan PT 3 menghasilkan afinitas ikatan yang lebih rendah dan terbentuk interaksi secara spesifik dengan sisi aktif PfLDH. Nilai afinitas ikatan yang dihasilkan setiap senyawa secara berturut-turut adalah -7,82; -6,96; -7,44; -8,68; -8,07; dan -8,59 kkal/mol. Senyawa kontrol positif pada percobaan ini dilakukan terhadap senyawa kurkumin yang memberikan nilai energi interaksi sebesar -6,46 kkal/mol. Elusidasi senyawa DS 1, DS 2, DS 3, PT 1, PT 2 dan PT 3 yang disintesis menunjukkan kesesuaian pada data spektroskopi IR, GC-MS/ MS-MS, 1H-NMR, dan 13C-NMR. Hasil uji aktivitas malaria secara in vitro terhadap P. falciparum strain 3D7 menunjukkan bahwa senyawa DS 1 dan DS 3 dikategorikan aktif dan berpotensi sebagai antimalaria dengan IC50 12,99 dan 8,07 mikro Molar, sedangkan senyawa DS 2, PT 1, PT 2, dan PT 3 dikategorikan cukup aktif dengan IC50 86,39; 39,59; 41,31; dan 32,48 mikro Molar.

Molecular docking, synthesis, and antimalarial bioactivity test of dibenzalcyclohexanone (2,6-bis(E)-benzylidine)cyclohexanone (DS 1); 2,6-bis(E)-4-methoxybenzylidine)cyclohexanone (DS 2); 2,6-bis(E)-3,4-methoxybenzylidine)cyclohexanone (DS 3); (E)-7-benzylidin-2,3-diphenyl-3,3a,4,5,6,7-hexahydro-2H-indozole (PT 1); (E)-7-(4-methoxybenzylidine)-3-(4-methoxyphenyl)-3,3a,4,5,6,7-hexahydro-2H-indozole (PT 2); and (E)-7-(4-methoxybenzylidine)-3-(3,4-dimethoxyphenyl)-3,3a,4,5,6,7-hexahydro-2H-indozole (PT 3) have been carried out. Molecular docking has been done using PfLDH protein. Synthesis of dibenzalcyclohexanone DS 1-3 was conducted through Claisen Schmidt condensation reaction between cyclohexanone and aromatic aldehyde derivatives for benzaldehyde, p-anisaldehyde, and veratraldehyde catalyzed by NaOH. Synthesis of conjugated pyrazoline compounds PT 1-3 was carried out by reacting the synthesized dibenzalcyclohexanone and phenylhydrazine with NaOH as catalyst using reflux. Structural elucidation of the synthesized compounds was carried out using FTIR, GC-MS, MS-MS, 1H-NMR and 13C-NMR spectrometers. The synthesized compounds have been tested in vitro for their bioactivity as antimalarial against Plasmodium falciparum strain 3D7. Molecular docking studies of compounds DS 1, DS 2, and DS 3 as well as PT 1, PT 2, and PT 3 resulted in lower binding affinity and interacted specifically with the active site of PfLDH. The binding affinities of each compound were -7.82; -6.96; -7.44; -8.68; -8.07; and -8.59 kcal/mol respectively. The positive control compound in this experiment was carried out on curcumin resulted ini binding affinity value of -6.46 kcal/mol. The elucidation of the synthesized compounds DS 1, DS 2, DS 3, PT 1, PT 2 and PT 3 showed suitability with IR, 1H-NMR, 13C-NMR and MS-MS spectroscopy data. In vitro antimalarial activity test against P. falciparum strain 3D7 showed that compounds DS 1 and DS 3 were categorized as active and potential antimalarial with IC50 12.99 and 8.07 micro Molar, while compounds DS 2, PT 1, PT 2, and PT 3 were quite active with IC50 of 86.39; 39.59; 41.31; and 32.48 micro Molar respectively.

Kata Kunci : dibenzalcyclohexanone, conjugated pyrazoline, in vitro antimalarial test, molecular docking