Sintesis N-fenilpirazolina dari Turunan Metoksibenzaldehida dan 2-asetilpiridin serta Uji Aktivitasnya sebagai Antimalaria

Halimah Syaadiyah, Prof. Dra. Tutik Dwi Wahyuningsih, M.Si., Ph.D.; Dr. Endang Astuti, M.Si.

2023 | Tesis | S2 Ilmu Kimia

Sintesis senyawa N-fenilpirazolina 1-5 berbahan dasar 2-asetilpiridin dan berbagai turunan metoksibenzaldehida serta evaluasi bioaktivitasnya sebagai senyawa antimalaria telah dilakukan. Kalkon disintesis melalui reaksi kondensasi Claisen-Schmidt dengan mereaksikan 2-asetilpiridin dan turunan benzaldehida yaitu:  benzaldehida, 4-metoksibenzaldehida, 2,4-dimetoksibenzaldehida, 3,4-dimetoksibenzaldehida, dan 3,4,5-trimetoksibenzaldehida. Reaksi dilakukan dengan metode sonikasi menggunakan katalis kalium hidroksida 40% pada suhu kamar selama 4 jam. Selanjutnya, N-fenilpirazolina 1-5 disintesis melalui reaksi siklokondensasi menggunakan metode refluks antara kalkon dengan fenilhidrazin menggunakan NaOH sebagai katalis.  Elusidasi struktur dilakukan dengan instrumentasi FT-IR, GC-MS atau KLT densitometer, 1H- dan 13C-NMR. Untuk mengevaluasi aktivitas antimalarianya, N-fenilpirazolina 1-5 diuji secara in vitro terhadap P. falciparum 3D7 dan FCR-3.

Sintesis N-fenilpirazolina 1-5 menghasilkan padatan kuning dengan persen hasil masing-masing sebesar 81, 94, 91, 83, dan 59%. Uji aktivitas antimalaria terhadap P. falciparum menunjukkan bahwa N-fenilpirazolina 4 dan 5 memiliki aktivitas antimalaria paling baik dengan nilai IC50 masing-masing  sebesar 6,70 dan 11,79 µM terhadap strain 3D7, serta 9,94 dan 16,97 µM terhadap strain FCR-3. Indeks resistensi N-fenilpirazolina sebesar 1-36-1,52 dan hasil analisis drug-likeness menunjukkan senyawa N-fenilpirazolina 1-5 memenuhi aturan Lipinski. Oleh karena itu, senyawa N-fenilpirazolina 4 dan 5 memiliki potensi yang sangat baik sebagai kandidat antimalaria baru.

  

Synthesis of N-phenylpyrazoline 1-5 from 2-acetylpyridine and various methoxybenzaldehyde derivatives and evaluation of their antimalarial bioactivity have been conducted. The synthesis of chalcone involved a Claisen-Schmidt condensation between 2-acetylpyridine and benzaldehyde derivatives, i.e., benzaldehyde, 4-methoxybenzaldehyde, 2,4-dimethoxybenzaldehyde, 3,4-dimethoxybenzaldehyde, 3,4,5-trimethoxybenzaldehyde. The reaction was carried out using sonication method with a 40% potassium hydroxide catalyst at room temperature for 4 h. Subsequently, the pyrazoline was synthesized through a cyclocondensation reaction by refluxing chalcone with phenylhyrazine employing NaOH as a catalyst. Structure elucidation was performed using FT-IR, GC-MS, or TLC densitometer, 1H- and 13C-NMR. To evaluate their antimalarials activity, N-phenylpyrazolines 1-5 were tested in vitro against P. falciparum 3D7 and FCR-3.

The synthesis of N-phenylpyrazoline 1-5 yielded yellow solids in 81, 94, 91, 83, and 59%, respectively. Antimalarial activity test against P.falciparum showed that N-phenylpyrazolines 4 and 5 exhibited the most potent antimalarial activity with IC50 values of 6.70 and 11.79 µM, respectively, against 3D7 strain, and 9.94 and 16.97 µM, respectively, against FCR-3 strain. The resistance index of N-phenylpyrazolines were 1.36-1.52, and the drug-likeness analysis revealed that N-phenylpyrazolines 1-5 comply with the Lipinski rule. Therefore, N-phenylpyrazoline 4 and 5 exhibit great potential as novel antimalarial candidates.

Kata Kunci : 2-asetilpiridin, antimalaria, kalkon, N-fenilpirazolina, P. falciparum / 2-acetylpyridine, antimalarial, chalcone, N-phenylpyrazoline, P. falciparum.