Sintesis, Karakterisasi Struktur, dan Kajian In Silico Potensi 2'-Hidroksicalkon dan Flavonol Tersubstitusi Trimetoksi sebagai Inhibitor Main Protease (MPro) SARS-CoV-2

Ihsan Ikhtiarudin, Neni Frimayanti, Musyirna Rahmah Nasution, Rabiatul Adawiyah, Enda Mora, Abdi Wira Septama

Abstract

Pada penelitian ini, 2'-hidroksicalkon (C345) dan flavonol (F345) tersubstitusi trimetoksi telah disintesis menggunakan metode iradiasi microwave dan metode pengadukan. Struktur kedua produk telah dikarakterisasi melalui analisis spektroskopi UV-Vis, FT-IR, 1H NMR, 13C NMR, dan HRMS. Hasil analisis spektroskopi menunjukkan bahwa kedua produk memiliki struktur yang sesuai dengan struktur molekul target yang diharapkan. Selain itu, hasil sintesis juga menunjukkan bahwa metode iradiasi microwave terbukti dapat mempercepat waktu reaksi (dari 1,5-3,0 jam menjadi 3-6 menit) dan meningkatkan rendemen produk murni pada sintesis senyawa C345 (55,31 %) dan F345 (83,65 %). Selanjutnya, hasil docking menunjukkan bahwa kedua senyawa dapat membentuk ikatan hidrogen dengan beberapa residu penting pada sisi aktif dan dapat terikat pada kedua situs katalik MPro SARS-CoV-2 (PDB ID:6M2N), yaitu His41 dan Cys145 melalui interaksi hidrofobik dengan nilai energi bebas pengikatan yang lebih negatif (-8,95 dan -9,02 kcal/mol) dibandingkan dengan baicalein sebagai inhibitor pembanding. Hasil kajian in silico lainnya juga menunjukkan bahwa kedua senyawa memiliki profil farmakokinetik yang baik dan memiliki sifat kemiripan dengan obat berdasarkan aturan Lipinski, Ghose, Veber, Egan, dan Muegge. Selain itu, senyawa F345 juga diprediksi memiliki risiko toksisitas yang lebih kecil dibandingkan dengan baicalein. 

Synthesis, Structural Characterization, and In Silico Study of the Potential of 2'-Hydroxychalcone and Trimethoxy-Substituted Flavonols as Inhibitors of the Main Protease (MPro) of SARS-CoV-2. In this study, trimethoxy-substituted 2'-hydroxychalcone (C345) and flavonol (F345) were synthesized using microwave irradiation and stirring methods. The structure of the two products were characterized by spectroscopic analyses including UV-Vis, FT-IR, 1H NMR, 13C NMR, and HRMS. The result of spectroscopic analyses showed that the products had structures consistent with the expected target molecules. In addition, the synthesis results showed that the microwave irradiation method was proven to speed up the reaction time (from 1.5-3.0 hours to 3-6 minutes) and increased the yield of pure product in the synthesis of compounds C345 (55.31 %) and F345 (83.65 %). Furthermore, the docking result showed that the two compounds can form hydrogen bonds with several important residues on the active site and also can bind to catalytic dyad of the SARS-CoV-2 MPro (PDB ID:6M2N), namely His41 and Cys145 through hydrophobic interactions with a more negative binding free energy (-8.95 and -9.02 kcal/mol) than baicalein as a reference inhibitor. The result of silico studies also showed that the two compounds exhibited good pharmacokinetic profiles and drug-likeness properties based on Lipinski, Ghose, Veber, Egan, and Muegge rules. In addition, compound F345 was also predicted to has a smaller toxicity risk compared to baicalein.

Keywords

2'-hydroxychalcone; covid-19; microwave irradiation; molecular docking; trimethoxyflavonol.

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References

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DOI: https://doi.org/10.20961/alchemy.20.1.78445.98-119

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