SYNTHESIS AND α-GLUCOSIDASE INHIBITORY EVALUATION OF N-BENZENESULFONYL PYRIDAZINONE

Abstract

Turunan piridazinon diketahui memiliki berbagai aktivitas biologis, termasuk potensi sebagai antidiabetik melalui penghambatan enzim α-glukosidase. Pada penelitian ini, turunan N-benzensulfonil piridazinon, yaitu 6-(3-bromofenil)-2-(fenilsulfonil)piridazin-3(2H)-on (7), telah disintesis dan dikonfirmasi strukturnya menggunakan analisis FTIR, ¹H-NMR, dan HRMS. Studi molecular docking dilakukan menggunakan struktur α-glukosidase lisosomal manusia (PDB ID: 5NN5) untuk memprediksi afinitas ikatan dan interaksi kunci pada sisi aktif enzim. Hasil docking menunjukkan bahwa senyawa 7 memiliki binding score (S) sebesar –10,96, lebih tinggi dibandingkan akarbosa (S = –18,24), serta menghasilkan interaksi ikatan hidrogen yang lebih sedikit. Uji penghambatan α-glukosidase secara in vitro menggunakan enzim α-glukosidase Saccharomyces cerevisiae menunjukkan aktivitas yang lemah, di mana senyawa 7 hanya menghambat enzim sebesar 2,5% pada konsentrasi 50 μM, dibandingkan 47,8% oleh akarbosa. Meskipun sesuai prediksi docking, kelarutan senyawa 7 yang sangat rendah diduga berkontribusi terhadap perbedaan signifikan aktivitas biologis tersebut. Dengan demikian, kerangka piridazinon tetap menjadi struktur yang menjanjikan untuk dimodifikasi lebih lanjut guna meningkatkan potensi dan khususnya kelarutan senyawanya.

Pyridazinone derivatives are known for a wide range of biological activities, including potential antidiabetic properties through α-glucosidase inhibition. In this study, the N-benzenesulfonyl pyridazinone derivative, 6-(3-bromophenyl)-2-(phenylsulfonyl)pyridazin-3(2H)-one (7) was synthesized and confirmed its structure by using FTIR, ¹H-NMR, and HRMS analyses. Molecular docking was performed using the human lysosomal α-glucosidase structure (PDB ID: 5NN5) to predict its binding affinity and key interactions within the active site. Docking results showed that compound 7 exhibited a binding score (S) of –10.96, lower than that of acarbose (S = –18.24), and formed fewer hydrogen-bond interactions. The in vitro α-glucosidase inhibitory assay using Saccharomyces cerevisiae α-glucosidase demonstrated weak activity, where compound 7 inhibited the enzyme by only 2.5% at 50 μM, compared to 47.8% inhibition by acarbose. Although the result as predicted, the poor solubility of compound 7 may have contributed to significant difference of their biological activity. Therefore, the pyridazinone scaffold remains a promising structural framework for further modification to enhance potency and specifically its solubility.