Medicinal chemistry (Shariqah (United Arab Emirates)) · 2026
Discovery of Novel 1,3,4-oxadiazole-based Inhibitors Against Urease and Diabetes: Design, Synthesis, SAR, Biological, and Molecular Docking Screening.
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Arshad Sabeen, Maalik Aneela, Rehman Wajid, Khan Yousaf, Sarfraz Hina, Rasheed Liaqat, Hawsawi Mohammed B, Alluhaibi Mustafa S, Alharbi Majed
Аннотация
INTRODUCTION: Heterocyclic compounds bearing oxygen and nitrogen atoms are key pharmacophores in modern drug design. Among them, 1,3,4-oxadiazoles are notable for their diverse biological activities, including anti-inflammatory, anticancer, antidiabetic, antibacterial, and enzyme inhibitory effects. This study focuses on the synthesis and evaluation of indazole-based 1,3,4-oxadiazole-benzenesulfonothioate hybrids as potential therapeutic agents.
METHODS: A multistep synthetic route was employed to develop a series of eighteen (18) analogues. The synthetic strategy involved the formation of methyl 5-methyl-1H-indazole-3-carboxylate, conversion to carbohydrazide, cyclization with CS2, and final coupling with substituted benzenesulfonyl chlorides to yield the target hybrids (1-18).
RESULTS: The urease inhibition potential of scaffolds ranged from IC50 = 17.88 ± 0.36 to 37.98 ± 0.80 μM as compared to the standard drug thiourea (IC50 = 29.45 ± 0.76 μM). The exceptional urease and α-glucosidase activity was shown by scaffolds (4, 7, 9, 11) due to the presence of electron- withdrawing groups (-F, NO2, and Cl). In comparison, the α-glucosidase inhibition potential shown by all the scaffolds was in the range (IC50 = 3.19 ± 0.27 - 12.24 ± 1.33 μM). Compound-9 showed promising inhibitory potential against urease, with an IC50 = 17.90 ± 0.30 μM, and α- glucosidase (IC50 = 3.19 ± 0.27 μM), both indicating minimum IC50 values.
DISCUSSION: The enhanced activity of compounds bearing electron-withdrawing groups (F, NO2, Cl) supports their role in modulating enzyme inhibition. In silico molecular docking further confirmed strong binding affinities with the active sites of target enzymes, correlating well with the experimental results.
CONCLUSION: The synthesized 1,3,4-oxadiazole derivatives demonstrate promising dual inhibitory activity against urease and α-glucosidase, suggesting their potential as lead compounds in the treatment of gastric infections and diabetes. This study contributes to the ongoing development of multifunctional therapeutic agents with improved efficacy and selectivity.
METHODS: A multistep synthetic route was employed to develop a series of eighteen (18) analogues. The synthetic strategy involved the formation of methyl 5-methyl-1H-indazole-3-carboxylate, conversion to carbohydrazide, cyclization with CS2, and final coupling with substituted benzenesulfonyl chlorides to yield the target hybrids (1-18).
RESULTS: The urease inhibition potential of scaffolds ranged from IC50 = 17.88 ± 0.36 to 37.98 ± 0.80 μM as compared to the standard drug thiourea (IC50 = 29.45 ± 0.76 μM). The exceptional urease and α-glucosidase activity was shown by scaffolds (4, 7, 9, 11) due to the presence of electron- withdrawing groups (-F, NO2, and Cl). In comparison, the α-glucosidase inhibition potential shown by all the scaffolds was in the range (IC50 = 3.19 ± 0.27 - 12.24 ± 1.33 μM). Compound-9 showed promising inhibitory potential against urease, with an IC50 = 17.90 ± 0.30 μM, and α- glucosidase (IC50 = 3.19 ± 0.27 μM), both indicating minimum IC50 values.
DISCUSSION: The enhanced activity of compounds bearing electron-withdrawing groups (F, NO2, Cl) supports their role in modulating enzyme inhibition. In silico molecular docking further confirmed strong binding affinities with the active sites of target enzymes, correlating well with the experimental results.
CONCLUSION: The synthesized 1,3,4-oxadiazole derivatives demonstrate promising dual inhibitory activity against urease and α-glucosidase, suggesting their potential as lead compounds in the treatment of gastric infections and diabetes. This study contributes to the ongoing development of multifunctional therapeutic agents with improved efficacy and selectivity.