Synthesis, biological evaluation and molecular docking studies of Mannich bases derived from 1, 3, 4-oxadiazole- 2-thiones as potential urease inhibitors

Purpose: To design and synthesize a series of new structural motifs of urease inhibitors, 3-[{(substituted phenyl) amino} methyl]-5-(3, 4, 5-trimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thiones and 3- {[(pyridin-2-yl)amino]methyl}-5-(3,4,5-trimethoxy phenyl)-1,3,4-oxadiazole-2(3H)-thiones from 1, 3, 4- oxadiazole-2-thione.Methods: Targeted Mannich base derivatives were synthesized by the reaction of 1, 3, 4-oxadiazole-2- thione with formaldehyde and respective aromatic amines. These structural motifs were subjected to 1H–NMR, 13C–NMR and mass spectrometric analysis. Compound 4, i.e., 1,3,4-oxadiazole-2-thione and its corresponding Mannich bases (5-17) were subjected to in silico screening as urease inhibitors, using crystal structure of urease (Protein Data Bank ID: 5FSE) as a model enzyme. Furthermore, the targeted compounds were evaluated for their in vitro urease inhibition and anti-oxidant activities using thiourea and propyl gallate as standards, respectively.Results: The docking score of targeted compounds predicted that they are promising urease inhibitors. Subsequently, in vitro studies on Jack bean urease supported the results from virtual screening, and found compounds 4, 5, 9,10,12, 13, 14 and 15 very potent urease inhibitors with half-maximal inhibitory concentration (IC50) values in the range of 5.93 ± 0.13 to 9.76 ± 0.11, relative to thiourea (IC50 = 21.25 ± 0.15). Compounds 4 – 6, and compounds 12 - 17 also exhibited higher antioxidant activities than propyl gallate.Conclusion: In view of their potent urease inhibition and antioxidant activities, these structural motifs have potentials as new candidates for the development of anti-ulcer drugs.Keywords: 1, 3, 4-Oxadiazole-2-thiones, Antioxidant, Molecular docking, Urease inhibition, Anti-ulcer

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