Abstract
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
Highlights
Compounds derived from 1,3,4-oxadiazole-2thione have received attention as new structural motifs for the design and development of novel drugs [1]
1,3,4-oxadiazole-2-thiones derivatives have been investigated as active jack bean urease inhibitors with promising anti-urease activities [13]
Chemicals and reagents used for the synthesis of target compounds were purchased from Sigma Aldrich and Merck (Lahore, Pakistan)
Summary
Compounds derived from 1,3,4-oxadiazole-2thione have received attention as new structural motifs for the design and development of novel drugs [1]. The inhibition of urease has attracted much attention as potential strategy for designing novel drugs against ulcer. More effective and more potent compounds with a whole new level of safety and specificity are still desired [11]. In this regard, high throughput virtual and in vitro biological assay of molecules to understand their molecular behaviour in specific environments, will aid the identification of potent molecules from a crude cocktail [12]. The aim of the current study was to synthesize Mannich bases derived from 1, 3, 4-oxadiazole-2-thione bearing 3, 4, 5-trimethoxy moiety and examine them as potential urease inhibitors and antioxidant agents
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