Muhammad Akram1, Abdul Rauf1, Aamer Saeed2, Faiz Ahmed1, Sidra Mubeen1, Muhammad Ashraf1, Safdar Hussain1, Ashfaq Mahmood Qureshi3
1Department of Chemistry, The Islamia University of Bahawalpur, Bahawalpur – 63100; 2Department of Chemistry, Quaid-i-Azam University, Islamabad – 45320; 3Institute of Chemical Sciences, Bahauddin Zakariya University, Multan - 60800, Pakistan.For correspondence:- Muhammad Akram Email:
Accepted: 15 October 2017 Published: 31 January 2018
Citation: Akram M, Rauf A, Saeed A, Ahmed F, Mubeen S, Ashraf M, et al. Synthesis, biological evaluation and molecular docking studies of Mannich bases derived from 1, 3, 4-oxadiazole-2-thiones as potential urease inhibitors. Trop J Pharm Res 2018; 17(1):127-134 doi: 10.4314/tjpr.v17i1.18
© 2018 The authors.
This is an Open Access article that uses a funding model which does not charge readers or their institutions for access and distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0) and the Budapest Open Access Initiative (http://www.budapestopenaccessinitiative.org/read), which permit unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited..
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
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