Synthesis, biological evaluation and molecular docking of N-phenyl thiosemicarbazones as urease inhibitors

Abdul Hameed; Khalid Mohammed Khan; Syeda Tazeen Zehra; Ramasa Ahmed; Zahid Shafiq; Syeda Mahwish Bakht; Muhammad Yaqub; Mazhar Hussain; Antonio de la Vega de León; Norbert Furtmann; Jürgen Bajorath; Hazoor Ahmad Shad; Muhammad Nawaz Tahir; Jamshed Iqbal

doi:10.1016/j.bioorg.2015.06.004

Synthesis, biological evaluation and molecular docking of N-phenyl thiosemicarbazones as urease inhibitors

Bioorg Chem. 2015 Aug:61:51-7. doi: 10.1016/j.bioorg.2015.06.004. Epub 2015 Jun 22.

Affiliations

¹ H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan. Electronic address: abdul.hameed@iccs.edu.
² H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
³ Institute of Chemical Sciences, Bahauddin Zakariya University, Multan, Pakistan.
⁴ Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan.
⁵ Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Dahlmannstr. 2, D-53113 Bonn, Germany; Pharmaceutical Institute, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
⁶ Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Dahlmannstr. 2, D-53113 Bonn, Germany.
⁷ Department of Physics, University of Sargodha, Sargodha, Pakistan.
⁸ Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan. Electronic address: drjamshed@ciit.net.pk.

PMID: 26119990
DOI: 10.1016/j.bioorg.2015.06.004

Abstract

Urease is an important enzyme which breaks urea into ammonia and carbon dioxide during metabolic processes. However, an elevated activity of urease causes various complications of clinical importance. The inhibition of urease activity with small molecules as inhibitors is an effective strategy for therapeutic intervention. Herein, we have synthesized a series of 19 benzofurane linked N-phenyl semithiocarbazones (3a-3s). All the compounds were screened for enzyme inhibitor activity against Jack bean urease. The synthesized N-phenyl thiosemicarbazones had varying activity levels with IC50 values between 0.077 ± 0.001 and 24.04 ± 0.14 μM compared to standard inhibitor, thiourea (IC50 = 21 ± 0.11 μM). The activities of these compounds may be due to their close resemblance of thiourea. A docking study with Jack bean urease (PDB ID: 4H9M) revealed possible binding modes of N-phenyl thiosemicarbazones.

Keywords: Benzofurane derivatives; Jack bean urease; Phenyl thiosemicarbazones; Thiosemicarbazides; Thiourea; Urease inhibitor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Canavalia / enzymology
Crystallography, X-Ray
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / metabolism
Molecular Conformation
Molecular Docking Simulation
Protein Binding
Protein Structure, Tertiary
Structure-Activity Relationship
Thiosemicarbazones / chemical synthesis
Thiosemicarbazones / chemistry*
Thiosemicarbazones / metabolism
Urease / antagonists & inhibitors*
Urease / metabolism

Substances

Enzyme Inhibitors
Thiosemicarbazones
Urease