Synthesis and characterization of new thiosemicarbazones, as potent urease inhibitors: In vitro and in silico studies

Muhammad Islam; Ajmal Khan; Muhammad Tariq Shehzad; Abdul Hameed; Nadeem Ahmed; Sobia Ahsan Halim; Mohammed Khiat; Muhammad Usman Anwar; Javid Hussain; René Csuk; Zahid Shafiq; Ahmed Al-Harrasi

doi:10.1016/j.bioorg.2019.03.008

Synthesis and characterization of new thiosemicarbazones, as potent urease inhibitors: In vitro and in silico studies

Bioorg Chem. 2019 Jun:87:155-162. doi: 10.1016/j.bioorg.2019.03.008. Epub 2019 Mar 6.

Authors

Affiliations

¹ Institute of Chemical Sciences, Bahauddin Zakariya University, Multan 60800, Pakistan; Natural and Medical Sciences Research Center, University of Nizwa, PO Box 33, 616 Birkat Al Mauz, Nizwa, Oman.
² Natural and Medical Sciences Research Center, University of Nizwa, PO Box 33, 616 Birkat Al Mauz, Nizwa, Oman.
³ Institute of Chemical Sciences, Bahauddin Zakariya University, Multan 60800, Pakistan.
⁴ Department of Chemistry, Forman Christian College (A Chartered University), Ferozepur Road, Lahore 54600, Pakistan.
⁵ Department of Biological Sciences and Chemistry, University of Nizwa, PO Box 33, 616 Birkat Al Mauz, Nizwa, Oman.
⁶ Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str.2, D-06120 Halle (Saale), Germany.
⁷ Institute of Chemical Sciences, Bahauddin Zakariya University, Multan 60800, Pakistan. Electronic address: [email protected].
⁸ Natural and Medical Sciences Research Center, University of Nizwa, PO Box 33, 616 Birkat Al Mauz, Nizwa, Oman. Electronic address: [email protected].

PMID: 30884309
DOI: 10.1016/j.bioorg.2019.03.008

Abstract

A new series of N-substituted thiosemicarbazones (3a-u) bearing 2-naphthyl and dihydrobenzofuranyl scaffolds were synthesized in good to excellent yields (78-95%). The synthesized compounds were characterized by advanced spectroscopic techniques, such as FTIR, ¹HNMR, ¹³CNMR and ESI-MS and evaluated as urease inhibitors. The structure of compound 3m was unambiguously confirmed by single crystal X-ray analysis. All compounds showed remarkable activities against urease enzyme with IC₅₀ values in range of 1.4-36.1 µM. The majority of the synthesized compounds showed higher activity than the standard compound thiourea. Molecular docking was performed to study the mode of interaction of these compounds and their structure-activity relationship. These studies revealed that the compounds bind at the active site and interacts with the nickel atom present in the binding site. The molecular docking demonstrated excellent co-relations with the experimental findings.

Keywords: Molecular docking; Spectroscopic techniques; Structure-activity relationship; Thiosemicarbazones; Urease inhibitors.

MeSH terms

Canavalia / enzymology*
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Molecular Docking Simulation
Molecular Structure
Structure-Activity Relationship
Thiosemicarbazones / chemical synthesis
Thiosemicarbazones / chemistry
Thiosemicarbazones / pharmacology*
Urease / antagonists & inhibitors*
Urease / metabolism

Substances

Enzyme Inhibitors
Thiosemicarbazones
Urease