Exploring biologically active hybrid pharmacophore N-substituted hydrazine-carbothioamides for urease inhibition: In vitro and in silico approach

Saira Naseem; Muhammad Ashraf; Samra Khan; Muhammad Rafiq; Muhammad Kashif; Jameel Rahman; Muhammad Khawar Rauf; Sobia Ahsan Halim; Jalal Uddin; Ajmal Khan; Ahmed Al-Harrasi; Zahid Shafiq

doi:10.1016/j.ijbiomac.2021.04.036

Exploring biologically active hybrid pharmacophore N-substituted hydrazine-carbothioamides for urease inhibition: In vitro and in silico approach

Int J Biol Macromol. 2021 Jul 1:182:534-544. doi: 10.1016/j.ijbiomac.2021.04.036. Epub 2021 Apr 9.

Authors

Affiliations

¹ Institute of Chemical Sciences, Bahauddin Zakariya University, Multan 60800, Pakistan.
² Institute of Chemistry, The Islamia University Bahawalpur, Bahawalpur 63100, Pakistan.
³ Institute of Chemical Sciences, Bahauddin Zakariya University, Multan 60800, Pakistan; Department of Chemistry, The Women University, Multan 60000, Pakistan.
⁴ School of Chemistry and Chemical Engineering, South China University of Technology, Guanzhou 510640, China.
⁵ Department of Chemistry, Emerson University Multan, Bosan Road, Multan, Pakistan.
⁶ Department of Chemistry, Govt. Post-Graduate Gordon College Rawalpindi, Pakistan.
⁷ Natural and Medical Sciences Research Center, University of Nizwa, PO Box 33, 616 Birkat Al Mauz, Nizwa, Oman.
⁸ Department of Pharmaceutical Chemistry, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia.
⁹ Natural and Medical Sciences Research Center, University of Nizwa, PO Box 33, 616 Birkat Al Mauz, Nizwa, Oman. Electronic address: ajmalkhan@unizwa.edu.om.
¹⁰ Natural and Medical Sciences Research Center, University of Nizwa, PO Box 33, 616 Birkat Al Mauz, Nizwa, Oman. Electronic address: aharrasi@unizwa.edu.om.
¹¹ Institute of Chemical Sciences, Bahauddin Zakariya University, Multan 60800, Pakistan. Electronic address: zahidshafiq@bzu.edu.pk.

PMID: 33839183
DOI: 10.1016/j.ijbiomac.2021.04.036

Abstract

Urease is potential target for various human's health complications, such as peptic ulcer, gastric cancer and kidney stone formation. The present study was based on synthesis of new hybrid pharmacophore N-substituted hydrazine-carbothioamides as potential urease inhibitors. Presented method gave excellent yield in range of 85-95% for hydrazine-carbothioamides derivatives (3a-s) after reaction of mono- and disubstituted hydrazides (1a-k) and substituted isothiocyanates (2a-d). All newly derivatives were characterized by advanced spectroscopic techniques (FTIR, ¹HNMR, ¹³CNMR, EMS) and were assessed for their urease inhibition potential. All analogs except for 3k, 3l and 3m demonstrated strong inhibitory potential for urease with IC₅₀ values of 8.45 ± 0.14 to 25.72 ± 0.23 μM as compared to standard thiourea (IC₅₀ 21.26 ± 0.35 μM). The structure-activity relationship and mode of interaction was established by molecular docking studies. It was revealed that the N-substituted hydrazine-carbothioamides interacted with nickel atoms present in the active site of urease and supported the correlations with the experimental findings. Therefore, the afforded hydrazine-carbothioamides derivatives are interesting hits for urease inhibition studies with future prospects of modification and optimization.

Keywords: Hydrazine-carbothioamides; Molecular docking studies; SAR studies; Urease inhibition.

MeSH terms

Binding Sites
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology
Hydrazines / chemistry*
Hydrazines / pharmacology
Molecular Docking Simulation
Protein Binding
Quantitative Structure-Activity Relationship*
Thioamides / chemistry*
Thioamides / pharmacology
Urease / antagonists & inhibitors*
Urease / chemistry
Urease / metabolism

Substances

Enzyme Inhibitors
Hydrazines
Thioamides
hydrazinecarbothioamide
Urease