Design, synthesis, in vitro, and in silico studies of 4-fluorocinnamaldehyde based thiosemicarbazones as urease inhibitors

Muhammad Islam; Saeed Ullah; Ajmal Khan; Zahra Batool; Suraj N Mali; Shailesh S Gurav; Kholood A Dahlous; Saikh Mohammad; Javid Hussain; Ahmed Al-Harrasi; Zahid Shafiq

doi:10.1038/s41598-024-83386-4

Design, synthesis, in vitro, and in silico studies of 4-fluorocinnamaldehyde based thiosemicarbazones as urease inhibitors

Sci Rep. 2025 Jan 3;15(1):609. doi: 10.1038/s41598-024-83386-4.

Authors

Muhammad Islam^{1

2}, Saeed Ullah³, Ajmal Khan^{3

4}, Zahra Batool⁵, Suraj N Mali⁶, Shailesh S Gurav⁷, Kholood A Dahlous⁸, Saikh Mohammad⁸, Javid Hussain⁹, Ahmed Al-Harrasi¹⁰, Zahid Shafiq¹¹

Affiliations

¹ Department of Basic Sciences and Humanities (Chemistry), Muhammad Nawaz Sharif University of Engineering and Technology (MNSUET), 60000, Multan, Pakistan.
² School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Tianjin, 300072, China.
³ Natural and Medical Sciences Research Centre, University of Nizwa, Birkat Al Mauz, P.O. Box 33, Nizwa, PC 616, Sultanate of Oman.
⁴ Department of Chemical and Biological Engineering, College of Engineering, Korea University, Seoul, 02841, Republic of Korea.
⁵ Institute of Chemical Sciences, Bahauddin Zakariya University, 60800, Multan, Pakistan.
⁶ School of Pharmacy, D.Y. Patil University (Deemed to be University), Sector 7, Nerul, Navi, Mumbai, 400706, India.
⁷ Department of Chemistry, VIVA College, Virar, Maharashtra, India.
⁸ Department of Chemistry, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia.
⁹ Department of Biological Sciences and Chemistry, University of Nizwa, Nizwa, Oman.
¹⁰ Natural and Medical Sciences Research Centre, University of Nizwa, Birkat Al Mauz, P.O. Box 33, Nizwa, PC 616, Sultanate of Oman. aharrasi@unizwa.edu.om.
¹¹ Department of Chemical and Biological Engineering, College of Engineering, Korea University, Seoul, 02841, Republic of Korea. zahidshafiq@bzu.edu.pk.

Abstract

Clinically significant problems such as kidney stones and stomach ulcers are linked to the activation of the urease enzyme. At low pH, this enzyme gives an ideal environment to Helicobacter pylori in the stomach which is the cause of gastric ulcers and peptic ulcers. In recent work, we have developed a library of 4-fluorocinnamaldehyde base thiosemicarbazones and assessed them for their potential against urease enzyme. The synthesized compounds displayed significant to moderate inhibition potential with IC₅₀ values ranging from 2.7 ± 0.5 µM to 29.0 ± 0.5 µM. compound 3c displayed the highest inhibition potential followed by 3a and 3b. Two compounds of the series 3f and 3 g remained inactive against urease. The kinetic study of compound 3c exhibited a competitive type of inhibition with a K_i value of 3.26 ± 0.0048 µM. SAR analysis was also thoroughly done. Molecular docking was used to analyze the interaction pattern of each derivative, and the outcomes demonstrated that the compounds had excellent binding interactions with the active site.

Keywords: 4-fluorocinnamaldehyde; ADME; Docking; FMO; Thiosemicarbazones; Urease inhibition.

MeSH terms

Catalytic Domain
Computer Simulation
Drug Design*
Enzyme Inhibitors* / chemical synthesis
Enzyme Inhibitors* / chemistry
Enzyme Inhibitors* / pharmacology
Helicobacter pylori / drug effects
Helicobacter pylori / enzymology
Humans
Kinetics
Molecular Docking Simulation*
Structure-Activity Relationship
Thiosemicarbazones* / chemical synthesis
Thiosemicarbazones* / chemistry
Thiosemicarbazones* / pharmacology
Urease* / antagonists & inhibitors
Urease* / chemistry
Urease* / metabolism

Substances

Urease
Thiosemicarbazones
Enzyme Inhibitors