Exploration of thiazine Schiff bases as promising urease inhibitors: Design, synthesis, enzyme inhibition, kinetic analysis, ADME/T evaluation, and molecular docking studies

Yousaf Khan; Mehwish Solangi; Khalid Mohammed Khan; Nisar Ullah; Jamshed Iqbal; Zahid Hussain; Imtiaz Ali Khan; Uzma Salar; Muhammad Taha

doi:10.1016/j.ijbiomac.2024.136361

Exploration of thiazine Schiff bases as promising urease inhibitors: Design, synthesis, enzyme inhibition, kinetic analysis, ADME/T evaluation, and molecular docking studies

Int J Biol Macromol. 2024 Oct 8;281(Pt 2):136361. doi: 10.1016/j.ijbiomac.2024.136361. Online ahead of print.

Authors

Yousaf Khan¹, Mehwish Solangi¹, Khalid Mohammed Khan², Nisar Ullah³, Jamshed Iqbal⁴, Zahid Hussain⁵, Imtiaz Ali Khan⁵, Uzma Salar⁶, Muhammad Taha⁷

Affiliations

¹ H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
² H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan; Pakistan Academy of Sciences, 3-Constitution Avenue Sector G-5/2, Islamabad, Pakistan. Electronic address: [email protected].
³ Chemistry Department, King Fahd University of Petroleum & Minerals, Dhahran, 31261, Saudi Arabia.
⁴ Pakistan Academy of Sciences, 3-Constitution Avenue Sector G-5/2, Islamabad, Pakistan; Center for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan; Institute of Intelligent Machines, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China.
⁵ Center for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan; Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan.
⁶ Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
⁷ Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P. O. Box 31441, Dammam, Saudi Arabia.

PMID: 39383915
DOI: 10.1016/j.ijbiomac.2024.136361

Abstract

Urease catalyzes the hydrolysis of urea, leading to an increase in stomach pH and supporting Helicobacter pylori survival, which is linked to several gastrointestinal disorders. In this study, thiazine-based Schiff bases were explored as promising urease inhibitors. Various spectroscopic techniques characterized the synthetic library of thiazine Schiff bases 2-36 and also evaluated for their inhibitory activities against urease. The derivatives demonstrated significant inhibitory potential with IC₅₀ values ranging from 0.14 ± 0.08 to 3.66 ± 0.21 μM, outperforming the standard inhibitor thiourea (IC₅₀ = 19.43 ± 0.18 μM). Structure-activity relationship (SAR) studies revealed that specific substitutions (type and positions) on the aryl ring significantly affect the inhibition potential. The most potent derivative, compound 7, possessed 2-methoxy-5-trifluoromethyl substitutions and exhibited an IC₅₀ of 0.14 ± 0.08 μM. Enzyme kinetics studies revealed that the most potent derivatives function as competitive inhibitors. Additionally, molecular docking studies provided insights into the binding interactions between the molecule and the urease active site, highlighting key residues involved in inhibitor binding. These findings highlight the therapeutic potential of thiazine-based Schiff bases as urease inhibitors and provide insights for the development of new anti-ulcer agents.

Keywords: Anti-ulcer activity; Enzyme kinetics; Molecular docking; Synthesis; Thiazine-Schiff bases.