Exploration of morpholine-thiophene hybrid thiosemicarbazones for the treatment of ureolytic bacterial infections via targeting urease enzyme: Synthesis, biochemical screening and computational analysis.
Rubina Munir, Sumera Zaib, Muhammad Zia-Ur-Rehman, Hira Javed, Ayesha Roohi, Muhammad Zaheer, Nabiha Fatima, Mashooq Ahmad Bhat, Imtiaz Khan
Author Information
Rubina Munir: Department of Chemistry, Kinnaird College for Women, Lahore, Pakistan.
Sumera Zaib: Department of Basic and Applied Chemistry, Faculty of Science and Technology, University of Central Punjab, Lahore, Pakistan.
Muhammad Zia-Ur-Rehman: Applied Chemistry Research Centre, PCSIR Laboratories Complex, Lahore, Pakistan.
Hira Javed: Department of Basic and Applied Chemistry, Faculty of Science and Technology, University of Central Punjab, Lahore, Pakistan.
Ayesha Roohi: Department of Chemistry, Kinnaird College for Women, Lahore, Pakistan.
Muhammad Zaheer: Applied Chemistry Research Centre, PCSIR Laboratories Complex, Lahore, Pakistan.
Nabiha Fatima: Department of Chemistry, Kinnaird College for Women, Lahore, Pakistan.
Mashooq Ahmad Bhat: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Imtiaz Khan: Department of Chemistry and Manchester Institute of Biotechnology, The University of Manchester, Manchester, United Kingdom.
An important component of the pathogenicity of potentially pathogenic bacteria in humans is the urease enzyme. In order to avoid the detrimental impact of ureolytic bacterial infections, the inhibition of urease enzyme appears to be an appealing approach. Therefore, in the current study, morpholine-thiophene hybrid thiosemicarbazone derivatives () were designed, synthesized and characterized through FTIR, H NMR, C NMR spectroscopy and mass spectrometry. A range of substituents including electron-rich, electron-deficient and inductively electron-withdrawing groups on the thiophene ring was successfully tolerated. The synthesized derivatives were evaluated for their potential to inhibit urease enzyme using the indophenol method. The majority of compounds were noticeably more potent than the conventional inhibitor, thiourea. The lead inhibitor, 2-(1-(5-chlorothiophen-2-yl)ethylidene)--(2-morpholinoethyl)hydrazinecarbothioamide () inhibited the urease in an uncompetitive manner with an IC value of 3.80 ± 1.9 µM. The findings of the docking studies demonstrated that compound has a strong affinity for the urease active site. Significant docking scores and efficient binding free energies were displayed by the lead inhibitor. Finally, the ADME properties of lead inhibitor () suggested the druglikeness behavior with zero violation.
