Synthesis of oxadiazole-coupled-thiadiazole derivatives as a potent β-glucuronidase inhibitors and their molecular docking study

Muhammad Taha; Syahrul Imran; Munther Alomari; Fazal Rahim; Abdul Wadood; Ashik Mosaddik; Nizam Uddin; Mohammed Gollapalli; Mohammed A Alqahtani; Yasser A Bamarouf

doi:10.1016/j.bmc.2019.05.049

Synthesis of oxadiazole-coupled-thiadiazole derivatives as a potent β-glucuronidase inhibitors and their molecular docking study

Bioorg Med Chem. 2019 Jul 15;27(14):3145-3155. doi: 10.1016/j.bmc.2019.05.049. Epub 2019 Jun 4.

Authors

Affiliations

¹ Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 31441, Dammam, Saudi Arabia. Electronic address: mtaha@iau.edu.sa.
² Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor D. E., Malaysia.
³ Department of Stem Cell Research, Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, P. O. Box. 1982, Dammam 31441, Saudi Arabia.
⁴ Department of Chemistry, Hazara University, Mansehra 21120, Pakistan.
⁵ Department of Biochemistry, Abdul Wali Khan University Mardan, Mardan 23200, Pakistan.
⁶ Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 31441, Dammam, Saudi Arabia.
⁷ Department of Chemistry, University of Karachi, Karachi 75270, Pakistan.
⁸ Department of Computer Information Systems, College of Computer Science & Information Technology (CCSIT) Imam Abdulrahman Bin Faisal University P.O. Box 1982, Dammam 31441, Saudi Arabia.

PMID: 31196753
DOI: 10.1016/j.bmc.2019.05.049

Abstract

A new series of oxadiazole with thiadiazole moiety (6-27) were synthesized, characterized by different spectroscopic techniques and evaluated for β-glucuronidase inhibitory potential. Sixteen analogs such as 6, 7, 8, 9, 10, 12, 13, 14, 17, 18, 20, 23, 24, 25, 26 and 27 showed IC₅₀ values in the range of 0.96 ± 0.01 to 46.46 ± 1.10 μM, and hence were found to have excellent inhibitory potential in comparison to standard d-saccharic acid 1,4-lactone (IC₅₀ = 48.4 ± 1.25 μM). Two analogs such as 16 and 19 showed moderate inhibitory potential while analogs 11, 15, 21 and 22 were found inactive. Our study identifies new series of potent β-glucuronidase inhibitors for further investigation. Structure activity relationships were established for all compounds which showed that the activity is varied due to different substituents on benzene ring. The interaction of the compounds with enzyme active site were confirmed with the help of docking studies, which reveals that the electron withdrawing group and hydroxy group make the molecules more favorable for enzyme inhibition.

Keywords: Molecular docking study; Oxadiazole-thiadiazole; SAR; β-Glucuronidase inhibition.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Glycoproteins / pharmacology
Glycoproteins / therapeutic use*
Molecular Docking Simulation / methods*
Oxadiazoles / chemical synthesis*
Oxadiazoles / chemistry

Substances

Glycoproteins
Oxadiazoles
beta-glucuronidase inhibitor