Inhibition potential of phenyl linked benzimidazole-triazolothiadiazole modular hybrids against β-glucuronidase and their interactions thereof

Muhammad Taha; Nizam Uddin; Muhammad Ali; El Hassane Anouar; Fazal Rahim; Gulraiz Khan; Rai Khalid Farooq; Mohammed Gollapalli; Naveed Iqbal; Muhammad Farooq; Khalid Mohammed Khan

doi:10.1016/j.ijbiomac.2020.06.006

Inhibition potential of phenyl linked benzimidazole-triazolothiadiazole modular hybrids against β-glucuronidase and their interactions thereof

Int J Biol Macromol. 2020 Oct 15:161:355-363. doi: 10.1016/j.ijbiomac.2020.06.006. Epub 2020 Jun 5.

Authors

Affiliations

¹ Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia. Electronic address: [email protected].
² Department of Chemistry, University of Karachi, Karachi 75270, Pakistan.
³ Natural and Medical Sciences Research Center, University of Nizwa, P.O. Box 33, Birkat Al Mauz, Nizwa 616, Sultanate of Oman.
⁴ Department of Chemistry, College of Science and Humanities in Al-Kharj , Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia.
⁵ Department of Chemistry, Hazara University, Mansehra 21300, Khyber Pakhtunkhwa, Pakistan.
⁶ Environmental Engineering Department, College of Engineering Building A13, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia.
⁷ Department of Neuroscience Research, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia.
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.
⁹ Department of Chemistry, University of Poonch Rawalakot AJK, Pakistan.
¹⁰ Department of Physics, Hazara University, Mansehra 21300, Khyber Pakhtunkhwa, Pakistan.
¹¹ H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.

PMID: 32512086
DOI: 10.1016/j.ijbiomac.2020.06.006

Abstract

β-Glucuronidase is responsible for the catalytic deconjugation of β-d-glucuronides. β-Glucuronidase has evolved to be a viable molecular target for numerous therapeutic treatments. It plays a pivotal role in the metabolism of drugs and endogenous substances. Herein, we report the inhibitory potentials of newly developed and modular benzimidazole-triazolothiadiazole hybrids spaced through a phenyl linker (1-26) and their interactions with the β-glucuronidase. All analogues showed IC₅₀ values in the range of 1.30 ± 0.10 to 44.10 ± 0.80 μM, and hence were found to have outstanding inhibitory potential as compare to the standard D-saccharic acid 1,4-lactone (IC₅₀ = 48.4 ± 1.25 μM). These modular hybrids were successfully synthesized, rigorously characterized through various spectroscopic techniques. Molecular docking studies further revealed the potential interactions between the inhibitor and active amino acid site in β-glucuronidase. These findings helped in identifying the potential for new drug candidates. A Plausible structure activity relationship (SAR) were established which suggested that variation in the inhibitory potential was mainly based upon the substituents attached to the phenyl ring.

Keywords: Benzimidazole; Molecular docking study; Structure-activity-relationship; Synthesis; Thiadiazole; β-Glucuronidase inhibitory potential.

MeSH terms

Benzimidazoles / chemistry*
Glucuronidase / chemistry*
Molecular Docking Simulation
Molecular Dynamics Simulation
Molecular Structure
Structure-Activity Relationship
Thiadiazoles / chemistry*

Substances

Benzimidazoles
Thiadiazoles
Glucuronidase