Exploring indole-based-thiadiazole derivatives as potent acetylcholinesterase and butyrylcholinesterase enzyme inhibitors

Muhammad Taha; Fazal Rahim; Nizam Uddin; Ihsan Ullah Khan; Naveed Iqbal; El Hassane Anouar; Mohammed Salahuddin; Rai Khalid Farooq; Mohammed Gollapalli; Khalid Mohammed Khan; Ameeduzzafar Zafar

doi:10.1016/j.ijbiomac.2021.08.065

Exploring indole-based-thiadiazole derivatives as potent acetylcholinesterase and butyrylcholinesterase enzyme inhibitors

Int J Biol Macromol. 2021 Oct 1:188:1025-1036. doi: 10.1016/j.ijbiomac.2021.08.065. Epub 2021 Aug 11.

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: mtaha@iau.edu.sa.
² Department of Chemistry, Hazara University, Mansehra 21120, Pakistan.
³ Department of Chemistry, University of Karachi, Karachi 75270, Pakistan.
⁴ Department of Chemistry, University of Poonch, Rawalakot, AJK, Pakistan.
⁵ Department of Chemistry, College of Science and Humanities in Al-Kharj, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia.
⁶ Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), 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 H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
¹⁰ Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia.

PMID: 34390751
DOI: 10.1016/j.ijbiomac.2021.08.065

Abstract

Indole based thiadiazole derivatives (1-18) were synthesized and evaluated for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition. The IC₅₀ values of the synthesized analogues ranging between 0.17 ± 0.05 to 33.10 ± 0.6 μM against (AChE) and 0.30 ± 0.1 to 37.60 ± 0.6 μM against (BChE) enzymes. Among the series compounds 8 (IC₅₀ = 0.17 ± 0.05 μM) (IC₅₀ = 0.30 ± 0.1 μM), 9 (IC₅₀ = 0.30 ± 0.05 μM) (IC₅₀ = 0.60 ± 0.05 μM) and 10 (IC₅₀ = 1.30 ± 0.1 μM) (IC₅₀ = 2.60 ± 0.1) were found to be the most potent analogues bearing para, ortho, and meta-fluoro substitutions on phenyl ring attached to thiadiazole. In addition, all the synthesized scaffolds were characterized by using ¹H NMR, ¹³C NMR spectroscopy, and high-resolution Mass Spectrometry (HR-MS). To apprehend the binding mode of interaction of the most potent synthesized derivatives, a molecular docking study was performed.

Keywords: Acetylcholinesterase; Butyrylcholinesterase; Indole-based-thiadiazole.

MeSH terms

Acetylcholinesterase / metabolism*
Alzheimer Disease / drug therapy
Butyrylcholinesterase / metabolism*
Catalytic Domain
Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / pharmacology*
Humans
Indoles / chemical synthesis
Indoles / chemistry
Indoles / pharmacology*
Inhibitory Concentration 50
Molecular Docking Simulation
Structure-Activity Relationship
Thiadiazoles / chemical synthesis
Thiadiazoles / chemistry
Thiadiazoles / pharmacology*

Substances

Cholinesterase Inhibitors
Indoles
Thiadiazoles
indole
Acetylcholinesterase
Butyrylcholinesterase