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Spiro Heterocyclic Compounds as Potential Anti-Alzheimer Agents (Part 2): Their Metal Chelation Capacity, POM Analyses and DFT Studies

Author(s):

Taibi Ben Hadda, Fatma Sezer Senol Deniz, Ilkay Erdogan Orhan, Hsaine Zgou, Abdur Rauf, Yahia Nasser Mabkhot, Brahim Bennani, Dalia R. Emam, Nabila Abdelshafy Kheder, Abdulrhman Asayari, Abdullatif Bin Muhsinah and Aneela Maalik*   Pages 1 - 10 ( 10 )

Abstract:


Background: One of the best methods to treat Alzheimer disease (AD) is through the effective use of cholinesterase inhibitors as vital drugs due to the identification of acetylcholine deficit in the AD patients.

Objective: The present study aims the investigation of spiro heterocyclic compounds as potential AD agents supported by their metal chelation capacity, POM analyses and DFT studies respectively.

Method: The cholinesterase inhibition and metal chelation ability was performed on ELISA microtiter assay. Whereas B3LYP method with 6-31+G(d,p) basis set was implemented to study HOMO-LUMO energy calculations. The pharmacokinetic properties of the synthesized molecules were studied through Petra, Osiris and Molinspiration (POM).

Results: The six spiro (1-6) skeletons were tested for their inhibitory potential and metal-chelation capacity. Our findings revealed that the tested spiro skeletons exerted none or lower than 50% inhibition against both cholinesterases, while compound 4 proved to be the most active molecule with 57.21±0.89% of inhibition toward BChE. The spiro molecule 3 exhibited the highest metal-chelation capacity (9.12±5.26%). Molecular docking model for the most active molecule exhibited promising bindings with AChE and BChE’s active site pertained to hydrophobic hydrogen bonds and positive ionizable interactions. The POM analyses gave the information about the flexibility at the site of coordination of spiro compounds (1-6).

Conclusion: The screening of spirocompounds (1-6) against cholinesterases revealed that some of them show considerable potential to inhibit AChE and BChE. Herein we propose that the spiro molecules after further derivatization could serve interesting AD inhibitor drugs.

Keywords:

Spiro molecules; anti-Alzheimer; cholinesterase; POM analysis; DFT studies, metal chelation

Affiliation:

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Umm AlQura University, Makkah 21955, Department of Pharmacognosy, Pharmacy Faculty, Gazi University, Ankara 06330, Department of Pharmacognosy, Pharmacy Faculty, Gazi University, Ankara 06330, Ibn Zohr University, Polydisciplinary Faculty, Ouarzazate, Department of Chemistry, University of Swabi, Anbar-23561, Khyber Pakhtunkhwa, Department of Pharmaceutical Chemistry, College of Pharmacy, King Khalid University, Abha 61421, LCO Laboratory, FSDM, Université Sidi Mohammed Ben Abdellah, Fès 30000, Department, Faculty of Science, Tanta University, 31527 Tanta, Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha , Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha , Department of Chemistry, COMSATS University Islamabad, Islamabad Campus, Park Road, Islamabad 45550



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