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

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.

In vitro potential antiviral SARS-CoV-19- activity of natural product thymohydroquinone and dithymoquinone from Nigella sativa

“…The invention of POM Theory leads us to identify each type of pharmacophore sites with real success, on the basis of semi-empirical data of about 7.000 antibacterial, antifungal, antitumor and antiviral commercial and new drugs. All details of therapeutic applications of POM Theory are given in the literature and the identification of different and various types of pharmacophore sites is well established [22] , [23] , [24] , [25] , [26] , [27] , [28] , [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] , [46] , [47] , [48] , [49] , [50] , [51] , [52] , [53] , [54] , [55] , [56] , [57] , [58] , [59] , [60] , [61] , [62] , [63] , [64] , [65] , [66] , [67] , [68] , [69] , [70] , [71] , [72] , [73] , [74] , [75] , [76] , [77] , [78] , [79] , [80] , [81] , [82] ,…”

How to face COVID-19: proposed treatments based on remdesivir and hydroxychloroquine in the presence of zinc sulfate. Docking/DFT/POM structural analysis

“…POM physicochemical analysis or ADME/T is important to qualify drugs and their efficacy as leading candidates against various biotargets, as like antibacterial (Grib et al, 2020 ; Hatzade et al, 2015 ; Jamalis et al, 2020 ; Jarrahpour et al, 2019 ; Mabkhot et al, 2015 , 2016 ; Messali et al, 2014 , 2015 ; Nasruddin et al, 2018 ; Rad et al, 2017 ; Rbaa et al, 2019 ; Sajid et al, 2016 ; Tatar et al, 2016 ), antifungal (Al-Maqtari et al, 2017 ; Khan et al, 2017 ; Rachedi et al, 2020 ; Radi et al, 2015 ; Tighadouni et al, 2016 ; Titi et al, 2019 ), antiviral (Chander et al, 2017 ; Lahsasni et al, 2015 ), antitumoral (Bechlem et al, 2020 ; Kamal et al, 2019 ; Piaz et al, 2018 ; Rachedi et al, 2019 , 2020 ; Youssoufi et al, 2015 ), antiparasitic drugs and various enzymes inhibitors (Amirkhanov et al, 2019 ; Ben Hadda et al, 2018 , 2020 ; Mabkhot et al, 2014 ; Rauf et al, 2017 ).…”

“…In addition to an excellent biological action, a drug molecule must have an excellent pharmacokinetic profile in the biological system. In the in silico method, Petra/Osiris/Molinspiration (POM), authenticated by almost 7,000 drug molecules that are available on the market, we have used well-known pharmacokinetic profiles in comparison with the five rules of Lipinski that found bio-availability predictions imperfectly (Ben Hadda et al, 2020 ).…”

Design, Synthesis, In Silico and POM Studies for the Identification of the Pharmacophore Sites of Benzylidene Derivatives

“…By using the theory of POM (Petra/Osiris/Molinspiration) analyses, it is now easier to identify and optimize most of the antibacterial [ 76 ], antifungal [ 77 ], antiviral [ 78 ], antiparasital [ 79 ] and antitumor [ 80 ] pharmacophore sites, one by one, on the basis of the different physico-chemical parameters and their different electronic charge repartition of corresponding heteroatoms. Moreover, the theory of POM analyses has been extended, with success, to other diverse and different biotargets [ 81 ].…”