Toward the cholinesterase inhibition potential of TADDOL derivatives: Seminal biological and computational studies. Issue 11 (27th July 2022)

• Record Type: Journal Article
• Authors: Costantino, Andrea R.; Charbe, Nitin; Duarte, Yorley; Gutiérrez, Margarita; Giordano, Ady; Prasher, Parteek; Dua, Kamal; Mandolesi, Sandra; Zacconi, Flavia C.
• Is Part Of: Archiv der Pharmazie. Volume 355:Issue 11(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-07-27
• Subjects: acetylcholinesterase inhibitors -- C2 symmetry -- molecular modeling analysis -- selective AChE inhibitors -- TADDOL derivatives; Pharmaceutical chemistry -- Periodicals; Pharmacology -- Periodicals; 615.19
• DOI: 10.1002/ardp.202200142
• Languages: English
• ISSNs: 0365-6233

Abstract

Abstract: Alzheimer's disease (AD) is a degenerative neurological disease characterized by gradual loss of cognitive skills and memory. The exact pathogenesis involved still remains unrevealed, but several studies indicate the involvement of an array of different enzymes, underlining the multifactorial character of the disease. Inhibition of these enzymes is therefore a powerful approach in the development of AD treatments, with promising candidates, including acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and monoamine oxidase. Interestingly, AChE is the target of a major pesticide family (organophosphates), with several reports indicating an intersection between the pesticide's activity and AD. In this study, various TADDOL derivatives were synthesized and their in vitro activities as AChE/BuChE inhibitors as well as their antioxidant activities were studied. Molecular modeling studies revealed the capability of TADDOL derivatives to bind to AChE and induce inhibition, especially compounds 2b and 3c furnishing IC50 values of 36.78 ± 8.97 and 59.23 ± 5.31 µM, respectively. Experimental biological activities and molecular modeling studies clearly demonstrate that TADDOL derivatives with specific stereochemistry have an interesting potential for the design of potent AChE inhibitors. The encouraging results for compounds 2b and 3c indicate them as promising scaffolds for selective and potent AChE inhibitors. Abstract : A series of new unsaturated TADDOL derivatives were synthesized by a simple and straightforward esterification method. Experimental biological activities and molecular modeling studies demonstrated that TADDOL derivatives 2b and 3c with specific stereochemistry exhibit competitive acetylcholinesterase (AChE) inhibitory properties. TADDOL derivatives have the potential for the design of potent AChE inhibitors, using simple synthetic methodologies.