Norditerpenoids with Selective Anti-Cholinesterase Activity from the Roots of Perovskia atriplicifolia Benth.

Sylwester Ślusarczyk,F Sezer Senol Deniz,Edward Krzyżak,Wiesław Oleszek,Priyanka Banerjee,Horacio Pérez-Sánchez,Renata Abel,Robert Preissner,Helena Den-Haan,José P Cerón-Carrasco,Łukasz Pecio,Adam Matkowski,Ilkay E Orhan

doi:10.3390/ijms21124475

Abstract

Inhibition of cholinesterases remains one of a few available treatment strategies for neurodegenerative dementias such as Alzheimer’s disease and related conditions. The current study was inspired by previous data on anticholinesterase properties of diterpenoids from Perovskia atriplicifolia and other Lamiaceae species. The acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition by the three new natural compounds—(1R,15R)-1-acetoxycryptotanshinone (1), (1R)-1-acetoxytanshinone IIA (2), and (15R)-1-oxoaegyptinone A (3)—as well as, new for this genus, isograndifoliol (4) were assessed. Three of these compounds exhibited profound inhibition of butyrylcholinesterase (BChE) and much weaker inhibition of acetylcholinesterase (AChE). All compounds (1–4) selectively inhibited BChE (IC50 = 2.4, 7.9, 50.8, and 0.9 µM, respectively), whereas only compounds 3 and 4 moderately inhibited AChE (IC50 329.8 µM and 342.9 µM). Molecular docking and in silico toxicology prediction studies were also performed on the active compounds. Natural oxygenated norditerpenoids from the traditional Central Asian medicinal plant P. atriplicifolia are selective BChE inhibitors. Their high potential makes them useful candidate molecules for further investigation as lead compounds in the development of a natural drug against dementia caused by neurodegenerative diseases.

Highlights

Acetylcholinesterase (AChE) inhibitors such as donepezil, galanthamine, rivastigmine, and tacrine are the most prescribed medications used to slow down the progression of cognitive decline in neurodegenerative diseases [1]
P. atriplicifolia contains a high amount of norditerpenoids, with cryptotanshinone being the major constituent [18]
The ongoing investigation of P. atriplicifolia phytochemistry has led to the isolation and elucidation of the structure of three new natural compounds and one compound new to this species

Summary

Introduction

Acetylcholinesterase (AChE) inhibitors such as donepezil, galanthamine, rivastigmine, and tacrine are the most prescribed medications used to slow down the progression of cognitive decline in neurodegenerative diseases [1]. Butyrylcholinesterase (BChE)—another member of the cholinesterase family—is postulated to upsurge in the late stages of Alzheimer’s disease and to accumulate in the amyloid plaques (Aβ) [2]. As such, it is regarded as a feasible target for anti-dementia drug discovery. There are reports of BChE inhibitors acting in a similar way to anti-AChE remedies in slowing down the development of dementia symptoms [3]. Cognitive improvement via cholinesterase inhibition can have broader applications as a form of complementary therapy, for example, during distress or as an aid in smoking cessation [6,7]

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Results

Conclusion