Dual Action of Dipyridothiazine and Quinobenzothiazine Derivatives-Anticancer and Cholinesterase-Inhibiting Activity.

Jakub Jończyk,Beata Morak-Młodawska,Ewelina Stawarska,Krystian Pluta,Barbara Malawska,Justyna Godyń,Małgorzata Jeleń

doi:10.3390/molecules25112604

Abstract

The inverse correlation observed between Alzheimer’s disease (AD) and cancer has prompted us to look for cholinesterase-inhibiting activity in phenothiazine derivatives that possess anticancer properties. With the use of in silico and in vitro screening methods, our study found a new biological activity in anticancer polycyclic, tricyclic, and tetracyclic compounds. The virtual screening of a library of 120 ligands, which are the derivatives of azaphenothiazine, led to the identification of 25 compounds that can act as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Biological assays revealed the presence of selective inhibitors of eeAChE (electric eel AChE) or eqBuChE (equine serum BuChE) and nonselective inhibitors of both enzymes among the tested compounds. Their potencies against eeAChE were in a submicromolar-to-micromolar range with IC50 values from 0.78 to 19.32 μM, while their IC50 values against eqBuChE ranged from 0.46 to 10.38 μM. The most potent among the compounds tested was the tetracyclic derivative, 6-(4-diethylaminobut-2-ynyl)-9-methylthioquinobenzothiazine 24, which was capable of inhibiting both enzymes. 9-Fluoro-6-(1-piperidylethyl)quinobenzothiazine 23 was found to act as a selective inhibitor of eqBuChE with an IC50 value of 0.46 μM. Compounds with such a dual antitumor and cholinesterase-inhibitory activity can be considered as a valuable combination for the treatment of both cancer and AD prevention. The results presented in this study might open new directions of research on the group of tricyclic phenothiazine derivatives.

Highlights

Alzheimer’s disease (AD) and cancer are widespread illnesses responsible for a number of deaths and, are considered as a medical and as a social and economic problem in the modern world
The in silico and in vitro tests performed in this study led to the identification of cholinesterase inhibitors among dipyridothiazine and quinobenzothiazine derivatives
Compounds with dual antitumor and cholinesterase-inhibitory properties can be useful both in the treatment of cancer and AD prevention [45]. Such a conclusion can be drawn based on the literature reports indicating a lower incidence of AD among people who have previously received chemotherapy

Summary

Introduction

Alzheimer’s disease (AD) and cancer are widespread illnesses responsible for a number of deaths and, are considered as a medical and as a social and economic problem in the modern world. The knowledge and understanding gained from these studies can be applied for developing new therapies and designing new effective drugs for the treatment of both diseases. AD is a progressive, complex neurodegenerative disorder that results in memory loss and affects the cognitive functions of the brain. According to the oldest pathophysiological hypothesis, memory impairments associated with AD are caused by the degradation and loss of cholinergic Molecules 2020, 25, 2604 neurons in the central nervous system (CNS) and the impairment of cholinergic neurotransmission [15]

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Results

Conclusion