Duran_2022_Biotechnol.Appl.Biochem__

Alzheimer's disease (AD) is a neurodegenerative disorder. The disease is characterized by dementia, memory impairment, cognitive impairment and speech impairment. Cholinesterases (ChEs; AChE, acetylcholinesterase and BChE, butyrylcholinesterase) inhibitors and their benefits of cholinergic replacement in the treatment of AD have been researched and documented by scientists in various ways to date. Recent studies prove that human carbonic anhydrases (hCAs) are also one of the important targets in the treatment of AD. Therefore, the development of new agents that can simultaneously modulate the various mechanisms or targets involved in the AD pathway may be a powerful strategy to treat AD, the current disease. Considering these data, the effects of the pyrimidines (1-7) were investigated in this study for the discovery and development of multitargeted ChEs and hCAs inhibitors associated with AD. In addition, the molecular docking analysis of the 4-amino-2-choloropyrimidine (2) was performed to understand the binding interactions on the active site of the enzyme. All compounds (1-7) showed satisfactory enzyme inhibitory potency in micromolar concentrations against AChE, BChE, hCAI, and hCAII with K(I) values ranging from 0.099 to 0.241 microM, from 1.324 to 3.418 microM, from 0.201 to 0.884 microM, from 1.867 to 3.913 microM respectively. Due to their ChEs and hCAs inhibition, these compounds (1-7) may be considered as leads for investigations in neurodegenerative diseases. All these results revealed that the 4-amino-5,6-dichloropyrimidine (7) (K(I) value of 0.201 +/- 0.041 microM for hCA I), the 4-amino-6-hydroxypyrimidine (4) (K(I) value of 1.867 +/- 0.296 microM for hCA II), the 4-amino-5,6-dichloropyrimidine (7) (K(I) value of 0.099 +/- 0.008 microM for AChE), and the 4-amino-2-chloropyrimidine (2) (K(I) value of 1.324 +/- 0.273 microM for BChE) from the pyrimidines in this series were the most promising derivatives, as they exhibited a good multifunctional inhibition at all experimental levels and in the in silico validation against these enzymes, for the treatment of AD. This article is protected by copyright. All rights reserved.