engleski

Design and synthesis of selective butyrylcholinesterase inhibitors as multi- target directed ligands in the treatment of Alzheimer’s disease

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease characterized by memory loss and personality changes. AD affects more than 50 million people worldwide with numbers continuously growing as a result of a globally aging population. The multifactorial nature of AD points to the existence of a number of possible targets, but the existing treatment of AD is manly symptomatic and based on increasing the concentration of the neurotransmitter acetylcholine (ACh) by inhibiting the action of the enzymes responsible for its hydrolysis, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). As during disease progression, BChE activity progressively increases by about 40–90% of its normal activity, BChE is important in the regulation of brain ACh levels in late AD. Also, selective inhibition of BChE, as shown with respect to AChE in rodents, has a beneficial effect on the cognitive abilities of rodents with AD and reduces accumulations of amyloid plaques in their brains. Consequently, the selective inhibition of BChE has evolved into a promising new approach in the treatment of middle and advanced AD. In our study, the carbamate group was chosen as a pharmacophore, because the carbamates currently or previously in use for the treatment of AD displayed significant positive effects on cognitive symptoms. With the aim to propose new drug candidate/s for the treatment of AD as selective inhibitors for BChE, we synthesized 25 biscarbamates with different substituents at the carbamoyl and hydroxyaminoethyl chain on the benzene ring and evaluated their inhibition potency toward AChE and BChE. All biscarbamates were proven to be very potent inhibitors of AChE and BChE with inhibition rate constants up to 106 M-1 min-1, with generally higher preference to BChE. Twenty-one biscarbamates were neither hepatotoxic, nephrotoxic nor neurotoxic. Ability to chelate at least one of biometals (Zn, Fe and Cu) was pointed out as additional beneficial property of these compounds thus they should be able to reduce the neurotoxic effects of biometal imbalances in AD brains. For three biscarbamates were determined to be able to pass the BBB by passive transport, while for nine biscarbamates this ability was slightly limited. According to our results, we could point to three carbamates as a promising compound for the development of more effective drugs for the treatment of middle and late stages of AD .

biscarbamates ; butyrylcholinesterase ; inhibition ; metal chelating ; Alzheimer’s disease

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