engleski

Exploring structure-activity relationship of new N-alkyl quaternary quinuclidines through cholinesterase inhibition and impact on cell homeostasis

Quinuclidine based derivatives are a class of compounds that has been attracting increased attention in modern drug discovery based on their anticholinergic, antimicrobial, antioxidative and antitumor activity. Guided by an interest to develop drugs with polypotent chemical structures which result in interaction with various molecular targets or receptors, we have synthesized and characterized 14 quaternary quinuclidine compounds with the variation in N-alkyl chain length and incorporation of alcohol or oxime headgroup at the position 3 of the quinuclidine ring. We analysed reversible inhibition of human acetylcholinesterase (AChE) and human butyrylcholinesterase (BChE) by these compounds and screened their cytotoxic effect on three selected cell types: neuronal cells (SH-SY5Y), hepatocytes (Hep G2) and kidney cells (HEK293). All of the tested compounds reversibly inhibited both AChE and BChE activity in the micromolar range. The most potent inhibitors were bisquaternary 3-hydroxy and 3-hydroxyimino compounds with C10 alkyl chains (Ki = 0.2 – 1.6 µM). Analysis of the impact of functional group revealed oximes with C8 to C12 alkyl chains and alcohols with C14 and C16 alkyl chains as more potent reversible inhibitors than their analogues. AChE showed high affinity toward compounds with a long alkyl side chain (C14 and C16). BChE affinity was not affected much by the length of the alkyl chain, although an opposite preference to AChE was observed. MTS assay showed toxicity (IC50 = 3 – 204 µM) of compounds with a long side alkyl chain (C12, C14 and C16) from both groups, alcohols and oximes. Neuronal cells were the least sensitive to the toxicity of the tested compounds. According to inhibition potency for both AChE and BChE and non- cytotoxic profile, it seems that quinuclidine oximes with short chain length (< C12) can be considered as candidates for further investigations with possible therapeutic potential in central nervous system.

Quinuclidine derivatives ; Cholinesterase ; Cytotoxicity

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