Aurones Of Amine And Carbamate Functionalities As Neuroprotective Agents With Multitargeting Potential: Synthesis, Structure-Activity Relationships And Mode Of Action Studies
| dc.contributor.author | Liew, Kok Fui | |
| dc.date.accessioned | 2016-12-06T06:50:13Z | |
| dc.date.available | 2016-12-06T06:50:13Z | |
| dc.date.issued | 2016-06 | |
| dc.description.abstract | Alzheimer’s disease (AD) is a complex multifactorial disease involving diverse mechanisms contributing to the onset of the disease. In the search for novel chemical entities to address the causative factors of the disease, the multitarget-directed ligand (MTDL) design strategy has been applied in the present study by incorporating selected structural motifs (various amines and carbamate) from two established Alzheimer drugs (donepezil and rivastigmine) into the aurone scaffold. These aurones were designed on the premise that the scaffold could be utilised to develop a reasonably small sized multitargeting compound (targeting cholinesterase, monoamine oxidase, and amyloid-beta aggregation) for neuroprotection while maintaining good drug-like properties. In this study, a series of aurone derivatives carrying amine and carbamate functionalities at various positions (ring A and/or B) of the scaffold was synthesized and characterized using spectroscopic techniques. These aurones were initially evaluated for their in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities. To further substantiate their multi-targeting properties, the aurones were evaluated on two Alzheimer’s disease (AD)-related activities, namely monoamine oxidase (MAO) and amyloid-beta (Aβ) aggregation inhibitions. In parallel, the metabolic stability and blood-brain barrier (BBB) permeability of selected potent aurones were examined to identify an optimal compound with a combination of multipotency and favourable pharmacokinetic profile. The neuroprotective effect of the most promising aurone 4-3 was then examined on two Caenorhabditis elegans (C. elegans) neurodegeneration models, namely Aβ-induced paralysis and 6-hydroxydopamine (6-OHDA)-induced neurodegeneration. Structure-activity relationship study revealed several potent selective AChE inhibitors carrying piperidine and pyrrolidine moieties at ring A or B, with submicromolar IC50 values. In addition to their AChE inhibitory activity, multi-targeting potential was observed in two aurones, namely aurone 2-2 (MAO-B inhibitor) and 4-3 (Aβ-aggregation inhibitor). Rat liver microsomal incubation of the aurones identified aurone 4-3 to be the most metabolically stable compared to the other aurones. BBB permeability evaluation using the parallel artificial membrane permeability assay (PAMPA) and porcine brain endothelial cells (PBEC) bidirectional permeability revealed all the tested aurones to be highly passive permeable across the BBB and the permeation of aurone 4-3 to involve active uptake mechanism across the BBB. In addition, the most promising aurone 4-3 also showed protection on the nematodes against both Aβ- and 6-OHDA-induced toxicities in the C.elegans neurodegeneration models. Hence, aurone 4-3 discovered in the present study represents a promising, drug-like lead for further development of the aurone scaffold as potential multi-potent agents for neurodegenerative diseases. | en_US |
| dc.identifier.uri | http://hdl.handle.net/123456789/3247 | |
| dc.subject | Alzheimer’s disease (AD) is a complex multifactorial disease involving | en_US |
| dc.subject | diverse mechanisms contributing to the onset of the disease. | en_US |
| dc.title | Aurones Of Amine And Carbamate Functionalities As Neuroprotective Agents With Multitargeting Potential: Synthesis, Structure-Activity Relationships And Mode Of Action Studies | en_US |
| dc.type | Thesis | en_US |
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