20.500.12556/RUL-130296 Synthesis, molecular modelling and biological evaluation of novel heterodimeric, multiple ligands targeting cholinesterases and amyloid beta Cholinesterases and amyloid beta are one of the major biological targets in the search for a new and efficacious treatment of Alzheimer's disease. The study describes synthesis and pharmacological evaluation of new compounds designed as dual binding site acetylcholinesterase inhibitors. Among the synthesized compounds, two deserve special attention-compounds 42 and 13. The former is a saccharin derivative and the most potent and selective acetylcholinesterase inhibitor (EeAChE IC$_5$$_0$ = 70 nM). Isoindoline-1,3-dione derivative 13 displays balanced inhibitory potency against acetyl- and butyrylcholinesterase (BuChE) (EeAChE IC$_5$$_0$ = 0.76 µM, EqBuChE IC$_5$$_0$ = 0.618 µM), and it inhibits amyloid beta aggregation (35.8% at 10 µM). Kinetic studies show that the developed compounds act as mixed or non-competitive acetylcholinesterase inhibitors. According to molecular modelling studies, they are able to interact with both catalytic and peripheral active sites of the acetylcholinesterase. Their ability to cross the blood-brain barrier (BBB) was confirmed in vitro in the parallel artificial membrane permeability BBB assay. These compounds can be used as a solid starting point for further development of novel multifunctional ligands as potential anti-Alzheimer's agents. cholinesterase inhibitors molecular modelling β-amyloid aggregation inhibitors Alzheimer’s disease multi-target-directed ligands (MTDL) PAMPA-BBB assay tarčna zdravila razvoj zdravil zaviralci acetilholinesteraze molekularno modeliranje Alzheimerjeva bolezen true false true Angleški jezik Slovenski jezik Članek v reviji 2021-09-13 10:08:43 2021-09-13 10:08:45 2022-09-09 04:15:45 0000-00-00 00:00:00 2016 0 0 24 str. iss. 4, art. 410 Vol. 21 2016 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.2:616.894 1420-3049 10.3390/molecules21040410 4051313 RAZ_Hebda_Michalina_2016.pdf RAZ_Hebda_Michalina_2016.pdf 1 2B82C8E2840666F94BA09522EC4B788F b0d528bb349705605329c73f4e0299552b85d209b7c9d143f43b7b681e716b03 e8c2ce76-1469-11ec-a523-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=147368 http://www.mdpi.com/1420-3049/21/4/410 0 90e810e9-1469-11ec-a523-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=147367 Fakulteta za farmacijo 0 0 0