Synthesis of aminoquinoline and adamantane hybrids and their in vitro inhibitory activity against enzymes of importance in symptomatic treatment of Alzheimer’s disease

[ K. Komatović]

103 str.

Hemija - Organska hemija / Chemistry - Organic Chemistry

Multifaktorska priroda Alchajmerove bolesti, neizlečivog neurodegenerativnog poremećaja, ukazala je na potrebu za razvojem višedirekcionih liganada. Cilj ovog rada je bio ispitivanje hibrida 4-aminohinolina i adamantana kao liganada usmerenih prema više meta značajnih u terapiji bolesti. Tokom izrade ove doktorske disertacije dizajnirano je i sintetisano 29 hibrida 4-aminohinolina i adamantana, primenom reakcija opisanih u literaturi i optimizacijom sintetskog puta. Modifikacije hibrida su izvršene promenom strukture linkera, supstituenta u položaju C(7) na hinolinu, okruženja terminalne amino-grupe i funcionalizacijom adamantana. Uz ustupljene hibride, ukupno 38 jedinjenja je ispitano kao višedirekcioni ligandi. Sva testirana jedinjenja su reverzibilno in vitro inhibirala holinesteraze. Najaktivniji inhibitori su 41 (Ki = 0,075 μM za hAChE; Ki = 0,091 μM za hBChE) i 67 (Ki = 0,097 μM za hAChE; Ki = 0,082 μM za hBChE). Hibrid 49 je pokazao dobar in vitro antioksidativni kapacitet, dok su 47, 48, 61 i 67 blagi antioksidanti. Prilikom ispitivanja sposobnosti helatacije biometala odabranih hibrida, 71 je kompleksirao jone Cu, Zn i Fe, a 41, 62, 67, 72 i 73 su kompleksirali jone Cu i Fe. Molekulskim dokingom 41 predviđen je dualni način vezivanja za obe holinesteraze. Kod 72, 73 i 74 se predviđa da supstituent na adamantil-grupi specifičnim interakcijama određuje način vezivanja za acetilholin-esterazu. Prema in silico izračunatim fizičkohemijskim svojstvima svih ispitivanih hibrida, njih devet se smatra oralno aktivnim i poseduje umeren potencijal prolaska kroz krvno˗moždanu barijeru. U okviru ove disertacije izdvojili su se inhibitori 41 i 67 kao najperspektivniji hibridi koji poseduju višedirekcionu aktivnost.

The multifactorial nature of Alzheimer's disease, an incurable neurodegenerative disorder, has highlighted the need for the development of multi-target directed ligands. The aim of this work was to investigate 4-aminoquinoline and adamantane hybrids as ligands directed towards multiple important targets in disease therapy. During the work on this PhD, 29 4-aminoquinoline and adamantane hybrids were designed and synthesised, using the literature reactions and optimising the synthetic route. The hybrids were modified by changing the linker structure, the C(7) substituent on quinoline, the terminal amino group encirclement and adamantane functionalisation. Along with the assigned hybrids, a total of 38 compounds were examined as multi-target directed ligands. All of the tested compounds reversibly inhibited cholinesterases in vitro. The most active inhibitors are 41 (Ki = 0.075 μM for hAChE; Ki = 0.091 μM for hBChE) and 67 (Ki = 0.097 μM for hAChE; Ki = 0.082 μM for hBChE). Hybrid 49 showed good in vitro antioxidant capacity, while 47, 48, 61 and 67 are mild antioxidants. In the biometal chelation study of the selected hybrids, 71 complexed Cu, Zn and Fe ions, and 41, 62, 67, 72 and 73 complexed Cu and Fe ions. Molecular docking predicts that 41 is a dual binding site inhibitor of both cholinesterases. For 72, 73 and 74, it is predicted that the adamantyl group substituent determines the mode of binding to acetylcholinesterase through specific interactions. According to the in silico calculated physicochemical properties of all tested hybrids, nine of them are considered orally active with a moderate potential to pass the blood-brain barrier. Within this dissertation, inhibitors 41 and 67 were singled out as the most promising multitarget directed hybrids.

Alchajmerova bolest, hibridi, 4-aminohinolini, adamantan, holinesteraze, antioksidativni potencijal, helatacija, molekulski doking, fizičko-hemijska svojstva

Alzheimer’s disease, hybrids, 4-aminoquinolines, adamantane, cholinesterases, antioxidative potential, chelation, molecular docking, physicochemical properties

616.8:547.7(043.3)

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