o:36972 Sinteza hibrida aminohinolina adamantana i njihova in vitro inhibitorna aktivnost na enzime od značaja za simptomatsku terapiju Alchajmerove bolesti doktorska disertacija Synthesis of aminoquinoline and adamantane hybrids and their in vitro inhibitory activity against enzymes of importance in symptomatic treatment of Alzheimer’s disease : doctoral dissertation sr Multifaktorska priroda Alchajmerove bolesti, neizlečivog neurodegenerativnog poremećaja,ukazala je na potrebu za razvojem višedirekcionih liganada. Cilj ovog rada je bio ispitivanje hibrida4-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-aminohinolinai adamantana, primenom reakcija opisanih u literaturi i optimizacijom sintetskog puta. Modifikacijehibrida su izvršene promenom strukture linkera, supstituenta u položaju C(7) na hinolinu, okruženjaterminalne amino-grupe i funcionalizacijom adamantana. Uz ustupljene hibride, ukupno 38 jedinjenjaje ispitano kao višedirekcioni ligandi. Sva testirana jedinjenja su reverzibilno in vitro inhibiralaholinesteraze. Najaktivniji inhibitori su 41 (Ki = 0,075 μM za hAChE; Ki = 0,091 μM za hBChE) i67 (Ki = 0,097 μM za hAChE; Ki = 0,082 μM za hBChE). Hibrid 49 je pokazao dobar in vitroantioksidativni kapacitet, dok su 47, 48, 61 i 67 blagi antioksidanti. Prilikom ispitivanja sposobnostihelatacije biometala odabranih hibrida, 71 je kompleksirao jone Cu, Zn i Fe, a 41, 62, 67, 72 i 73 sukompleksirali jone Cu i Fe. Molekulskim dokingom 41 predviđen je dualni način vezivanja za obeholinesteraze. Kod 72, 73 i 74 se predviđa da supstituent na adamantil-grupi specifičniminterakcijama određuje način vezivanja za acetilholin-esterazu. Prema in silico izračunatim fizičkohemijskimsvojstvima svih ispitivanih hibrida, njih devet se smatra oralno aktivnim i poseduje umerenpotencijal prolaska kroz krvno˗moždanu barijeru.U okviru ove disertacije izdvojili su se inhibitori 41 i 67 kao najperspektivniji hibridi kojiposeduju višedirekcionu aktivnost. The multifactorial nature of Alzheimer's disease, an incurable neurodegenerative disorder, hashighlighted the need for the development of multi-target directed ligands. The aim of this work wasto investigate 4-aminoquinoline and adamantane hybrids as ligands directed towards multipleimportant targets in disease therapy.During the work on this PhD, 29 4-aminoquinoline and adamantane hybrids were designedand synthesised, using the literature reactions and optimising the synthetic route. The hybrids weremodified by changing the linker structure, the C(7) substituent on quinoline, the terminal amino groupencirclement and adamantane functionalisation. Along with the assigned hybrids, a total of 38compounds were examined as multi-target directed ligands. All of the tested compounds reversiblyinhibited 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 49showed good in vitro antioxidant capacity, while 47, 48, 61 and 67 are mild antioxidants. In thebiometal 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 siteinhibitor of both cholinesterases. For 72, 73 and 74, it is predicted that the adamantyl groupsubstituent determines the mode of binding to acetylcholinesterase through specific interactions.According to the in silico calculated physicochemical properties of all tested hybrids, nine of themare 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 multitargetdirected hybrids. Hemija - Organska hemija / Chemistry - Organic Chemistry Datum odbrane: 21.07.2025. 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 91552100 178614025 91552101 9981 2025-11-05T10:47:21.053Z 45 no 46 Katarina B., 1991- Komatović 130277641 2025 63 mentor Mario, 1963- Zlatović 12648295 2025 63 član komisije Dejan, 1967- Opsenica 30557031 2025 63 član komisije Deana, 1963- Andrić 12616295 2025 63 član komisije Zorana, 1970- Ferjančić 14047335 2025 63 član komisije Anita Bosak 130660617 2025 103 str. 5497304 http://phaidrabg.bg.ac.rs/o:36972 no yes 12 2025-11-05T10:47:21.320Z 70 11 1066775 1066794 1066797 Alchajmerova bolest, hibridi, 4-aminohinolini, adamantan, holinesteraze,antioksidativni potencijal, helatacija, molekulski doking, fizičko-hemijska svojs Alzheimer’s disease, hybrids, 4-aminoquinolines, adamantane, cholinesterases,antioxidative potential, chelation, molecular docking, physicochemical properties 616.8:547.7(043.3) 1738 11A19 2025