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Diaminoalkyladamantane derivatives with substituted quinolines as inhibitors of parasite Plasmodium falciparum and botulinum neurotoxin

dc.contributor.advisorŠolaja, Bogdan
dc.contributor.otherMilić, Dragana
dc.contributor.otherOpsenica, Igor
dc.contributor.otherĐurković-Daković, Olgica
dc.creatorTerzić-Jovanović, Nataša
dc.date.accessioned2017-05-31T10:17:03Z
dc.date.available2017-05-31T10:17:03Z
dc.date.available2020-07-03T10:14:43Z
dc.date.issued2017-03-08
dc.identifier.urihttp://eteze.bg.ac.rs/application/showtheses?thesesId=4958
dc.identifier.urihttp://nardus.mpn.gov.rs/handle/123456789/8116
dc.identifier.urihttps://fedorabg.bg.ac.rs/fedora/get/o:15580/bdef:Content/download
dc.identifier.urihttp://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=48952591
dc.description.abstractRezime: Malarija je jedna od najrasprostranjenijih bolesti, koja preti približno polovini svetske populacije i koja je u zemljama u razvoju glavni uzrok smrtnosti dece uzrasta do 5 godina. Nagli razvoj rezistentnih formi parazita na postojeće antimalarike stvara potrebu za razvojem novih lekova. Jedna od strategija za razvoj novih lekova, kojom se smanjuju troškovi i skraćuje vreme potrebno za pronalazak novih aktivnih supstanci je hemijska modifikacaja postojećih hinolinskih antimalarika poznatog mehanizma dejstva. U okviru ove doktorske teze izvršena je sinteza serije aminohinolinskih derivata kod koje su adamantanski fragmenti preko amido-aminskih i diaminskih premostnih nizova povezani sa različito supstituisanim hinolinskim jezgrima. Određena je antimalarijska aktivnost svih sintetisanih jedinjenja. Rezultati bioloških testova potvrdili su antimalarijsku aktivnost, a dodatno je utvrđena i inhibitorna aktivnost pojedinih derivata prema botulinum neurotoksinu tipa A (BoNT/A LC). Botulinum neurotoksini (BoNTs) sa letalnom dozom (LC50) od 1-5 ng/kg telesne težine su najsmrtonosniji otrovi poznati čoveku. Zbog svoje velike toksičnosti, lakoće proizvodnje i transporta svrstavaju se od Centra za kontrolu i prevenciju bolesti SAD u A kategoriju agenasa sa najvećim rizikom za korišćenje u bioterorizmu. Nepostojanje odobrenog farmakološkog pristupa za tretman intoksikacije, stvara veliku potrebu za razvojem inhibitora BoNT. U toku rada dobijeni su sledeći rezultati: (i) Sintetisano je osam amido-adamantanskih aminohinolina (99a-d i 100a-d). Svi sintetisani amidni derivati poseduju nedovoljno dobru in vitro antimalarijsku aktivnost (IC50 = 6 - 1400 nM). Na osnovu indeksa rezistencije (IR) uočena je viša aktivnost amido-adamantanskih aminohinolina prema CQS soju (D6) u poređenju sa CQR (W2) i multirezistentnim (TM91C235) sojem. Najaktivnije jedinjenje iz ove serije pokazuje in vitro aktivnost prema CQS soju D6, 100a: IC90(D6) = 157 nM osam puta nižu od aktivnosti CQ (IC90(D6) = 20 nM)...sr
dc.description.abstractMalaria is one of the most devastating diseases which threatens half the world's population and remains a major cause of mortality among children aged < 5 years in developing countries. The wide-spread resistance of various strains to current antimalarials potentiates the need for development of new drugs. One of the strategies for the development of new therapeutics, that reduces costs and shortens the time needed for the discovery of new active substances, is chemical modification of quinoline-based drugs with known mechanism of action. Antimalarial and BoNT/ LC inhibitory activities of variously substituted 4- aminoquinolines coupled to adamantane carrier were described within this PhD thesis. Botulinum neurotoxins (BoNTs) are the most potent of known toxins (LC50 = 1- 5 ng/kg). Due to ease of production, spreading and lethality BoNTs are listed as category A biothreat agens by the U.S. Centers for Disease Control and Prevention (CDC). The absence of an approved pharmacological approach for the treatment of intoxication, creates an urgent need to develop inhibitors BoNT. The results are summarized as follows: (i) Eight derivatives with an amide functionality linking the 4,7-ACQ moiety to adamantane (99a-d and 100a-d) were synthesized. All synthesized compounds are poorly active (IC50 = 6 - 1400 nM). Analysis of the resistance index (RI) showed that compounds are more active against D6 strain than against the CQ-resistant W2 and multidrug resistant TM91C235 strain. The most active amide within the series is eight times less active (100a: IC90 (D6) = 157 nM) against the CQ- sensitive D6 strain than CQ (IC90 (D6) = 20 nM). (ii) The series of ten aminoquinoline derivatives in which the adamantane fragment is connected to quinoline core through unbranched diamine linker was synthesized (106a-d, 106i, 107a-107i and 107i). Eight out of ten synthetic derivatives exhibited better IC90 activity against CQ-sensitive D6 strain compared to CQ (1), seven are more potent against multi-resistant C235 strain and one against MFQ-sensitive W2... strain than MFQ (14).en
dc.formatapplication/pdf
dc.languagesr
dc.publisherУниверзитет у Београду, Хемијски факултетsr
dc.rightsopenAccessen
dc.sourceУниверзитет у Београдуsr
dc.titleDerivati diaminoalkiladamantana sa supstituisanim hinolinima kao inhibitori parazita Plasmodium falciparum i botulinum neurotoksinasr
dc.title.alternativeDiaminoalkyladamantane derivatives with substituted quinolines as inhibitors of parasite Plasmodium falciparum and botulinum neurotoxinen
dc.typedoctoralThesis
dc.rights.licenseBY-NC-ND
dcterms.abstractШолаја, Богдан; Ђурковић-Даковић, Олгица; Опсеница, Игор; Милић, Драгана; Терзић-Јовановић, Наташа; Деривати диаминоалкиладамантана са супституисаним хинолинима као инхибитори паразита Пласмодиум фалципарум и ботулинум неуротоксина; Деривати диаминоалкиладамантана са супституисаним хинолинима као инхибитори паразита Пласмодиум фалципарум и ботулинум неуротоксина;
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/29842/Disertacija.pdf
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/29843/IzvestajKomisije9321.pdf


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