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The development of novel 4,10-diazachrysene and 1,5-naphthyridine derivatives as Ebola virus inhibitors

dc.contributor.advisorŠolaja, Bogdan
dc.contributor.otherMilić, Dragana
dc.contributor.otherOpsenica, Igor
dc.contributor.otherNikodinović-Runić, Jasmina
dc.contributor.otherPopsavin, Velimir
dc.creatorSelaković, Života
dc.date.accessioned2019-12-24T16:13:30Z
dc.date.available2019-12-24T16:13:30Z
dc.date.issued2019-07-10
dc.identifier.urihttp://eteze.bg.ac.rs/application/showtheses?thesesId=7017
dc.identifier.urihttps://fedorabg.bg.ac.rs/fedora/get/o:20625/bdef:Content/download
dc.identifier.urihttp://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=51648783
dc.identifier.urihttp://nardus.mpn.gov.rs/123456789/11673
dc.description.abstractEbolavirus je rod virusa iz familije Filoviridae, endemski prisutan u Subsaharskoj Africi. Vrste koje pripadaju ovom rodu uzročnici su smrtonosne hemoragijske groznice kod ljudi i primata, a otkrivene su, kao i njima srodni virusi marburga, u drugoj polovini 20. veka, kada su registrovani prvi slučajevi. U ovom trenutku ne postoji odobrena vakcina niti lek protiv ove opasne infekcije. Nekoliko imunoterapeutika, kao i složenih makromolekulskih formulacija, predstavlja obećavajuće kandidate za lek, a ostvaren je i napredak u istraživanjima sa malim molekulima. Oslanjajući se na ranija istraživanja u našoj istraživačkoj grupi, u okviru ove teze sintetisane su dve grupe jedinjenja za koje se pretpostavljalo da mogu imati antivirusnu aktivnost – derivati 4,10-diazahrizena i 1,5-naftiridina. Ukupno je testirano 29 jedinjenja, a po aktivnosti naročito su se istakla dva diazahrizenska derivata koji su imali veoma dobru in vitro aktivnost i štitili su 9/10, odnosno 10/10 inficiranih miševa pri dozi 10 mg/kg. Urađen je veći broj ogleda sa ciljem utvrđivanja mehanizma dejstva ova dva jedinjenja, pri čemu je otkriveno da ona inhibiraju ulazak virusa u ćeliju domaćina, na način koji se razlikuje od do sada poznatih inhibitora ulaska virusa. Dobijeni rezultati ukazuju da su molekuli razvijeni u ovoj tezi značajni i jedinstveni i da zavređuju dalja ispitivanja.sr
dc.description.abstractEbolavirus is a genus of viruses from the Filoviridae family, endemic to Sub-Saharan Africa. Species from this genus cause a lethal hemorrhagic fewer in humans and non-human primates. Like the related Marburgviruses, they were discovered in the second half of the 20th century, when first cases were reported. Presently, there is no approved vaccine or other therapeutics to treat this dangerous infection. Several immunotherapeutics, as well as sophisticated macromolecular formulations, have shown promising results, and advances have also been made in small molecule research. Based on our previous results we developed two new chemotypes as possible antivirals – derivatives of 4,10-diazachrysene and 1,5-naphthyridine, respectively. A total of 29 compounds were tested, with two of them showing very good results: they had excellent in vitro activity and they protected 9/10 and 10/10 infected mice from a fatal Ebola challenge, respectively (10 mg/kg dose). A number of experiments were carried out to determine the mechanism of action of these two compounds, and it was discovered that they prevent viral entry into cells, albeit in a manner that differed from other known entry inhibitors. The results obtained in this thesis show that the developed compounds are unique and worthy of further examinationen
dc.formatapplication/pdf
dc.languagesr
dc.publisherУниверзитет у Београду, Хемијски факултетsr
dc.relationinfo:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/172008/RS//
dc.rightsAutorstvo-Nekomercijalno-Bez prerade 3.0 Srbija (CC BY-NC-ND 3.0)
dc.sourceУниверзитет у Београдуsr
dc.subjectfilovirusisr
dc.subjectfilovirusesen
dc.subjectvirus ebolesr
dc.subjectmali molekuli kao inhibitorisr
dc.subjectdiazahrizensr
dc.subjectnaftiridinsr
dc.subjectmehanizam dejstvasr
dc.subjecttoksičnostsr
dc.subjectfarmakokinetikasr
dc.subjectEbola virusen
dc.subjectsmall molecule inhibitorsen
dc.subjectdiazachryseneen
dc.subjectnaphthyridineen
dc.subjectmechanism of actionen
dc.subjecttoxicityen
dc.subjectpharmacokineticsen
dc.titleRazvoj novih 4,10-diazahrizenskih i 1,5-naftiridinskih inhibitora virusa ebolesr
dc.title.alternativeThe development of novel 4,10-diazachrysene and 1,5-naphthyridine derivatives as Ebola virus inhibitorsen
dc.typePhD thesis


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