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Ovaj rad dio je istraživanja provedenog na Zavodu za farmaceutsku kemiju Farmaceutsko-biokemijskog fakulteta Sveučilišta u Zagrebu koji obuhvaća dizajniranje, sintetiziranje i biološku evaluaciju derivata harmina s antimalarijskim djelovanjem. Cilj ovog rada bila je sinteza i karakterizacija dosad neopisana četiri 1,2,3-triazolna derivata harmina koji u svojoj strukturi sadrže derivate cimetne kiseline. Sinteza je započeta prevođenjem derivata cimetne kiseline do odgovarajućih azida (3a,b) prema dolje navedenoj shemi, a harmin i harmol, alkohol nastao demetiliranjem harmina, prevedeni su u odgovarajuće alkine (5 i 6) u reakciji s propargil bromidom. Bakar (I)-katalizirajućom azid-alkin ciklizacijom u kojoj su početni reaktanti bili azidi derivata cimetne kiseline (3a,b) i alkini (5 i 6) dobiveni su konačni produkti 7a,b i 8a,b. Strukture svih sintetiziranih spojeva potvrđene su uobičajenim spektroskopskim metodama (IR, 1H i 13C NMR, MS). Čvrstim produktima određeno je talište. Sva četiri spoja zadovoljavaju Lipinskijeva i Veberova pravila, a dobru oralnu bioraspoloživost predviđa im i alat SwissADME. Sintetiziranim derivatima će u daljnjim istraživanjima biti ispitano biološko djelovanje. This paper is a part of ongoing reaserch at the Department of Medicinal Chemistry, Faculty of Pharmacy and Biochemistry, University of Zagreb. Main focus of the research is design, synthesis and biological evaluation of novel harmine derivates as potential antimalarial drugs. The aim of this diploma thesis was the synthesis and characterization of four novel harmine 1,2,3-triazole derivates containing cinnamic acid derivates in their structure. Synthesis began with transformation of cinnamic acid derivates to azides (3a,b) in a four step procedure. On the other hand, harmine and harmole (4), an alcohol generated by demethylation of harmine, were transformed in alkynes 5 and 6, in the reaction of alkylation using propargyl bromide. The copper(I)-catalyzed azidealkyne cycloaddition, in which cinnamic acid derivates azides (3a,b) and alkynes (5 and 6) were used, resulted in the formation of final compounds 7a,b (N-derivatives) and 8a,b (O-derivatives). Structures of the newly prepared compounds were confirmed using conventional analytical and spectroscopic methods (IR, 1H and 13C NMR, MS). Melting points of the solid compounds were also determined. All four novel derivatives meet all of the Lipinski and Veber criteria for good oral bioavailability of potential drugs. SwissADME web tool predicts good oral bioavailability of all four derivatives. Further studies will investigate antimalarial activity of the new harmine derivatives. |
