Synthesis and characterization of novel harmine and coumarin 1,2,3-triazole derivates

Ovaj rad dio je istraživanja provedenog na Zavodu za farmaceutsku kemiju Farmaceutsko-biokemijskog fakulteta Sveučilišta u Zagrebu koji obuhvaća dizajn, sintezu te biološku evaluaciju derivata harmina s potencijalnim antimalarijskim djelovanjem. Cilj ovog rada bila je sinteza i karakterizacija novih 1,2,3-triazolskih hibrida harmina i kumarina. Sinteza je započeta prevođenjem derivata kumarina do odgovarajućih azida 2a-c prema dolje navedenoj shemi. Harmin i fenol 5 dobiven iz 5-metoksitriptamina zatim su prevedeni u odgovarajuće alkine 6 i 7 u reakciji s propargil-bromidom. Bakar(I)-kataliziranom reakcijom alkin-azid cikloadicije u kojoj su početni reaktanti bili alkini 6 i 7 te azidi 2a-c dobiveni su konačni produkti 8a-b i 9a-b. Strukture svih novosintetiziranih spojeva potvrđene su spektroskopskim metodama (IR, 1H i 13C NMR, MS) te im je određena temperatura tališta. Sva četiri konačna produkta zadovoljavaju Lipinskijeva i Veberova pravila, a web alat SwissADME im predviđa dobru oralnu bioraspoloživost. Biološko djelovanje novosintetiziranih derivata bit će ispitano u daljnjim istraživanjima.This paper is a part of ongoing research at the Department of Medicinal Chemistry, Faculty of Pharmacy and Biochemistry, University of Zagreb, which includes design, synthesis, and biological evaluation of novel harmine derivatives as potential antimalarial drugs. The aim of this diploma thesis was the synthesis and characterization of novel harmine 1,2,3-triazole derivatives comprising coumarin in their structure. Synthesis began with transformation of coumarin derivatives to azides 2a-c shown in set out below scheme. Both harmine and phenol 5, which was generated from 5-methoxytryptamine, were transformed into alkynes 6 and 7 in the reaction of alkylation using propargyl bromide. The copper(I)-catalyzed alkyne-azide cycloaddition, in which alkynes 6 and 7, and coumarin derivatives 2a-c were used, resulted in the formation of the final compounds 8a-b (O-derivatives) and 9a-b (N-derivatives). Structures of the newly synthesized compounds were confirmed using spectroscopic methods (IR, 1H and 13C NMR, MS), while melting points were determined for solid compounds. All four novel derivatives fulfill all the Lipinski’s and Veber’s criteria for good oral bioavailability of potential drugs. SwissADME web tool predicts good oral bioavailability as well. Biological activity of the newly synthesized compounds will be examined in further studies