| Abstract | Ovaj diplomski rad nastavak je istraživanja na Zavodu za farmaceutsku kemiju Farmaceutsko-biokemijskog fakulteta
Sveučilišta u Zagrebu. Istraživanje obuhvaća dizajniranje, sintezu i ispitivanje biološkog djelovanja derivata harmina s
mogućim antimalarijskim i/ili citostatskim učinkom. Cilj ovog rada bila je sinteza i karakterizacija novih hibrida
klorokina i harmina, spajanjem klorokinskog amina 1 s primarnim aminima (3, 8, 13 i 18) temeljenim na β-karbolinskom
alkaloidu harminu pomoću uree kao poveznice. Sinteza je započeta sintezom pojednostavljenog derivata klorokina,
amina 1. Harminski derivati, amini 3 i 8 dobiveni su iz harmina, amin 13 iz 5-metoksitriptamina, a amin 18 iz metiltriptofanata.
Sinteza urea provedena je korištenjem dviju metoda: korištenjem benotriazolida 5 (BtH metoda) ili coupling
reagensa 1,1'-karbonildiimidazola (CDI metoda). Benzotriazolid harmina 5, tzv. aktivna urea, dobivena je iz amina 3 i
klorida 1-benzotriazol karboksilne kiseline (BtcCl, 4), a aminolizom aktivne uree 5 pomoću amina 1 u bazičnim uvjetima
dobivena je urea 19. CDI metodom iz amina 8, 13 ili 18 te amina 1 mehanizmom nukleofilne supstitucije sintetizirane
su uree 20–22.
Novosintetizirani spojevi karakterizirani su standardnim analitičkim i spektroskopskim metodama: IR, 1H i 13C NMR i
MS te im je određena temperatura tališta, a online platformom SwissADME predviđeni su fizikalno-kemijski parametri
koji utječu na farmakokinetiku novosintetiziranih spojeva. Sva četiri konačna spoja gotovo potpuno zadovoljavaju
Lipinskijeva i Veberova pravila te im web alat SwissADME predviđa dobru oralnu bioraspoloživost. Međutim, uree 19–
22 pokazale su se kao inhibitori CYP enzima te supstrati P-glikoproteina zbog čega je potrebna daljnja optimizacija
strukture spojeva. U daljnjim istraživanjima koja su u tijeku ispituje se citostatsko i antimalarijsko djelovanje
novosintetiziranih spojeva, no ista prelaze okvire ovoga rada. |
| Abstract (english) | This master’s thesis is a continuation of research at the Department of Medicinal Chemistry, Faculty of Pharmacy and
Biochemistry, University of Zagreb. The research covers the design, synthesis, and evaluation of the biological activity
of harmine derivatives with potential antimalarial and/or cytostatic activity. The aim of this master's thesis was the
synthesis and characterization of novel chloroquine-harmine hybrids prepared by linking chloroquine amine 1 with
primary amines (3, 8, 13, and 18) based on the β-carboline alkaloid harmine using urea as a linker. The synthesis began
with the preparation of a simplified chloroquine derivative, amine 1. Harmine derivatives, amines 3 and 8, were obtained
from harmine, amine 13 from 5-methoxytryptamine, and amine 18 from methyl tryptophanate. Title ureas were obtained
using either benzotriazole 5 (BtH method) or a coupling reagent 1,1'-carbonyldiimidazole (CDI method). The harmine
benzotriazolide 5 (active urea) was synthesized from amine 3 and 1-benzotriazole carboxylic acid chloride (BtcCl, 4).
Urea 19 was obtained by aminolysis of the active urea 5 with amine 1 under basic conditions. Ureas 20–22 were
synthesized using the CDI method from amines 8, 13, or 18 and amine 1 through a mechanism of nucleophilic
substitution.
The newly synthesized compounds were characterized using standard analytical and spectroscopic methods: IR, 1H and
13C NMR, and MS. Their melting points were determined, and physicochemical parameters that could impact the
pharmacokinetics of the newly synthesized compounds were predicted using the SwissADME online platform. All four
final compounds mostly comply with Lipinski's and Veber's rules, and the SwissADME tool predicts good oral
bioavailability. However, further optimization of the compounds’ structures is necessary as ureas 19–22 have been found
to inhibit CYP enzymes and act as P-glycoprotein substrates. Evaluation of the cytostatic and antimalarial activities of
novel ureas is in progress, however, this is beyond the scope of this thesis. |
