Sinteza, karakterizacija i biološko djelovanje semikarbazida, urea i ureidoamida primakina

doctoral thesis

• Title (english): Synthesis, characterization and biological activity of primaquine semicarbazides, ureas and ureidoamides
• Author: Kristina Pavić
• Mentor: Branka Zorc (mentor)
• Committee member: Zrinka Rajić Džolić (predsjednik povjerenstva)
• Committee member: Maja Jazvinšćak Jembrek (član povjerenstva); MBZ: 233712
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of medicinal chemistry); Zagreb
• Defense date and country: 2017, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Pharmacy
• Universal decimal classification (UDC): 615 - Pharmacology. Therapeutics. Toxicology

Abstract

U okviru ovog doktorskog rada, koji predstavlja nastavak istraživanja o mogućnostima derivatizacije antimalarijskog lijeka primakina (PQ) u Zavodu za farmaceutsku kemiju Farmaceutsko-biokemijskog fakulteta Sveučilišta u Zagrebu, sintetizirane su bis-uree PQ 11 te uree i semikarbazoni 12 s velikim arilnim i hidroksialkilnim supstituentima, konjugati PQ i derivata cimetne kiseline (DCK) amidnog 15 i acilsemikarbazidnog tipa 16 te ureidoamidi PQ 20. Većina derivata PQ pripremljena je koristeći benzotriazolsku metodu – klorid 1-benzotriazolkarboksilne kiseline (BtcCl) s nukleofilima daje cijeli niz vrlo reaktivnih prekursora koji su upotrijebljeni u sintezi navedenih derivata PQ. Za pripremu bis-urea 11 primijenjena su dva sintetska pristupa. U prvom pristupu produkti su „rasli” sa semikarbazidne strane, a PQ je ulazio u molekulu zadnji, dok su u drugom pristupu produkti sintetizirani iz zajedničkog prekursora semikarbazida PQ 9. Drugi pristup bio je prikladniji za pripremu cijele serije bis-urea. Derivati PQ 12 sintetizirani su iz benzotriazolida 8, 2c ili 2d i odgovarajućih amina ili izravno iz PQ i izocijanata. PQ-DCK amidi 15 i acilsemikarbazidi 16 pripremljeni su iz odgovarajućih klorida 14 i PQ ili semikarbazida PQ 9. Amidi 15d,e,g pripremljeni su dodatno aminolizom benzotriazolida DCK 13 primakinom. Derivati PQ i aminokiselina ureidoamidi 20 pripravljeni su iz PQ i odgovarajućih amida N-(1-benzotriazolkarbonil)aminokiselina 19.
Svi sintetizirani spojevi karakterizirani su uobičajenim analitičkim i spektroskopskim metodama te im je in vitro ispitano citostatsko djelovanje, kao i antioksidativno djelovanje na temelju sposobnosti redukcije 1,1-difenil-2-pikrilhidrazila (DPPH) te inhibicije lipidne peroksidacije linolne kiseline i lipooksigenaze. Najbolje citostatsko djelovanje na staničnu liniju MCF-7 adenokarcinoma dojke pokazao je spoj 16j, a slijedio ga je 11f s povoljnijim omjerom citostatske aktivnosti i citotoksičnosti. Najjaču sposobnost redukcije DPPH pokazali su spojevi 16d,g,i,j,k, najjači inhibitori lipidne peroksidacije bili su spojevi 20c i 12d, a najsnažniji inhibitor lipooksigenaze bio je spoj 16d. Iz dobivenih rezultata može se zaključiti da su bis-uree i acilsemikarbazidni derivati primakina aktivniji od urea i amida te mogu poslužiti kao vodeći spojevi u razvoju novih citostatika i antioksidansa.

Abstract (english)

This doctoral thesis describes synthesis of various primaquine (PQ) derivatives: bis-ureas 11, ureas and semicarbazones 12 with bulky aryl or hydroxyalkyl substituents, PQ-cinnamic acid conjugates (PQ-CAD) of the amide 15 and acylsemicarbazide type 16, and ureidoamides 20, as a continuation of the previous work on the derivatization of the antimalarial drug PQ developed at the Department of Medicinal Chemistry, Faculty of Pharmacy and Biochemistry in Zagreb. Most PQ derivatives were prepared utilizing benzotriazole as a synthetic auxiliary – 1-benzotriazolecarboxylic acid chloride (BtcCl) reacts readily with nucleophiles affording a variety of highly reactive synthetic precursors for the synthesis of the title compounds. Two synthetic approaches for the preparation of the PQ bis-ureas 11 were applied. In the first approach, the products grew from the semicarbazide part, and PQ entered the molecule at the final stage. In the second approach, one common precursor PQ semicarbazide 9 was introduced, from which various PQ bis-ureas were prepared. Derivatives 12 were obtained in the reaction of benzotriazolide 8, 2c or 2d with corresponding amines or directly from PQ and isocyanate. PQ-CAD amides 15 and acylsemicarbazides 16 were prepared from the corresponding chlorides 14 and PQ or PQ semicarbazide 9, respectively. Additionally, amides 15d,e,g were obtained by aminolysis of CAD benzotriazolide 13 with PQ. Ureidoamide derivatives of PQ and amino acids 20 were synthesized in the reaction of PQ and corresponding N-(1-benzotriazolecarbonyl)amino acid amides 19.
Common analytical and spectroscopic methods for the characterization of the synthesized compounds were used. Their cytostatic activity, antioxidative activity by DPPH reducing ability, and inhibition of linoleic acid lipid peroxidation and lipoxygenase were evaluated in vitro. The most prominent cytostatic activity on MCF-7 breast adenocarcinoma cell line was exerted by compound 16j, followed by 11f having more favourable ratio of antiproliferative activity and cytotoxicity. Compounds 16d,g,i,j,k had the strongest DPPH reducing ability, whereas compounds 20c and 12d showed the highest inhibition of linoleic acid lipid peroxidation. The most potent lipoxigenase inhibitor was compound 16d. The obtained results indicate that PQ bis-ureas and acylsemicarbazides are more active than ureas and amides, and therefore could be considered as lead compounds in development of novel cytostatics and antioxidants.

• Keywords: primakin; semikarbazid; bis-urea; urea; sinteza; citostatsko djelovanje; antioksidativno djelovanje
• Keywords (english): primaquine; semicarbazide; bis-urea; urea; synthesis; cytostatic activity; antioxidative activity
• Language: croatian
• URN:NBN: urn:nbn:hr:163:457377
• Study programme: Title: Pharmacy and biochemistry; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor znanosti (doktor znanosti)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2017-12-11 16:08:15