Derivati nesteroidnih protuupalnih lijekova i aminokiselina - sinteza, karakterizacija i biološko djelovanje

doctoral thesis

• Title (english): Derivatives of nonsteroidal anti-inflammatory drugs and amino acids - synthesis, characterization and biological activity
• Author: Zrinka Rajić Džolić; MBZ: 264323
• Mentor: Branka Zorc (mentor)
• Committee member: Marica Medić-Šarić (predsjednik povjerenstva)
• Committee member: Branka Zorc (član povjerenstva)
• Committee member: Marijeta Kralj (član povjerenstva); MBZ: 187794
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of medicinal chemistry); Zagreb
• Defense date and country: 2008, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Pharmacy
• Universal decimal classification (UDC): 615 - Pharmacology. Therapeutics. Toxicology

Abstract

Sintetizirana je serija novih strukturnih analoga 3,5-disupstituiranih hidantoina 5a-h s lipofilnim
supstituentima na C-5, N-3 ili na oba atoma intramolekulskom ciklizacijom amida
N-(1-benzotriazolkarbonil)aminokiselina 4a-h. Sintetizirani su derivati NSAID 6–12: reducirani derivati
ketoprofena 6a,b, NSAID benzotriazolidi 7a-h, NSAID hidroksamske kiseline i njihovi derivati 8a-y,
derivati ketoprofena 9a-i, 10a-f, 11a-f i 3-hidroksipropilamidi NSAID 12a-e. Reducirani derivati
ketoprofena 6 pripravljeni su katalitičkim hidrogeniranjem ketoprofena uz Pd/C ili Pd/C(en). NSAID s
karboksilnom funkcionalnom (ibuprofen, fenoprofen, diklofenak, indometacin, ketoprofen, 6a,b) u reakciji
s kloridom 1-benzotriazol-karboksilne kiseline (1) dali su odgovarajuće NSAID benzotriazolide 7, koji su
bili polazni spojevi u sintezi derivata NSAID 8–12. Razvijena je nova sintetska metoda za pripravu NSAID
hidroksamskih kiselina i derivata 8, reakcijom NSAID benzotriazolida 7 i odgovarajućih hidroksilamina
(hidroksilamin, N-metilhidroksilamin, O-metilhidroksilamin, O-etilhidroksilamin i O-benzilhidroksilamin)
ili katalitičkim hidrogeniranjem O-benzilnih derivata NSAID hidroksamskih kiselina. Derivati ketoprofena
9, 10 i 3-hidroksipropilamidi NSAID 12 sintetizirani su iz NSAID benzotriazolida 7 i odgovarajućih
amina, dok su derivati ketoprofena 11 sintetizirani katalitičkim hidrogeniranjem amida ketoprofena 10 uz
Pd/C(en).
Provedena su sljedeća biološka ispitivanja: antitumorsko, antimikrobno, antivirusno i
antioksidacijsko djelovanje, inhibicija ureaze, lipooksigenaze i lipidne peroksidacije. Najbolje
antitumorsko djelovanje pokazao je 8c, najbolje antimikrobno 8b,d, najbolje antivirusno 5a i 8y, a najbolje
antioksidacijsko djelovanje 8o. Najjači inhibitor ureaze bio je 8f, a lipooksigenaze 11f. Najbolji inhibitor
lipidne peroksidacije bio je 9e.

Abstract (english)

3,5-Disubstituted hydantoin derivatives 5a-h with lipophilic substituents at C-5, N-3 or both
atoms were prepared by the intramolecular cyclization of the corresponding
N-(1-benzotriazolecarbonyl)amino acid amides 4a-h. The following NSAID derivatives 6–12 were
prepared: the reduced ketoprofen derivatives 6a,b, NSAID benzotriazolides 7a-h, NSAID hydroxamic
acids and their derivatives 8a-y, ketoprofen derivatives 9a-i, 10a-f, 11a-f and NSAID
3-hydroxypropylamides 12a-e. The reduced ketoprofen derivatives 6 were prepared by the catalytic
hydrogenation of ketoprofen with Pd/C or Pd/C(en) catalyst. NSAIDs bearing carboxylic group (ibuprofen,
fenoprofen, diclofenac, indomethacin, ketoprofen, 6a,b) reacted with 1-benzotriazole carboxylic acid
chloride (1) affording benzotriazolides 7, which were the starting compounds in the synthesis of NSAID
derivatives 8–12. A new synthetic method for the synthesis of NSAID hydroxamic acids and their
derivatives was developed. They were obtained in the reaction of NSAID benzotriazolides 7 with an
appropriate hydroxylamine (hydroxylamine, N-methylhydroxylamine, O-methylhydroxylamine,
O-ethylhydroxylamine or O-benzylhydroxylamine) or by the catalytic hydrogenation of O-benzyl
derivatives of NSAID hydroxamic acids. Ketoprofen derivatives 9, 10 and NSAID 3-hydroxypropylamides
12 were prepared from NSAID benzotriazolides 7, in the reaction with an appropriate amine, while
compounds of the series 11 were obtained by the catalytic hydrogenation of ketoprofen amides 10 with
Pd/C(en).
The compounds were evaluated for their biological activity: antitumor, antimicrobial, antiviral
and antioxidant activity, inhibition of urease, lipoxygenase and linoleic acid lipid peroxidation. The best
antitumor activity was exerted by 8c, antimicrobial by 8b,d, antiviral by 5a and 8y, and antioxidant by 8o.
The strongest inhibitor of urease was 8f, while 11f was the strongest inhibitor of lipoxygenase. Compoung
9e showed the highest inhibition of linoleic acid lipid peroxidation.

• Keywords: aminokiselina; hidantoin; nesteroidni protuupalni lijekovi; hidroksamska kiselina; amid; sinteza; biološko djelovanje
• Keywords (english): amino acid; hydantoin; nonsteroidal anti-inflammatory drugs; hydroxamic acid; amide; synthesis; biological activity
• Language: croatian
• URN:NBN: urn:nbn:hr:163:773431
• 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: 2017-11-23 11:30:21