Derivatives of nonsteroidal anti-inflammatory drugs and amino acids - synthesis, characterization and biological activity

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.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