Development of new thiourea derivatives of naproxen: synthetis, physico-chemical and biological characterization

[N. V. Nedeljković]

127 listova

Uvod: Funkcionalizacijom karboksilne grupe naproksena u tioureidnu grupu primenom sterno voluminoznih i lipofilnih aromatičnih amina i estara aromatičnih aminokiselina mogu se sintetisati novi molekuli koji potencijalno imaju istu ili snažniju antiinflamacijsku i citotoksičnu aktivnost u odnosu na polazni naproksen. Materijal i metode: Reakcijom naproksena, kalijum-tiocijanata i jedinjenja sa amino grupom sintetisani su odgovarajući tioureidni derivati naproksena. Strukturna analiza je izvršena određivanjem temperature topljenja i spektroskopskim metodama. Lipofilnost je ispitana primenom shake-flask metode, reverzno-fazne hromatografije na tankom sloju (RP-TLC) i reverzno-fazne visokoefikasne tečne hromatografije (RPHPLC). Procena gastrointestinalne apsorpcije je sprovedena primenom PAMPA testa i bioparticione micelarne hromatografije (BMC). Veza između parametara apsorpcije i hemijske strukture ispitivanih jedinjenja utvrđena je analizom kvantitativnih odnosa strukture i permeabilnosti (QSPR) i kvantitativnih odnosa strukture i retencije (QSRR). Ispitivanim jedinjenjima je procenjena antiinflamacijska i citotoksična aktivnost, kao i potencijal inhibicije SOH-2 i 5-LOX enzima. Rezultati: Sintetisano je 14 tioureidnih derivata naproksena. Među ispitanim jedinjenjima najveće vrednosti RP-TLC i RP-HPLC hromatografskih parametara poseduju derivati 6 i 7. Samo je derivat 7 pokazao veći stepen pasivne gastrointestinalne apsorpcije u odnosu na naproksen. Jedinjenja 2, 4 i 7 pokazala su najsnažniji antiinflamacijski potencijal. Sva sintetisana jedinjenja poseduju slabiju SOH-2 inhibitornu aktivnost u odnosu na naproksen, dok je značajna inhibicija 5-LOX enzima zabeležena za jedinjenja 1-5. Najizraženiji citotoksični efekat ostvarili su derivati 3 i 8 na HeLa tumorsku ćelijsku liniju.

Introduction: By functionalizing the carboxyl group of naproxen into a thioureа group using sterically voluminous and lipophilic aromatic amines and esters of aromatic amino acids, novel molecules can be synthesized that potentially have the same or stronger anti-inflammatory and cytotoxic activity compared to the parent naproxen. Material and methods: Corresponding thioureа derivatives of naproxen were synthesized by the reaction of naproxen, potassium thiocyanate and compounds with an amino group. Structural analysis was performed by determining the melting point and spectroscopic methods. Lipophilicity was tested using the shake-flask, RP-TLC and RP-HPLC methods. Assessment of gastrointestinal absorption was carried out using the PAMPA and BMC tests. The relationship between the absorption parameters and the chemical structure of the tested compounds was determined by analyzing quantitative structure-permeability ratios (QSPR) and quantitative structure-retention ratios (QSRR). Anti-inflammatory and cytotoxic activity, as well as the inhibition potential of COX-2 and 5-LOX enzymes, were evaluated with the investigated compounds. Results: Fourteen thiourea derivatives of naproxen were synthesized. Among the tested compounds, derivatives 6 and 7 have the highest values of RP-TLC and RP-HPLC chromatographic parameters. Only derivative 7 showed a higher degree of passive gastrointestinal absorption compared to naproxen. Compounds 2, 4, and 7 showed the strongest anti-inflammatory potential. All synthesized compounds have weaker COX-2 inhibitory activity compared to naproxen, while significant inhibition of 5-LOX enzyme was observed for compounds 1-5. Derivatives 3 and 8 had the most pronounced cytotoxic effect on the HeLa tumor cell line.

Tioureidni derivati naproksena, lipofilnost, pasivna gastrointestinalna apsorpcija, hemometrijska analiza, antiinflamacijska aktivnost, COX-2 i 5-LOX inhibicija, citotoksična aktivnost.

Thiourea derivatives of naproxen, lipophilicity, passive gastrointestinal absorption, chemometric analysis, anti-inflammatory activity, COX-2 and 5-LOX inhibition, cytotoxic activity.

615.33.015:54(043.3)

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