Alkenyl and arylidene 2-thiohydantoins: synthesis, kinetics and mechanism of formation, biological and electrochemical evaluation, coordination potential

[P. B. Stanić]

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APSTRAKT Istraživanja u sklopu ove doktorske disertacije su bila fokusirana na sintezu dve serije novih alkenilskih derivata 2-tiohidantoina iz α-aminokiselina i arilidenskih derivata 2-tiohidantoina iz aromatičnih aldehida. Kinetika i mehanizam nastajanja aminokiselinskih derivata 2-tiohidantoina u reakciji metil estra nekoliko izabranih α-aminokiselina sa alil-izotiocijanatom ispitivani su pomoću 1H NMR spektroskopije i teorije funkcionala gustine. Antimelanogena aktivnost novosintetisanih derivata 2-tiohidantoina, kao i njihova toksičnost, ispitivane su in vivo na modelu embriona zebrice, u cilju određivanja mogućnosti njihove primene u tretmanu poremećaja hiperpigmentacije kože kod čoveka. U cilju određivanja potencijalnih targeta inhibitora melanogeneze, primenjen je molekulski doking. Antikorozivna svojstva četiri arilidenska derivata 2-tiohidantoina 6a-g su ispitivana na mekom čeliku u 0,5 M HCl gravimetrijskim, elektrohemijskim i mikroskopskim metodama u cilju razvijanja novih potencijalnih inhibitora korozije mekog čelika. Koordinacioni potencijal odabranih derivata 2-tiohidantoina je ispitivan u reakcijama sa cisplatinom i solima Pd(II), praćenim 1H NMR spektroskopijom u DMSOd6 kao rastvaraču, kao i upotrebom teorije funkcionala gustine. Određeni su način koordinovanja, red i mehanizam reakcije, a ispitivan je uticaj DMSO na ove reakcije. Urađena je molekulska doking analiza pretpostavljenih kompleksa sa DNK kao targetom, u cilju predviđanja njihove antitumorske aktivnosti. Na kraju, ispitivana je reakcija arilidenskog derivata 6b sa trans-[CuCl2(dmso)2]n kompleksom. Umesto dobijanja odgovarajućeg tiohidantoinskog kompleksa bakra, odigrala se izomerizacija trans-[CuCl2(dmso)2]n do dinuklearnog cis-[{CuCl(dmso)2}(μ-Cl)]2. Ispitivan je uticaj derivata 6b na izomerizaciju.

ABSTRACT Research within the framework of this dissertation was focused on the synthesis of two series of novel alkenyl 2-thiohydantoin derivatives from α-amino acids and arylidene 2-thiohydantoin derivatives from aromatic aldehydes. Kinetics and mechanism of formation of amino acid derived 2-thiohydantoins in the reaction of methyl esters of some selected amino acids with allyl isothiocyanate were studied by 1H NMR spectroscopy and density functional theory. The antimelanogenic activity of the obtained 2-thiohydantoin derivatives, as well as their toxicity, was tested in vivo using the zebrafish model, in order to adress the possibility of their application in the treatment of skin hyperpigmentation disorders. Molecular docking was performed on selected biological targets. The anticorrosive activity of four arylidene 2-thiohydantoin derivatives was tested by gravimetric, electrochemical and microscopic methods on mild steel in 0.5 M HCl to develop new potential corrosion inhibitors for mild steel. The coordination potential of some selected derivatives was studied in reactions with cisplatin and Pd(II) salts, monitored by 1H NMR spectroscopy in DMSO-d6, and also by using density functional theory. The coordination modes, the reaction order, the mechanism and the influence of DMSO have been determined. Molecular docking of the proposed complexes with DNA, as a potential target, was performed in order to predict their antitumor activities. The reaction of one arylidene derivative with the trans-[CuCl2(dmso)2]n complex was studied. Instead of obtaning the corresponding copper 2-thiohydantoin complex, isomerization of trans-[CuCl2(dmso)2]n to dinuclear cis-[{CuCl(dmso)2}(μ-Cl)]2 was observed. Influence of the 2-thiohydantoin derivative on the isomerization was examined.

2-tiohidantoin, kinetika i mehanizam, NMR spektroskopija, teorija funkcionala gustine, inhibicija melanogeneze, inhibicija korozije, koordinacija, molekulski doking

2-thiohydantoin, kinetics and mechanism, NMR spectroscopy, density functional theory, melanogenesis inhibition, corrosion inhibition, coordination, molecular docking

547.31(043.3)

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