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dc.creatorLazić, Anita
dc.creatorMandić, Željko D.
dc.creatorValentić, Nataša
dc.creatorUšćumlić, Gordana
dc.creatorTrišović, Nemanja
dc.date.accessioned2021-03-10T14:07:54Z
dc.date.available2021-03-10T14:07:54Z
dc.date.issued2019
dc.identifier.issn0367-598X
dc.identifier.urihttp://TechnoRep.tmf.bg.ac.rs/handle/123456789/4266
dc.description.abstractTo create new anticonvulsant drugs, two series of spirohydantoins derived from beta-tetralone bearing a 4-substituted benzyl group (1a-1g) or a 2-(4-substituted phenyl)-2-oxoethyl group (2a-2f) in position 3 of the hydantoin ring were synthesized. The chemical structure of these compounds was confirmed by determination of the melting point, elemental analysis and FT-IR, H-1 NMR, C-13 NMR and UV-Vis spectroscopic methods. Effects of the substituents in the benzyl moiety on the shift of the absorption maxima of compounds 1a-1g and 2a-2f were analyzed using the Hammett's equation. Namely, a split in the Hammett plot at the parent compounds 1a and 2a revealed different electronic transitions within the molecules with the electron-donating substituents from those bearing the electron-accepting substituents, thus the electron-accepting effect on the shift of the absorption maxima being considerably stronger. The influence of the chemical structure on the pharmacokinetically relevant properties of the investigated hydantoin derivatives was evaluated using the Lipinski's rule of five, Veber, Egan and Ghose's empirical criteria, as well as different in silico methods. When compared to phenytoin (5,5-diphenylhydantoin) as the referent drug, compounds with a halogen or electron-donating substituent are expected to possess better intestinal absorption and passage through the blood-brain barrier. Depending on the nature of the substituent present in the benzyl moiety, compounds 1a-1g and 2a-2f can be potent activators/inhibitors of some cytochrome P450 izoenzymes including CYP1A2, CYP2C19 and CYP2C9. Regarding biological activity profile, compounds with the electron-accepting substituents are likely to reveal the pharmacological potential similar to that of phenytoin, while those bearing electron-donating substituents are predicted to have the antimigrenic activity. All compounds were found to bear a low risk of being mutagenic or tumorigenic. The calculated molecular descriptors indicate that the investigated compounds fulfill necessary empirical criteria which qualify them as interesting drug candidates.en
dc.publisherSavez hemijskih inženjera, Beograd
dc.relationinfo:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/172013/RS//
dc.rightsopenAccess
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.sourceHemijska industrija
dc.subjectSpirohydantoinsen
dc.subjectSolvatochromismen
dc.subjectPharmacological activityen
dc.subjectADMET propertiesen
dc.subjectAnticonvulsantsen
dc.subjectAntimigrenicen
dc.titleNew spirohydantoins derived from beta-tetralone: design, synthesis and evaluation of their pharmacokinetically relevant propertieen
dc.typearticle
dc.rights.licenseBY-NC-ND
dc.citation.epage92
dc.citation.issue2
dc.citation.other73(2): 79-92
dc.citation.rankM23
dc.citation.spage79
dc.citation.volume73
dc.identifier.doi10.2298/HEMIND181203007L
dc.identifier.fulltexthttp://TechnoRep.tmf.bg.ac.rs/bitstream/id/1943/4263.pdf
dc.identifier.scopus2-s2.0-85069649749
dc.identifier.wos000466161800002
dc.type.versionpublishedVersion


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