TY  - JOUR
AU  - Lazić, Anita
AU  - Mandić, Željko D.
AU  - Valentić, Nataša
AU  - Ušćumlić, Gordana
AU  - Trišović, Nemanja
PY  - 2019
UR  - http://TechnoRep.tmf.bg.ac.rs/handle/123456789/4266
AB  - To 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.
PB  - Savez hemijskih inženjera, Beograd
T2  - Hemijska industrija
T1  - New spirohydantoins derived from beta-tetralone: design, synthesis and evaluation of their pharmacokinetically relevant propertie
EP  - 92
IS  - 2
SP  - 79
VL  - 73
DO  - 10.2298/HEMIND181203007L
ER  - 

@article{
author = "Lazić, Anita and Mandić, Željko D. and Valentić, Nataša and Ušćumlić, Gordana and Trišović, Nemanja",
year = "2019",
abstract = "To 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.",
publisher = "Savez hemijskih inženjera, Beograd",
journal = "Hemijska industrija",
title = "New spirohydantoins derived from beta-tetralone: design, synthesis and evaluation of their pharmacokinetically relevant propertie",
pages = "92-79",
number = "2",
volume = "73",
doi = "10.2298/HEMIND181203007L"
}

Lazić, A., Mandić, Ž. D., Valentić, N., Ušćumlić, G.,& Trišović, N.. (2019). New spirohydantoins derived from beta-tetralone: design, synthesis and evaluation of their pharmacokinetically relevant propertie. in Hemijska industrija
Savez hemijskih inženjera, Beograd., 73(2), 79-92.
https://doi.org/10.2298/HEMIND181203007L

Lazić A, Mandić ŽD, Valentić N, Ušćumlić G, Trišović N. New spirohydantoins derived from beta-tetralone: design, synthesis and evaluation of their pharmacokinetically relevant propertie. in Hemijska industrija. 2019;73(2):79-92.
doi:10.2298/HEMIND181203007L .

Lazić, Anita, Mandić, Željko D., Valentić, Nataša, Ušćumlić, Gordana, Trišović, Nemanja, "New spirohydantoins derived from beta-tetralone: design, synthesis and evaluation of their pharmacokinetically relevant propertie" in Hemijska industrija, 73, no. 2 (2019):79-92,
https://doi.org/10.2298/HEMIND181203007L . .

TY  - CONF
AU  - Lazić, Anita M.
AU  - Mandić, Željko
AU  - Trišović, Nemanja P.
AU  - Ušćumlić, Gordana S.
PY  - 2018
UR  - http://TechnoRep.tmf.bg.ac.rs/handle/123456789/6789
AB  - Among the diverse pharmacological activity reported for spirohydantoin and the closely related spirosuccinimides, their anticonvulsant and antiproliferative activities are commonly encountered. Of all cyclic ureide derivatives, Phenytoin (5,5-diphenylhydantoin) is one of the well-known commercially available anticonvulsants, which is also widely used as an antiarrhythmic agent. However, the clinical use of 5,5-diphenylhydantoin is limited by its central nervous adverse effects in addition to a wide variety of drug interactions [1]. With the aim of developing new analogs with a more efficient therapeutic effect, a series of 1-(4-substitutedbenzyl)-3’,4’-dihydro-2’H-spiro[imidazolidine-4,1’-naphtalene]-2,5-diones, have been synthesized, characterized by melting points, FT-IR, 1H and 13C NMR spectroscopic techniques, and evaluated for anticonvulsant activity. The objective of the present investigation is to identify the pharmacological impact of the spirocyclic attachment of a semi-rigid tetralin residue at C-5 of the imidazolidine-2,4-dione ring and to explore the effect of substitution at N-3 on anticonvulsant activity.
PB  - Beograd : Serbian Chemical Society
C3  - Book of Abstracts / Sixth Conference of Young Chemists of Serbia, Belgrade, 27th October 2018
T1  - Synthesis and characterization of 1-(4-substitutedbenzyl)-3’,4’-dihydro-2’H-spiro[imidazolidine-4,1’-naphtalene]-2,5-dione derivatives as potential anticonvulsant agents
T1  - Sinteza i karakterizacija 1-(4-supstituisanih benzil)-3’,4’-dihidro-2’H-spiro[imidazolidin-4,1’-naftalen]-2,5-diona potencijalnih antikonvulzivnih agenasa
SP  - 56
UR  - https://hdl.handle.net/21.15107/rcub_technorep_6789
ER  - 

@conference{
author = "Lazić, Anita M. and Mandić, Željko and Trišović, Nemanja P. and Ušćumlić, Gordana S.",
year = "2018",
abstract = "Among the diverse pharmacological activity reported for spirohydantoin and the closely related spirosuccinimides, their anticonvulsant and antiproliferative activities are commonly encountered. Of all cyclic ureide derivatives, Phenytoin (5,5-diphenylhydantoin) is one of the well-known commercially available anticonvulsants, which is also widely used as an antiarrhythmic agent. However, the clinical use of 5,5-diphenylhydantoin is limited by its central nervous adverse effects in addition to a wide variety of drug interactions [1]. With the aim of developing new analogs with a more efficient therapeutic effect, a series of 1-(4-substitutedbenzyl)-3’,4’-dihydro-2’H-spiro[imidazolidine-4,1’-naphtalene]-2,5-diones, have been synthesized, characterized by melting points, FT-IR, 1H and 13C NMR spectroscopic techniques, and evaluated for anticonvulsant activity. The objective of the present investigation is to identify the pharmacological impact of the spirocyclic attachment of a semi-rigid tetralin residue at C-5 of the imidazolidine-2,4-dione ring and to explore the effect of substitution at N-3 on anticonvulsant activity.",
publisher = "Beograd : Serbian Chemical Society",
journal = "Book of Abstracts / Sixth Conference of Young Chemists of Serbia, Belgrade, 27th October 2018",
title = "Synthesis and characterization of 1-(4-substitutedbenzyl)-3’,4’-dihydro-2’H-spiro[imidazolidine-4,1’-naphtalene]-2,5-dione derivatives as potential anticonvulsant agents, Sinteza i karakterizacija 1-(4-supstituisanih benzil)-3’,4’-dihidro-2’H-spiro[imidazolidin-4,1’-naftalen]-2,5-diona potencijalnih antikonvulzivnih agenasa",
pages = "56",
url = "https://hdl.handle.net/21.15107/rcub_technorep_6789"
}

Lazić, A. M., Mandić, Ž., Trišović, N. P.,& Ušćumlić, G. S.. (2018). Synthesis and characterization of 1-(4-substitutedbenzyl)-3’,4’-dihydro-2’H-spiro[imidazolidine-4,1’-naphtalene]-2,5-dione derivatives as potential anticonvulsant agents. in Book of Abstracts / Sixth Conference of Young Chemists of Serbia, Belgrade, 27th October 2018
Beograd : Serbian Chemical Society., 56.
https://hdl.handle.net/21.15107/rcub_technorep_6789

Lazić AM, Mandić Ž, Trišović NP, Ušćumlić GS. Synthesis and characterization of 1-(4-substitutedbenzyl)-3’,4’-dihydro-2’H-spiro[imidazolidine-4,1’-naphtalene]-2,5-dione derivatives as potential anticonvulsant agents. in Book of Abstracts / Sixth Conference of Young Chemists of Serbia, Belgrade, 27th October 2018. 2018;:56.
https://hdl.handle.net/21.15107/rcub_technorep_6789 .

Lazić, Anita M., Mandić, Željko, Trišović, Nemanja P., Ušćumlić, Gordana S., "Synthesis and characterization of 1-(4-substitutedbenzyl)-3’,4’-dihydro-2’H-spiro[imidazolidine-4,1’-naphtalene]-2,5-dione derivatives as potential anticonvulsant agents" in Book of Abstracts / Sixth Conference of Young Chemists of Serbia, Belgrade, 27th October 2018 (2018):56,
https://hdl.handle.net/21.15107/rcub_technorep_6789 .

TY  - CONF
AU  - Mandić, Željko
AU  - Lazić, Anita M.
AU  - Božić, Bojan Đ.
AU  - Ušćumlić, Gordana S.
PY  - 2016
UR  - http://TechnoRep.tmf.bg.ac.rs/handle/123456789/6762
AB  - Derivati tetrantoina (7,8-benzo-1,3-diazaspiro[4.5]dekan-2,4-diona) (Slika ) su jedinjenja širokog
spektra biološke aktivnosti. Mnogi od njih su poznata antikonvulzivna, antivirusna i antikancerogena jedinjenja, a uspešno se koriste i u lečenju dijabetesa. U okviru ovog rada, sintetizovan
je tetrantoin i njegovi derivati koji u položaju 3 hidantoinskog prstena sadrže supstituisanu benzil
grupu (supstituent X: H, CH3, OCH3, Cl, Br, CN). Struktura navedenih jedinjenja potvrđena je
temperaturama topljenja, 1 H i 13 C NMR, Ft-IR i UV spektroskopskim metodama. Na osnovu
strukturnih i lipofilnih karakteristika diskutovana je potencijalna biološka aktivnost sintetizovanih jedinjenja.
AB  - Derivatives of tetrantoin (7,8-benzo-1,3-diazaspiro[4.5]decane-2,4-dione) (Figure) are the compounds of a wide range of biological activities. Many of them are known anticonvulsant, anticancer and antiviral compounds, and are successfully used in the treatment of diabetes. In this work, was synthesized tetrantoin and its derivatives which in the 3-position of the hydantoin ring containing a substituted benzyl group (the substituent X: H, CH3, OCH3, Cl, Br, CN). The structure of these compounds was confirmed by melting point, 1H and 13C NMR, FT-IR and UV spectroscopic methods. Based on structural lipophilic characteristics is discussed the potential biological activity of the synthesized compounds.
PB  - Beograd : Srpsko hemijsko društvo
C3  - Kratki izvodi radova / Četvrta konferencija mladih hemičara Srbije, Beograd, 5. novembar 2016
T1  - Sinteza, struktura i svojstva 7,8-benzo-1,3-diazaspiro[4.5]dekan-2,4-diona i njegovih derivata
T1  - Synthesis, structure and properties of 7,8-benzo-1,3-diazaspiro[4.5]decane-2,4-dione and its derivatives
SP  - 55
UR  - https://hdl.handle.net/21.15107/rcub_technorep_6762
ER  - 

@conference{
author = "Mandić, Željko and Lazić, Anita M. and Božić, Bojan Đ. and Ušćumlić, Gordana S.",
year = "2016",
abstract = "Derivati tetrantoina (7,8-benzo-1,3-diazaspiro[4.5]dekan-2,4-diona) (Slika ) su jedinjenja širokog
spektra biološke aktivnosti. Mnogi od njih su poznata antikonvulzivna, antivirusna i antikancerogena jedinjenja, a uspešno se koriste i u lečenju dijabetesa. U okviru ovog rada, sintetizovan
je tetrantoin i njegovi derivati koji u položaju 3 hidantoinskog prstena sadrže supstituisanu benzil
grupu (supstituent X: H, CH3, OCH3, Cl, Br, CN). Struktura navedenih jedinjenja potvrđena je
temperaturama topljenja, 1 H i 13 C NMR, Ft-IR i UV spektroskopskim metodama. Na osnovu
strukturnih i lipofilnih karakteristika diskutovana je potencijalna biološka aktivnost sintetizovanih jedinjenja., Derivatives of tetrantoin (7,8-benzo-1,3-diazaspiro[4.5]decane-2,4-dione) (Figure) are the compounds of a wide range of biological activities. Many of them are known anticonvulsant, anticancer and antiviral compounds, and are successfully used in the treatment of diabetes. In this work, was synthesized tetrantoin and its derivatives which in the 3-position of the hydantoin ring containing a substituted benzyl group (the substituent X: H, CH3, OCH3, Cl, Br, CN). The structure of these compounds was confirmed by melting point, 1H and 13C NMR, FT-IR and UV spectroscopic methods. Based on structural lipophilic characteristics is discussed the potential biological activity of the synthesized compounds.",
publisher = "Beograd : Srpsko hemijsko društvo",
journal = "Kratki izvodi radova / Četvrta konferencija mladih hemičara Srbije, Beograd, 5. novembar 2016",
title = "Sinteza, struktura i svojstva 7,8-benzo-1,3-diazaspiro[4.5]dekan-2,4-diona i njegovih derivata, Synthesis, structure and properties of 7,8-benzo-1,3-diazaspiro[4.5]decane-2,4-dione and its derivatives",
pages = "55",
url = "https://hdl.handle.net/21.15107/rcub_technorep_6762"
}

Mandić, Ž., Lazić, A. M., Božić, B. Đ.,& Ušćumlić, G. S.. (2016). Sinteza, struktura i svojstva 7,8-benzo-1,3-diazaspiro[4.5]dekan-2,4-diona i njegovih derivata. in Kratki izvodi radova / Četvrta konferencija mladih hemičara Srbije, Beograd, 5. novembar 2016
Beograd : Srpsko hemijsko društvo., 55.
https://hdl.handle.net/21.15107/rcub_technorep_6762

Mandić Ž, Lazić AM, Božić BĐ, Ušćumlić GS. Sinteza, struktura i svojstva 7,8-benzo-1,3-diazaspiro[4.5]dekan-2,4-diona i njegovih derivata. in Kratki izvodi radova / Četvrta konferencija mladih hemičara Srbije, Beograd, 5. novembar 2016. 2016;:55.
https://hdl.handle.net/21.15107/rcub_technorep_6762 .

Mandić, Željko, Lazić, Anita M., Božić, Bojan Đ., Ušćumlić, Gordana S., "Sinteza, struktura i svojstva 7,8-benzo-1,3-diazaspiro[4.5]dekan-2,4-diona i njegovih derivata" in Kratki izvodi radova / Četvrta konferencija mladih hemičara Srbije, Beograd, 5. novembar 2016 (2016):55,
https://hdl.handle.net/21.15107/rcub_technorep_6762 .