New spirohydantoins derived from beta-tetralone: design, synthesis and evaluation of their pharmacokinetically relevant propertie
Апстракт
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 properti...es 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.
Кључне речи:
Spirohydantoins / Solvatochromism / Pharmacological activity / ADMET properties / Anticonvulsants / AntimigrenicИзвор:
Hemijska industrija, 2019, 73, 2, 79-92Издавач:
- Savez hemijskih inženjera, Beograd
Финансирање / пројекти:
- Проучавање синтезе, структуре и активности органских једињења природног и синтетског порекла (RS-MESTD-Basic Research (BR or ON)-172013)
DOI: 10.2298/HEMIND181203007L
ISSN: 0367-598X
WoS: 000466161800002
Scopus: 2-s2.0-85069649749
Колекције
Институција/група
Tehnološko-metalurški fakultetTY - 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 . .