Naslov
Optical stability of oxazepam and chiral 1,4- benzodiazepines. DFT study of the racemization mechanism

Autori
Božičević, Lucija ; Sremec, Helena ; Hok, Lucija ; Šakić, Davor ; Vrček, Valerije

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Computational Chemistry Day 2018 // Book of Abstracts / - Zagreb : Prirodoslovno-matematički fakultet Sveučilišta u Zagrebu, 2018, 22-23

ISBN
978-953-6076-45-1

Skup
Computational Chemistry Day 2018

Mjesto i datum
Zagreb, Hrvatska, 12.05.2018

Vrsta sudjelovanja
Poster

Vrsta recenzije
Domaća recenzija

Ključne riječi
DFT ; oxazepam ; racemization ; mechanism ; benzodiazepine

Sažetak
Optical stability is of utmost importance in pharmaceutical chemistry and biomedicine. In this work, the attention is focused on oxazepam which displays extreme chiral instability under physiological conditions (37 °C, pH 7.4), and may serve as a model for the whole family of 1, 4-benzodiazepin-2-ones. Several reaction mechanisms underlying the racemization of oxazepam were proposed in the literature (Scheme 1). In several kinetic studies the reaction rate constant k was measured and values varied from 0.16 min-1 (23 °C, pH 7) to 0.02 min-1 (20 °C). According to the Eyring equation, these values correspond to the free energy barrier range of 87 – 91 kJ/mol. We assume that all processes below or close to the target experimental barrier (ΔG‡ ≤ 91 kJ/mol) may contribute to the measured reaction rate. We used quantum chemical models to calculate geometries and energies or respective intermediates and transition state structures. All structures were optimized with the B3LYP functional and the standard basis set 6- 31+G(d). We also determined the Gibbs energies of solvation using the SMD continuum solvation model at the B3LYP/6-31+G(d) level (ε = 78.4). Initial configurations of water complexes were created using a locally modified version of the stochastic search method (http://andrija.pharma.hr/Andrija/SCRIPT.html) According to our computational results we claim that the enantiomerization of oxazepam in water follows the mechanism of the ring-chain tautomeric rearrangement. No other mechanism, suggested earlier in the literature, matches the experimental data in terms of Gibbs free energy.

Izvorni jezik
Engleski

Znanstvena područja
Farmacija

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