Prediction of Drug Candidates' Sensitivity Toward Autoxidation: Computational Estimation of C-H Dissociation Energies of Carbon-Centered Radicals

Andersson, Thomas; Broo, Anders; Evertsson, Emma

doi:10.1002/jps.23986

Cited by 119 publications

(61 citation statements)

References 20 publications

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“…However, BDE is a measure of the bond strength in a chemical bond and it is defined as the standard energy (may also be used as enthalpy) change when a bond is broken by a reaction, with reactants and products of the reaction . The BDE is indicator of primary site(s) of auto‐oxidation of organic compounds and drugs . Considering eugenial C (Figure A) the Fukui function demonstrate the hydrogen atoms of C7, C2 and C15 from cyclopropa[e] nucleus showed high numeric values and they are the main regions of susceptibility in the oxidation process.…”

Section: Resultsmentioning

confidence: 99%

In silico and in vitro degradation studies of isolated phloroglucinols eugenial C and eugenial D from Eugenia umbelliflora fruits

Farias

Amorin

Santos

et al. 2019

Phytochemical Analysis

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Introduction Eugenia umbelliflora fruits are an important source of phloroglucinols, as eugenial C and eugenial D, related to antimicrobial activity against Staphylococcus aureus. However, for the establishment of new antimicrobial substances, it is essential to know their stability profile, in view of driving the administration route and the release system development. Methodology The in silico approaches, based on the Fukui indices and bond dissociation analysis, were performed. Eugenial C and eugenial D, isolated from the green fruits of E. umbelliflora, with purity > 90%, were submitted to stress degradation including: acid (0.5 mM hydrochloric acid) and alkaline (0.5 mM sodium hydroxide) hydrolysis, and oxidation (0.25% hydrogen peroxide), in different periods, monitoring by high‐performance liquid chromatography with ultraviolet detector (HPLC‐UV). Eugenial C was also submitted to UV‐visible radiation (2,400 lux/h) and dry/humid heating (40°C, 75% relative humidity). Results In silico studies indicated that both molecules have regions of high susceptibility to nucleophilic and electrophilic attack as well as sites likely to suffer auto‐oxidation. Under in vitro tests, both phloroglucinols proved to be very unstable under hydrolysis (eugenial C and D were degraded 23.8% and 89.0% in acid and 78.4% and 97.8% in alkaline conditions, respectively) and oxidation (eugenial C and D degraded 31.9% and 28.6%, respectively), both during 5 min. Eugenial C degraded 12.6% and 63.8% under dry and humid heat, respectively, without photosensitivity. Conclusion The in vitro stress tests monitored by HPLC‐UV were in agreement with in silico degradation prediction. Phloroglucinols could be unstable if administered by oral route and also under environmental conditions demanding a protective release system.

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Section: Resultsmentioning

confidence: 99%

In silico and in vitro degradation studies of isolated phloroglucinols eugenial C and eugenial D from Eugenia umbelliflora fruits

Farias

Amorin

Santos

et al. 2019

Phytochemical Analysis

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“…Sensitivity towards the autoxidation mechanism can be predicted by the DFT calculations since the correlation between this mechanism and bond dissociation energy for hydrogen abstraction (H-BDE) has been established [91]. This is of great practical importance, since oxidative reactions are very significant for the removal of organic pollutants through their degradation [92].…”

Section: Sensitivity Towards Autoxidation and Influence Of Watermentioning

confidence: 99%

Computational evaluation of the reactivity and pharmaceutical potential of an organic amine: A DFT, molecular dynamics simulations and molecular docking approach

Abraham

Muthu²,

Prasana

et al. 2019

Spectrochimica Acta Part A: Molecular and Biomolecular Spectros

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2- [N-(carboxymethyl)anilino] acetic acid (PIDAA) molecule has been spectroscopically characterized and computationally investigated for its fundamental reactive properties by a combination of density functional theory (DFT) calculations, molecular dynamics (MD) simulations and molecular docking procedure. A comparison drawn between the simulated and experimentally attained spectra by FT-Raman and FT-IR showed concurrence. The natural bond orbital (NBO) analysis enabled in comprehending the stability and charge delocalization in the title molecule. The first hyperpolarizability which is an important parameter for future studies of nonlinear optics (NLO) was calculated to check the potential of the molecule to be an NLO material. Besides, frontier molecular orbitals (FMO), electron localization function (ELF) and localized orbital locator (LOL) analysis were performed. Energy gap (ΔE), electronegativity (χ), chemical potential (μ), global hardness (η), softness (S), Mulliken population analysis on atomic charges and thermodynamic properties of the title compound at different temperatures have been calculated. The local reactive properties of PIDAA have been addressed by MEP and ALIE surfaces, together with bond dissociation energy for hydrogen abstraction (H-BDE). MD simulations have been used in order to identify atoms with pronounced interactions with water molecules. The pharmaceutical potential of PIDAA has been considered by the analysis of drug likeness parameters and molecular docking procedure. The biological activity of the molecule in terms of molecular docking has been analyzed theoretically for the treatment of SARS and minimum binding energy calculated. The Ramachandran plot was used to check the stereochemistry of the protein structure. In addition, a comparison of the physiochemical parameters of PIDAA and commercially available drugs (Yu et al., 2004;Tan et al., 2004;Elshabrawy et al., 2014;Chu et al., 2004;Gopal Samy and Xavier, 2015) were carried out.

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“…Values between 70 to 75 kcal mol -1 and between 85 and 90 kcal mol -1 could also be taken into consideration. 78 On the other hand, values lower than 70 kcal mol -1 are not suitable for the autoxidation mechanism. 22,76,78 At the same time, BDE values for the rest single acyclic bonds might serve as indicators of molecule sites where degradation could commence.…”

Section: Reactive and Degradation Properties Based On Autoxidation Anmentioning

confidence: 99%

4-[(4-acetylphenyl)amino]-2-methylidene-4-oxobutanoic acid, a newly synthesized amide with hydrophilic and hydrophobic segments: Spectroscopic characterization and investigation of its reactive properties

Mary

Al‐Abdullah

Aljohar

et al. 2018

JSCS

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The FT-IR and FT-Raman spectra of 4-[(4-acetylphenyl)amino]-2-methylidene-4-oxobutanoic acid were recorded. The vibrational wave numbers were computed by DFT quantum chemical calculations and the vibrational assignments were realized using the potential energy distribution. The theoretically predicted geometrical parameters were in agreement with the XRD data. Determination and visualization of molecule sites prone to electrophilic attacks were performed by mapping the average local ionization energies (ALIE) to the electron density surface. Furthermore, determination of possible reactive centres of title molecule was realized by calculation of the Fukui functions. Intramolecular non-covalent interactions were also determined and visualized. In addition, prediction of molecule sites possibly prone to autoxidation was performed by calculation of the bond dissociation energies (BDE), while the stability of the title molecule in water was assessed by calculation of radial distribution functions (RDF) obtained after molecular dynamics (MD) simulations.

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Prediction of Drug Candidates' Sensitivity Toward Autoxidation: Computational Estimation of C-H Dissociation Energies of Carbon-Centered Radicals

Cited by 119 publications

References 20 publications

In silico and in vitro degradation studies of isolated phloroglucinols eugenial C and eugenial D from Eugenia umbelliflora fruits

In silico and in vitro degradation studies of isolated phloroglucinols eugenial C and eugenial D from Eugenia umbelliflora fruits

Computational evaluation of the reactivity and pharmaceutical potential of an organic amine: A DFT, molecular dynamics simulations and molecular docking approach

4-[(4-acetylphenyl)amino]-2-methylidene-4-oxobutanoic acid, a newly synthesized amide with hydrophilic and hydrophobic segments: Spectroscopic characterization and investigation of its reactive properties

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