Flavonoid Oxidation Potentials and Antioxidant Activities-Theoretical Models Based on Oxidation Mechanisms and Related Changes in Electronic Structure.

Herein, I will review our efforts to develop a comprehensive and robust model for the estimation of the first oxidation potential, Ep1, and antioxidant activity, AA, of flavonoids that would, besides enabling fast and cheap prediction of Ep1 and AA for a flavonoid of interest, help us explain the relationship between Ep1, AA and electronic structure. The model development went forward with enlarging the set of flavonoids and, that way, we had to learn how to deal with the structural peculiarities of some of the 35 flavonoids from the final calibration set, for which the Ep1 measurements were all made in our laboratory. The developed models were simple quadratic models based either on atomic spin densities or differences in the atomic charges of the species involved in any of the three main oxidation mechanisms. The best model takes into account all three mechanisms of oxidation, single electron transfer-proton transfer (SET-PT), sequential proton loss electron transfer (SPLET) and hydrogen atom transfer (HAT), yielding excellent statistics (R2 = 0.970, S.E. = 0.043).

Estimating flavonoid oxidation potentials: mechanisms and charge-related regression models.

In this paper, I tested our quadratic regression models for the estimation of flavonoid oxidation potentials based on spin populations, the differences in the net atomic charges between a cation and a neutral flavonoid, between a radical and an anion of a flavonoid, and between a radical and a neutral flavonoid on a larger set of flavonoids (N = 35). By including six new flavonoids (5,6,7-trihydroxyflavone, 3,3',4',7-tetrahydroxyflavone, 3,7-dihydroxyflavone, 4',7-dihydroxyflavone, 4',5,7-trihydroxyisoflavone, and 6-hydroxyflavone), we created a respectable calibration set of 35 flavonoids with their oxidation potentials all measured at the same conditions by the same experimentalist. The best model was based on the mean values of the three variables using differences in the net atomic charges (R 2 = 0.970, S.E. = 0.043), which are connected with the three different mechanisms of electrochemical oxidation, SET-PT, SPLET, and HAT.

Evaluation of the Key Structural Features of Various Butyrylcholinesterase Inhibitors Using Simple Molecular Descriptors.

In this study, we developed several QSAR models based on simple descriptors (such as topological and constitutional) to estimate butyrylcholinesterase (BChE) inhibition potency, pKi (or pIC50), of a set of 297 (289 after exclusion of outliers) structurally different compounds. The models were similar to the best model that we obtained previously for acetylcholinesterase AChE and were based on the valence molecular connectivity indices of second and third order (2χv and 3χv), the number of aliphatic hydroxyl groups (nOH), AlogP Ghose-Crippen octanol-water partition coeff. (logP), and O-060-atom-centred fragments (Al-O-Ar, Ar-O-Ar, R..O..R and R-O-C=X). The best models with two and three descriptors yielded r = 0.787 and S.E. = 0.89, and r = 0.827 and S.E. = 0.81, respectively. We also correlated nine scoring functions, calculated for 20 ligands whose complexes with BChE we found in the Protein Data Bank as crystal structures to pKi (or pIC50). The best correlations yielded PLP1 and PLP2 (Piecewise Linear Pairwise potential functions) with r = 0.619 and 0.689, respectively. Correlation with certain simple topological and constitutional descriptors yielded better results, e.g., 3χv (r = 0.730), on the same set of compounds (N = 20).

Use of connectivity index and simple topological parameters for estimating the inhibition potency of acetylcholinesterase.

Acetylcholinesterase (AChE) has proven to be an effective drug target in the treatment of neurodegenerative diseases such as Alzheimer's, Parkinson's and dementia. We developed a novel QSAR regression model for estimating potency to inhibit AChE, pK i, on a set of 75 structurally different compounds including oximes, N-hydroxyiminoacetamides, 4-aminoquinolines and flavonoids. Although the model included only three simple descriptors, the valence molecular connectivity index of the zero-order, 0 χv , the number of 10-membered rings (nR10) and the number of hydroxyl groups (nOH), it yielded excellent statistics (r = 0.937, S.E. = 0.51). The stability of the model was evaluated when an initial set of 75 compounds was broadened to 165 compounds in total, with the increase of the range of pK i (exp) from 6.0 to 10.2, yielding r = 0.882 and S.E. = 0.89. The predictive power of the model was evaluated by calculating pK i values for 55 randomly chosen compounds (S.E.test = 0.90) from the calibration model created on other 110 compounds (S.E. = 0.89), all taken from the pool of 165 compounds.

Anatomical Variations of the Bifid Mandibular Canal on Panoramic Radiographs in Citizens from Zagreb, Croatia.

BACKGROUND: The bifid mandibular canal (BMC) is an anatomical variation with reported prevalence ranging from 0.08 to 65%. Identifying anatomical variations of mandibular canal is very important in order to prevent possible complications during oral surgical and other dental procedures. OBJECTIVES: The aim of this study was to determine the prevalence and to classify the morphology of BMCs using digital panoramic radiographs. MATERIAL AND METHODS: A retrospective study was conducted that included 1008 digital panoramic radiographs (412 female and 596 male) used to identify the type of BMC. Panoramic radiographs were analyzed by three oral surgeons and one dentist, and BMCs were classified into six different types, 4 types according to Langlais et al. (types 1-4), and two new types (types 5 and 6) described by authors. RESULTS: The prevalence of BMC was 4.66% (n=47), with no significant differences in gender between BMC types (P=0.947; χ2=0.74). The prevalence of type 1 BMC was 0.79% (n=8), type 2 2.08% (n=21), type 3 0.30% (n=3), type 4 0% (n=0), type 5 0.89% (n=9) and type 6 0.60% (n=6). CONCLUSION: This study revealed a relatively high prevalence of BMCs among Zagreb citizens. Furthermore, two new types of BMCs were described. These results stress the importance of a careful and thorough radiographic analysis prior to each invasive procedure in the mandible.

Primary School Teachers' Knowledge on Tooth Avulsion.

OBJECTIVE: Permanent teeth trauma is most frequent in children aged 7-9 years, and the primary school teachers (PSTs) are often the first to notice it. The aim of this study was to evaluate the competence in tooth avulsion clinical issues and knowledge on dental trauma of PSTs, as they can occasionally take on the role of school nurses. MATERIAL AND METHODS: Questionnaires were handed to 312 PSTs from 24 randomly selected primary schools in Zagreb, Croatia. An algorithm was designed for PST competence assessment. RESULTS: Response rate amounted to 81.37% (N=255). Only 3.14% (N=8) of the PSTs would replant the permanent tooth properly and only 43.92% of them (N=112) would immediately take the child to a doctor of dental medicine. Dry tissue, as a transport medium for an avulsed tooth, was chosen by 50.20% (N=128) of the respondents. Altogether, 4.71% (N=12) of PSTs were graded as competent in case of child's tooth avulsion. CONCLUSION: These results provided significant implications for school health, showed the educators' serious lack of knowledge in cases of dental trauma and stressed a need for continuous education of PSTs on the topic.

Development of a simple QSAR model for reliable evaluation of acetylcholinesterase inhibitor potency.

With the aging of the western population, more and more people are affected by the neurodegenerative Alzheimer's and Parkinson's disease. Inhibitors of acetylcholinesterase (AChE) have proven to be effective in the treatment of disease symptoms. We report the QSAR regression model for the estimation of potency of a set of 94 structurally diverse compounds (oximes, N-hydroxyiminoacetamides, 4-aminoquinolines and flavonoids) to inhibit AChE, pKi (AChE). The model is based on three simple descriptors: the valence molecular connectivity index of the zero-order, 0χv, combined with the number of 10-membered rings (nR10) and number of hydroxyl groups in a molecule (nOH). QSAR model yielded r = 0.947, S.E. = 0.51 and S.E.cv= 0.53; the range of pKi (exp) = 6.03. It showed its stability when the set of 94 compounds was enlarged, comprising 184 compounds in total (r = 0.886, S.E. = 0.85 and S.E.cv = 0.88; the range of pKi (exp) = 10.21), resulting in regression parameters which were similar, although only for 0χv coefficients within the limits of S.E. (0.167(13) and 0.172(16) for the set with 94 and 184 compounds, respectively. The predictive power of the model was shown by the prediction of pKi values for 61 randomly chosen compounds (S.E.test = 0.86) from the calibration model made on the other 123 compounds (S.E. = 0.85), all taken from the pool of 184 compounds. QSAR descriptors 0χv, nR10 and nOH were well chosen for describing the interactions of the AChE active site (amino acid interaction) with ligands through the estimation of the inhibitory potency.

The relationship between antioxidant activity, first electrochemical oxidation potential, and spin population of flavonoid radicals.

I have shown that by averaging antioxidant activity (AA) values measured by different methods it is possible to obtain an excellent correlation (R2=0.960) between the first electrochemical oxidation potential, Ep1, and AA. Separate correlations using the AA values obtained with each of the four methods [R2 were 0.561 for diphenyl-1-picrylhydrazyl (DPPH), 0.849 for Folin Ciocalteu reagent (FCR), 0.848 for the ferric-reducing ability of plasma (FRAP), and 0.668 for the Trolox equivalent antioxidant capacity (TEAC)] were all worse, and in some cases not useful at all, such as the one for DPPH. Also, the sum of atomic orbital spin populations on the carbon atoms in the skeleton of radicals ( s(C) Σ AOSPRad), calculated with the semi-empirical parameterisation method 6 (PM6) in water, was used to correlate both Ep1 and AA, yielding R2=0.926 and 0.950, respectively. This showed to be a much better variable for the estimation of Ep1 and AA than the bond dissociation energy (BDE), R2=0.854 and 0.901 for Ep1 and AA, respectively, and especially the ionisation potential (IP), R2=0.445 and 0.435 for Ep1 and AA, respectively.

Surface Roughness of Glass Ionomer Cements after Application of Different Polishing Techniques.

Glass Ionomer Cements (GIC) have been widely used in clinical practice since they have a wide range of positive characteristics: chemical bonding to the tooth surface, fluoride release, a heat-expansion coefficient similar to the tooth, do not require an absolutely dry working area, less volumetric contraction, good color stability. Physical properties can be improved by using external energy such as ultrasound and radiant heat (thermo-curing), which also accelerates chemical curing. Objectives: The aim of this study was to determine the most effective polishing technique and to compare the surface roughness of two Glass Ionomer Cements after treatment with heat (thermo-curing), and without heat treatment during the setting process. Materials and methods: Two polishing systems (Tungsten carbide burs and Sof-Lex discs) were used on two types of GIC (Equia Fil and Ketac Molar Universal). Bluephase 16i LED (Vivadent, Schaan Liechtenstein) light was used for the specimens treated with heat (thermo-curing). Samples without heat treatment are left for 10 minutes to chemically cure. Surface profilometar was used for measuring the mean surface roughness value (Ra). Results: Group with Mylar strip (control group) of each material showed the lowest (Ra) value. The Equia Fil material samples treated with heat (thermo-curing) achieved lower surface roughness values (Ra), and showed lower surface roughness values (Ra) after polishing with a Sof-Lex discs (p<0.05). The results for Ketac Molar Universal samples showed no statistically significant difference (p>0.05) between polishing with Sof-Lex discs and Tungsten carbide burs. Conclusion: Based on the obtained results, it can be concluded that the smoothest surface roughness is achieved by the Mylar strip. Some types of Glass Ionomer Cements can obtain better surface polishing with heat treatment (thermo-curing).

A new, simplified model for the estimation of polyphenol oxidation potentials based on the number of OH groups.

We present a new and simpler regression model for the estimation of the first oxidation potentials (Ep1) of flavonoids based on the number of phenolic, alcoholic, and carboxylic OH groups. In the regression we included the Ep1 of 12 polyphenols (mostly flavonols and catechins) that were measured in our laboratory at pH 3. The model yielded r=0.986 and SE=0.040. Later successive inclusions of previously reported Ep values into the regression model, 7 at pH 3, the model (N=19) yielded r=0.980, SE=0.046 and 19 at pH 7 the model (N=38), yielded r=0.985, SE=0.044.

A comprehensive evaluation of novel oximes in creation of butyrylcholinesterase-based nerve agent bioscavengers.

A well-considered treatment of acute nerve agents poisoning involves the exogenous administration of butyrylcholinesterase (BChE, EC 3.1.1.8) as a stoichiometric bioscavenger efficient in preventing cholinergic crises caused by acetylcholinesterase (AChE, EC 3.1.1.7) inhibition. An additional improvement in medical countermeasures would be to use oximes that could reactivate BChE as well to upgrade bioscavenging from stoichiometric to oxime-assisted catalytic. Therefore, in this paper we investigated the potency of 39 imidazolium and benzimidazolium oximes (36 compounds synthesized for the first time) to be considered as the reactivators specifically designed for reactivation of phosphylated human BChE. Their efficiency in the reactivation of paraoxon-, VX-, and tabun-inhibited human BChE, as well as human AChE was tested and compared with the efficiencies of HI-6 and obidoxime, used in medical practice today. A comprehensive analysis was performed for the most promising oximes defining kinetic parameters of reactivation as well as interactions with uninhibited BChE. Furthermore, experimental data were compared with computational studies (docking, QSAR analysis) as a starting point in future oxime structure refinement. Considering the strict criteria set for in vivo applications, we determined the cytotoxicity of lead oximes on two cell lines. Among the tested oxime library, one imidazolium compound was selected for preliminary in vivo antidotal study in mice. The obtained protection in VX poisoning outlines its potential in development oxime-assisted OP-bioscavenging with BChE.

Simple graph-theoretical model for flavonoid binding to P-glycoprotein.

Three sets of flavonoid derivatives (N=32, 40, and 74) and logarithms of their dissociation constants (log Kd) that describe flavonoid affinity toward P-glycoprotein were modelled using six connectivity indices. The best results were obtained with the zero-order valence molecular connectivity index (0χv) for all three sets. Standard errors of the calibration models were around 0.3, and of the constants from the test sets even a little lower, 0.22 and 0.24. Despite using only one descriptor, our model proved better in internal (cross-validation) and especially in external (test set) statistics than much more demanding methods used in previous 3D QSAR modelling.

Prediction of Stability Constants of Zinc(II) Complexes with 2-aminobenzamide and Amino Acids.

We developed a model for the stability (log ß(ZnLB)) of Zn(2+) mixed complexes (N = 16) with 2-aminobenzamide (L) and four amino acids (B) glycine, alanine, valine, and phenylalanine at 300, 310, 320, and 330 K. The model was based on the quadratic regression function of the molecular valence connectivity index of the third order, (3)χ(v), yielded S.E. = 0.02. We also developed an overall model for K(1), K(2) and ß(ZnLB) of the same system at all of the four temperatures (N= 48). This model yielded S.E. = 0.05.

Modelling of copper(II) binding to pentapeptides related to atrial natriuretic factor using the 3χv connectivity index.

Using molecular graph theory we studied the binding of NSFRY-NH2 and 12 related pentapeptide amides to Cu(II) as a model system for atrial natriuretic factor (ANF) peptide interactions with copper. Linear regression models based on the valence connectivity index of the 3rd order (3χv) reproduced experimental stability constants (log ß) for 1N, 2N, 3N, and 4N coordinated complexes with the standard error of 0.30-0.39 log ß units. We developed separate models for seven tyrosinic (N=28) and five non-tyrosinic peptides (N=20), and a common model for both kinds of peptides (N=48) with an indicator (dummy) variable. The results indicate additional aromatic stabilisation in 4N complexes due to metal cation-π interactions with tyrosine but not with the phenylalanine residue. We have also amended the log K and log K* values to correct miscalculations published by Janicka-Klos et al. in 2013.

Prediction of stability constants of lanthanide complexes with amino acids by model based on connectivity index 3χv.

In order to model the stability of lanthanide complexes with amino acids, we used a set of 20 mono-complexes of La(3+), Ce(3+), Pr(3+), Nd(3+) and Sm(3+) with glycine, alanine, valine and leucine. The quadratic model based on the (3)χ(v) index gave r = 0.978, S.E. = 0.08. The predictive power of the model was tested by splitting the initial set of complexes on training (N = 15) and test set (N = 5). This enabled the logarithm of the stability constant, log K(1), of the leucine complex of neodymium(III) and all four complexes of samarium(III) to be predicted with S.E. = 0.11.

Theoretical model for the prediction of the stability of Co2+, Ni2+, Cu2+, Zn2+, and Cd2+ mono-complexes with monocarboxylic acids based on 3chi(v) connectivity index.

The quadratic model for the prediction of stability constants of transition metal (Co2+, Ni2+, Cu2+, Zn2+, and Cd2+) complexes with four monocarboxylic amino acids (methanoic, ethanoic, propanoic, and butanoic) was developed. The model yielded regression coefficient r = 0.996, and standard error S.E. = 0.05 (N = 20). As a test of goodness of the model, we predicted log K1 of three Co2+ complexes (with methanoic, propanoic and butanoic acid) from the training set (N = 17), consisted of the constants of other metal complexes and log K1 of [CoAc]+. The model yielded predictions with the S.E. = 0.08.

Comparison of two methods for the estimation of stability of copper(II) bis-complexes with aromatic ligands relevant to Alzheimer's disease.

In order to compare the density functional theory (DFT) and the method with the molecular valence connectivity index of the 3rd order (3χv) in the estimation of stability constants log ß2, we used copper(II) complexes with thioflavin-based intercalation compounds designed for application in Alzheimer's disease. Correlation of ten log ß2 values calculated by DFT with 3χv yielded r=0.988 and S.E.=0.85. The correlations of indices I(NG), HOMA and 3χv with log ß2, and the intercorrelations between the indices revealed the crucial influence of 3χv on the prediction of the stability of these complexes.

Estimation of Stability of Cadmium(II) Mono-Complexes with Monodentate and Bidentate Ligands by Models Based on 3χv Connectivity Index.

Based on the quadratic function used previously for the estimation of copper(II) amino acid mono-complexes, we developed the model for the estimation of the stability constant K1 of cadmium(II) complexes with five amino acids (glycine, alanine, 2-aminobutanoic, 2-aminopentanoic, and 2-aminohexanoic acid). The model gave R2 = 0.960 and S.E. = 0.03. Also, for the first time we proposed (univariate linear) model for the estimation of K1 of complexes with monodentate ligands, namely the Cd(II) complexes with methanoic, ethanoic, propanoic, 2-methylpropanoic, butanoic, 2-methylbutanoic, 2-hydroxyethanoic, 2-hydroxypropanoic and 2-hydroxybutanoic acid. The model is capable to discriminate monodentate from bidentate ligands; much better statistic was obtained (R2 = 0.966 and S.E. = 0.05) if 2-hydroxybutanoic acid was assumed to be bidentate.