Prediction of p38 map kinase inhibitory activity of 3, 4-dihydropyrido [3, 2-d] pyrimidone derivatives using an expert system based on principal component analysis and least square support vector machine.

A quantitative structure-activity relationship (QSAR) study is suggested for the prediction of biological activity (pIC50) of 3, 4-dihydropyrido [3,2-d] pyrimidone derivatives as p38 inhibitors. Modeling of the biological activities of compounds of interest as a function of molecular structures was established by means of principal component analysis (PCA) and least square support vector machine (LS-SVM) methods. The results showed that the pIC50 values calculated by LS-SVM are in good agreement with the experimental data, and the performance of the LS-SVM regression model is superior to the PCA-based model. The developed LS-SVM model was applied for the prediction of the biological activities of pyrimidone derivatives, which were not in the modeling procedure. The resulted model showed high prediction ability with root mean square error of prediction of 0.460 for LS-SVM. The study provided a novel and effective approach for predicting biological activities of 3, 4-dihydropyrido [3,2-d] pyrimidone derivatives as p38 inhibitors and disclosed that LS-SVM can be used as a powerful chemometrics tool for QSAR studies.

Prediction of partition coefficient of some 3-hydroxy pyridine-4-one derivatives using combined partial least square regression and genetic algorithm.

A quantiatative structure property relationship (QSPR) treatment was used to a data set consisting of diverse 3-hydroxypyridine-4-one derivatives to relate the logarithmic function of octanol:water partition coefficients (denoted by log po/w) with theoretical molecular descriptors. Evaluation of a test set of 6 compounds with the developed partial least squares (PLS) model revealed that this model is reliable with a good predictability. Since the QSPR study was performed on the basis of theoretical descriptors calculated completely from the molecular structures, the proposed model could potentially provide useful information about the activity of the studied compounds. Various tests and criteria such as leave-one-out cross validation, leave-many-out cross validation, and also criteria suggested by Tropsha were employed to examine the predictability and robustness of the developed model.

Synthesis and tyrosinase inhibitory properties of some novel derivatives of kojic acid.

Tyrosinase is a multifunctional oxidase that is widely distributed in nature. It is a key enzyme in melanin biosynthesis and is involved in determining the color of mammalian skin and hair. In addition it is responsible for the undesirable enzymatic browning that occurs in plant-derived foods, limiting the shelf-life of fresh-cut products with the resultant economic loss. In recent years there has been considerable interest to study the inhibitory activity of tyrosinase and a number of inhibitory compounds derived from natural sources or partly/fully synthetic have been described. However, the current conventional methods to control tyrosinase action are inadequate. Considering the significant industrial and economic impact of the inhibitors of tyrosinase, this study was set to seek new potent inhibitors of this enzyme. A series of 3-hydroxypyridine-4-one derivatives were prepared in high yield and evaluated for their inhibitory activity on tyrosinase enzyme using dopachrome method. Our results show that all synthesized compounds have inhibitory effect on tyrosinase activity for the oxidation of L-DOPA. Among compounds studied those containing two free hydroxyl group (ie Va and V'a) were more potent than their analogues with one hydroxyl group (ie Vb and V'b). Also substitution of a methyl group on position N(1) of the hydroxypyridinone ring seems to confer more inhibitory potency.

Quantitative structure activities relationships of some 2-mercaptoimidazoles as CCR2 inhibitors using genetic algorithm-artificial neural networks.

Quantitative relationships between structures of twenty six of 2-mercaptoimidazoles as C-C chemokine receptor type 2 (CCR2) inhibitors were assessed. Modeling of the biological activities of compounds of interest as a function of molecular structures was established by means of genetic algorithm multivariate linear regression (GA-MLR) and genetic algorithm (GA-ANN). The results showed that, the pIC50 values calculated by GA-ANN are in good agreement with the experimental data, and the performance of the artificial neural networks regression model is superior to the multivariate linear regression-based (MLR) model. With respect to the obtained results, it can be deduced that there is a non-linear relationship between the pIC50 s and the calculated structural descriptors of the 2-mercaptoimidazoles. The obtained models were able to describe about 78% and 93% of the variance in the experimental activity of molecules in training set, respectively. The study provided a novel and effective approach for predicting biological activities of 2-mercaptoimidazole derivatives as CCR2 inhibitors and disclosed that combined genetic algorithm and GA-ANN can be used as a powerful chemometric tools for quantitative structure activity relationship (QSAR) studies.

Synthesis, analysis and cytotoxic evaluation of some hydroxypyridinone derivatives on HeLa and K562 cell lines.

A range of iron bidentae ligands containing the chelating moiety 3- hydroxypyridin-4-ones (HPOs) have been synthesized via a single or a three-step synthetic pathway. In the single-step reaction, maltol was directly reacted by suitable primary amine and in the second synthetic method; benzylated maltol was reacted with related amines to give 1-substuted-2-methyl-3-benzyloxypyridin-4-one derivatives. Finally, removal of the benzyl group under acidic conditions was performed by catalytic hydrogenation to yield the favored bidentate chelators as HCl salt. The partition coefficient of the free ligands and their iron (III) complexes between an aqueous phase buffered at pH 7.4 and 1-octanol were also determined. The cytotoxic effects of these iron chelators against HeLa and K562 cell lines were evaluated using MTT assay and the results showed that cytotoxicity was closely related to the lipophilicity of compounds so that the most lipophilic compound (4g) revealed the highest activity and compound 4e as a more hydrophilic agent (Kpart; 0.05) showed the lowest cytotoxic effect.

A QSAR study of some cyclobutenediones as CCR1 antagonists by artificial neural networks based on principal component analysis.

BACKGROUND AND PURPOSE OF THE STUDY: A quantitative structure activity relationship (QSAR) model based on artificial neural networks (ANN) was developed to study the activities of 29 derivatives of 3-amino-4-(2-(2-(4-benzylpiperazin-1-yl)-2-oxoethoxy) phenylamino) cyclobutenedione as C-C chemokine receptor type 1(CCR1) inhibitors. METHODS: A feed-forward ANN with error back-propagation learning algorithm was used for model building which was achieved by optimizing initial learning rate, learning momentum, epoch and the number of hidden neurons. RESULTS: Good results were obtained with a Root Mean Square Error (RMSE) and correlation coefficients (R(2)) of 0.189 and 0.906 for the training and 0.103 and 0.932 prediction sets, respectively. CONCLUSION: The results reflect a nonlinear relationship between the Principal components obtained from calculated molecular descriptors and the inhibitory activities of the investigated molecules.

A modeling study of aldehyde inhibitors of human cathepsin K using partial least squares method.

Quantitative relationships between molecular structure of forty eight aldehyde compounds with their known Cathepsin K inhibitory effects were discovered by partial least squares (PLS) method. Evaluation of a test set of 10 compounds with the developed PLS model revealed that this model is reliable with a good predictability. Since the QSAR study was performed on the basis of theoretical descriptors calculated completely from the molecular structures, the proposed model could potentially provide useful information about the activity of the studied compounds. Various tests and criteria such as leave-one-out cross validation, leave-many-out cross validation, and also criteria suggested by Tropsha were employed to examine the predictability and robustness of the developed model.

Synthesis and biological evaluation of bidentate 3-hydroxypyridin-4-ones iron chelating agents.

A series of 3-hydroxypyridin-4-one derivatives (HPOs) were synthesized and their partition coefficient values (K(part)) were determined. The cytotoxic effects of these iron chelators against Hela cancer cells were also evaluated. The IC(50) of HPOs was determined using MTT assay. Among these ligands, compound 4e (K(part)=5.02) with an IC(50) of 30 µM and 4f (K(part)=0.1) with an IC(50) of 700 µM showed the lowest and highest IC(50)s, respectively. In conclusion, the introduction of a more hydrophobic functional group (such as butyl in compound 4e) on the nitrogen of pyridinone ring resulted in higher cytotoxic activity of ligands.