General Physiology and Biophysics Vol, No.4, p–,
Design, synthesis, and structure-activity relationship study of conformationally constrained analogs of indolecarboxamides as novel CB1. Synthesis and structureactivity relationship of mono-indole-, bis-indole-, and tris- indole-based sulfonamides as potential anticancer agents. Ratchanok Pingaew. Full Paper. Antioxidant, Cytotoxic Activities, and Structure–Activity. Relationship of Gallic Acid-based Indole Derivatives. Hamid Khaledi1, Abeer A. Alhadi1.
Totally, descriptors were on this group of inhibitors. These models have also generated. The number of descriptors was then reduced been used to select more effective descriptors to obtain through an objective feature selection. This procedure a hybrid computational model for a rough prediction of was performed in three steps. Firstly, descriptors that inhibitory activity. Secondly, descriptors with derivatives has also been compared.
Finally, pairs of variables Molecular dataset with a correlation coefficient greater than 0. After these were obtained from the work of Meanwell et al3 This three steps, the number of descriptors was reduced to A binary vector algorithm GA variable subset selection methods were with the dimension of 58 represented the individual in used for the selection of the most relevant descriptors the population.
In other words, the defined from the pool of 58 descriptors.What is STRUCTURE-ACTIVITY RELATIONSHIP? What does STRUCTURE-ACTIVITY RELATIONSHIP mean?
A value of 0 in terms of root mean square error calculated from the indicated that the corresponding feature was not following equation: GA selected the best features from n these possible feature subsets during different where yi is the desired output, yo is the predicted generations. In each generation, the population was probabilistically modified which generates new value by model, and n is the number of molecules in chromosomes having a better chance of solving the our data set.
The population thereby evolves toward descriptors were examined for establishing the best higher fitness This procedure is shown in Fig. The size of descriptor subset used for In our study, two point binary crossover and binary model establishment was increased until no mutation were performed as recombinant operators.
After model development with The roulette wheel selection strategy was also used in TSET members, the best model was further examined the algorithm for parent selection.
The relevant by the PSET compounds.
The best subset of descriptors selected in QSAR-1 0. A number of was fed into neural networks to develop QSAR The different fitness functions were assessed and the neural networks used in this study were all three- optimal fitness function as the object of minimization layered fully-connected feed-forward networks.
Such by GA was found as follows: Each neuron in the network was connected to all neurons in neighboring layer s through adjustable weights. Network training is the process of adjusting such weights, wherein the error is somehow minimized.
The number of input layer neurons is equal to the number of descriptors. We had only one output layer neuron, while the number of hidden layer neurons was a matter of optimization8. The neural networks with Fig. The definition of the descriptors in the above- All calculations in present work were carried out in mentioned equations is shown in Table 2.
According to Matlab environment V 7. When using the previously mentioned equations, the RMSE for predicted activity Results and Discussion was found to be 0. Also, the correlation coefficient R2 non-linear feature selection methods were used to select calculated for the PSET was as good as 0. One of the the most significant descriptors stepwise-MLR and most important advantages of this model was its ability GA.
The following MLR equations were generated for The descriptors which were selected twice and more each group of compounds: The descriptors that were Table 2 selected at least six times by the model were employed found to be 0. These parameters are illustrated the TSET.
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The correlation coefficient R2 of this in Table 5. ANN model, because the ANN with simpler structure After a hundred generations, the best parameters which made the better results in Jack-knife test. The selected parameters with different The value of the selected descriptors by GA-ANN hidden units and their corresponding fitness values are model was presented in Table 6.
Different results were obtained when the same amidic side chain was linked at position 2 of the indole moiety.
Compounds 48—56 showed little or no activity in the guinea-pig ileum bioassay. It was found that none of the accessible conformations of compound 53, taken as a model for this class of compounds, fits with either of the conformations of astemizole considered in this study. This is reflected by the higher d1 distance showed by the minimum energy conformation of compound 53 compared with that of compound 32 table V. It is also worth noting that in this case the presence of a strong electrostatic interaction with the protonated basic nitrogen and the amidic carbonyl group greatly limits the conformational freedom of the molecule.
A similar situation occurs in the case of the piperazine derivative Its greater d1 value of 7. Superimposition of astemizole minimum energy conformation, gray and 32 black. In conclusion, a good H1-antagonist activity was shown by the derivatives in which the basic chain was linked at position 3 of the indole system by means of a carboxamide bridge, with a benzyl group at the indole nitrogen atom, which can fit into an appropriate cavity on the receptor site. The molecular modelling results seem to suggest that the pharmacologically active conformation of astemizole could be similar to that indicated as conf.
Superimposition of astemizole conformation 2, gray and 32 black. This conformation possesses the right distances between the protonated nitrogen and the centroid of at least one of the aromatic rings for potent H1-antagonist activity. DMSO-d6 was used as the solvent, unless otherwise indicated. Mass spectra were obtained on a HewlettPackard A spectrometer using a direct injection probe and an electron beam energy of 70 eV.
Magnesium sulfate was always used as the drying agent. Evaporations were made in vacuo rotating evaporator. Analytical TLC was carried out on Merck 0. Silica gel 60 70— mesh was used for column chromatography and silica gel 60 — mesh was used for flash chromatography.
The following products were prepared according to literature: The precipitate formed was collected, washed with small portions of anhydrous ethyl ether and dried under vacuum to give pure 6 as a yellow microcrystalline solid 1. The reaction mixture was left to stir at room temperature for 48—72 h, monitoring the reaction by TLC analysis.
Structure-activity relationships of indole- and pyrrole-derived cannabinoids.
The precipitate present was filtered off and the filtrate was concentrated to dryness. The oily residue was solubilized in chloroform, washed with saturated sodium hydrogen carbonate aqueous solution and water, and concentrated again. The crude product obtained was purified by recrystallization from the appropriate solvent.
Yields, recrystallization solvents and melting points are listed in table I. The spectrometric data for 12, which is representative of the title compounds, are listed below. N-[ 1-Benzylindoleyl glyoxylyl]dimethylaminoethylamine General procedure for the synthesis of 5substituted 1- 4-substituted benzyl indolecarbaldehydes 17—22 Sodium hydride 0. After acidification to pH 6 with 2 N hydrochloric acid, the solid formed was collected, washed with water and purified by recrystallization, after filtration, when necessary, on a silica gel column.
Yields, recrystallization solvents, melting points and spectrometric data for the newly synthesized compounds are listed below. General procedure for the synthesis of 5substituted 1- 4-substituted benzyl indolecarboxylic acids 23—28 A solution of 2. The reaction mixture was left to stir, in the dark, at room temperature, for 16 h. The resulting solution was concentrated to half volume and acidified to pH 3 with 2 N hydrochloric acid.
The precipitate formed was collected, washed with water, and purified by recrystallization. This intermediate was obtained by refluxing for 1 h a mixture of ethyl pyruvate 1.
CiteSeerX — Structure-activity relationships of indole- and pyrrole-derived cannabinoids’, The
The crude product obtained was purified by flash chromatography eluting system: A mixture of 1. After cooling, the precipitate formed was collected, dried under vacuum and purified by recrystallization from benzene, giving 0. After carbon dioxide evolution had ceased, a solution of the appropriate amine 2.
The resulting solution was concentrated to dryness, and the oily residue, dissolved in chloroform, was washed with saturated sodium hydrogen carbonate aqueous solution, and then with water. After drying, the chloroform solution was concentrated to dryness, and the crude product was purified by flash chromatography eluting system: