Quinoline Hydrazone Derivatives as New Antibacterials against Multidrug Resistant Strains.

To develop novel antimicrobial agents a series of 2(4)-hydrazone derivatives of quinoline were designed, synthesized and tested. QSAR models of the antibacterial activity of quinoline derivatives were developed by the OCHEM web platform using different machine learning methods. A virtual set of quinoline derivatives was verified with a previously published classification model of anti-E. coli activity and screened using the regression model of anti-S. aureus activity. Selected and synthesized 2(4)-hydrazone derivatives of quinoline exhibited antibacterial activity against the standard and antibiotic-resistant S. aureus and E. coli strains in the range from 15 to 30 mm by the diameter of growth inhibition zones. Molecular docking showed the complex formation of the studied compounds into the catalytic domain of dihydrofolate reductase with an estimated binding affinity from -8.4 to -9.4 kcal/mol.

Design of (quinolin-4-ylthio)carboxylic acids as new Escherichia coli DNA gyrase B inhibitors: machine learning studies, molecular docking, synthesis and biological testing.

Spread of multidrug-resistant Escherichia coli clinical isolates is a main problem in the treatment of infectious diseases. Therefore, the modern scientific approaches in decision this problem require not only a prevention strategy, but also the development of new effective inhibitory compounds with selective molecular mechanism of action and low toxicity. The goal of this work is to identify more potent molecules active against E. coli strains by using machine learning, docking studies, synthesis and biological evaluation. A set of predictive QSAR models was built with two publicly available structurally diverse data sets, including recent data deposited in PubChem. The predictive ability of these models tested by a 5-fold cross-validation, resulted in balanced accuracies (BA) of 59-98% for the binary classifiers. Test sets validation showed that the models could be instrumental in predicting the antimicrobial activity with an accuracy (with BA = 60-99 %) within the applicability domain. The models were applied to screen a virtual chemical library, which was designed to have activity against resistant E. coli strains. The eight most promising compounds were identified, synthesized and tested. All of them showed the different levels of anti-E. coli activity and acute toxicity. The docking results have shown that all studied compounds are potential DNA gyrase inhibitors through the estimated interactions with amino acid residues and magnesium ion in the enzyme active center The synthesized compounds could be used as an interesting starting point for further development of drugs with low toxicity and selective molecular action mechanism against resistant E. coli strains. The developed QSAR models are freely available online at OCHEM http://ochem.eu/article/112525 and can be used to virtual screening of potential compounds with anti-E. coli activity.

A descrição matemática do desempenho eletroanalítico do compósito poli(alaranjado da acridina)-oxihidróxido de vanádio na detecção eletrorredutiva da entacapona / The mathematical description for the electroanalytical function of poly (acridine orange) - vanadium oxyhydroxide in electroreductive detection of entacapone

RESUMO Por meio de uma análise teórica, foi avaliado o desempenho do compósito do oxihidróxido do vanádio trivalente com o polímero do corante alaranjado da acridina, na detecção eletroquímica do fármaco antiparquinsônico entacapona. O processo eletroanalítico é baseado na eletrorredução do fármaco mencionado. Do desenvolvimento e da análise do modelo matemático correspondente, mediante a teoria de estabilidade linear e anáise de bifurcações, foi possível concluir que o compósito pode ser um modificador eficiente para a determinação da entacapona. Os comportamentos oscilatórios e monotônico, neste sistema, também são passíveis de realizar.

SUMMARY By means of a theoretical analysis, the function of trivalent vanadium oxyhydroxyde composite with the polymer of the acridine orange dye for electrochemical evaluation of entacapone antiparkinsonic drug has been evaluated. The electroanalytical process is based on the electrochemical reduction of the mentioned drug. From development and analysis of the correspondent mathematical model by means of linear stability theory and bifurcation analysis, it was possible to conclude that the composite is an efficient electrode modifier for entacapone determination. The oscillatory and monotonic instabilities in this system are also capable to realize.

Doebner-type pyrazolopyridine carboxylic acids in an Ugi four-component reaction.

Substituted 1H-pyrazolo[3,4-b]pyridine-4- and 1H-pyrazolo[3,4-b]pyridine-6-carboxamides have been synthetized through a Doebner-Ugi multicomponent reaction sequence in a convergent and versatile manner using diversity generation strategies: combination of two multicomponent reactions and conditions-based divergence strategy. The target products contain as pharmacophores pyrazolopyridine and peptidomimetic moieties with four points of diversity introduced from readily available starting materials including scaffold diversity. A small focused compound library of 23 Ugi products was created and screened for antibacterial activity.

Directed Search of Biologically Active Compounds among Hydrogenated Isoindolylalkyl(alkylaryl-,aryl-)carboxylic Acids with Quinazoline Fragment that Modify the Carbohydrate Metabolism: Design, Synthesis and Modification.

An effective synthesis of (3H-quinazoline-4-ylidene)hydrazides of N-carboxyalkyl-(arylalkyl-,aryl-)isoindoline-1,3-diones, using activated N-protected aminoacids and 4-hydrazinoquinazoline was proposed in the framework methodology of directed search of hypoglycemic agents (fragment-oriented design, molecular docking). These hydrazides prepared via cyclocondensation under acid catalysis were converted to the corresponding 2-([1,2,4]triazolo[1,5-c]quinazoline-2-yl-) alkyl-(alkylaryl-,aryl-)-hydroisoindole-1,3(2H)-diones. The structure of synthesized compounds was established using IR, 1H and 13C NMR spectroscopy and LC-MS and the features of spectral pattern were discussed. The results of pharmacological screening revealed a series of compounds, that are short-acting hypoglycemic agents like prandial regulators of glucose (Mitiglinide). The SAR analysis showed, that the introduction of a hydrogenated 1,3-dioxoisoindole moiety bonded through linker groups with 4-hydrazinoquinazoline and triazolo[1,5-c]quinazoline cycles is reasonable in the context of searching for short-acting hypoglycemic agents and requires further research.

A descrição matemática do desempenho do novo derivado acridínico na detecção eletroanalítica do conteúdo total do ácido gálico em alfarroba / The mathematical description of the function of a novel acridinic derivative in the electroanalytical detection of total gallic acid content in carob

RESUMO A possibilidade do uso de um novo derivado de acridina, munido de um grupo doador de elétrons, como modificador de elétrons para a detecção do conteúdo total do ácido gálico em goma de alfarroba tem sido avaliada mediante uma análise teórica. O modelo matemático correspondente foi analisado mediante a teoria de estabilidade linear e análise de bifurcações. Foi mostrado que o derivado fosfazoico da acridina pode servir de modificador eficiente para a detecção eletroanalítica do conteúdo total do ácido gálico em alfarroba. As causas dos comportamentos oscilatório e monotônico também foram detectadas.

SUMMARY The possibility of the use of the novel acridinic derivative, containing an electron donor moiety in the total gallic acid content determination in carob gum has been evaluated by means of a theoretical analysis. The correspondent mathematical model has been analyzed by linear stability theory and bifurcation analysis. It was shown that the phosphazoic acridine derivative may serve as an efficient electrode modifier for electroanalytical determination of the total content of gallic acid in carob. The causes for the oscillatory and monotonic behavior have also been stipulated.