Synthesis and preliminary biological evaluation of antibacterial and antifungal 5-arylidene tetramic acid-cadmium(II) complexes.

The synthesis and biological evaluation of 5-arylidene-N-acetyl-tetramic acids cadmium(II) complexes are reported. Eleven novel compounds were prepared, characterized by nuclear magnetic resonance experiments and screened for their antimicrobial activity against five bacterial species (Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus [MRSA]) and two fungi (Candida albicans and Cryptococcus neoformans). The complexes showed similar or enhanced activities against MRSA in comparison to the corresponding ligands and, additionally, promising antifungal activities against C. neoformans. The most active compounds 3c and 3h showed remarkable activities against MRSA (minimum inhibitory activity [MIC] values of 32 and 4 µg/ml, respectively) and C. neoformans (MIC values of 8 and 16 µg/ml, respectively), accompanied by no human cell toxicity and hemolytic activity within the tested concentration range. The results demonstrate that appropriately functionalized tetramic acids attached with lipophilic alkanoyl chain and after complexation with cadmium(II) ions may act as valuable lead compounds for further investigations toward the development of novel antibacterial and/or antifungal agents.

Synthesis, biological evaluation and structure-activity relationships of 5-arylidene tetramic acids with antibacterial activity against methicillin-resistant Staphylococcus aureus.

The steady rise of the antimicrobial resistance is a major global threat to human health that requires the urgent need for novel antibiotics. In this work we report the synthesis of a small library of 3-subsituted-5-arylidene tetramic acids in order to investigate the scope of our previously established methodology via an intermediate oxazolone and their antimicrobial activity. From this series of 14 tetramic acids, 11 derivatives are novel and one of them is a Schiff base, which was structurally characterized with single-crystal X-ray analysis and NMR spectroscopy. The compounds incorporating a lipophilic acyl group at carbon-3 of the ring showed moderate to high activity with minimum inhibitory activity of 4-32 µg/mL against methicillin-resistant Staphylococcus aureus (MRSA), accompanied by no human cell toxicity and hemolytic activity within the tested concentration range. The substituent at para position of the aryl ring seemed to have no or little effect on the antimicrobial activity of these compounds.

Synthesis, characterization and antimicrobial activity of N-acetyl-3-acetyl-5-benzylidene tetramic acid-metal complexes. X-ray analysis and identification of the Cd(II) complex as a potent antifungal agent.

This study aims at the further expansion of knowledge on the antimicrobial activities of the tetramic acid moiety and the effect of metal complexation. Complexes of the N-acetyl-3-acetyl-5-benzylidenetetramic acid with Mn, Co, Ni, Cu, Zn and Cd were synthesized and screened against 5 key ESKAPE pathogens (Escherichia coli, methicillin-resistant Staphylococcus aureus (MRSA), Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa) and 2 fungi (Cryptococcus neoformans and Candida albicans). The cadmium complex was found to effectively inhibit the fungus Cryptococcus neoformans with minimum inhibitory concentration (MIC) of 8 µg/mL, with no human cell toxicity and hemolytic activity within the tested concentration range. The biologically active tetramic acid­cadmium complex was structurally characterized by single-crystal X-ray analysis. Furthermore, the thermal stability of the ligand and the complexes was investigated along with NMR and EPR studies of the Cd(II) and Co(II) complexes respectively.

X-Ray Crystallographic Analysis, EPR Studies, and Computational Calculations of a Cu(II) Tetramic Acid Complex.

In this work we present a structural and spectroscopic analysis of a copper(II) N-acetyl-5-arylidene tetramic acid by using both experimental and computational techniques. The crystal structure of the Cu(II) complex was determined by single crystal X-ray diffraction and shows that the copper ion lies on a centre of symmetry, with each ligand ion coordinated to two copper ions, forming a 2D sheet. Moreover, the EPR spectroscopic properties of the Cu(II) tetramic acid complex were also explored and discussed. Finally, a computational approach was performed in order to obtain a detailed and precise insight of product structures and properties. It is hoped that this study can enrich the field of functional supramolecular systems, giving place to the formation of coordination-driven self-assembly architectures.

Ruthenium-catalyzed selective hydrogenation of bis-arylidene tetramic acids. Application to the synthesis of novel structurally diverse pyrrolidine-2,4-diones.

Catalytic hydrogenation of 3,5-bis-arylidenetetramic acids, known for their biological activity, has been developed. The chemoselective ruthenium-catalyzed reduction of the exocyclic carbon-carbon double bonds on pyrrolidine-2,4-dione ring system, containing other reducible functions, has been investigated. Depending on the substrate the yield of the hydrogenation process can reach up to 95%. The structural elucidation has been established using NMR and HRMS spectral data.

Functionalized 4-hydroxy coumarins: novel synthesis, crystal structure and DFT calculations.

A novel short-step methodology for the synthesis in good yields of functionalized coumarins has been developed starting from an activated precursor, the N-hydroxysuccinimide ester of O-acetylsalicylic acid. The procedure is based on a tandem C-acylation-cyclization process under mild reaction conditions. The structure of 3-methoxycarbonyl-4-hydroxy coumarin has been established by X-ray diffraction analysis and its geometry was compared with optimized parameters by means of DFT calculations.

In silico exploration for identifying structure-activity relationship of MEK inhibition and oral bioavailability for isothiazole derivatives.

In this study, quantitative structure-activity/property models are developed for modeling and predicting both MEK inhibitory activity and oral bioavailability of novel isothiazole-4-carboxamidines. The models developed are thoroughly discussed to identify the key components that influence the inhibitory activity and oral bioavailability of the selected compounds. These selected descriptors serve as a first guideline for the design of novel and potent MEK inhibitors with desired ADME properties.

A combined LS-SVM & MLR QSAR workflow for predicting the inhibition of CXCR3 receptor by quinazolinone analogs.

A novel QSAR workflow is constructed that combines MLR with LS-SVM classification techniques for the identification of quinazolinone analogs as "active" or "non-active" CXCR3 antagonists. The accuracy of the LS-SVM classification technique for the training set and test was 100% and 90%, respectively. For the "active" analogs a validated MLR QSAR model estimates accurately their I-IP10 IC(50) inhibition values. The accuracy of the QSAR model (R (2) = 0.80) is illustrated using various evaluation techniques, such as leave-one-out procedure (R(LOO2)) = 0.67) and validation through an external test set (R(pred2) = 0.78). The key conclusion of this study is that the selected molecular descriptors, Highest Occupied Molecular Orbital energy (HOMO), Principal Moment of Inertia along X and Y axes PMIX and PMIZ, Polar Surface Area (PSA), Presence of triple bond (PTrplBnd), and Kier shape descriptor ((1) kappa), demonstrate discriminatory and pharmacophore abilities.

Solid-phase synthesis of optically active substituted 2 aminofuranones using an activated carbonate linker.

An efficient three-step solid-phase synthesis of diverse 3,5-disubstituted-2-aminofuranones has been developed. alpha-Hydroxy acids loaded on a nitrophenyl carbonate derivative of Wang resin are used as acylating agents for the C-acylation of active methylene compounds and the resulting intermediates provided, through a cyclative cleavage reaction, the desired product.

Predictive QSAR workflow for the in silico identification and screening of novel HDAC inhibitors.

A linear Quantitative Structure-Activity Relationship (QSAR) is developed in this work for modeling and predicting HDAC inhibition by 5-pyridin-2-yl-thiophene-2-hydroxamic acids. In particular, a five-variable model is produced by using the Multiple Linear Regression (MLR) technique and the Elimination Selection-Stepwise Regression Method (ES-SWR) on a database that consists of 58 recently discovered 5-pyridin-2-yl-thiophene-2-hydroxamic acids and 69 descriptors. The physical meaning of the selected descriptors is discussed in detail. The validity of the proposed MLR model is established using the following techniques: cross validation, validation through an external test set and Y-randomization. Furthermore, the domain of applicability which indicates the area of reliable predictions is defined. Based on the produced model, an in silico-screening study explores novel structural patterns and suggests new potent lead compounds.

Synthesis and evaluation of the antioxidant and anti-inflammatory activity of novel coumarin-3-aminoamides and their alpha-lipoic acid adducts.

In the present work a series of novel coumarin-3-carboxamides and their hybrids with the alpha-lipoic acid were designed, synthesized and tested as potent antioxidant and anti-inflammatory agents. The new compounds were evaluated for their antioxidant activity, their activity to inhibit in vitro lipoxygenase and their in vivo anti-inflammatory activity. In general, the derivatives were generally found to present antioxidant and anti-inflammatory activities. Discussion is made based on the results for the structure-activity relationships in order to define the structural features required for activity.

A novel QSAR model for predicting the inhibition of CXCR3 receptor by 4-N-aryl-[1,4] diazepane ureas.

A linear quantitative structure-activity relationship (QSAR) model is presented for modeling and predicting the inhibition of CXCR3 receptor. The model was produced by using the multiple linear regression (MLR) technique on a database that consists of 32 recently discovered 4-N-aryl-[1,4] diazepane ureas. The key conclusion of this study is that 3k, ChiInf8, ChiInf0, AtomCompTotal and ClogP affect significantly the inhibition of CXCR3 receptor by diazepane ureas. The selected physicochemical descriptors serve as a first guideline for the design of novel and potent antagonists of CXCR3.

Coordination behavior of 3-ethoxycarbonyltetronic acid towards Cu(II) and Co(II) metal ions.

Tetronic acids, 4-hydroxy-5H-furan-2-ones, constitute a class of heterocyclic compounds with potent biological and pharmacological activity. The beta, beta'-tricarbonyl moiety plays an integral role in biological systems and forms a variety of metal complexes. In this report, we present the complexation reactions of 3-ethoxycarbonyl tetronic acids with acetates and chlorides of Cu(II) and Co(II). These complexes have been studied by means of EPR spectroscopy and magnetic susceptibility measurements. From the obtained results, a preliminary complexation mode of the ligand is proposed.

Identification of a series of novel derivatives as potent HCV inhibitors by a ligand-based virtual screening optimized procedure.

This paper presents the results of a ligand-based virtual screening optimized procedure on 98 compounds which have been recently evaluated as inhibitors of genotype 1 HCV polymerase. First, quantitative structure-activity patterns are investigated for the selected compounds and then structural modifications are proposed to afford novel active patterns. An accurate and reliable QSAR model involving five descriptors that is able to predict successfully the HCV inhibitory potency against genotype 1 HCV polymerase is presented. Furthermore, the effects of various structural modifications on biological activity are investigated and biological activities of novel structures are estimated using the developed QSAR model. More specifically a search for optimized pharmacophore patterns by insertions, substitutions, and ring fusions of pharmacophoric substituents of the main building block scaffolds is described. The detection of the domain of applicability defines compounds whose estimations can be accepted with confidence.

Design and synthesis of novel quinolinone-3-aminoamides and their alpha-lipoic acid adducts as antioxidant and anti-inflammatory agents.

A series of N-substituted-quinolinone-3-aminoamides and their hybrids containing the alpha-lipoic acid functionality were designed and synthesized as potential bifunctional agents combining antioxidant and anti-inflammatory activity. The new compounds were evaluated for their antioxidant activity and for their ability to inhibit in vitro lipoxygenase as well as for their anti-inflammatory activity in vivo. In general, the derivatives were found to be potent antioxidant or anti-inflammatory agents. The results are discussed in terms of structure-activity relationships and an attempt is made to define the structural features required for activity.

Optimization of biaryl piperidine and 4-amino-2-biarylurea MCH1 receptor antagonists using QSAR modeling, classification techniques and virtual screening.

This paper presents the results of an optimization study on biaryl piperidine and 4-amino-2-biarylurea MCH1 receptor antagonists, which was accomplished by using quantitative-structure activity relationships (QSARs), classification and virtual screening techniques. First, a linear QSAR model was developed using Multiple Linear Regression (MLR) Analysis, while the Elimination Selection-Stepwise Regression (ES-SWR) method was adopted for selecting the most suitable input variables. The predictive activity of the model was evaluated using an external validation set and the Y-randomization technique. Based on the selected descriptors, the Support Vector Machines (SVM) classification technique was utilized to classify data into two categories: "actives" or "non-actives". Several attempts were made to optimize the scaffold of most potent compounds by inducing various structural modifications. Potential derivatives with improved activities were identified, as they were classified "actives" by the SVM classifier. Their activities were estimated using the produced MLR model. A detailed analysis on the model applicability domain defined the compounds, whose estimations can be accepted with confidence.

A novel QSPR model for predicting θ (lower critical solution temperature) in polymer solutions using molecular descriptors.

In this study, we present a new model that has been developed for the prediction of θ (lower critical solution temperature) using a database of 169 data points that include 12 polymers and 67 solvents. For the characterization of polymer and solvent molecules, a number of molecular descriptors (topological, physicochemical,steric and electronic) were examined. The best subset of descriptors was selected using the elimination selection-stepwise regression method. Multiple linear regression (MLR) served as the statistical tool to explore the potential correlation among the molecular descriptors and the experimental data. The prediction accuracy of the MLR model was tested using the leave-one-out cross validation procedure, validation through an external test set and the Y-randomization evaluation technique. The domain of applicability was finally determined to identify the reliable predictions.

A novel simple QSAR model for the prediction of anti-HIV activity using multiple linear regression analysis.

A quantitative-structure activity relationship was obtained by applying Multiple Linear Regression Analysis to a series of 80 1-[2-hydroxyethoxy-methyl]-6-(phenylthio) thymine (HEPT) derivatives with significant anti-HIV activity. For the selection of the best among 37 different descriptors, the Elimination Selection Stepwise Regression Method (ES-SWR) was utilized. The resulting QSAR model (R (2) (CV) = 0.8160; S (PRESS) = 0.5680) proved to be very accurate both in training and predictive stages.

A novel RBF neural network training methodology to predict toxicity to Vibrio fischeri.

This work introduces a neural network methodology for developing QSTR predictors of toxicity to Vibrio fischeri. The method adopts the Radial Basis Function (RBF) architecture and the fuzzy means training strategy, which is fast and repetitive, in contrast to most traditional training techniques. The data set that was utilized consisted of 39 organic compounds and their corresponding toxicity values to Vibrio fischeri, while lipophilicity, equalized electronegativity and one topological index were used to provide input information to the models. The performance and predictive ability of the RBF model were illustrated through external validation and various statistical tests. The proposed methodology can be used to successfully model toxicity to Vibrio fischeri for a heterogeneous set of compounds.

A novel QSAR model for predicting induction of apoptosis by 4-aryl-4H-chromenes.

A linear quantitative structure-activity relationship (QSAR) model is presented for modeling and predicting induction of apoptosis by 4-aryl-4H-chromenes. The model was produced by using the multiple linear regression (MLR) technique on a database that consists of 43 recently discovered 4-aryl-4H-chromenes. Among the 61 different physicochemical, topological, and structural descriptors that were considered as inputs to the model, seven variables were selected using the elimination selection-stepwise regression method (ES-SWR). The physical meaning of each descriptor is discussed. The accuracy of the proposed MLR model is illustrated using the following evaluation techniques: cross-validation, validation through an external test set, and Y-randomization. Furthermore, the domain of applicability which indicates the area of reliable predictions is defined.