2. Universidad Cardenal Herrera-CEU

Quinolones are one of the most extensively used therapeutic families of antibiotics. However, the increase in antibiotic-resistant bacteria has rendered many of the available compounds useless. After applying our prediction model of activity against E. coli to a library of 1000 quinolones, two quinolones were selected to be synthesized. Additionally, a series of zwitterionic quinolonates were also synthesized. Quinolones and zwitterionic quinolonates were obtained by coupling the corresponding amine with reagent 1 in acetonitrile. Antibacterial activity was assessed using a microdilution method. All the compounds presented antibacterial activity, especially quinolones 2 and 3, selected by the prediction model, which had broad-spectrum activity. Furthermore, a new type of zwitterionic quinolonate with antibacterial activity was found. These compounds can lead to a new line of antimicrobials, as the structures, and, therefore, their properties, are easily adjustable in the amine in position 4 of the pyridine ring.

Currently, the development of resistance of Enterobacteriaceae bacteria is one of the most important health problems worldwide. Consequently, there is a growing urge for finding new compounds with antibacterial activity. Furthermore, it is very important to find antibacterial compounds with a good pharmacokinetic profile too, which will lead to more efficient and safer drugs. In this work, we have mathematically described a series of antibacterial quinolones by means of molecular topology. We have used molecular descriptors and related them to various pharmacological properties by using multilinear regression (MLR) analysis. The regression functions selected by presenting the best combination of a number of quality and validation metrics allowed for the reliable prediction of clearance (CL), and minimum inhibitory concentration 50 against Enterobacter aerogenes (MIC50Ea) and Proteus mirabilis (MIC50Pm). The obtained results clearly reveal that the combination of molecular topology methods and MLR provides an excellent tool for the prediction of pharmacokinetic properties and microbiological activities in both new and existing compounds with different pharmacological activities.

The variability of methicillin-resistant Staphylococcus aureus (MRSA), its rapid adaptive response against environmental changes, and its continued acquisition of antibiotic resistance determinants have made it commonplace in hospitals, where it causes the problem of multidrug resistance. In this study, we used molecular topology to develop several discriminant equations capable of classifying compounds according to their anti-MRSA activity. Topological indices were used as structural descriptors and their relationship with anti-MRSA activity was determined by applying linear discriminant analysis (LDA) on a group of quinolones and quinolone-like compounds. Four extra equations were constructed, named DFMRSA1, DFMRSA2, DFMRSA3 and DFMRSA4 (DFMRSA was built in a previous study), all with good statistical parameters, such as Fisher–Snedecor F (>68 in all cases), Wilk’s lambda (<0.13 in all cases), and percentage of correct classification (>94% in all cases), which allows a reliable extrapolation prediction of antibacterial activity in any organic compound. The results obtained clearly reveal the high efficiency of combining molecular topology with LDA for the prediction of anti-MRSA activity.

In this study, molecular topology was used to develop several discriminant equations capable of classifying compounds according to their antibacterial activity. Topological indices were used as structural descriptors and their relation to antibacterial activity was determined by applying linear discriminant analysis (LDA) on a group of quinolones and quinolone-like compounds. Four equations were constructed, named DF1, DF2, DF3, and DF4, all with good statistical parameters such as Fisher–Snedecor’s F (over 25 in all cases), Wilk’s lambda (below 0.36 in all cases) and percentage of correct classification (over 80% in all cases), which allows a reliable extrapolation prediction of antibacterial activity in any organic compound. From the four discriminant functions, it can be extracted that the presence of sp3 carbons, ramifications, and secondary amine groups in a molecule enhance antibacterial activity, whereas the presence of 5-member rings, sp2 carbons, and sp2 oxygens hinder it. The results obtained clearly reveal the high e ciency of combining molecular topology with LDA for the prediction of antibacterial activity.

Background: Due to antibiotic resistance and the lack of investment in antimicrobial R&D, QSAR methods appear as an ideal approach for the discovery of new antibiotics. Result/Methodology: Molecular topology and LDA were used to construct a model to predict activity against Escherichia coli. This model establishes new SARs, of which, molecular size and complexity (Nclass), stand out for their discriminant power. This model was used for the virtual screening of the Index Merck database, with results showing a high success rate as well as a moderate restriction. Conclusions: The model efficiently finds new active compounds. The topological index Nclass can act as a filter in other QSAR models predicting activity against E. coli.

In this paper, a multilinear regression (MLR) analysis has been carried out in order to accurately predict physicochemical properties and biological activities of a group of antibacterial quinolones by means of a set of structural descriptors called topological indices. The aim of this work is to develop prediction equations for these properties after collecting the maximum number of data from the literature on antibacterial quinolones. The five regression functions selected by presenting the best combination of various statistical parameters, subsequently validated by means of internal validation (intercorrelation, Y-randomization and leave-one-out cross-validation tests), allowed the reliable prediction of minimum inhibitory concentration 50 versus Staphylococcus aureus (MIC50Sa), Streptococcus pyogenes (MIC50Spy) and Bacteroides fragilis (MIC50Bf), mean residence time (MRT) after oral administration and volume of distribution (VD). We conclude that the combination of molecular topology methods and MLR provides an excellent tool for the prediction of pharmacological properties.