1. Investigación

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.

Drug repurposing appears as an increasing popular tool in the search of new treatment options against bacteria. In this paper, a tree-based classification method using Linear Discriminant Analysis (LDA) and discrete indexes was used to create a QSAR (Quantitative Structure-Activity Relationship) model to predict antibacterial activity against Escherichia coli. The model consists on a hierarchical decision tree in which a discrete index is used to divide compounds into groups according to their values for said index in order to construct probability spaces. The second step consists in the calculation of a discriminant function which determines the prediction of the model. The model was used to screen the DrugBank database, identifying 134 drugs as possible antibacterial candidates. Out of these 134 drugs, 8 were antibacterial drugs, 67 were drugs approved for di erent pathologies and 55 were drugs in experimental stages. This methodology has proven to be a viable alternative to the traditional methods used to obtain prediction models based on LDA and its application provides interesting new drug candidates to be studied as repurposed antibacterial treatments. Furthermore, the topological indexes Nclass and Numhba have proven to have the ability to group active compounds e ectively, which suggests a close relationship between them and the antibacterial activity of compounds against E. coli.

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.