2. Universidad Cardenal Herrera-CEU

In this paper, molecular topology was used to develop a mathematical model 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, widely used nowadays because of their broad spectrum of activity, well tolerance profile and advantageous pharmacokinetic properties. The topological model of activity obtained included two discriminant functions, selected by a combination of various statistical paremeters such as Fisher-Snedecor F and Wilk's lambda, and allows the reliable prediction of antibacterial activity in any organic compound. After a virtual pharmacological screening on a library of 6375 compounds, the model has selected 263 as active compounds, from which 40% have proven antibacterial activity. The results obtained clearly reveal the high efficiency of molecular topology for the prediction of pharmacological activities. These models are very helpful in the discovery of new applications of natural and synthetic molecules with different chemical or biological properties. Therefore, we finally present 158 strong candidates to be developed as novel antibacterials.

Molecular topology was used to develop a mathematical model capable of classifying compounds according to antimicrobial activity against methicillin resistant Staphylococcus aureus (MRSA). Topological indices were used as structural descriptors and their relation to antimicrobial activity was determined by using linear discriminant analysis. This topological model establishes new structure activity relationships which show that the presence of cyclopropyl, chlorine and ramification pairs at a distance of two bonds favor this activity, while the presence of tertiary amines decreases it. This model was applied to a combinatorial library of a thousand and one 6-fluoroquinolones, from which 117 theoretical active molecules were obtained. The compound 10 and five new quinolones were tested against MRSA. They all showed some activity against MRSA, although compounds 6, 8 and 9 showed anti-MRSA activity similar to ciprofloxacin. This model was also applied to 263 theoretical antibacterial agents described by us in a previous work, from which 34 were predicted as theoretically active. Anti-MRSA activity was found bibliographically in 9 of them (ensuring at least 26% of success), and from the rest, 3 compounds were randomly chosen and tested, finding mitomycin C to be more active than ciprofloxacin. The results demonstrate the utility of the molecular topology approaches for identifying new drugs active against MRSA.