Topological pattern for the search of new active drugs against methicillin resistant Staphylococcus aureus

• Published in: European journal of medicinal chemistry Vol. 138; pp. 807 - 815
• Main Authors: Bueso-Bordils, Jose I., Perez-Gracia, Maria T., Suay-Garcia, Beatriz, Duart, Maria J., Martin Algarra, Rafael V., Lahuerta Zamora, Luis, Anton-Fos, Gerardo M., Aleman Lopez, Pedro A.
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 29.09.2017; Elsevier
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Chemistry, Medicinal; Dose-Response Relationship, Drug; Life Sciences & Biomedicine; Linear discriminant analysis; Methicillin-Resistant Staphylococcus aureus - drug effects; Microbial Sensitivity Tests; Molecular Structure; Molecular topology; Pharmacology & Pharmacy; QSAR; Quantitative Structure-Activity Relationship; Quinolone; SARM; Science & Technology; Virtual combinatorial chemistry; Molecular topology; Quinolone; Linear discriminant analysis; QSAR; Virtual combinatorial chemistry; SARM; DESIGN; ACIDS; VITRO ANTIBACTERIAL ACTIVITY; FLUOROQUINOLONE DERIVATIVES; IN-VITRO; BIOLOGICAL-ACTIVITY; AGENTS; ANTIMICROBIAL ACTIVITY
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.07.010

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. [Display omitted] •Active and inactive quinolones against MRSA were selected.•An anti-MRSA prediction model has been developed using Molecular Topology-LDA.•New structure activity relationships have been established.•A virtual screening was performed on 1264 quinolone and non-quinolone compounds.•Four of the nine assayed compounds showed similar activity to Ciprofloxacin.