title: A topological-substructural molecular design (TOPS-MODE) approach to determining pharmacokinetics and pharmacological properties of 6-fluoroquinolone derivatives.
abstract: The topological-substructural molecular design approach was used to estimate the human bioavailability (F) and the minimum inhibitory concentration (MIC90) against Streptococcus pneumoniae from a data set of 17 and 19 fluoroquinolone derivatives, respectively. Both pharmacokinetics and pharmacological properties were well described by the present approach. The total spectral moments and local spectral moments that include the different fluoroquinolone rings, polar and non-polar areas and their interactions were calculated and weighted with the standard dipole moments and the electronegative difference between the atoms that form a bond. In order to obtain a qualitative model that permits the classification of drugs with high and moderate bioavailability, a linear discriminant analysis was carried out. The percentage of correct classification was 100% for compounds of the training set. The leave-one-out cross validation procedure showed an 88.23% of correct classification. Also, a quantitative model, by the piecewise linear regression was developed. The theoretically predicted values for human bioavailability was assessed by a correlation with in vivo rat bioavailability and the regression equation was used to predict this biopharmaceutical property for two new pre-clinical 6-fluoroquinolone derivatives. On the other hand, a linear regression model that explained the 84% of variance was developed to predict the MIC90 values. Finally, the role of a pharmacokinetic and pharmacological relationship in the design of new fluoroquinolones was evaluated in the Sitafloxacin framework, where 13 substituents were analyzed; halogens and methoxy groups had the best contributions to both properties. The present approach proved to be a good method for studying the pharmacokinetics and the pharmacological properties of new 6-fluoroquinolone candidates in drug development studies.
authors.affiliation: Department of Drug Design, Chemical Bioactive Centre, Central University of Las Villas, Villa Clara, Cuba.
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Cabrera Pérez
authors.forename: Ana Ruiz
authors.initials: AR
authors.lastname: García
authors.forename: Carlos Fernández
authors.initials: CF
authors.lastname: Teruel
authors.forename: Isabel González
authors.initials: IG
authors.lastname: Alvarez
authors.forename: Marival Bermejo
authors.initials: MB
authors.lastname: Sanz
mesh_terms: D000818:Animals; D001682:Biological Availability; D015195:Drug Design; D024841:Fluoroquinolones / Q000737:chemistry* / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar
chemical_list: D024841:Fluoroquinolones