title: Search of chemical scaffolds for novel antituberculosis agents.
abstract: A method to identify chemical scaffolds potentially active against Mycobacterium tuberculosis is presented. The molecular features of a set of structurally heterogeneous antituberculosis drugs were coded by means of structural invariants. Three techniques were used to obtain equations able to model the antituberculosis activity: linear discriminant analysis, multilinear regression, and shrinkage estimation-ridge regression. The model obtained was statistically validated through leave-n-out test, and an external set and was applied to a database for the search of new active agents. The selected compounds were assayed in vitro, and among those identified as active stand reserpine, N,N,N',N'-tetrakis-(2-pyridylmethyl)-ethylenediamine (TPEN), trifluoperazine, pentamidine, and 2-methyl-4,6-dinitro-phenol (DNOC). They show activity comparable to or superior to ethambutol, used in combination with other drugs for the prevention and treatment of Mycobacterium avium complex and drug-resistant tuberculosis.
authors.affiliation: Unidad de Investigación de Diseño de Fármacos y Conectividad Molecular, Departamento de Química Física, Facultad de Farmacia, Universitat de València, Av. Vicent Andrés Estellés s/n, 46100 Burjassot, Spain.
authors.forename: Angeles
authors.initials: A
authors.lastname: García-García
authors.forename: Jorge
authors.initials: J
authors.lastname: Gálvez
authors.forename: Jesus Vicente
authors.initials: JV
authors.lastname: de Julián-Ortiz
authors.forename: Ramón
authors.initials: R
authors.lastname: García-Domenech
authors.forename: Carlos
authors.initials: C
authors.lastname: Muñoz
authors.forename: Remedios
authors.initials: R
authors.lastname: Guna
authors.forename: Rafael
authors.initials: R
authors.lastname: Borrás
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology*; D003198:Computer Simulation; D015195:Drug Design; D008956:Models, Chemical; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D012044:Regression Analysis
chemical_list: D000995:Antitubercular Agents