title: Structure-activity relationships of a series of tariquidar analogs as multidrug resistance modulators.
abstract: Tariquidar (XR9576) analogs, modulators of cancer multidrug resistance (MDR), were subjected to QSAR and 3D-QSAR analyses. The structural features contributing to anti-MDR activity were identified by the Free-Wilson analysis and pharmacophore search using Hoechst 33342 as a template. 3D-QSAR CoMFA and CoMSIA models were derived and tested. The best models yielded an external predictivity of 0.66-0.75 squared correlation coefficient and outlined HB-acceptor, steric, and hydrophobic fields as the most important 3D properties. On the basis of the QSAR and 3D-QSAR analyses it was suggested that the strong inhibitory potency of the compounds studied is related to the presence of a bulky aromatic ring system with a 3rd positioned heteroatom toward the anthranilamide nucleus in the opposite end of the tetrahydroquinoline group. The results can help in directing the rational design of new generations of potent P-glycoprotein MDR modulators.
authors.affiliation: Institute of Pharmacy, University of Bonn, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Globisch
authors.forename: Ilza K
authors.initials: IK
authors.lastname: Pajeva
authors.forename: Michael
authors.initials: M
authors.lastname: Wiese
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D001665:Binding Sites; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000502:physiology; D019008:Drug Resistance, Neoplasm; D057927:Hydrophobic and Hydrophilic Interactions; D008956:Models, Chemical; D025341:Principal Component Analysis; D021281:Quantitative Structure-Activity Relationship; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011804:Quinolines; C402343:tariquidar