title: SAR studies of dihydro-beta-agarofuran sesquiterpenes as inhibitors of the multidrug-resistance phenotype in a Leishmania tropica line overexpressing a P-glycoprotein-like transporter.
abstract: A series of dihydro-beta-agarofuran sesquiterpenes isolated from the leaves of Maytenus cuzcoina (1-10) or semisynthetic derivatives (11-30) have been tested on a multidrug-resistant Leishmania tropica line overexpressing a P-glycoprotein-like transporter to determine their ability to revert the resistance phenotype and to modulate intracellular drug accumulation. Almost all natural compounds showed potent reversal activity with different degrees of selectivity. Compounds 2, 7, and 8 are the most effective reversal agents tested against the multidrug resistance phenotype of Leishmania. Three-dimensional quantitative structure-activity relationships using the comparative molecular similarity indices analysis (CoMSIA) were employed to characterize the steric (contribution of 5.4%), electrostatic (58.9%), lipophilic (10.0%), and hydrogen-bond-donor (13.3%) and -acceptor (7.5%) requirements of these sesquiterpenes as modulators at the P-glycoprotein-like transporter. The most salient features of these requirements are the H-bond interaction between the substituents at the C-2 and C-6 positions with the receptor.
authors.affiliation: Instituto de Parasitología y Biomedicina "López-Neyra", Consejo Superior de Investigaciones Científicas, c/Ventanilla 11, 18001 Granada, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Cortés-Selva
authors.forename: Mercedes
authors.initials: M
authors.lastname: Campillo
authors.forename: Carolina P
authors.initials: CP
authors.lastname: Reyes
authors.forename: Ignacio A
authors.initials: IA
authors.lastname: Jiménez
authors.forename: Santiago
authors.initials: S
authors.lastname: Castanys
authors.forename: Isabel L
authors.initials: IL
authors.lastname: Bazzocchi
authors.forename: Leonardo
authors.initials: L
authors.lastname: Pardo
authors.forename: Francisco
authors.initials: F
authors.lastname: Gamarro
authors.forename: Angel G
authors.initials: AG
authors.lastname: Ravelo
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis*; D000818:Animals; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D005452:Fluoresceins / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D007895:Leishmania tropica / Q000187:drug effects* / Q000378:metabolism; D008958:Models, Molecular; D010641:Phenotype; D021281:Quantitative Structure-Activity Relationship; D012717:Sesquiterpenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D018528:ATP-Binding Cassette Transporters; D005452:Fluoresceins; D005456:Fluorescent Dyes; D012717:Sesquiterpenes; D014344:Trypanocidal Agents; C007740:fluorexon