title: In silico screening with benzofurane- and benzopyrane-type MDR-modulators.
abstract: Development of inhibitors of the drug efflux pump P-glycoprotein is a versatile approach to overcome multi drug resistance (MDR) in tumor therapy. In an approach to lower the conformational flexibility of the lead compound propafenone, we synthesized a set of dihydrobenzofuranes and benzopyranones. In the case of the 4 diastereomeric dihydrobenzofuranes, no significant differences in activity regarding the configuration on the side-chains at the dihydrofurane moiety (cis or trans) was observed. This may be due to the high flexibility of the side-chains, which still allow mutually overlap of pharmacophores. The benzopyranones showed a good correlation between lipophilicity and activity with gnerally lower logpotency/logP ratios. This decrease may be due to the rigidization of the molecules. In an in silico screening approach, a set of diverse propafenone-type compounds was used to establish a pharmacophore model, which was used to screen the world drug index. Among the hits retrieved there are several compounds, which were previously described as MDR-modulators. This demonstrates the validity of the model.
authors.affiliation: Institute of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria.
authors.forename: Sascha
authors.initials: S
authors.lastname: Rebitzer
authors.forename: Danilo
authors.initials: D
authors.lastname: Annibali
authors.forename: Stephan
authors.initials: S
authors.lastname: Kopp
authors.forename: Monika
authors.initials: M
authors.lastname: Eder
authors.forename: Thierry
authors.initials: T
authors.lastname: Langer
authors.forename: Peter
authors.initials: P
authors.lastname: Chiba
authors.forename: Gerhard F
authors.initials: GF
authors.lastname: Ecker
authors.forename: Christian R
authors.initials: CR
authors.lastname: Noe
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D001572:Benzofurans / Q000737:chemistry* / Q000494:pharmacology*; D001578:Benzopyrans / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D004353:Drug Evaluation, Preclinical / Q000379:methods; D018432:Drug Resistance, Multiple / Q000502:physiology; D006801:Humans; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001572:Benzofurans; D001578:Benzopyrans