title: Stereoselective preparation of pyridoxal 1,2,3,4-tetrahydro-β-carboline derivatives and the influence of their absolute and relative configuration on the proliferation of the malaria parasite Plasmodium falciparum.
abstract: We have selectively synthesized by Pictet-Spengler condensation of tryptophan and pyridoxal the four stereoisomers of a pyridoxal β-carboline derivative that was designed to inhibit the proliferation of Plasmodium falciparum. Biological investigation of the four compounds revealed that they all inhibit the growth of P. falciparum. With an IC50 value of 8 ± 1 μM, the highest inhibitory effect on the proliferation of the parasite was found for the 1,3-trans-substituted tetrahydro-β-carboline that was obtained from d-tryptophan. Lower activity was found for its enantiomer, while the two diastereomeric cis-products were markedly less effective. Apparently a distinct spacial orientation of the carboxyl group of the substituted tetrahydropyridine unit of the compounds is needed for high activity, while the absolute configuration of the molecules is of lesser importance.
authors.affiliation: Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
authors.forename: Renate
authors.initials: R
authors.lastname: Brokamp
authors.affiliation: Biochemical Parasitology, Bernhard Nocht Institute for Tropical Medicine, Bernhard Nocht Str. 74, D-20359 Hamburg, Germany.
authors.forename: Bärbel
authors.initials: B
authors.lastname: Bergmann
authors.affiliation: Biochemical Parasitology, Bernhard Nocht Institute for Tropical Medicine, Bernhard Nocht Str. 74, D-20359 Hamburg, Germany.
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Müller
authors.affiliation: Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. Electronic address: stefan.bienz@chem.uzh.ch.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bienz
mesh_terms: D002243:Carbolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development; D011730:Pyridoxal / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011789:Quantum Theory; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D002243:Carbolines; D011730:Pyridoxal
keywords: Malaria; PLP dependent enzyme; Plasmodium falciparum; Pyridoxal; Tetrahydro-β-carboline