title: Preparation and antiprotozoal evaluation of promising β-carboline alkaloids.
abstract: The synthesis of β-carbolines and their in vitro antiplasmodial and antileishmanial activities were described herein. These molecules have also been studied concerning their in vitro cytotoxicity toward the human cell line THP1, in order to calculate their respective selectivity indexes (SI). Among the 20 tested molecules, four exhibited significant antiplasmodial activity on the W2 multi-resistant Plasmodium falciparum strain (0.7 < IC₅₀ < 1.7 μM), in comparison with two references drugs (chloroquine and doxycycline), and a low cytotoxicity. These β-carbolines were also evaluated concerning their in vitro antileshmanial activity on Leishmania donovani promastigotes, permitting to identify an antileshmanial hit compound, displaying quite promising activity (IC₅₀ = 6.1 μM) in comparison with amphotericin B and pentamidine chosen as reference drugs. Finally, structure-activity relationships were discussed, pointing out that molecules presenting a para-substituted phenyl moiety at position 1 of the β-carboline ring displayed the best biological profile.
authors.affiliation: UMR CNRS 6264, Laboratoire Chimie Provence, Aix-Marseille Université-Laboratoire de Pharmacochimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean-Moulin, 13385 Marseille Cedex 05, France. armand.gellis@univmed.fr
authors.forename: Armand
authors.initials: A
authors.lastname: Gellis
authors.forename: Aurélien
authors.initials: A
authors.lastname: Dumètre
authors.forename: Gilles
authors.initials: G
authors.lastname: Lanzada
authors.forename: Sébastien
authors.initials: S
authors.lastname: Hutter
authors.forename: Evelyne
authors.initials: E
authors.lastname: Ollivier
authors.forename: Patrice
authors.initials: P
authors.lastname: Vanelle
authors.forename: Nadine
authors.initials: N
authors.lastname: Azas
mesh_terms: D000470:Alkaloids / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000666:Amphotericin B / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002243:Carbolines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology; D004318:Doxycycline / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D006801:Humans; D020128:Inhibitory Concentration 50; D007893:Leishmania donovani / Q000187:drug effects*; D010419:Pentamidine / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000470:Alkaloids; D000981:Antiprotozoal Agents; D002243:Carbolines; D010419:Pentamidine; D000666:Amphotericin B; D002738:Chloroquine; D004318:Doxycycline