title: Inhibitory effect of phenothiazine- and phenoxazine-derived chloroacetamides on Leishmania major growth and Trypanosoma brucei trypanothione reductase.
abstract: A number of phenothiazine-, phenoxazine- and related tricyclics-derived chloroacetamides were synthesized and evaluated in vitro for antiprotozoal activities against Leishmania major (L. major) promastigotes. Several analogs were remarkably potent inhibitors, with antileishmanial activities being comparable or superior to those of the reference antiprotozoal drugs. Furthermore, we explored the structure-activity relationships of N-10 haloacetamides that influence the potency of such analogs toward inhibition of L. major promastigote growth in vitro. With respect to the mechanism of action, selected compounds were evaluated for time-dependent inactivation of Trypanosoma brucei trypanothione reductase. Our results are indicative of a covalent interaction which could account for potent antiprotozoal activities.
authors.affiliation: Institute for Molecular Infection Biology, University of Wuerzburg, Josef-Schneider-Str. 2, D-97080 Wuerzburg, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Marcu
authors.affiliation: Institute for Molecular Infection Biology, University of Wuerzburg, Josef-Schneider-Str. 2, D-97080 Wuerzburg, Germany. Electronic address: uta.schurigt@uni-wuerzburg.de.
authors.forename: Uta
authors.initials: U
authors.lastname: Schurigt
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Corrensstraße 48, D-48149 Muenster, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Müller
authors.affiliation: Institute for Molecular Infection Biology, University of Wuerzburg, Josef-Schneider-Str. 2, D-97080 Wuerzburg, Germany.
authors.forename: Heidrun
authors.initials: H
authors.lastname: Moll
authors.affiliation: Biochemistry Center of Heidelberg University (BZH), Im Neuenheimer Feld 504, D-69120 Heidelberg, Germany.
authors.forename: R Luise
authors.initials: RL
authors.lastname: Krauth-Siegel
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Corrensstraße 48, D-48149 Muenster, Germany. Electronic address: prinzh@uni-muenster.de.
authors.forename: Helge
authors.initials: H
authors.lastname: Prinz
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018320:Leishmania major / Q000187:drug effects* / Q000254:growth & development; D015394:Molecular Structure; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010078:Oxazines / Q000737:chemistry* / Q000494:pharmacology; D021261:Parasitic Sensitivity Tests; D010640:Phenothiazines / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology*
chemical_list: D000081:Acetamides; D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D010078:Oxazines; D010640:Phenothiazines; C013874:chloroacetamide; C039203:phenoxazine; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; C031637:phenothiazine
keywords: Antileishmanial activity; Chloroacetamides; Phenothiazines; Phenoxazines; Trypanothione reductase