Inhibitory effect of phenothiazine- and phenoxazine-derived chloroacetamides on Leishmania major growth and Trypanosoma brucei trypanothione reductase

Ana Marcu; Uta Schurigt; Klaus Müller; Heidrun Moll; R Luise Krauth-Siegel; Helge Prinz

doi:10.1016/j.ejmech.2015.11.023

Inhibitory effect of phenothiazine- and phenoxazine-derived chloroacetamides on Leishmania major growth and Trypanosoma brucei trypanothione reductase

Eur J Med Chem. 2016 Jan 27:108:436-443. doi: 10.1016/j.ejmech.2015.11.023. Epub 2015 Nov 23.

Authors

Ana Marcu¹, Uta Schurigt², Klaus Müller³, Heidrun Moll¹, R Luise Krauth-Siegel⁴, Helge Prinz⁵

Affiliations

¹ Institute for Molecular Infection Biology, University of Wuerzburg, Josef-Schneider-Str. 2, D-97080 Wuerzburg, Germany.
² Institute for Molecular Infection Biology, University of Wuerzburg, Josef-Schneider-Str. 2, D-97080 Wuerzburg, Germany. Electronic address: uta.schurigt@uni-wuerzburg.de.
³ Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Corrensstraße 48, D-48149 Muenster, Germany.
⁴ Biochemistry Center of Heidelberg University (BZH), Im Neuenheimer Feld 504, D-69120 Heidelberg, Germany.
⁵ Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Corrensstraße 48, D-48149 Muenster, Germany. Electronic address: prinzh@uni-muenster.de.

PMID: 26708110
DOI: 10.1016/j.ejmech.2015.11.023

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.

Keywords: Antileishmanial activity; Chloroacetamides; Phenothiazines; Phenoxazines; Trypanothione reductase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetamides / chemical synthesis
Acetamides / chemistry
Acetamides / pharmacology*
Antiprotozoal Agents / chemical synthesis
Antiprotozoal Agents / chemistry
Antiprotozoal Agents / pharmacology*
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Leishmania major / drug effects*
Leishmania major / growth & development
Molecular Structure
NADH, NADPH Oxidoreductases / antagonists & inhibitors*
NADH, NADPH Oxidoreductases / metabolism
Oxazines / chemistry*
Oxazines / pharmacology
Parasitic Sensitivity Tests
Phenothiazines / chemistry*
Phenothiazines / pharmacology
Structure-Activity Relationship
Trypanosoma brucei brucei / drug effects
Trypanosoma brucei brucei / enzymology*

Substances

Acetamides
Antiprotozoal Agents
Enzyme Inhibitors
Oxazines
Phenothiazines
chloroacetamide
phenoxazine
NADH, NADPH Oxidoreductases
trypanothione reductase
phenothiazine