Michael Acceptor Based Antiplasmodial and Antitrypanosomal Cysteine Protease Inhibitors with Unusual Amino Acids

Autoren

Alexander Breuning
Björn Degel
Franziska Schulz
Christian Büchold
Martin Stempka
Uwe Machon
Saskia Heppner
Christoph Gelhaus
Matthias Leippe
Matthias Leyh
Caroline Kisker
Jennifer Rath
August Stich
Jiri Gut
Philip J Rosenthal
Carsten Schmuck
Tanja Schirmeister

DOI

10.1021/jm900946n

eISSN

1520-4804

ISSN

0022-2623

Ausgabe der Veröffentlichung

5

Zeitschrift

Journal of Medicinal Chemistry

Sprache

en

Online publication date

2010

Paginierung

1951 - 1963

Datum der Veröffentlichung

2010

Status

Published

Herausgeber

American Chemical Society (ACS)

Herausgeber URL

http://dx.doi.org/10.1021/jm900946n

Datum der Datenerfassung

2023

Titel

Michael Acceptor Based Antiplasmodial and Antitrypanosomal Cysteine Protease Inhibitors with Unusual Amino Acids

Ausgabe der Zeitschrift

53

Datenquelle: Crossref

Abstract

New peptidic Michael acceptor based cysteine protease inhibitors displaying antiparasitic activity were identified by testing a broad series of 45 compounds in total, containing Asn, Gln, or Phe. As target enzymes, falcipain-2 and -3 from P. falciparum and rhodesain from T. b. rhodesiense were used. In the case of the Asn/Gln containing compounds, the trityl-protected, diastereomeric E-configured vinylogous dipeptide esters 16 (Boc-(S)-Phg-(R/S)-vGln(Trt)-OEt) were discovered as most active inhibitors concerning both protease inhibition and antiparasitic acitivity, with inhibition constants in the submicromolar range. The compounds were shown to display time-dependent and competitive inhibition. In the case of the Phe containing compounds, the maleic acid derivatives 42 and 43 (BnO-Phe<--Mal-Phe-OBn, BnO-Phe<--Mal-Phe-Ala-OBn, Mal = maleic acid) displayed good inhibition of rhodesain as well as good antitrypanosomal activity, while the fumaric acid derived E-analogue 14 (BnO-Phe<--Fum-Phe-OBn) only displayed inhibition of the target enzymes but no antiparasitic activity. Inhibition by these Phe derivatives was shown to be time-independent and competitive.

Addresses

Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, Germany.

Autoren

Alexander Breuning
Björn Degel
Franziska Schulz
Christian Büchold
Martin Stempka
Uwe Machon
Saskia Heppner
Christoph Gelhaus
Matthias Leippe
Matthias Leyh
Caroline Kisker
Jennifer Rath
August Stich
Jiri Gut
Philip J Rosenthal
Carsten Schmuck
Tanja Schirmeister

DOI

10.1021/jm900946n

eISSN

1520-4804

Externe Identifier

PubMed Identifier: 20131843

Open access

false

ISSN

0022-2623

Ausgabe der Veröffentlichung

5

Zeitschrift

Journal of medicinal chemistry

Schlüsselwörter

Plasmodium falciparum
Trypanosoma brucei brucei
Cysteine Endopeptidases
Cysteine Proteinase Inhibitors
Antimalarials
Trypanocidal Agents
Magnetic Resonance Spectroscopy
Spectrometry, Mass, Electrospray Ionization
Inhibitory Concentration 50
Structure-Activity Relationship

Sprache

eng

Medium

Print

Paginierung

1951 - 1963

Datum der Veröffentlichung

2010

Status

Published

Datum der Datenerfassung

2010

Titel

Michael acceptor based antiplasmodial and antitrypanosomal cysteine protease inhibitors with unusual amino acids.

Sub types

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

Ausgabe der Zeitschrift

53

Datenquelle: Europe PubMed Central

Abstract

New peptidic Michael acceptor based cysteine protease inhibitors displaying antiparasitic activity were identified by testing a broad series of 45 compounds in total, containing Asn, Gln, or Phe. As target enzymes, falcipain-2 and -3 from P. falciparum and rhodesain from T. b. rhodesiense were used. In the case of the Asn/Gln containing compounds, the trityl-protected, diastereomeric E-configured vinylogous dipeptide esters 16 (Boc-(S)-Phg-(R/S)-vGln(Trt)-OEt) were discovered as most active inhibitors concerning both protease inhibition and antiparasitic acitivity, with inhibition constants in the submicromolar range. The compounds were shown to display time-dependent and competitive inhibition. In the case of the Phe containing compounds, the maleic acid derivatives 42 and 43 (BnO-Phe<--Mal-Phe-OBn, BnO-Phe<--Mal-Phe-Ala-OBn, Mal = maleic acid) displayed good inhibition of rhodesain as well as good antitrypanosomal activity, while the fumaric acid derived E-analogue 14 (BnO-Phe<--Fum-Phe-OBn) only displayed inhibition of the target enzymes but no antiparasitic activity. Inhibition by these Phe derivatives was shown to be time-independent and competitive.

Autoren

Alexander Breuning
Björn Degel
Franziska Schulz
Christian Büchold
Martin Stempka
Uwe Machon
Saskia Heppner
Christoph Gelhaus
Matthias Leippe
Matthias Leyh
Caroline Kisker
Jennifer Rath
August Stich
Jiri Gut
Philip J Rosenthal
Carsten Schmuck
Tanja Schirmeister

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/20131843

DOI

10.1021/jm900946n

eISSN

1520-4804

Ausgabe der Veröffentlichung

5

Zeitschrift

J Med Chem

Schlüsselwörter

Antimalarials
Cysteine Endopeptidases
Cysteine Proteinase Inhibitors
Inhibitory Concentration 50
Magnetic Resonance Spectroscopy
Plasmodium falciparum
Spectrometry, Mass, Electrospray Ionization
Structure-Activity Relationship
Trypanocidal Agents
Trypanosoma brucei brucei

Sprache

eng

Country

United States

Paginierung

1951 - 1963

Datum der Veröffentlichung

2010

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2010

Titel

Michael acceptor based antiplasmodial and antitrypanosomal cysteine protease inhibitors with unusual amino acids.

Sub types

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

Ausgabe der Zeitschrift

53

Datenquelle: PubMed

Michael Acceptor Based Antiplasmodial and Antitrypanosomal Cysteine Protease Inhibitors with Unusual Amino Acids

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