Bis-acridines as lead antiparasitic agents: Structure-activity analysis of a discrete compound library in vitro

Abstract

ABSTRACT Parasitic diseases are of enormous public health significance in developing countries—a situation compounded by the toxicity of and resistance to many current chemotherapeutics. We investigated a focused library of 18 structurally diverse bis-acridine compounds for in vitro bioactivity against seven protozoan and one helminth parasite species and compared the bioactivities and the cytotoxicities of these compounds toward various mammalian cell lines. Structure-activity relationships demonstrated the influence of both the bis-acridine linker structure and the terminal acridine heterocycle on potency and cytotoxicity. The bioactivity of polyamine-linked acridines required a minimum linker length of approximately 10 Å. Increasing linker length resulted in bioactivity against most parasites but also cytotoxicity toward mammalian cells. N alkylation, but less so N acylation, of the polyamine linker ameliorated cytotoxicity while retaining bioactivity with 50% effective concentration (EC 50 ) values similar to or better than those measured for standard drugs. Substitution of the polyamine for either an alkyl or a polyether linker maintained bioactivity and further alleviated cytotoxicity. Polyamine-linked compounds in which the terminal acridine heterocycle had been replaced with an aza-acridine also maintained acceptable therapeutic indices. The most potent compounds recorded low- to mid-nanomolar EC 50 values against Plasmodium falciparum and Trypanosoma brucei ; otherwise, low-micromolar potencies were measured. Importantly, the bioactivity of the library was independent of P. falciparum resistance to chloroquine. Compound bioactivity was a function of neither the potential to bis-intercalate DNA nor the inhibition of trypanothione reductase, an important drug target in trypanosomatid parasites. Our approach illustrates the usefulness of screening focused compound libraries against multiple parasite targets. Some of the bis-acridines identified here may represent useful starting points for further lead optimization.

Autoren

Conor R Caffrey
Dietmar Steverding
Ryan K Swenerton
Ben Kelly
Deirdre Walshe
Anjan Debnath
Yuan-Min Zhou
Patricia S Doyle
Aaron T Fafarman
Julie A Zorn
Kirkwood M Land
Jessica Beauchene
Kimberly Schreiber
Heidrun Moll
Alicia Ponte-Sucre
Tanja Schirmeister
Ahilan Saravanamuthu
Alan H Fairlamb
Fred E Cohen
James H McKerrow
Jennifer L Weisman
Barnaby CH May

DOI

10.1128/aac.01418-06

eISSN

1098-6596

ISSN

0066-4804

Ausgabe der Veröffentlichung

6

Zeitschrift

Antimicrobial Agents and Chemotherapy

Sprache

en

Paginierung

2164 - 2172

Datum der Veröffentlichung

2007

Status

Published

Herausgeber

American Society for Microbiology

Herausgeber URL

http://dx.doi.org/10.1128/aac.01418-06

Datum der Datenerfassung

2022

Titel

Bis-Acridines as Lead Antiparasitic Agents: Structure-Activity Analysis of a Discrete Compound Library In Vitro

Ausgabe der Zeitschrift

51

Datenquelle: Crossref

Abstract

Parasitic diseases are of enormous public health significance in developing countries-a situation compounded by the toxicity of and resistance to many current chemotherapeutics. We investigated a focused library of 18 structurally diverse bis-acridine compounds for in vitro bioactivity against seven protozoan and one helminth parasite species and compared the bioactivities and the cytotoxicities of these compounds toward various mammalian cell lines. Structure-activity relationships demonstrated the influence of both the bis-acridine linker structure and the terminal acridine heterocycle on potency and cytotoxicity. The bioactivity of polyamine-linked acridines required a minimum linker length of approximately 10 A. Increasing linker length resulted in bioactivity against most parasites but also cytotoxicity toward mammalian cells. N alkylation, but less so N acylation, of the polyamine linker ameliorated cytotoxicity while retaining bioactivity with 50% effective concentration (EC(50)) values similar to or better than those measured for standard drugs. Substitution of the polyamine for either an alkyl or a polyether linker maintained bioactivity and further alleviated cytotoxicity. Polyamine-linked compounds in which the terminal acridine heterocycle had been replaced with an aza-acridine also maintained acceptable therapeutic indices. The most potent compounds recorded low- to mid-nanomolar EC(50) values against Plasmodium falciparum and Trypanosoma brucei; otherwise, low-micromolar potencies were measured. Importantly, the bioactivity of the library was independent of P. falciparum resistance to chloroquine. Compound bioactivity was a function of neither the potential to bis-intercalate DNA nor the inhibition of trypanothione reductase, an important drug target in trypanosomatid parasites. Our approach illustrates the usefulness of screening focused compound libraries against multiple parasite targets. Some of the bis-acridines identified here may represent useful starting points for further lead optimization.

Addresses

Sandler Center for Basic Research in Parasitic Diseases, BH508, University of California, San Francisco, 1700 4th Street, San Francisco, CA 94158-2330, USA. caffrey@cgl.ucsf.edu

Autoren

Conor R Caffrey
Dietmar Steverding
Ryan K Swenerton
Ben Kelly
Deirdre Walshe
Anjan Debnath
Yuan-Min Zhou
Patricia S Doyle
Aaron T Fafarman
Julie A Zorn
Kirkwood M Land
Jessica Beauchene
Kimberly Schreiber
Heidrun Moll
Alicia Ponte-Sucre
Tanja Schirmeister
Ahilan Saravanamuthu
Alan H Fairlamb
Fred E Cohen
James H McKerrow
Jennifer L Weisman
Barnaby CH May

DOI

10.1128/aac.01418-06

eISSN

1098-6596

Externe Identifier

PubMed Identifier: 17371810
PubMed Central ID: PMC1891397

Funding acknowledgements

Wellcome Trust: 079838
NIAID NIH HHS: AI35707
Wellcome Trust:
NIAID NIH HHS: P01 AI035707

Open access

false

ISSN

0066-4804

Ausgabe der Veröffentlichung

6

Zeitschrift

Antimicrobial agents and chemotherapy

Schlüsselwörter

HL-60 Cells
Animals
Humans
Schistosoma mansoni
Plasmodium falciparum
Trypanosoma brucei brucei
Polyamines
Acridines
Antiparasitic Agents
Combinatorial Chemistry Techniques
Parasitic Sensitivity Tests
Structure-Activity Relationship
Eukaryota

Sprache

eng

Medium

Print-Electronic

Online publication date

2007

Paginierung

2164 - 2172

Datum der Veröffentlichung

2007

Status

Published

Datum der Datenerfassung

2007

Titel

Bis-acridines as lead antiparasitic agents: structure-activity analysis of a discrete compound library in vitro.

Sub types

Research Support, Non-U.S. Gov't
research-article
Journal Article
Research Support, N.I.H., Extramural

Ausgabe der Zeitschrift

51

Files

https://aac.asm.org/content/51/6/2164.full.pdf https://europepmc.org/articles/PMC1891397?pdf=render

Datenquelle: Europe PubMed Central

Abstract

Parasitic diseases are of enormous public health significance in developing countries-a situation compounded by the toxicity of and resistance to many current chemotherapeutics. We investigated a focused library of 18 structurally diverse bis-acridine compounds for in vitro bioactivity against seven protozoan and one helminth parasite species and compared the bioactivities and the cytotoxicities of these compounds toward various mammalian cell lines. Structure-activity relationships demonstrated the influence of both the bis-acridine linker structure and the terminal acridine heterocycle on potency and cytotoxicity. The bioactivity of polyamine-linked acridines required a minimum linker length of approximately 10 A. Increasing linker length resulted in bioactivity against most parasites but also cytotoxicity toward mammalian cells. N alkylation, but less so N acylation, of the polyamine linker ameliorated cytotoxicity while retaining bioactivity with 50% effective concentration (EC(50)) values similar to or better than those measured for standard drugs. Substitution of the polyamine for either an alkyl or a polyether linker maintained bioactivity and further alleviated cytotoxicity. Polyamine-linked compounds in which the terminal acridine heterocycle had been replaced with an aza-acridine also maintained acceptable therapeutic indices. The most potent compounds recorded low- to mid-nanomolar EC(50) values against Plasmodium falciparum and Trypanosoma brucei; otherwise, low-micromolar potencies were measured. Importantly, the bioactivity of the library was independent of P. falciparum resistance to chloroquine. Compound bioactivity was a function of neither the potential to bis-intercalate DNA nor the inhibition of trypanothione reductase, an important drug target in trypanosomatid parasites. Our approach illustrates the usefulness of screening focused compound libraries against multiple parasite targets. Some of the bis-acridines identified here may represent useful starting points for further lead optimization.

Autoren

Conor R Caffrey
Dietmar Steverding
Ryan K Swenerton
Ben Kelly
Deirdre Walshe
Anjan Debnath
Yuan-Min Zhou
Patricia S Doyle
Aaron T Fafarman
Julie A Zorn
Kirkwood M Land
Jessica Beauchene
Kimberly Schreiber
Heidrun Moll
Alicia Ponte-Sucre
Tanja Schirmeister
Ahilan Saravanamuthu
Alan H Fairlamb
Fred E Cohen
James H McKerrow
Jennifer L Weisman
Barnaby CH May

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/17371810

DOI

10.1128/AAC.01418-06

Externe Identifier

PubMed Central ID: PMC1891397

Funding acknowledgements

Wellcome Trust:
Wellcome Trust: 079838
NIAID NIH HHS: P01 AI035707
NIAID NIH HHS: AI35707

ISSN

0066-4804

Ausgabe der Veröffentlichung

6

Zeitschrift

Antimicrob Agents Chemother

Schlüsselwörter

Acridines
Animals
Antiparasitic Agents
Combinatorial Chemistry Techniques
Eukaryota
HL-60 Cells
Humans
Parasitic Sensitivity Tests
Plasmodium falciparum
Polyamines
Schistosoma mansoni
Structure-Activity Relationship
Trypanosoma brucei brucei

Sprache

eng

Country

United States

Paginierung

2164 - 2172

PII

AAC.01418-06

Datum der Veröffentlichung

2007

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2007

Titel

Bis-acridines as lead antiparasitic agents: structure-activity analysis of a discrete compound library in vitro.

Sub types

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Ausgabe der Zeitschrift

51

Datenquelle: PubMed

Bis-acridines as lead antiparasitic agents: Structure-activity analysis of a discrete compound library in vitro

Files

Werkzeuge