A critical evaluation of pyrrolo[2,3-d]pyrimidine-4-amines as Plasmodium falciparum apical membrane antigen 1 (AMA1) inhibitors

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Abstract

We have determined that a previously reported class of pyrrolo[2,3-d]pyrimidine-4-amines exhibit low binding to apical membrane antigen 1 (AMA1) and suffer from unattractive qualities, such as aggregation. We attempted to remove these traits by generating molecules with improved solubility, but this did not translate into enhanced binding affinity or inhibition of parasite growth in erythrocytes. These results indicate that anti-malarial activity is not primarily due to inhibition of AMA1 function, but mediated by an alternate or additional mechanism of action.
Original languageEnglish
Pages (from-to)1500 - 1506
Number of pages7
JournalMedChemComm
Volume5
Issue number10
DOIs
Publication statusPublished - 2014

Cite this

@article{abd901e847764d578818e790a4fd8435,
title = "A critical evaluation of pyrrolo[2,3-d]pyrimidine-4-amines as Plasmodium falciparum apical membrane antigen 1 (AMA1) inhibitors",
abstract = "We have determined that a previously reported class of pyrrolo[2,3-d]pyrimidine-4-amines exhibit low binding to apical membrane antigen 1 (AMA1) and suffer from unattractive qualities, such as aggregation. We attempted to remove these traits by generating molecules with improved solubility, but this did not translate into enhanced binding affinity or inhibition of parasite growth in erythrocytes. These results indicate that anti-malarial activity is not primarily due to inhibition of AMA1 function, but mediated by an alternate or additional mechanism of action.",
author = "Shane Devine and Lim, {San Sui} and Chandrashekaran, {Indu Rajmohan} and MacRaild, {Christopher Andrew} and Drew, {Damien R} and Cael Debono and Raymond Lam and Anders, {Robin F} and Beeson, {James G} and Martin Scanlon and Scammells, {Peter John} and Norton, {Raymond Stanley}",
year = "2014",
doi = "10.1039/c4md00090k",
language = "English",
volume = "5",
pages = "1500 -- 1506",
journal = "MedChemComm",
issn = "2040-2503",
publisher = "The Royal Society of Chemistry",
number = "10",

}

TY - JOUR

T1 - A critical evaluation of pyrrolo[2,3-d]pyrimidine-4-amines as Plasmodium falciparum apical membrane antigen 1 (AMA1) inhibitors

AU - Devine, Shane

AU - Lim, San Sui

AU - Chandrashekaran, Indu Rajmohan

AU - MacRaild, Christopher Andrew

AU - Drew, Damien R

AU - Debono, Cael

AU - Lam, Raymond

AU - Anders, Robin F

AU - Beeson, James G

AU - Scanlon, Martin

AU - Scammells, Peter John

AU - Norton, Raymond Stanley

PY - 2014

Y1 - 2014

N2 - We have determined that a previously reported class of pyrrolo[2,3-d]pyrimidine-4-amines exhibit low binding to apical membrane antigen 1 (AMA1) and suffer from unattractive qualities, such as aggregation. We attempted to remove these traits by generating molecules with improved solubility, but this did not translate into enhanced binding affinity or inhibition of parasite growth in erythrocytes. These results indicate that anti-malarial activity is not primarily due to inhibition of AMA1 function, but mediated by an alternate or additional mechanism of action.

AB - We have determined that a previously reported class of pyrrolo[2,3-d]pyrimidine-4-amines exhibit low binding to apical membrane antigen 1 (AMA1) and suffer from unattractive qualities, such as aggregation. We attempted to remove these traits by generating molecules with improved solubility, but this did not translate into enhanced binding affinity or inhibition of parasite growth in erythrocytes. These results indicate that anti-malarial activity is not primarily due to inhibition of AMA1 function, but mediated by an alternate or additional mechanism of action.

UR - http://pubs.rsc.org/en/Content/ArticleLanding/2014/MD/C4MD00090K#!divAbstract

U2 - 10.1039/c4md00090k

DO - 10.1039/c4md00090k

M3 - Article

VL - 5

SP - 1500

EP - 1506

JO - MedChemComm

JF - MedChemComm

SN - 2040-2503

IS - 10

ER -