Journal article
A critical evaluation of pyrrolo[2,3-d]pyrimidine-4-amines as Plasmodium falciparum apical membrane antigen 1 (AMA1) inhibitors
SM Devine, SS Lim, IR Chandrashekaran, CA Macraild, DR Drew, CO Debono, R Lam, RF Anders, JG Beeson, MJ Scanlon, PJ Scammells, RS Norton
Medchemcomm | ROYAL SOC CHEMISTRY | Published : 2014
DOI: 10.1039/c4md00090k
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. This journal is
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Grants
Awarded by Australian National Health and Medical Research Council (NHMRC)
Funding Acknowledgements
The authors would like to thank Brad Sleebs for fruitful discussions on this project, Samuel Hughes for preliminary work on the synthesis, and Jason Dang for obtaining HRMS data. This work was supported in part by an Australian National Health and Medical Research Council (NHMRC) project grant (1025150) and program grant (637406). R.S.N. and J.G.B acknowledge fellowship support from the NHMRC. The Burnet Institute is supported by the NHMRC Independent Research Institutes Infrastructure Support Scheme, and Operational Infrastructure Support from the State Government of Victoria, Australia.