TY - JOUR
T1 - Parallel synthesis of 9-aminoacridines and their evaluation against chloroquine-resistant Plasmodium falciparum
AU - Anderson, Marc O.
AU - Sherrill, John
AU - Madrid, Peter B.
AU - Liou, Ally P.
AU - Weisman, Jennifer L.
AU - DeRisi, Joseph L.
AU - Guy, R. Kiplin
PY - 2006/1/15
Y1 - 2006/1/15
N2 - A parallel synthetic strategy to the 9-aminoacridine scaffold of the classical anti-malarial drug quinacrine (2) is presented. The method features a new route to 9-chloroacridines that utilizes triflates of salicylic acid derivatives, which are commercially available in a variety of substitution patterns. The route allows ready variation of the two diversity elements present in this class of molecules: the tricyclic aromatic heterocyclic core, and the disubstituted diamine sidechain. In this study, a library of 175 compounds was designed, although only 93 of the final products had purities acceptable for screening. Impurity was generally due to incomplete removal of 9-acridones (18), a degradation product of the 9-chloroacridine synthetic intermediates. The library was screened against two strains of Plasmodium falciparum, including a model of the drug-resistant parasite, and six novel compounds were found to have IC50 values in the low nanomolar range.
AB - A parallel synthetic strategy to the 9-aminoacridine scaffold of the classical anti-malarial drug quinacrine (2) is presented. The method features a new route to 9-chloroacridines that utilizes triflates of salicylic acid derivatives, which are commercially available in a variety of substitution patterns. The route allows ready variation of the two diversity elements present in this class of molecules: the tricyclic aromatic heterocyclic core, and the disubstituted diamine sidechain. In this study, a library of 175 compounds was designed, although only 93 of the final products had purities acceptable for screening. Impurity was generally due to incomplete removal of 9-acridones (18), a degradation product of the 9-chloroacridine synthetic intermediates. The library was screened against two strains of Plasmodium falciparum, including a model of the drug-resistant parasite, and six novel compounds were found to have IC50 values in the low nanomolar range.
KW - Acridine
KW - Malaria
KW - Parallel synthesis
UR - http://www.scopus.com/inward/record.url?scp=28844438791&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=28844438791&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2005.08.017
DO - 10.1016/j.bmc.2005.08.017
M3 - Article
C2 - 16216519
AN - SCOPUS:28844438791
SN - 0968-0896
VL - 14
SP - 334
EP - 343
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 2
ER -
