pubs.acs.org/acsmedchemlett
validate the targets of diarylureas and understand their
action in parasites. Additionally, further structural optimiza-
tion of diarylureas will be required to overcome concerns for
physicochemical properties and cross-resistance.
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(5)
Kessl, J. J.; Meshnick, S. R.; Trumpower, B. L. Modeling the
molecular basis of atovaquone resistance in parasites and
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Herein is reported the evaluation of a library of diarylureas
for antimalarial activity against two strains of P. falciparum
(3D7 and K1). The most promising subseries of diarylureas
contained a 4-aminoquinaldinyl moiety (A ring) as one of the
aryl rings of the urea, a novel structural feature in the class.
The further investigation on the B ring of this series revealed
compounds in this series that were more active against the
chloroquine-sensitive strain 3D7 than the chloroqine-resistant
strain K1 and with absolute potencies in 3D7 equivalent to
chloroquine. The major liability observed in this class of
compounds is that they tend to be quite insoluble. To enable
clinical development, this liability will need to be addressed
in future studies.
(6)
(7)
ꢀ
(8)
(9)
Domínguez, J. N.; Leon, C.; Rodrigues, J.; Domínguez,
N. G. d.; Gut, J.; Rosenthal, P. J. Synthesis and Evaluation of
New Antimalarial Phenylurenyl Chalcone Derivatives. J. Med.
Chem. 2005, 48, 3654–3658.
Madapa, S.; Tusi, Z.; Sridhar, D.; Kumar, A.; Siddiqi, M. I.;
Srivastava, K.; Rizvi, A.; Tripathi, R.; Puri, S. K.; Keshava,
G. B. S.; Shukla, P. K.; Batra, S. Search for new pharmaco-
phores for antimalarial activity. Part I: Synthesis and anti-
malarial activity of new 2-methyl-6-ureido-4-quinolinamides.
Bioorg. Med. Chem. 2009, 17, 203–221.
SUPPORTING INFORMATION AVAILABLE Synthetic pro-
cedures for diarylureas; complete LC-MS characterization data of
all diarylureas; complete antimalarial data, cytotoxicity data, per-
meability, and solubility data for all listed compounds; pharmaco-
phore feature profile; kinase binding profile data; 1H NMR spectra
and chromatographic data of novel compounds 4{12, 1-4}, 4{13, 7},
4{13, 12}, 4{13, 21-24}, 4{13, 27-28}, 4{13, 41-45}, 4{13, 49-50},
4{13, 60}, 4{19, 1-4}, and 4{19, 8-9}. This material is available
(10) Madapa, S.; Tusi, Z.; Mishra, A.; Srivastava, K.; Pandey, S. K.;
Tripathi, R.; Puri, S. K.; Batra, S. Search for new pharmaco-
phores for antimalarial activity. Part II: Synthesis and anti-
malarial activity of new 6-ureido-4-anilinoquinazolines.
Bioorg. Med. Chem. 2009, 17, 222–234.
(11) Francis, S. E.; Sullivan, D. J., Jr.; Goldberg, D. E. Hemoglobin
metabolism in the malaria parasite Plasmodium falciparum.
Annu. Rev. Microbiol. 1997, 51, 97–123.
AUTHOR INFORMATION
Corresponding Author: *To whom correspondence should be
addressed. Tel: 901-595-9050. Fax: 901-595-5715. E-mail: kip.guy@
stjude.org.
(12) Coombs, G. H.; Goldberg, D. E.; Klemba, M.; Berry, C.; Kay, J.;
Mottram, J. C. Aspartic proteases of Plasmodium falciparum
and other parasitic protozoa as drug targets. Trends Parasitol.
2001, 17, 532–537.
(13) Francis, S. E.; Banerjee, R.; Goldberg, D. E. Biosynthesis and
Maturation of the Malaria Aspartic Hemoglobinases Plas-
mepsins I and II. J. Biol. Chem. 1997, 272, 14961–14968.
(14) Seymour, K. K.; Lyons, S. D.; Phillips, L.; Rieckmann, K. H.;
Christopherson, R. I. Cytotoxic Effects of Inhibitors of de Novo
Pyrimidine Biosynthesis upon Plasmodium falciparum. Bio-
chemistry 1997, 33, 5268–5274.
(15) Anderson, M. O.; Yu, H.; Penaranda, C.; Maddux, B. A.;
Goldfine, I. D.; Youngren, J. F.; Guy, R. K. Parallel synthesis
of diarylureas and their evaluation as inhibitors of insulin-like
growth factor receptor. J. Comb. Chem. 2006, 8, 784–790.
(16) Ward, P.; Equinet, L.; Packer, J.; Doerig, C. Protein kinases of
the human malaria paratiste Plasmodium falciparum: The
kinome of a divergent eukaryote. BMC Genomics 2004, 5 (1),
79.
Funding Sources: This work was supported by the National
Institute of Allergy and Infectious Disease at NIH (AI075517), the
American Lebanese Syrian Associated Charities (ALSAC), and St.
Jude Children's Research Hospital.
ACKNOWLEDGMENT We are grateful to Taosheng Chen and
Jimmy Cui from High Throughput Screening Core, Chemical Biology
& Therapeutics Department, St. Jude Children's Research Hospital,
for their support in antimalarial and cytotoxicity screening. We are
also grateful to High Throughput Synthesis Core and High Through-
put Analytical Core, Chemical Biology & Therapeutics Department,
St. Jude Children's Research Hospital, for their support in the syn-
thesis and purification of diarylureas.
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2010 American Chemical Society
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DOI: 10.1021/ml100083c ACS Med. Chem. Lett. 2010, 1, 460–465
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